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JOURNAL OF INTERNAL MEDICINE OF INDIA � JULY 2017 � VOL. 11 � NO. 4 � RNI No. 69152/98

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Editorial

© JIMI � JULY 2017 � VOL. 11 3


Dear all, It is a great pleasure to inform you that the Journal of Internal Medicine of India-UP Chapter has now been indexed with Copernicus. We have already achieved many great milestones involving various aspects of internal medicine, prevention, epidemiology, statistics, health economics and plan to develop and implement authoritative guidelines and standards for care as a part of professional education for the benefit of our members.

0.86; 95% [CI], 0.75 to 0.97; P<0.001 for non inferiority and P = 0.02 for superiority whereas EMPA-REG trial stands at a hazard ratio 0.86; 95.02% [CI], 0.74 to 0.99; P<0.001 for non inferiority and P = 0.04 for superiority). So, considering the P value for inferiority and superiority CANVAS program had an extra edge over EMPA-REG[3,4].

This year world diabetes day campaign was dedicated to women and diabetes and our right to a healthy future. The right for women to have access to diabetes prevention and care equates to healthier generation and brighter future.

It's been since 2008 Food and Drug Administration (FDA) guidance for industry “Diabetes Mellitus — Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes”, sponsors were asked to demonstrate that their new therapy will not lead to unacceptable increase in cardiovascular risk[1]. European Medicine Agency (EMA) subsequently too added the criteria for overall assessment of safety of new anti-diabetic drugs and need to undergo assessment of cardiovascular safety[2].Eight Cardiovascular outcome trials were completed till this time and among which EMPA-REG and CANVAS were the two trials that were associated with empagliozin and canagliozin respectively[3,4,5]. Other two trials involving SGLT2 inhibitors, DECLARE-TIMI for dapagliozin and VERTIS-CV for ertugliozin is expected to be completed by 2019[6,7]. EMPA-REG result was published in the year 2015 and is the first of the trial with any antiglycaemic drug that draws the attention of being cardiovascular protective rather than satisfying the FDA guidance of being cardiovascular safe. Leader (liraglutide) and Sustain-6 (semaglutide) did follow in the same line being cardio protective as to that of EMPA-REG.[8,9]

The result of CANVAS program was highly awaited for various reasons among the health care professionals. It was a first of its kind to have a population with highest population with cardiovascular risk, a patient population of 10,132 along with a study duration of 6 years. Apart from it there was always a concern among the HCP about the extrapolation of the study result of EMPA-REG in real world based on a single trial. However, with the CANAVS program showing similar cardiac benefit hope to hold a better belief with SGLT2 inhibitor class. Both the trials showed similar relative reduction of its primary outcome 3point MACE of 14 %, nonetheless statistically it is not same and so the results. CANVAS program had a HR of

Apart from the primary outcome, other secondary outcomes in both trials CANVAS (all-cause mortality and CV death) and EMPA-REG (primary outcome plus hospitalization for unstable angina) showed decrease as compared to placebo but were not significant statistically. However other exploratory outcomes like Hospitalization for heart failure was significantly reduced in both the trials [EMPA-REG (HR:0.65; 95%CI, 0.50–0.85)and CANVAS Program (HR: 0.67; 95% CI, 0.52-0.87)]. The individual MACE were also analyzed, EMPA-REG showed a significant reduction in CV death, a non significant reduction in nonfatal MI but increased in stroke incidence which is again non significant statistically. The CANVAS program had its individual MACE outcomes better than the placebo but not statistically significant. Mean HbA1c decreased in the CANVAS program stands at 0.58 % and in EMPA-REG trial there was 0.36 % reduction as compared to placebo in the background of standard of care[3,4].

Both progression and regression of albuminuria had been studied in CANVAS program; significant decreased progression was seen in the canagliozin group than among those in placebo, hazard ratio of 0.73 (95% CI, 0.67 to 0.79) and regression stands with hazard ratio, 1.70; 95% CI,1.51 to 1.91. Also, composite outcome of sustained 40% reduction in eGFR, the need for renal-replacement therapy, or death from renal causes was found to occur less frequently significantly in the treatment arm then placebo (HR 0.60; 95% CI, 0.47 to 0.77)[3]

The renal outcome of EMPA-REG trial was pretty good with a significant decreased progression of albuminuria corresponding to 38% as compared to placebo (HR 0.62; 95% CI 0.54-0.7)]. Composite outcome of doubling of serum creatinine level accompanied by eGFR of <45 ml/min/1.73 m2, initiation of renal replacement therapy, or death from renal disease was significantly lower in empagliozin group than placebo (HR 0.54; 95% CI,0.40-0.75). No regression of albuminuria was estimated in the analysis of EMPA-REG trial. [10]

Two distinguished adverse events were noted in CANVAS program; fractures [HR 1.26 (1.04–1.52)] and amputation [1.97 (1.41-2.75)] were seen and found to be significantly increased in the canagliozin arm, though no mechanism hold true till the writing of this manuscript.

4 © JIMI � JULY 2017 � VOL. 11

Fracture was also found in EMPA-REG but not significant as compared to placebo. There was no reporting in regard to amputation in EMPA-REG trial as it was not captured in the adverse event report; however, a recent article published mentioned the incidence of lower limb amputation to be not significant in the trial which was assessed based on the AE narratives and manual review of the pool safety data [3,4,11]

It is always a debate to compare outcome of two therapies from separate trials and more difficult specially in case of CVOT's. Both CANVAS and EMPA-REG is an adaptive clinical trial with various amendments in due course of the trial along with varying patient parameters. The most important difference is the patient profile: EMPA-REG comprises >99% of pat ients with es tabl ished cardiovascular risk whereas CANVAS program constitutes 65% and rest 35% cardiovascular risk. So, based on this population parameters there is always concern to what extent the results can be extrapolated and be useful to real world scenario as the patient population visiting a clinic differs to that of trial population. The number of patients recruited in EMPA-REG was 7020 with a median follow up of 3.1 year in comparison to CANVAS program where 10142 patients were recruited with 3.6 years' median follow up.14 years is the duration of diabetes in CANVAS program whereas EMPA-REG trial included patients with more than 10 years was 57%. Other reasons which doesn't favour comparison is the possibility of dissimilarity of routine care background in the patients involved in the trial along with the diverse definition of end points [3,4,5]. SGLT2 inhibitors paved a new window in the treatment of type 2 diabetes mellitus by its unique mode of action. DECLARE TIMI and VERTIS-CV in the coming years will provide more information to the class of drugs. Recently few CVOT have included head to head direct comparison of drugs which will help better in understanding the efficacy of the molecules.[5] More such studies are needed that too with a broader large patient population for a longer duration with more relevant end points. Lots of hypothesis were put forward regarding the substantial cardio-nephro protective action of SGLT2 inhibitors yet more research need to be done to vindicate the proper mechanism behind it.

ReferencesFederal Drug Administration (FDA). Guidance for industry diabetes mellitus—evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. 2008. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf. Accessed 20 Dec 2016.European Medicines Agency (EMA). Guideline on clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus. Verfügbar unter. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129256.pdf(2012). Accessed 31 July 2017.Neal B, Perkovic V, Mahaffey K, de Zeeuw D, Fulcher G, Erondu N et al. Canagliozin and Cardiovascular and Renal Events in Type 2 Diabetes. New England Journal of Medicine. 2017;.Zinman B, Wanner C, Lachin J, Fitchett D, Bluhmki E, Hantel S et al. Empagliozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. New England Journal of Medicine. 2015;373(22):2117-2128.Schnell O, Rydén L, Standl E, Ceriello A. Current perspectives on cardiovascular outcome trials in diabetes. Cardiovascular Diabetology. 2016;15:139Multicenter Trial to Evaluate the Effect of Dapagliozin on the Incidence of Cardiovascular Events (DECLARE-TIMI58) https://clinicaltrials.gov/ct2/show/NCT01730534?term=NCT01730534&rank=1.Cardiovascular Outcomes Following Ertugliozin Treatment in Type 2 Diabetes Mellitus Participants With Vascular D i s e a s e , T h e V E R T I S C V S t u d y ( M K - 8 8 3 5 - 0 0 4 ) https://clinicaltrials.gov/ct2/show/NCT01986881?term=NCT01986881&rank=1.Marso S, Daniels G, Brown-Frandsen K, Kristensen P, Mann J, Nauck M et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. New England Journal of Medicine. 2016;375(4):311-322.Marso S, Bain S, Consoli A, Eliaschewitz F, Jódar E, Leiter L et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. New England Journal of Medicine. 2016;375(19):1834-1844.Wanner C, Inzucchi S, Lachin J, Fitchett D, von Eynatten M, Mattheus M et al. Empagliozin and Progression of Kidney Disease in Type 2 Diabetes. New England Journal of Medicine. 2016;375(4):323-334Kohler S, Zeller C, Iliev H, Kaspers S. Safety and Tolerability of Empagliozin in Patients with Type 2 Diabetes: Pooled Analysis of Phase I–III Clinical Trials. Advances in Therapy. 2017;34(7):1707-1726.

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Contents

ORIGINAL ARTICLE

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© JIMI � JULY 2017 � VOL. 11


Prevalence of Low Bone Mineral Density in Ankylosing Spondylitis:A preliminary study from a tertiary care center in North India.

Anupam Wakhlu, Durgesh Srivastava, Rasmi Ranjan Sahoo, Danveer Bhadu,Meha Sharma, Saumya Ranjan Tripathy

Prevalence of Anemia in Hostel Living Girls of Greater Noida.

Bushra Shaida, Anshu Nanda

3.

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Effectiveness and Safety of A Combination of Intra-Articular Corticosteroidand Local Anesthetic In Indian Patients With Knee Osteoarthritis: A Pilot Study

Rakesh Kumar Jagdish, MK Bhatnagar, Ayush Malhotra, Shailly

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A Paradigmal shift of hypertension in Sub-Himalayan region

Ravi Kant, Vinita Thapaliyal, Priyanka Gupta

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39

Study of Pattern of Rheumatologic and Musculoskeletal Disorders andTheir Awareness Among Patients Attending Rheumatology Clinic

Rakesh Kumar Jagdish, M.K. Bhatnagar, Ayush Malhotra

REVIEW ARTICLE

Role Of Pulmonary Rehabilitation In Cases Of PulmonaryImpairment After Tuberculosis

Antriksh Srivastava, Vinisha Chandra, Mohan Bandhu Gupta,Gajendra Vikram Singh, Santosh Kumar

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7. Metformin - Marching Beyond Diabetes

Arvind Kumar Mishra, Rohit Anand, Shilpa, Rohin

CASE REPORT

© JIMI � JULY 2017 � VOL. 11 6

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Unusual Presentation Of Aortic Dissection

Rohit Bhagat, Amitesh Aggarwal

Rifampicin Induced Thrombocytopenia

AnamikaVerma, Nikhil Gupta, Rajendra Prasad

10. Cryptococcal Meningitis in an Immunocompetent Patient

Saurabh sharma, Ravi kant, Balram ji Omar, Priyanka Gupta

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Prevalence of Low Bone Mineral Density in AnkylosingSpondylitis: A preliminary study from a tertiary care

center in North India.

Original Article

1 2 3 4Anupam Wakhlu , Durgesh Srivastava , Rasmi Ranjan Sahoo , Danveer Bhadu ,

5 6Meha Sharma , Saumya Ranjan Tripathy

© JIMI � JULY 2017 � VOL. 11


AbstractBackground: To assess the prevalence of low bone mineral density (BMD) in ankylosing spondylitis (AS).

Methods: This is an observational study including 90 diagnosed AS patients fulfilling the modified New York criteria for the classification of AS (1984) attending the department of Rheumatology, King George's Medical University, Lucknow, India done over a period of 6 months. Patients were divided into 2 groups

based on the duration of disease: early (<5 years) (Group A) and long standing disease (�5 years) (Group

B). Dual Energy X-ray Absorptiometry (DEXA: GE, Lunar) was used for estimation of BMD (g/cm2) and z score at bilateral proximal femur and lumbar spine (L1–L4). Statistical analysis was done by using Mann-Whitney U and Chi-Square tests for quantitative and qualitative data respectively. P value of <0.05 was considered significant.

Results: There were 48 patients in Group A and 42 in Group B. The mean age of patients was 35.33 ±12.24 years, with Group A patients being younger than Group B (25.17 ±4.34 vs 46.95 ±6.67 years, p<0.05). Males were predominant in Group A (87.5%) whereas male: female ratio was 1:1 in Group B. Prevalence of low BMD did not vary among group A and B patients (41.7% vs 47.6%, p=0.67). The z score at lumbar spine and left neck of femur did not differ significantly whereas z score at right neck of femur was significantly low in Group A patients (p=0.036).

Conclusion: Low BMD is fairly prevalent in AS but prevalence was not associated with duration of disease in this study.

Keywords: Osteoporosis; Ankylosing Spondylitis; Fracture; Bone Mineral Density; BMD

Osteoporosis is prevalent in ankylosing spondylitis (AS) and associated with increased risk of vertebral fracture [1].The causes of osteoporosis are multifactorial.In one study, juvenile-onset disease, morning stiffness over half an hour and elevated ESR were risk factors for low BMD at the lumbar spine whereas male sex, advanced age, hip involvement and irregular treatment were risk factors for

[2]bone loss at the femur . Bone loss starts early in the disease course and is mainly due to inammation [3].Proinammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) contribute to bone loss in AS patients. A high prevalence of low BMD

[4]in early AS (<10 years) has been reported .

Introduction:

P r o f e s s o r , S e n i o r R e s i d e n t , , C o n s u l t a n t Rheumatologist1 Department of Rheumatology, King George's Medical University, Lucknow-226003, Uttar

2 Pradesh, Department of Rheumatology, All India Institute of Medical Sciences, New Delhi-110029,3 Venkateshwar Hospital, New DelhiCorresponding author:Professor Anupam Wakhlu, DM (Clinical Immunology)Department of Rheumatology:King George's Medical University, Lucknow, UP, India, 226003Mob: 09005784228Email: [email protected]

This study aims to assess BMD in North Indian AS patients and to observe association with duration of disease.

New bone formation in AS may result in spuriously high BMD measurements at the spine.BMD at the femoral neck may be accurate in detecting osteoporosis in ASas it

[5,6]correlates with increased risk of vertebral fracture .

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BMD Measurement:The BMD was measured at the proximal femur and lumbar spine (L1–L4)in g/cm2 using a DEXA machine (GE, Lunar). For BMD measurement in young adults, the International Society for Clinical Densitometry (ISCD) recommendation was used with Z-scores of −2.0 or lower defined as either “low bone mineral density for chronological age” or “below the expected range for age” and those above −2.0 being “within the expected range for

[7]age” . Quality control procedures were ensured as per manufacturer's recommendations.

(e) Data management and analysis:Statistical analysis was done by Graphpad Prism 5.01. Quantitative data were expressed as mean and standard deviation whereas qualitative data as frequency and percentage. Mann-Whitney Uand Chi-Square tests were used to compare quantitative and qualitative data respectively. Spearman's rank correlation was used to analyze relationship between BMD and age. P value of <0.05 was considered statistically significant.

Materials and Methods:

Study design: Observational / Cross-sectional study.Setting:Present study was conducted in the Department of Rheumatology, King George's Medical University, Lucknow, India over a period of 6 months. Participant selection:

Inclusion criteria: 90 AS patients fulfilling the modified New York criteria for the classification of AS (1984) attending the department of Rheumatology, King George's Medical University, were included in the study. The study protocol was explained to all the subjects and patients willing to provide written informed consent were recruited. In patients where vitamin D estimation could not be done due to financial or other constraints, we ensured that calcium & vitamin D was or had been therapeutically supplemented for at least 3 months prior to BMD examination.

(a)(b)

Exclusion Criteria:To assess the prevalence of low bone mineral density (BMD) in ankylosing spondylitis (AS).

Patients with other inammatory arthritides e.g. reactive arthritis, psoriatic arthritis, enteropathic arthritis, rheumatoid Arthritis and gout.

Severe vitamin D deficiency (25-OH vitamin D <10ng/ml).

Patients on drugs interfering with BMD (anticonvul-sants, bisphosphonates).

Past history of fragility fractures.

Patients with secondary cause of osteoporosis (e.g. known cases of diabetes mellitus, celiac disease, hyperparathyroidism).

Chronic liver disease Chronic renal disease (CKD stage 3 or more)

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(d) Data collection: All participants were subjected to detailed history and physical examination. Details were collected regarding duration of disease,other comorbidities, and relevant previous investigations. Based on the duration of disease, patients were divided

into 2 groups: Group A: < 5 years and Group B: � 5

yearsof disease and clinical parameters were compared.

Results:Out of 90 patients, 48 had early disease (group A) and 42 had long standing disease (group B). Males were predominant in group A (87.5%) whereas male:female ratio was 1:1 in group B. The demographic characteristics of patients are shown in Table 1.Group A patients had active disease compared to group B. The inammatory parameters of patients are shown in Table 2.Low BMD was prevalent in our study (44.5%), however, it was not different among the groups. The prevalence of low BMD in patients is shown in Table 3.The average z scores at the spine and neck of femur (left) were not different among the groups whereas that at the neck of femur (right) was significantly different. The average z scores at the spine and neck of femur are shown in Table 4.The average z scores at the spine, neck of femur (right and left) did not correlate with age. The scatter plots of z scores at different locations in patient are shown in Figure 1.There was no correlation of BMD at the spine and neck of femur with ESR, CRP and ASDAS ESR.

Discussion:The present study demonstrates that low BMD is fairy prevalent in patients of AS. Osteoporosis is described to be a common complication in AS. In our study including predominantly young males, the prevalence of osteoporosis was 44.5%. Bone loss in AS is associated with elevated levels of acute phase reactants, proinammatory

[5]cytokines and bone turnover markers . Other factors

8 © JIMI � JULY 2017 � VOL. 11



that may contribute to osteoporosis in AS are low body mass index and vitamin D deficiency.Though vitamin D levels could not measured in all patients owing to financial or other constraints, we ensured that calcium & vitamin D was or had been therapeutically supplemented for at least 3 months prior to BMD examination. Further, this is a preliminary study done mainly to assess the overall prevalence of low BMD in young as patients. The causes of low BMD, other than inammation, documented in the present study, are subject to further study. The high prevalence of osteoporosis in our study warrants routine screening for osteoporosis in young AS patients, possibly as the standard of care. One study recommended assessment of BMD within 10 years of

[8]diagnosis of AS . However, the high frequency of osteoporosis within 5 years of disease,as seen in our study, suggests early screening might be beneficial.There was no correlation of low BMD with duration of disease in our study. Vasdev et al have similarly reported

[9 ]no association with duration of disease . They havereported a prevalence of osteoporosis at spine and femur neck of 28.75% and 11.54% respectivelyand demonstrated no correlation with inammatory markers and disease activity indices. However, some studies have demonstrated a positive correlation between duration of

[10]disease and low BMD . This difference could be due to genetic diversity of the study population, sample size, level of disease activity, treatment given and response to therapy.BMD and age of patients did not correlate in the present study. Bone loss increases as age advances and osteoporosis is associated with advancing age. The study by Klingberg et al reported a positive association between

[10]age and osteoporosis in AS patients . The lack of positive association between age and BMD in our study could possibly be due to sample size.Given the high prevalence of low BMD seen in our patients, a larger study needs to be planned to look for factors inuencing BMD in AS patients. These factors could include routine factors inuencing osteoporosis, disease activity, calcium & vitamin D deficiency, prior steroid use, specific therapy used for AS and response to treatment. Bone loss in AS has been shown to be inuenced by the disease activity in some studies. Possibly, adequate control of disease activity may prevent

bone loss to a certain extent in young AS patients. In this regard, it is pertinent to note that majority of Indian AS patients do not have access to biologic therapy, which remains the recommended cornerstone for management of AS world over. Most of our patients are on NSAID's, sulfasalazine and physiotherapy with or without the initial use of steroids. It would be interesting and pertinent to analyze the change in BMD of a sub group of AS patients who have received anti TNF therapy and see whether significant improvement is observed. Other than reversible causes affecting BMD, persistent low BMD in AS would require therapy, given the higher risk of spinal fracture in these patients.There are nospecific guidelines for the management of

[ 1 1 , 1 2 ]osteoporos is in AS . However , the main recommendation is to control disease activity to prevent bone loss. This concept has been further supported by studies using anti-TNF agents showing a favourable outcome on BMD in AS.One study assessed the consensus among rheumatologists for the management of

[13]osteoporosis in AS using a questionnaire . One-third of them opted for routine screening using DEXA scan. Majority advised physiotherapy (98.7%) and one-third recommended diet modification. For the treatment of osteopenia, 54.2% advised management with calcium and vitamin D whereas 21.3% recommended prescribing a bisphosphonate. Regarding osteoporosis (T score < -2.5), majority advised bisphosphonate. Therefore, where indicated, the management ofosteoporosis in AS is similar to that for osteoporosis from other causes. Adequate replacement of calcium and vitamin D, physiotherapy and bisphosphonates are the most commonly used

modalities. The role of hormone replacement therapy is limited as AS is mainly a disease of young males.Limitations of the present study include small sample size. Follow-up BMD to assess response to treatment in this cohort needs to be observed in a larger study.

Conclusion:Low BMD is fairly prevalent in AS in this cohort of patients. The factors contributing to this low BMD, effect of AS treatment on BMD and whether BMD assessment needs to become standard of care for therapeutic decisions needs to be studied in a larger cohort of patients.

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© JIMI � JULY 2017 � VOL. 11

Table 4: Average Z scores at the spine and neck of femur

Frequency (%) p value

Group A (N=48) 20 (41.7%)

0.67Group B (N=42) 20 (47.6%)


References:Ulu MA, Batmaz İ, Dilek B, Çevik R. Prevalence of osteoporosis and vertebral fractures and related factors in patients with ankylosing spondylitis. Chin Med J 2014;127:2740-7.

Wang DM, Zeng QY, Chen SB, Gong Y, Hou ZD, Xiao ZY. Prevalence and risk factors of osteoporosis in patients with ankylosing spondylitis: a 5-year follow-up study of 504 cases. ClinExp Rheumatol. 2015;33:465-70.

Grazio S, Kusic Z, Cvijetic S, Grubisic F, Balenovic A, Nemcic T, et al. Relationship of bone mineral density with disease activity and functional ability in patients with ankylosing spondylitis: a cross-sectional study. Rheumatol Int 2012;32:2801-8.

Van der Weijden MA, Claushuis TA, Nazari T, Lems WF, Dijkmans BA, van der Horst-Bruinsma IE. High prevalence of low bone mineral density in patients within 10 years of onset of ankylosing spondylitis: a systematic review. Clin Rheumatol 2012;31:1529-35.

Magrey M, Khan MA. Osteoporosis in ankylosing spondylitis. Curr Rheumatol Rep2010;12:332-6.

Kaya A, Ozgocmen S, Kamanli A, Ardicoglu O. Bone loss in ankylosing spondylitis: does syndesmophyte formation have an inuence on bone density changes? Med PrincPract. 2009;18:470-6.

Schousboe JT, Shepherd JA, Bilezikian JP, Baim S. Executive Summary of the 2013 ISCD Position Development Conference on Bone Densitometry. JCD 2013;16:455-467.

Davey-Ranasinghe N, Deodhar A. Osteoporosis and vertebral fractures in ankylosing spondylitis. CurrOpin Rheumatol. 2013;25:509-16.

Vasdev V, Bhakuni D, Garg MK, Narayanan K, Jain R, Chadha D. Bone mineral density in young males with ankylosing spondylitis. Int J Rheum Dis. 2011;14:68-73.

Klingberg E, Lorentzon M, Mellström D, Geijer M, Göthlin J, Hilme E, et al. Osteoporosis in ankylosing spondylitis -prevalence, risk factors and methods of assessment. Arthritis Res Ther. 2012;14:R108.

Bessant R, Keat A. How should clinicians manage osteoporosis in ankylosing spondylitis? J Rheumatol 2002;29:1511-9.

Magrey M, Khan MA. Osteoporosis in ankylosing spondylitis. Curr Rheumatol Rep 2010;12:332-6.

Bessant R, Harris C, Keat A. Audit of the diagnosis, assessment, and treatmentof osteoporosis in patients with ankylosing spondylitis. J Rheumatol. 2003;30:779-82.

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Table 1: Demographic characteristics of patients

Female 6 (12.5%) 20 (47.6%) 26 (28.9%)

Group A (N=48) Group B (N=42) Total (N=90)Age (Mean±SD) 25.17 ±4.34 46.95 ±6.67 35.33 ±12.24

Male 42 (87.5%) 22 (52.4%) 64 (71.1%)

Table 2: In�ammatory parameters of patientsGroup A (N=48) Group B (N=42) p value

ESR in mm/hr(Mean±SD) 50±12 18±9 0.001*

CRP mg/dl(Mean±SD)(0-6 mg/dl)

32±9 12±4 0.01*

ASDAS ESR (WG)(Mean±SD) 3.5±0.5 1.9±0.4 0.01*

*p value signi�cant

Table 3: Prevalence of low BMD in patients

p valueSite Group A (N=48) Group B (N=42)

Lumbar Spine AP-1.62±1.52 -1.56±1.73 0.97

Neck of femur-Right-1.12±1.28 -1.64±1.0 0.036*

(Mean±SD)Neck of femur-Le�

-1.4±1.29 -1.41±1.28 0.97

*p value signi�cant

10 © JIMI � JULY 2017 � VOL. 11

1-Nutrition & Dietetics, Assistant Professor, Sharda University, 2 -Clinical Research, Assistant Professor, Sharda University

Prevalence of Anemia in Hostel Living Girls ofGreater Noida.

Original Article

1 2Bushra Shaida , Anshu Nanda

AbstractPresent study was undertaken to find the prevalence of anemia in girls of age group 18- 23 years of Greater Noida, who were residing in various hostels of the city. A total of 100 girls were selected from four different hostels of Greater Noida, Gautum Budh Nagar, India. Data collection was done using different nutritional assessment methods viz. Anthropometric measurements (Height, weight and BMI), Biochemical examination (estimation of blood hemoglobin using Sahli's Hemoglobinometer) Clinical examination and Dietary survey (24 hour dietary recall method).Data on anthropometry revealed that out of total girls screened (N=100), mean height and weight in the given age group was significantly (p<0.05%) less than the National Center for Health Statistics standards. Hemoglobin test revealed that 56% (56 girls) had hemoglobin level below the normal (12 g dlG1) values, indicating anemia, out of which approximately half 62.5%(35girls) were mild anemic and 37.5%(21girls) were moderate anemic. Feeling breathlessness and easily tired were experienced by 71.4 %( 40 girls) and 28.57 %(16 girls) of the subjects respectively. Consumption of all the nutrients by majority of the girls was comparatively less than the recommended dietary allowances.Significant association between parity index and prevalence of anemia as found in the present study calls for measures to improve the nutritional status of girls staying away from home so that they can bring up healthy future of India.

IntroductionAnemia in pregnant women and adolescent girls has serious health implications. One of the leading maternal and mortality factor is severe anemia during pregnancy. Severe anemia also contributes in prenatal morbidity and mortality by retarding intrauterine growth and causing

[1, 2 & 3]pre-term delivery . Anemia in adolescent girls affects their physical work capacity and reproductive physiology [4]. According to a World Health Organization (WHO)

[5]report , the global prevalence of anemia among pregnant women is 55.9%. In India, the prevalence of anemia in pregnant women has been reported to be in the range of

[7–11]33% to 89% . According to the limited number of studies from India, the prevalence of anemia in adolescent

[12, 13]girls is also fairly high . Various nutritional, inammatory and infectious state of the body results in anemia; iron deficiency anemia being the most common which result from inadequate intake and low absorption

[14, 15]of dietary iron . India launched the National

Nutritional Anaemia Prophylaxis Programme (NNAPP) in 1970. Under the program, iron and folic acid tablets are distributed to pregnant women. However, no impact of this program on the prevalence of anemia was observed in

[8]an evaluation conducted during 1985–86 . Consequently, certain modifications were made in the NNAPP to make it

[14]more effective and efficient . The present paper reports the prevalence of anemia among adolescent girls in various hostels of Greater Noida.

© JIMI � JULY 2017 � VOL. 11 11


MethodsThe study was confined to hostel living girls of Greater Noida, Uttar Pradesh. A total of 100 girls of age group 18-23 years were selected randomly. A combination of survey and laboratory test was used in order to obtain the information required.

Diet survey: A dietary survey was conducted as described by Swaminathan. The food frequency was recorded in terms of cereals, pulses, milk and milk products, green leafy vegetable, roots and tubers, fruits, meat and poultry, fats and oils and sugar. The daily dietary recall for three

Normal (Hb > 12 gm/dl)

Mild (Hb > 10 gm/dl < 11.9 gm/dl)

Moderate (Hb > 07gm/dl < 10 gm/dl)

Severe (Hb < 07gm/dl)

No. of Girls 44(out of 100) 35( out of 56) 21(out of 56) 00(out of 56) Percentage (%) 44 62.5 37.5 00

Result And DiscussionData obtained was analyzed with respect to the objectives of the present study which were to find the prevalence of anemia among 100 girls of age group 18- 23 years.

Clinical Examination: All the subjects were physically examined for the presence or absence of any clinical signs and symptoms of anemia, including paleness of nails and conjunctiva of the eye. The procedure of Gibson was followed for the clinical survey.

Hemoglobin estimation: Hemoglobin level of subjects was estimated by using Sahli's Apparatus method. The WHO cut off values published by ICMR Task Force for assessment of anemia in the girls was used for the assessment.

© JIMI � JULY 2017 � VOL. 11 12


consecutive days was taken and was averaged out for one

day. The daily nutrient intake was calculated with the

help of food composition tables of Gopalan et al. The

calculated daily nutrient intake in terms of energy,

protein, ascorbic acid, iron and folic acid were then

compared against recommended dietary allowances for

Indians.

Anthropometric Assessment: Nutritional status of all the

subjects was assessed by measuring height (cm) and

weight (kg). Height and weight was compared with

National Center for Health Statistics (NCHS) standards.

Height of each subject was measured in a standing

position to the nearest 0.1 cm using non-stretchable steel

tape. A personal weighing machine was used to measure

the body weight to the nearest 0.5 kg.

The individuals were kept under minimum clothing and without shoes. Then mean BMI was also calculated using the above data which help to estimate the percentage of body fat. WHO norms were taken into account for assessment of body fat using BMI.

Prevalence of Anemia among Hostel living Girls (18-23 years):Out of the total girls screened (N=100), 65.33% had Hb level below the normal value (12 gm/dl) indicating anemia. Out of this, 53.33% were mild anemic and 12% were moderate anemic. None of them were severe anemic.

Anthropometric measurement-calculating BMIBMI is a heuristic proxy for human body fat based on an individual's weight and height. In the present study, out of 100 girls 32% girls had normal BMI, 44% girls had below normal BMI thus they are underweight, 26% have above normal BMI i.e they are overweight.70% girls who were overweight are anemic while 50% girls who were underweight are anemic, thus the result shows that anemia had significant role in weight management.

Diet and nutrient intakeNon – Vegetarian predominates with 42.6%, followed by vegetarian (32%) and ovo-vegetarian (16%). 43% skip breakfast on daily basis, out of which 18% skip breakfast 3-4 times per week, 20% skip breakfast 2-3 times per week. 10% were absolute breakfast skippers. The food consumed daily by the subjects included cereals, fats and oils and sugar. Regarding the consumption of pulses it was found that a good portion (98%) of the subjects consumed the item daily and 18% consumed 4-6 times per week as depicted in table 3. Consumption of milk and milk products by the subjects was also found to be frequent, 55 % consumed milk on daily basis, whereas 30% consumed milk 4-6 times per week. Percentage of the girls (32%) consuming green leafy vegetables 4-6 times per week was higher than those 20% who were consuming daily. The survey showed that consumption of roots and tubers was quite frequent in comparison to most of the other foods except cereals, fats and oils and sugar. Majority of the non- vegetarian and ovo-vegetarians consumed meat and poultry occasionally, where as only 8% consumed it on daily basis.Intake of nutrients i.e iron, folic acid in girls of 18-23years age group was comparatively less than the recommended dietary allowances (RDA) of the given age group, published by the ICMR. Iron was inadequate inspite of adequacy of meat and poultry. The reason may be lower intake of foods and intake of adequate amount of junk foods in between the major meals.

© JIMI � JULY 2017 � VOL. 11 13


The anthropometric measurement, clinical status and Hemoglobin status etc that are unsatisfactory and reections of the low nutrient intake of the girls.

Skip Breakfast Degree of Anemia 1-2 t/week 2-3 t/week 3-4 t/week Don÷t skip Normal 4% 5% - 30% Mild 5% - 10% 15% Moderate - 4% - 20% Severe 30% 6% - -

Table 2 - Breakfast consumption pattern of girls

Table 3- Food consumption frequency of girls

Food Groups Daily 4-6 t/weeks 2-4 t/weeks 1-2 t/weeks Occasionally Never

Cereal 100% - - - - -

Pulses 92% 4% 2% 2% Milk and Milk Products

55% 30% - - 25% 5%

Green leafy vegetables 20% 32% 20% 8% - - Root and tubers 20% 30% 22% - 18% 2% Fruits 53% 23% 10% 4% - -- Meat and Poultry 8% 12% - - - 60% Fats 100% - - - - - Sugar 100% - - - - -

Clinical signs of anemia in girls As shown in table no 4 various clinical symptoms of anemia were present among girls (18-23 years). Feeling breathlessness, and easily tiredness were experienced by 32% and 88% of the subjects respectively. Pail nails were observed in 10% and spoon shaped nails in 8% of the subjects. Conjunctiva paleness was noticed only in a small proportion (5%) of the subjects. The high prevalence of anemia among the girls surveyed could be related to the inadequate diet, unhygienic environment in hostels and lack of education in girls related to anemia.

Table no 4: Percentage of girls showing Clinical signs of anemia

To sum up all the observations among hostel living girls of age group (18-23 year) of Greater Noida. Following conclusion has been extracted:

Out of 100 girls surveyed 44% and 26% have below normal BMI and above normal BMI respectively, which concludes 70% girls were unhealthy.

Prevalence of anemia is seen in 56% of girls.

Breakfast consumption by anemic girls was almost very insignificant.

Intake of different nutrient like iron, folic acid, vitamin C is comparatively low as recommended by ICMR.

Activity levels of almost all anemic girls have been decreased.

Awareness of girls regarding anemia was also found to be insignificant.

Thus it was concluded that there was an urgent need to improve nutritional status of girls by proper intake of all nutrients and to give them awareness regarding anemia so that they can bring up the healthy future of India.

References

World Health Organization. Prevention and management of anaemia in pregnancy. WHO/FHE/MSM/93.5. Geneva: WHO, 1993

Brabin BJ, Hakimi M, Pelletier D. An analysis of anaemia and pregnancy-related maternal mortality. J Nutr 2001;131(2S-2):604S–15S.

Prema K, Neel Kumari S, Rama Lakshmi BA. Anaemia and adverse obstetric outcome. Nutr Rep Int 1981; 23:637–43.

Seshadri S. Nutritional anaemia in South Asia. In: Gillespie SK, ed. Malnutrition in South Asia: A regional profile. UNICEF Regional Office for South Asia, 1997:75–124.

Seshadri S, Sharma K, Raj AE, Thekore B, Saiyed F. Iron supplementation to control pregnancy anaemia. Proc Nutr Soc India 1994;41:131–40.

Sood SK, Ramachandran K, Mathur M, Gupta K, Ramalinga-swami V, Swaranbai TC, Ponnaiah J, Mathur VI, Baher SJ. W.H.O. sponsored collaborative studies on nutritional anaemia in India.

ICMR Task Force Study. Evaluation of the National Nutritional Anaemia Prophylaxis Programme. New Delhi: Indian Council of Medical Research, 1989.

ICMR Task Force Study. Field supplementation trials in pregnant women with 60 mg, 120 mg and 180 mg of iron with 500 mcg of folic acid. New Delhi: Indian Council of Medical Research, 1992.

Christian P, Abbi R, Gujral S, Gopaldas T. At risk status of pregnant women of Panchmahals (Gujarat) and Chandrapur (Maharashtra). Arogya J Health Sci 1989;15: 85–91.

Agarwal DK, Agarwal KN, Tripathi AM. Nutritional status in rural pregnant women of Bihar and Uttar Pradesh. Indian Pediatr 1987;24:119–25.

Sarin AR. Severe anaemia of pregnancy: recent experience. J Gynaecol Obstetr 1995;50(suppl)27:545–9

Kanani S, Ghanekar J. Anaemia and adolescent girls: A review of research evidence and intervention strategies, 1997. Department of Food and Nutrition, MS University of Baroda and UNICEF, India.

Vir SC. Iron deficiency anaemia control—a public health programme priority. Proc Nutr Soc India 2000; 47:45–73.

Rao BSN. Studies on iron deficiency anaemia. Indian J Med Res 1978;suppl 68:58.

Toteja GS, Singh P. Micronutrient profile of Indian population. New Delhi: Indian Council of Medical Research, 2004.

Swaminathan, M., 2002. Essentials of Food and Nutrition 2nd Edn., Bappco Publication, 2: 337-338.

Gopalan, C., B.V. Ramasastri and S.C. Balasubramanian, 2002. Nutritive Value of Indian Foods. NIN (ICMR) Hyderabad, 94.

Indian Council of Medical Research, 2000. Nutrient Requirement and Recommended Dietary Allowances for Indians. NIN, Hydrabad, pp: 67-89.

INACG., 1985. Measurement of iron status. International National Anemia Consultative Group: Washington, D.C., pp: 45.

Gibson, R.S., 1990. Principles of Nutritional Assessment', Oxford University Press, New York, Oxford, 257: 577-855.

© JIMI � JULY 2017 � VOL. 11 14


Conclusion

1.

2.

3.

4.

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6.

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18.

19.

20.

21.

Effectiveness and Safety of A Combination of Intra-Articular Corticosteroid and Local Anesthetic In

Indian Patients With Knee Osteoarthritis: A Pilot Study

Original Article

1 2 3 4Rakesh Kumar Jagdish , Dr. MK Bhatnagar , Dr. Ayush Malhotra , Dr. Shailly

Background: Osteoarthritis is a chronic degenerative disorder of multifactorial etiology characterized by the loss of articular cartilage, resulting in joint pain, stiffness, swelling, and disability without any clear answer to its treatment and cure. Studies from intra-articular steroid with local anesthetic uses in osteoarthritis are rare from India.

Objective: To determine the effectiveness and safety of administering a combination of intra-articular corticosteroid and local anesthetic in Indian patients with knee osteoarthritis.

Methods: This, prospective, open-label, observational single-center pilot study was conducted at the Rheumatology Clinic of a tertiary care centre, from December 2015 to December 2016. This, prospective, open-label, observational single-center pilot study included patients(n=20) between 35-70 years of age, suffering from chronic knee pain for at least three months prior to inclusion, with a clinical or radiological diagnosis of knee osteoarthritis, dissatisfied with previous non-surgical management. Patients were administered injection methylprednisolone 80mg (2ml) plus lignocaine 1% (0.5ml) intra-articularly which were followed with five scheduled visits i.e. baseline (visit 1), day 1 (visit 2), 6 weeks (visit 3), 12 weeks (visit 4), and 24 weeks (visit 5). Patients were evaluated on a Visual Analogue Scale [VAS] for pain and patient reported self-assessment questionnaire to evaluate other clinical effectiveness parameters.

Results: Mean age of the study population was 52.55+7.91 years. Majority (85%) were females. After administration of the injection, pain (as measured by the VAS scale) improved within a day and there was complete (100%) pain relief in all patients (as per subjective assessment) at week 1. The VAS score reduced from 8.90+0.968 at baseline to 6.35+1.387 on day 1 (mean reduction of 2.55+1.191) and 5.30+0.923 at week 1 (mean reduction of -3.60+1.273). For each of the clinical effectiveness parameters, a significantly greater proportion of patients showed 'improved' status than those who 'worsened' or remained the same. Seventy percent (14/20) patients reported 'decreased' frequency of non-steroidal anti-inammatory drug (NSAID) usage (p=0.0368).

Conclusion: Combination injection of intra-articular corticosteroid and local anesthetic is safe and effective in Indian patients with osteoarthritis. It achieves immediate pain relief, with effects lasting for at least 6 months and helps decrease NSAID usage in most patients.

Keywords: osteoarthritis; injections, intra-articular; anesthetics, local; visual analog scale; anti-inammatory agents, non-steroidal

© JIMI � JULY 2017 � VOL. 11 15


Abstract

IntroductionOsteoarthritis is a chronic degenerative disorder of multifactorial etiology characterized by the loss of articular cartilage, resulting in joint pain, stiffness, swelling, and disability. It is the most common joint disease worldwide and most commonly affects the knee joint. In India, the prevalence of knee osteoarthritis is 28.7%. Osteoarthritis of the knee joint is one of the

foremost causes of global disability and is ranked as the 11th highest contributor to global disability along with hip osteoarthritis. On account of the effects of disability, co-morbid disease, and treatment costs, osteoarthritis inicts a tremendous economic burden. Additionally indirect costs such as loss of productivity, lost wages, and costs associated with the need for home care and child care further add to the disease burden.

In addition to the sizable economic burden, progressive

functional disability associated with osteoarthritis

substantially impacts quality of life in patients. Hence

treatment of osteoarthritis primarily aims at controlling

pain, and improving functional disability and health-

related quality of life. The American College of

Rheumatology (ACR) 2012 recommendations suggest

severa l t rea tment modal i t i es inc luding non-

pharmacological techniques like weight loss, patient

education, and regular exercise and pharmacological

drugs such as acetaminophen, oral and topical non-

steroidal anti-inammatory drugs (NSAIDs), tramadol,

and intra-articular steroids, while conditionally

recommending against the use of chondroitin sulfate,

glucosamine, and topical capsaicin. Acetaminophen,

aspirin and NSAIDs, that are commonly used as pain

relief medications can lead to gastric complications,

ulcers, increased risk for hospitalization, adverse side

effects, and death. Likewise tramadol is associated with

adverse effects such as constipation, dizziness, nausea,

somnolence, headache etc. that limit its use.

MethodsThis, prospective, open-label, observational single-center pilot study was conducted at the Rheumatology Clinic of the Medicine Department of Santosh Medical College and Hospital, Ghaziabad, from December 2015 to December 2016.

Patient SelectionAdults between 35-70 years of age, suffering from chronic knee pain (pain score at least 3 cm on Visual Analogue Scale [VAS] for at least three months prior to inclusion, with a clinical or radiological diagnosis of knee osteoarthritis, dissatisfied with previous non-surgical management including analgesics and other drugs were included after informed consent. Those with severe, advanced, destructive arthritis with deformity, neuropathic or septic arthritis, post-operative arthritis/artificial joint, hypersensitivity to study medications or contrast solutions, or those who had previously received an intra-articular injection (corticosteroid, hyaluronic acid preparation or other) were excluded.

© JIMI � JULY 2017 � VOL. 11 16


1-Assistant Professor of Medicine and Incharge Rheumatology Clinic, Santosh Medical College & Hospital, Ghaziabad.(Corresponding Author).Visiting Consultant Rheumatologist Max and Kailash Hospital, Noida2-Professor of Medicine, Santosh Medical College & Hospital, Ghaziabad. Ex Director Professor, Lady Harding Medical College, New Delhi.3 -Junior Resident of Medicine ,Santosh Medical College and Hospital, Ghaziabad.4 -Junior Resident of Chest Medicine, Chest and TB Hospital, Govt. Medical College, Patiala.

combination in clinical practice. Nonetheless the combination of intra-articular steroids and local anesthetics is routinely administered universally (either in the same syringe or separately) to treat osteoarthritis.

The potential advantage of rapid onset and prolonged duration of action offered (which enables instant pain relief and anti-inammatory response) by combination of intra-articular steroids and local anesthetics, as well as the controversy surrounding its safety makes it imperative to examine its effectiveness and safety in patients with knee osteoarthritis. However, studies exploring the effectiveness and safety of this combination are limited especially in India. Therefore, this pilot study was conducted to determine the effectiveness and safety of administering a combination of intra-articular corticosteroid and local anesthetic in Indian patients with knee osteoarthritis.

Intra-articular steroids on the other hand exhibit a better long-term safety profile with no deleterious effects on the anatomical structure of the knee Further, intra-articular steroids also significantly reduce osteoarthritic knee pain, stiffness and joint function , which in turn helps in improving quality of life, and delaying surgical interventions in patients with knee osteoarthritis.

Intra-articular corticosteroids are often used along with local anesthetics to treat osteoarthritis probably due to the rationale that the local anesthetic component acts quickly after administration, to provide immediate pain relief, and its action may last until the corticosteroid component starts to exert its effect. While some studies suggest that a combination local anesthetic/corticosteroid may have potential negative effects on intra-articular cell viability and cell metabolism, and may lead to chondrotoxicity , others support continued safe use of this

© JIMI � JULY 2017 � VOL. 11


Study procedures and data collectionAt baseline, patients were administered injection methylprednisolone 80mg (2ml) plus lignocaine 1% (0.5ml) intra-articularly under all aseptic precautions. The duration of observation was 24 weeks with five scheduled visits i.e. baseline (visit 1), day 1 (visit 2), 6 weeks (visit 3), 12 weeks (visit 4), and 24 weeks (visit 5). At baseline, data regarding demography, occupation, socio-economic status, previous alternative treatment (ayurvedic, homeopathy, other), disease duration etc. was collected on case record forms. On all five visits, pain was measured on VAS scale (0-10cm). (Figure 1)

Figure 1. Visual analog scale

Abbreviations: VAS � Visual analog scale

At 24 weeks, each patient was asked to fill up a patient self-assessment questionnaire indicating the status ('improved', 'worsened' or 'same'; with respect to baseline) of 'clinical effectiveness' parameters such as range of motion of the joint; clinical symptoms like localized swelling, heat, and tenderness; duration of early morning stiffness; duration of post inactivity stiffness; increased self-dependence, self-esteem and overall confidence; overall mobility and presence in social gatherings; and overall well-being and lifestyle. In the same questionnaire, the patient was asked to indicate the change in frequency of NSAID usage (with respect to baseline) as 'increased', 'decreased' or 'same'. Throughout the study patients were encouraged to report any complications/adverse events, increased difficulty in movements, or restriction of mobility after intra-articular injection.

Endpoints and assessmentsE�ectiveness outcomes Effectiveness was assessed on the basis of change in VAS score, proportion of patients with 'improved' clinical effectiveness parameters and proportion of patients with 'reduced' NSAID usage at 24 weeks.

Safety outcomesSafety was assessed as incidence of adverse events (AEs), serious adverse events (SAEs), and adverse drug reactions (ADRs). An AE was defined as any untoward medical occurrence that did not necessarily have a causal relationship with treatment. When the attending

Statistical analysisSample size calculationAssuming that a mean difference of 1.5 cm on the VAS between visits is a clinically significant improvement and a standard deviation (SD) of 2.25 cm with 80% power at 5% significance level, a sample size of 20 patients was required.

physician, identified the AE as 'related', 'cannot rule out the possible relation', or 'undeterminable', the AE was considered an ADR. If the AE or ADR was severe enough (as determined by the attending physician) to cause death, a life-threatening condition, hospitalization or prolonged hospitalization, persistent or significant disability, congenital diseases or anomalies in the next generation, or other medically important conditions, it was classified as a serious AE (SAE) or a serious ADR (SADR).

Statistical Methods All data recorded were summarized and analyzed using descriptive and inferential statistics. Mean, SD, and range (minimum–maximum) were provided for continuous variables. Frequency and percentage were presented for categorical variables. For statistical analyses of change in VAS scores, a longitudinal data model was applied to assess multiple repeated-measures using the MIXED procedure of the SAS system with random effect for subject (random intercept model). A fixed effects analyses was conducted to determine whether there were effects of time points (baseline [Day 0]), Day 1, week 1, week 6, week 12 and week 24 after the intra-articular injection). A 95% confidence interval (CI) was presented and tests were

17

Baseline characteristics N=20

Age (years)

Mean (SD) 52.55 (7.91)

[Min; Max] [40; 65]35-40 years 1 (5)41-50 years 9 (45)51-60 years 6 (30)61-70 years 4 (20)

Gender n (%)

Female 17 (85)

Male 3 (15)

Socio-economic Status n (%)

Low 4 (20)

Lower Middle 6 (30%)

Middle

5 (25)

Upper Middle

1 (5)

Higher Middle

4 (20)

Co-morbid conditions

Hypertension

5 (25)

Diabetes mellitus

5 (25)

Metabolic syndrome

1 (5)

Vitamin D3 deciency

5 (25)

Previous alternative treatment n (%)

Ayurvedic

5 (25)

Homeopathy

6 (30)

None

9 (45)

Disease duration

<2years

4 (20)

>2 years

16 (80)

Table 1. Baseline characteristics

Abbreviations: n – number of patient; SD – standard deviation; Min – minimum; Max – maximum

Improvement in pain as measured by the VAS scale was seen from day 1 (visit 2). The VAS score reduced from 8.90+0.968 at baseline to 6.35+1.387 on day 1 (mean reduction of 2.55+1.191) and 5.30+0.923 at week 1 (mean reduction of -3.60+1.273). At week 1, there was complete (100%) pain relief in all patients as per subjective assessment. After week 1, improvement in VAS score continued in 70% patients at 6 weeks, 80% patients at 12 weeks and 70% patients at 24 weeks. At 24 weeks, total reduction is VAS score was 5.00+1.298 as compared to baseline. (Table 2 and figure 2)

Change is VAS score

© JIMI � JULY 2017 � VOL. 11 18


performed at a two sided 5% significance level. T-test were used to explore the differences between assessment time points. Data was explored for normality and satisfaction of parametric statistics, and no transformations were required. The statistical analyses were performed using SAS 9.3 (SAS Institute, Cary NC).

ResultsA total of 20 patients with osteoarthritis were included; all completed the study.

The mean+SD age of the included (n=20) patients was 52.55+7.91 years. Majority (85%; n=17) of the study population comprised females. Most patients (80%; n=16) had a disease duration of >2 years and had received previous treatment, of which about 55% (n=11) had received alternative treatment including homeopathic (30%; n=6) or ayurvedic treatment (25%; n=5). Hypertension (25%; n=5), diabetes mellitus (25%; n=5), and Vitamin D3 deficiency (25%; n=5) were the most common co-morbid conditions. (Table 1)

Baseline characteristics:

Table 2. Change in Visual analog scale from baseline to 24 weeks

Visit

VAS (cm) N=20

Change from Baseline (cm) N=20

Percent change from baseline (%)

Baseline Mean (SD) 8.90 (0.968) - - [Min; Max] [7; 10] - -

Day 1 Mean (SD) 6.35 (1.387) -2.55 (1.191) -28.75 (14.248) [Min; Max] [3; 8] [-4; 0] [-57.14; 0]

Week 1 Mean (SD) 5.30 (0.923) -3.60 (1.273) -39.86 (11.518) [Min; Max] [4; 7] [-6; -2] [-60; -22.22]

Week 6 Mean (SD) 4.65 (1.089) -4.25 (1.372) -47.30 (12.546) [Min; Max] [3; 7] [-7; -2] [-70; -25]



Abbreviations: VAS – Visual analog scale; SD – standard deviation; Min – minimum; Max – maximum.

Figure 2. Change in Visual analog scale from baseline to 24 weeks

Abbreviations: VAS – Visual analog scale

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Between 12 and 24 weeks, the VAS score worsened in 7 (35%) patients. Interestingly 5/7 patients who showed worsening of VAS score had co-morbid conditions such as hypertension and/or diabetes.

Proportion of patients with 'improved' self-reported clinical effectiveness parameters For each of the clinical effectiveness parameters (evaluated on the basis of patient self-assessment questionnaire), a significantly greater proportion of patients showed 'improved' status than those who 'worsened' or remained the same. (Table 3)

Table 3. Patient self-assessment (Clinical effectiveness parameters and NSAID usage)

Patient self-assessment

Clinical effectiveness parameters Improved

n (%)

Same

n (%)

Worsened

n (%)

P value for proportion of patients who improved

Range of motion of joint 12 (60) 8 (40) 0 0.0339

Clinical symptoms like localized swelling, heat, and tenderness

13 (65) 7 (35 0 0.0112

Duration of early morning stiffness

13 (65) 7 (35) 0 0.0112

Duration of post inactivity stiffness

12 (60) 8 (40) 0 0.0339

Increased self-dependence, self-esteem and overall condence

12 (60) 8 (40) 0 0.0339

Overall mobility and presence

in social gatherings 12 (60) 8 (40) 0 0.0339

Overall well-being and lifestyle 12 (60) 8 (40) 0 0.03339

NSAID usage Decreased (n%)

Same

n (%)

Increased

n (%)

P value for proportion of patients who decreased

13 (65) 5 (25) 2 (10) 0.0368

Abbreviations: n – number of patients; NSAID: non-steroidal anti-inammatory drugs

Proportion of patients with 'reduced' NSAID usage at 24 weeks A total of 70% (14/20) patients reported 'decreased' frequency of NSAID usage (p=0.0368)SafetyNo adverse events were reported.

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In this prospective, observational single-center pilot study conducted to determine the effectiveness and safety of a combination of intra-articular corticosteroid and local anesthetic in patients with osteoarthritis, improvement in joint pain (as measured by the VAS) was observed the very next day after the injection was administered with complete pain relief within a week. In a majority of patients, the pain relief lasted up to 24 weeks after the single injection. Patients who showed a decrease in pain-relief after 12 weeks had other co-morbid conditions like hypertension and/or diabetes. Patients showing 'improved' clinical effectiveness parameters were significantly greater in proportion than those showing 'worsened' or 'same' status. Further a significant majority of patients reported 'decreased' NSAID usage in the 24 weeks after treatment.

Discussion

In our study improvement in joint pain was observed within a day of initiating treatment; however complete pain relief was achieved at week 1. A systematic review and meta-analysis that included both randomized controlled trials and systematic reviews concerning use of intra-articular steroid injections in knee osteoarthritis shows both clinically and statistically (as measured by VAS) significant pain relief within one week of treatment. As compared to this meta-analysis, the earlier onset of pain relief (within a day) observed in our study was probably due to the fact that none of the studies included in the meta-analysis used a local anesthetic along with the intra-articular corticosteroid to ensure that the observed pain relief was only due to the corticosteroid administration. It can thus be inferred that the effect of the local anesthetic in our study led to immediate pain relief, after which the corticosteroid component took over and achieved complete pain relief at week 1. Also, unlike the above meta-analysis that shows short-lived pain relief for a maximum duration of 3-4 weeks after a single injection of intra-articular corticosteroid, in our study pain relief in most patients lasted for 24 weeks. In fact, 5/7 patients who experienced worsening of pain between 12 weeks and 24 weeks had co-morbid diabetes and/or hypertension, both of which are known to adversely impact the prognosis of osteoarthritis.

In addition to relief in joint pain, significant number of patients reported improvement in several other clinical effectiveness parameters such as range of motion, clinical symptoms like localized swelling, heat, and tenderness, duration of early morning stiffness and duration of post inactivity stiffness, self-dependence, self-esteem and overall confidence, overall mobility and presence in social gatherings and overall well-being and lifestyle. Similarly, a randomized double-blind study conducted at the Department of Orthopedics, TMMCRC, Moradabad between July and December 2014 shows that in addition to

the beneficial effects in achieving short/long-term pain relief in knee osteoarthritis, intra-articular corticosteroids particularly methyl prednisolone (which was used in our study) provides more immediate improvement in pain, stiffness and joint function without any adverse effects.

On account of the deleterious digestive, renal, and cardiovascular adverse effects observed with NSAIDs usage, it is recommended that physicians prescribing NSAIDs for pain relief in osteoarthritis should consider factors such as co-morbid conditions, contraindications, and concomitant drugs and then prescribe the lowest possible dose for the shortest required time in patients at risk of adverse effects. A majority of patients in our study were able to reduce NSAID usage after administration of the intra-articular steroid and local anesthetic combination. Moreover, despite a short-term beneficial effect observed with intra-articular corticosteroid administration, it can be useful to control acute exacerbations while waiting for NSAIDs to work, in patients who need rapid pain relief for an upcoming activity, where sleep is interrupted due to pain. Hence a combination of intra-articular steroid and local anesthetic should be considered in patients with osteoarthritis unable to obtain relief with NSAIDs or in those experiencing gastro-intestinal or other side effects with NSAIDs.

There were no adverse effects of the treatment observed in our study, indicating that the drug combination was safe and well tolerated by all patients. The safety of intra-articular steroids is also supported by several other studies. In fact the absence of major side effects is one of the primary reasons due to which intra-articular corticosteroid injections have become one of the mainstays in the management of osteoarthritis, particularly knee osteoarthritis.

Strengths and limitations of the studyThis open-label, prospective, observational study was conducted in a real-world setting, and hence the study population reects actual clinical practice. In addition to assessing improvement in joint pain in terms of VAS, the study also explores other key factors like reduction in NSAID usage after the treatment. However, this open-label study did not have a control group which could have been a source of potential bias (selection bias). Also, in this study, osteoarthritis was not evaluated by a symptom driven scale like Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Hence further studies with larger sample size, inclusion of a control group and assessments based on additional clinical scores may be required to validate these findings. Nonetheless, this pilot study establishes the evidence for further evaluation of intra-articular corticosteroid

© JIMI � JULY 2017 � VOL. 11 21


anesthetic combination in randomized clinical trials as well as observational registries in India.

Conclusion

In conclusion, this observational study shows that a single combination injection of intra-articular corticosteroid and local anesthetic achieves immediate pain relief in patients with osteoarthritis, and the effects lasts in most patients for at least 6 months. Most patients receiving this treatment are able to decrease their NSAID usage, thus reducing its side effects, and the treatment regimen does not show any adverse effects as well. Despite certain limitations, the findings of this study lay the foundation for further large-scale randomized controlled trials that can be designed to evaluate the efficacy and safety of this combination.

Conict of Interest -noneAcknowledgments

The authors thank Dr. Alina Gomes for interpretation of the data as well as medical writing assistance in the development of this manuscript.

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1-Associate Professor, Department of Medicine, AIIMS Rishikesh 2-Dietician, Department of Medicine, AIIMS Rishikesh 3- Sr. Resident, Department of Medicine, AIIMS Rishikesh

A Paradigmal shift of hypertension inSub-Himalayan region

Original Article

1 2 3Ravi Kant , Vinita Thapaliyal , Priyanka Gupta

ABSTRACT

A survey was conducted in rural areas of Uttrakhand, to make a total sample size of 300 adults using WHO STEPS questionnaire using purposive random sampling.13.6 % of males from Dehradun, 15.3% of males from Rudraprayag, 5.9% males from Uttarkashi were having systolic hypertension. Whereas, 8.8% woman from Dehradun and 6.1% woman from Uttarkashi were having systolic hypertension.28.8 % of males from Dehradun, 32.3% of males from Rudraprayag, 13.7% males from Uttarkashi have systolic hypertension. Whereas, 20.6% woman from Dehradun 17.1% from Rudraprayag and 26.5% woman from Uttarkashi were having diastolic hypertension. Three predictor variables zone, gender and age were statistically significant.

IntroductionDegenerative diseases have strongly fixed their foothold in this modern world and get complexed with widespread adoption of unhealthy lifestyles that worsened the scenario more. India is suffering from dual burden of under nutrition and the rapidly steadily increasing epidemic of diseases of allied. Non-communicable diseases (NCDs) are not only a majorcause of deaths (60%)but also constitutes almost 43% burden of diseaseglobally in 2002, and by 2020, it is estimated to

[1]account for 73% of deaths and 60% of disease burden . In India, deaths from degenerative diseases are estimated to almost double, from about 4 million in 1990 to about 8

[2]million a year by 2020 . The major factors of the increasing burden of NCDs in India are globalization, nutrition transition, urbanization and economic growth. Rapid urbanization is characterized by poor dietary practices, poor lifestyle, low level of physical activity and obesity, all of which are major determinants of NCDs. All these contributing factors are linked to life style management and are accompanied by change from rural to urban lifestyle practices. Even in villages there is gradual shift to urbanized lifestyle. In India, around 28% of the total population was living in urban areas in 2001, with an estimation of about 50%, with 605–618 million by

[3]2021–2025 . The growth in the urban areas is not uniform; demographic trends shows that, the growth rate in the urban was stabilized at 3% over the past decade (1991–2001), the growth rate of the slum was double at

(4)5–6% . Urban poor end up having the worst of both

worlds – modern lifestyle, which makes them at higher risk of Degenerative diseases, and poverty, and hence, low healthcare purchasing ability. It is necessary to document the shift in diet and physical activity with transition from rural to urban lifestyle. Good understanding of the problem can enable us to take preventive and promotive steps so that we make the shift to urbanized lifestyles without or with minimal adverse health outcomes.

Geographically, the Uttrakhand is one of the unstable, ecologically fragile, economically underdeveloped, and the densely populated mountain ecosystems. With fast growing urbanization and infrastructure, there is more connectivity in the villages and hence the area has undergone fast urbanization and with this there is easy access to markets. Hence, major areas of cultivated land are being used for more infrastructure expansion, services

[4]and economic activities in the region . Hence there is gradual regional shift from traditional crop farming and animal husbandry system to village-based production of vegetables, owers, fruits and milk for sale in urban areas. This has impact on the traditional resource development process and land use pattern. The shift in the physical activity pattern and dietary changes is major cause of demographic and socio economic changes.

Uttarakhand is diverse state because of location and scattered population in hilly and plain region with higher population density in plain region; for example, four districts (Dehradun, Nainital, Haridwar, and Udham Singh Nagar) have 55 percent of the state's population. Between 2001 and 2011, there was a decrease in the population growth rate; however, the density of

© JIMI � JULY 2017 � VOL. 11 24


population has increased from 159 persons per square [5]kilometer in 2001 to 189 in 2011 . Demographic transition

is a pointing shift in population dynamics analogous with socio economic development (i.e. rising economies, education, employment, improvement in health status and life expectancy and changes in life style). This has been accompanied by an epidemiological transition [6].There is a steady growth in degenerative diseases of aging and life-style problems such as hypertension, diabetes, stroke and other cardiovascular ailments even when life expectancy has increased. There are sources which show the emergence of the epidemiological transition has often been linked with epidemics of chronic heart diseases (including hypertension, IHD, and cerebrovascular disease), type 2 diabetes mellitus, and

[7]other chronic diseases . Extreme weather conditions had been responsible for certain negative life-style practice and outcomes such as smoking , tobacco chewing , other form of tobacco use, alcohol drinking , consumption of fruits and vegetables less than recommended among residents of Uttrakhand

[8]region . Furthermore, people of Uttarakhand are living below the poverty line. State is facing high prevalence rate of the some of the communicable diseases such as tuberculosis, malaria. Moreover these negative life-style pract ices leading to high prevalence of Non-

[9]communicable diseases. .The present study was undertaken to measure the physical activity and its association with obesity and various other vital statistics among adult of Uttrakhand. Such study would address the paucity of data regarding obesity, hypertension in a rural area and to timely institute preventive measures to decrease the harmful effects of these vital statistics of NCDs.

Material and Methods: A survey was conducted in three zones of Uttrakhand (Uttarkashi , Rudraprayag, Dehradun) India representing the rural, semi rural, urban population of the state. For the study, 100 adults were selected from each of the 3 rural zones respectively to make a total sample size of 300 adults Every household was visited and one man and woman were selected from eligible age groups from alternate households. If more than one eligible individual were present in particular household, one of them was randomly selected.

Data Collection: The data was collected using WHO STEPS questionnaire approach. Interview technique was used by the investigator herself after ensuring the confidentiality of the information. After filling the questionnaire, the respondents were called to a separate room for anthropometric measurements and variables such as weight (kgs )using Karda digital weighing scale, height (cms) using stadiometer, BMI (kgs/m2), WC (waist circumference in cms), were recorded using standard

[10]procedures.

The data was collected using WHO STEPS questionnaire approach. Interview technique was used by the investigator herself after ensuring the confidentiality of the information. After filling the questionnaire, the respondents were called to a separate room for anthropometric measurements and variables such as weight (kgs )using Karda digital weighing scale, height (cms) using stadiometer, BMI (kgs/m2), WC (waist circumference in cms), were recorded using standard

[10]procedures.

Blood pressure was measured using a Mercury Sphygmomanometer. Two blood pressure readings were taken with the subject in a relaxed sitting position with the back supported by the chair backrest and average of both reading was taken. Hypertension was classified using

[11]JNC -8 criteria.

The modified classification of BMI for Asian populations was used in this study to define overweight (23-24.99kg/m2) & obesity (> 25 kg/m2). 9,10 Cut-off points used to define Central obesity were Waist Hip Ratio >0.90 in men &>0.80 in women was taken as high. Body Fat percentage >25% in males and >30% in females was taken

[12]as high.

Analysis was carried out using SPSS version 17.0. Pearson's Chi-square test was used to evaluate differences between groups for categorized variables. Normally distributed data was within 90% confidence intervals.

Sample Size: The sample size calculated was 269 with confidence interval of 90% and margin of error 5 %

Sample Size = z2 x p(1-p) _______________ e 2

1+( z2 x p(1-p) _______________ e 2N

Where N = Population Size

e = Margin of error

Z = z Score

________________________________

Though the calculated sample size was 269 but a sample of 300 participants were included for the study. Written informed consent was obtained from each study participant

© JIMI � JULY 2017 � VOL. 11 25


Results:For the study, 100 adults each were selected from each of the 3 zones (Uttarkashi, Rudraprayag, Dehradun). The overall response of the study was 100%.Out of the 300 adults, 176 (58.7%) were males whereas 124 (41.3%) were females.

The mean age of males from Dehradun, Rudraprayag, Uttarkashi were 31.5±8.1, 36.9±8.7*,33.1±9.1 respectively. Whereas, the mean age of females from Dehradun, Rudraprayag, Uttarkashi were 33.6±7.9, 36.8±8.4, 34.2±10.1 respectively. The Literacy level of the population was 96 % where as 4 % population has never attended school. The mean year of schooling were least in Uttarkashi zone ( p<0.001).

Anthropometry:On comparing anthropometric characteristics of males and females when classified according to 3 zones (Table1) males from Dehradun had significantly higher weight and BMI as compared to males from Rudraprayag and Uttarkashi (p<0.05). There was no significant difference in weight and BMI of males from Rudraprayag and Uttarkashi (p>0.05) (Table 1). There was no significant difference in the waist circumference of the males from 3 zones) (p>0.05) (Table 1). In females, females from Dehradun had significantly higher weight, BMI and waist circumference as compared to females from Rudraprayag and Uttarkashi (p<0.05) (Table 1).

Males

(n=176)

Females (n=124)

Dehradun

(n=66)

Rudraprayag

(n=59)

Uttarkashi

(n=51)

Dehradun

(n=34)

Rudraprayag

(n=41)

Uttarkashi

(n=49)

Age (years)

31.5±8.1

36.9±8.7*

33.1±9.1

33.6±7.9

36.8±8.4

34.2±10.1

Height (cm)

168.7±4.6

163.4±6.0*

166.0±6.7#

154.2±6.2

151.3±4.0

154.2±6.1$

Weight (kg) 69.8±7.5 62.8±6.0* 62.9±6.4# 61.4±93 54.7±6.7* 53.6±6.6#

BMI (kg/m2) 24.5±2.1 23.4±3.3* 22.8±2.9# 25.7±2.7 23.9±3.0* 22.5±1.9#$

Waist

circumference

(cm)

88.5±9.0 86.0±10.4 85.4±8.2 89.8±13.9 78.8±10.9* 78.8±6.4#

Data presented as Mean±SD

*p<0.05 for comparison between Dehradun and Rudraprayag

#p<0.05 for comparison between Dehradun and Uttarkashi

$p<0.05 for comparison between Rudraprayag and Uttarkashi

Hypertension13.6 % of males from Dehradun, 15.3% of males from Rudraprayag, 5.9% males from Uttarkashi have systolic hypertension. Whereas, 8.8% woman from Dehradun and 6.1% woman from Uttarkashi were having systolic hypertension.

© JIMI � JULY 2017 � VOL. 11 26


There was no significant association between systolic BP status and zone in both males (χ2=2.842, p=0.558) and females (χ2=3.694, p=0.449) indicating that percentage of non hypertensive, pre-hypertensive and hypertensive was similar based on systolic BP (Figure 1).

Figure 1: Percentage of non hypertensive, pre-hypertensive and hypertensive based on systolic

BP in males and females when classified according to zone

28.8 % of males from Dehradun, 32.3% of males from Rudraprayag, 13.7% males from Uttarkashi have systolic hypertension. Whereas, 20.6% woman from Dehradun 17.1% from Rudraprayag and 26.5% woman from Uttarkashi were having diastolic hypertension.

There was a significant association of diastolic BP status and zone in males with higher percentage of pre-hypertensive and hypertensive from Uttarkashi followed by Rudraprayag and lastly Dehradun (χ2=26.627, p<0.01) . There was no significant association between diastolic BP status and zone in females (χ2=2.173, p=0.704) indicating that percentage of non hypertensive, pre-hypertensive and hypertensive was similar in females based on diastolic BP (Figure 2).

Figure 2. Depicting diastolic blood pressure .

© JIMI � JULY 2017 � VOL. 11 27


Regression Analysis:

Of the five predictor variables only three were statistically significant: Zone, education and age (Table 4).Dehradun and Rudraprayag adults had higher odds of being overweight/ obese as compared to Uttarkashi adults (Table 2). Adults who had cleared secondary school or were graduate had higher odds of being overweight/ obese. Odds of being overweight/ obese also increased with an increase in age (Table 2).

Characteristic N No (%) of overweight/obese from total

β Odds ratio P value

Gender Male 176 98 (55.7) Reference Female 124 70 (56.5) -0.278 00.757 (0.438 –

1.309) 0.319

Zone Dehradun 100 75 (75) Reference <0.01 Rudraprayag 100 49 (49) 1.44 4.237 (2.160 –

8.310) <0.01

Uttarkashi 100 44 (44) -0.023 0.977 (0.536 – 1.815)

0.942

Marital Status Married 225 133 (59.1) Reference 0.453 Unmarried 65 30 (46.2) 0.664 1.942 (0.399 –

9.453) 0.411

Widow/divorced/separated 8 5 (50) 0.258 1.295 (0.224 – 7.479)

0.773

Education No Formal Education 3 1 (33.3) Reference 0.291 Less than primary 3 2 (66.7) -2.511 0.081 (0.006 –

1.156) 0.064

Primary school 33 15 (45.5) -0.359 0.699 (0.048 – 10.253)

0.794

Secondary school 35 19 (54.3) -1.266 0.282 (0.091 – 0.876)

0.029

High school 113 57 (50.4) -0.760 0.468 (0.152 – 1.436)

0.184

Graduate 73 45 (61.6) -0.951 0.386 (0.153 – 0.978)

0.045

Post graduate 3 28 (77.8) -0.764 0.46 (0.171 – 1.269)

0.135

Age -- -- 0.0457 1.048 (1.009 – 1.008)

0.015

Table 2 : Independent association of variables with overweight/obesity (Logistic regression analysis

© JIMI � JULY 2017 � VOL. 11 28


Sensitivity, specificity and cut off values for identifying the risk of hypertension

ROC curves were not significant for weight, BMI or waist circumference in Rudraprayag adults (p>0.05). In adults from Dehradun, ROC curve was significant for BMI for identifying the risk for hypertension (p<0.05) In Uttarkashi adults, weight, BMI and waist ROC were all significant for identifying the risk of hypertension (p<0.05) (Table 3)

AUC (95% CI) Cut-off value Sensitivity Specificity P value Dehradun Weight 0.554 (0.440 – 0.667) 65.5 52.8% 48.9% 0.367 BMI 0.635 (0.526 – 0.745) 24.7 62.3% 57.4% 0.020 Waist 0.559 (0.446 – 0.673) 85.5 62.3% 34% 0.307

Rudraprayag Weight 0.579 (0.466 – 0.692) 56.5 60.4% 48.9% 0.174 BMI 0.511 (0.398 – 0.626) 22.4 60.4% 36.2% 0.844 Waist 0.492 (0.378 – 0.606) 81.5 62.3% 36.2% 0.890 Uttarkashi Weight 0.685 (0.565 – 0.804) 54.5 72.9% 60% 0.004 BMI 0.657 (0.540 – 0.774) 22.2 70% 60% 0.013 Waist 0.681 (0.568 – 0.794) 80 70% 63.3% 0.004

Table 3: Sensitivity, specificity and cut off values for identifying the risk of hypertension according to Zone

Discussion and Conclusion:

Risk factors for Noncommunicable disease (NCD) risk were reportedamong the rural households, hypertension varied from 22% in Maharashtra to 16% in Tamil Nadu & prevalence ofobesity was less than 4% in the above mentioned states (BMI >30kg/ m2) as per reports of

[13]Integrated disease surveillance project .

The results have shown the variation regarding the epidemic of NCDs around the world where the problem has been invariably used in the future tense for the developing world and that too specifically prevalent in the urban settings. In our study, the observed rates of hypertension and high BMI are unacceptably high among the adult population of the rural areas and are no more dependent on the factors like education & socio-economic status. This study depicted significant positive correlation between all the anthropometric indicators and systolic and diastolic blood pressure except for WHR. Many investigators have earlier reported significant positive correlation of body mass index with systolic and diastolic

[14-17]blood pressure.

The study depicted positive correlation with weight, BMI, waist only for Uttarkashi adults. The most sensitive variable in Dehradun is BMI sensitivity: specificity 62.3% :

57.4 % where as in Rudraprayag and Uttarkashi the most sensitive variable is weight.

The main objective of our analyses was to determine the r e g i o n a l r e p r e s e n t a t i v e p r e v a l e n c e o f b e i n g hypertensivein different rural zones in different BMI categories. Large trials are needed to study the impact of strategies aimed at behaviour change that would target these factors as well as those identified previously inan attempt to reduce the prevalence of Hypertension. Thehigh response rate, sound epidemiologic design, and use of the modified Asian-specific definition of being overweight or obese are major strengths of our findings, which are generalizable at least in the northern part of the country. In conclusion, our study showed that 1 in 4 people in our rural area over the age of 20 years is overweight or obese. We have demonstrated alarming rates of obesity among youths and women, indicating where, in particular, interventions should be targeted. Owing to the better association of hypertension with lower BMI cut-off value (less than 23 kg/m2), our findings support the use of Asian-specific thresholds for the definition of being overweight in this population. Immediate efforts are needed at a national level to control this problem.

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References

Study of Pattern of Rheumatologic and MusculoskeletalDisorders and Their Awareness Among Patients

Attending Rheumatology Clinic

Original Article

1 2 3Rakesh Kumar Jagdish , M.K. Bhatnagar , Ayush Malhotra

ABSTRACT

Rheumatological disorders are characterized by a wide spectrum of diseases like inammatory diseases with articular, extra articular and systemic manifestations, degenerative joint and spine diseases, soft tissue rheumatism and metabolic bone diseases still rheumatology is less understood sub-specialty of internal medicine. We planned this study to assess the pattern of rheumatologic and musculoskeletal disorders and their awareness among patients attending newly started rheumatology clinic at Santosh medical college and hospital, Ghaziabad in first 500 new cases. All patients with age 15 years and above with rheumatological diagnosis were included in the study. Detailed history and physical examination done and information regarding the awareness about rheumatological branch, diseases and the commonly used medications like calcium, vitamin D supplements and non-steroidal anti-inammatory drugs (NSAIDs) were recorded. Out of first 500 cases 39% cases were of inammatory joint diseases followed by 22.8% cases of degenerative joint diseases, 15% cases of soft tissue rheumatism, 13.6% cases were of metabolic bone diseases, 8.8% cases of infection related arthritis and 0.8% cases were of benign hypermobility syndrome (BJHS). Among all parameters, awareness about calcium was maximum (42.52%), followed by awareness for vitamin D (23.68%), NSAIDs awareness (21.36%) and least for rheumatology branch (12.32%). Co morbidities were present in 37.4% of cases. Hypertension ( 7.6% ), anaemia ( 7% ), hypothyroidism (6%), diabetes ( 5.6% ), obesity ( 2.6%), dyslipidaemia (2.4%), vitamin B 12 deficiency ( 2.4%) and metabolic syndrome in 2.2% cases .All cardio metabolic risk factors constituted 20.4% of cases. We conclude that inammatory joint diseases are most common in a specialised rheumatology clinic, followed by degenerative joint and spine diseases, soft tissue rheumatism, and metabolic bone diseases. Cardio metabolic risk factors are predominately associated with rheumatological patients and therefore we suggest that proactive screening of these factors should be routinely done for prevention of complications. Patients need more and more public awareness programme to increase their knowledge towards the rheumatology branch and commonly used medicines .Training programmes for physicians should be stated in rheumatology at each institution.

Keywords: Pattern of haematological diseases , Rheumatology clinic, Inammatory joint diseases ,Osteoarthritis , Soft tissue Rheumatism, Infection related arthritis, metabolic bone diseases, Awareness, Co-morbidities.

AIM: To assess the pattern of rheumatologic and musculoskeletal disorders and their awareness regarding calcium, vitamin D, NSAIDs, use and rheumatological diseases in freshly diagnosed patients attending rheumatology clinic in Santosh medical college and hospital, Ghaziabad.

INTRODUCTION:

India is world's second largest population with rapidly developing medical tourism in various medical and surgical fields but rheumatology is still less understood specialty as compared to other subspecialties of internal medicine. Rheumatic disorders are one of the largest health problems and commonest cause of morbidity in the world. Rheumatological disorders are characterized by a

© JIMI � JULY 2017 � VOL. 11 31


large variety of diseases not only inammatory rheumatic and systemic diseases but also degenerative joint and spine diseases, soft tissue rheumatism and metabolic bone diseases. Musculoskeletal symptoms can also be due to metabolic, endocrine, neoplastic and infectious conditions. The prevalence of musculoskeletal disorders varies between different studies from world ranging from

11% to more than 50% and these conditions represent 28% of disability compensation schemes1,2 and in Indian studies prevalence of rheumatological complains varies from 18.5% to 23.9% in general population3. Rheumatology as such in an infant state in India so far even health care workers are not aware of what type of patients a rheumatologist sees. Public and patients awareness is the needed as the number of patients of various forms of arthritis and other musculoskeletal diseases are constantly on rise. This may be due to multiple factors for increasing numbers like 1) life style changes-increasing stress, indoor and sedentary life style 2) environmental factors-like increasing pollution in air, water and soil 3) certain genetic predispositions 4) increasing awareness in public to seek medical attention for these problems, rather than ignoring them 5) improving medical knowledge and investigation facilities in current years. Purpose of the study is to discuss about the pattern of patient coming to specialized rheumatology OPD and their awareness regarding commonly used medicines and about the rheumatology branch in general.

MATERIALS AND METHODS:

This was prospective study of first 500 diagnosed patients who attended a hospital based newly started outpatientrheumatology clinic, at Santosh medical college andhospital, Ghaziabad, from march 2016 to march 2017. All patients with age 15 years and above with rheumatological diagnosis were included in the study. Patients with traumatic joint disease and all patients below age 15 years were excluded. Detailed history and physical examination were done. Relevant investigations were carried out. Since it was newly started clinic information regarding the awareness about rheumatological branch, diseases and the commonly used medications like calcium, vitamin D supplements and non-steroidal anti-inammatory drugs (NSAIDs) were also recorded. Diagnosis of rheumatology diseases were based on the American college of rheumatology (ACR)/ European league against rheumatism (EULAR) classification criteria. Some patients having multiple diagnoses, only primary diagnosis and co morbidities were included. Simple statistical calculations were employed to determine the percentages and patterns of the rheumatological disorders. Percentage of each disease was calculated based on the total number of rheumatology cases included in the study. Ethical approval was obtained for this research work.

RESULTS:

Patients were aged from >15 years, with a mean age of 45.59 years . Female constituted 71% of all patients.Patients were grouped separately in the following categories as shown in table 1.

Table1-Major categories and pattern of first 500 rheumatic patients seen

S.N. Major category Number and percentage

Male Female Mean Age in years

1. Inflammatory and autoimmune spine, joint and systemic diseases

195 (39%) 59 (11.8%)

136 (27.2%)

41.79

2. Degenera�ve joint and spine diseases

114 (22.8%) 41 (8.2%)

73 (14.6)

60.25

3. So� �ssue rheuma�sm 75 (15%) 18 (3.6%) 57 (11.4%) 43.80 4. Metabolic bone diseases 68 (13.6%) 15 (3%) 53 (10.6%) 37.97 5. Infec�on related joint diseases 44 (8.8%) 12 (2.4%) 32 (6.4%) 40.76 6. Hypermobility disorder (BJHS) 4 (0.8%) 0 4 (0.8%) 29.25 Total 500 (100%) 146

(29.2%) 354 (70.8%)

45.59 years

Out of first 500 cases 39% cases were related to inammatory/autoimmune diseases followed by 22.8% cases of degenerative joint diseases, 15% cases of soft tissue rheumatism, 13.6% cases were related to metabolic bone diseases, 8.8% cases of infection related arthritis, 0.8% cases were of benign hypermobility syndrome (BJHS).

© JIMI � JULY 2017 � VOL. 11 32


1-Assistant Professor Medicine and In-charge Rheumatology Clinic, Santosh Medical College and Hospital, Ghaziabad, Uttar Pradesh.(Corresponding author)

2-Professor of Medicine, Santosh Medical College and Hospital Ghaziabad, Ex Director Professor of Medicine, Lady Hardinge Medical College, New Delhi.

3-Junior Resident of Medicine, Santosh Medical College and Hospital, Ghaziabad, Uttar Pradesh.

Table-2: Pattern of Inammatory /autoimmune spine, joint and systemic diseases

S.N. Inflammatory / autoimmune spine, joint and systemic diseases

Number and percentage from total study popula�on (n500)

Male Female Mean age In years

1. Rheumatoid arthri�s 112(22.4%) 17(3.4%) 95(19%) 42.68 2. Spondyloarthri�s(SpA-see

table 3 for details) 45(9%) 29(5.8%) 16(3.2%) 38.67

3. Connec�ve �ssue diseases (CTD-see table 4 for details)

17(3.4%) 3(0.6%) 14(2.8%) 43.36

4. Undifferen�ated inflammatory arthri�s

15(3%) 7(1.4%) 8(1.6%) 42.9

5. Palindromic rheuma�sm 3(0.6%) 0 3(0.6%) 29.60 6. Gout 3(0.6%) 3 0 53.34 Total 195(39%) 59(11.8%) 136(27.2%) 41.79 years

Among Inammatory /autoimmune spine, joint and systemic diseases rheumatoid arthritis (RA-22.4%) was most common followed by, spondyloarthritis (SpA-9%), Connective tissue diseases (CTD-3.4%), undifferentiated chronic inammatory arthritis (3%), palindromic rheumatism (0.6%) and gouty arthritis (0. 6%). Mean age was 41.79 years with female preponderance except for gouty arthritis.

Among different Connective tissue diseases (CTD), systemic lupus erythematosus (SLE) was the most common in 1% of total study population, followed by undifferentiated CTD (0.6%), sjogren's syndrome (0.4%), systemic sclerosis (0.4%), mixed connective tissue diseases (MCTD-0.2%), Primary Vasculitis (0.4%), other diseases like Sarcoidosis in 0.4% cases were seen. Mean age was 38.66 years, with female preponderance except for primary vasculitis and Sarcoidosis.

Table-3: Pattern of spondyloarthritis (SpA) in Inammatory /autoimmune diseases

S.N. Pa�ern of spondyloarthri�s (SpA)

Number and percentage from total study popula�on (N-500)


1. Ankylosing spondyli�s (AS) 17 (3.4%) 15(3%) 2(0.4%) 41.58

2. Reac�ve arthri�s (ReA) 14 (2.8%) 8(1.6%) 6(1.2%) 36.21

3. Psoria�c arthri�s (PsA) 4 (0.8%) 1(0.2%) 3(0.6%) 45.25

4. Inflammatory Bowel Disease (IBD) related

2 (0.4%) 1(0.2%) 1(0.2%) 42.50

5. Undifferen�ated SpA 7 (1.4%) 4(0.8%) 3(0.6%) 35

6. JIA SpA variant 1 (0.2%) 1(0.2%) 0 15 Total 45 (9%) 30(6%) 15(3%) 38.66 years

Among 45 cases (9%) of spondyloarthritis, ankylosing spondylitis (AS) was most common in 3.4% of cases, followed by reactive arthritis (ReA) in 2.8% cases, undifferentiated SpA (1.4%), psoriatic arthritis (PsA) in 0.8% cases, Inammatory bowel diseases (IBD) related (0.4%), Juvenile idiopathic arthritis (JIA) with SpA variant in 0.2% of cases. Mean age was 38.66 years, males were predominant in all except in reactive arthritis and undifferentiated SpA where M: F ratio is nearly equal.

© JIMI � JULY 2017 � VOL. 11 33


Table 4: Pattern of degenerative joint and spine diseases

S.N. Degenera�ve joint and spine diseases

Number andpercentage


1. Knee osteoarthri�s 78 (15.6%) 29(5.8%) 44(8.8%) 63.97

2. Secondary OA 17( 3.4%) 6(1.2%) 11(2.2%) 45.11

3. Spinal OA and related spondylosis

14(2.8%) 4(0.8%) 10(2%) 61.32

4. Generalized nodular OA 4(0.8%) 2(0.8%) 2(0.4%) 53.50

5. Hands-1st CMC joint 1(0.2%) 0 1(0.2%) 40

Total 114(22.8%) 41(8.2%) 73(14.6%) 60.25 years

Among degenerative joint diseases (22.8% of total study population), knee osteoarthritis was most common in 15.6% of cases, followed by secondary osteoarthritis in 3.4% (secondary to inammatory joint disease), the spinal osteoarthritis with related spondylosis in 2.8% of cases. Mean age was 60.25 years with Female preponderance.

Table-5: Pattern of Soft tissue rheumatism

S.N. So� Tissue Rheuma�sm Number andpercentage (n-500)

Male Female Mean age

1. Fibromyalgia 27(5.4%) 2(0.4%) 25(5%) 40.16

2. Non specific aches and pains 20(4%) 9(1.8%) 11(2.2%) 45.30

3. Tendini�s/peritendini�s/epicondyli�s 8(1.6%) 3(0.6%) 5(1%) 44.62

4. Planter fascii�s/enthesopathies 7(1.4%) 0 7(1.4%) 43.14

5. Rotator cuff syndrome / frozen shoulder

6(1.2%) 2(0.4%) 4(0.4%) 51.20

6. Trigger finger (Flexor tenosynovi�s) 3(0.6%) 2(0.4%) 1(0.2%) 57.66

7. Carpal tunnel syndrome 3(0.6%) 0 3(0.6%) 36

8. Bursi�s 1(0.2%) O 1(0.2%) 48

Total 75(15%) 18(3.6%) 57(11.4%) 43.80 years

Among soft tissue rheumatism (15% of all study population, Fibromyalgia was most commonly seen in 5.4% cases, followed by non specific aches and pains in 4% of cases. Tendinitis, epicondylitis, planter fasciitis, enthesopathies, rotator cuff syndrome, frozen shoulder, exor tenosynovitis, carpal tunnel syndrome and bursitis were in less number of cases. Mean age was 43.80 years with female preponderance.

S.N. Metabolic bone disease Number andpercentage (n-500)


1. Vitamin d deficiency only 40 (8%) 9(1.8%) 31(6.2%) 32.22 2. Osteomalacia 18(3.6%) 3(0.6%) 15(3%) 40.023 3. Osteoporosis 8(1.6%) 1(0.2%) 7(1.4%) 62.12 4. Miscellaneous –HOAP 2(0.4%) 2(0.4%) 0 38 Total 68(13.6%) 15(3%) 53(10.6%) 37.97 years

Among metabolic bone diseases total cases of vitamin D deficiency were 58(11.6%), Vitamin D deficiency only (without any electrolyte or enzyme problem) was most commonly seen in 8% of cases, followed by Osteomalacia (vitamin D deficiency with electrolyte or enzyme problem) in 3.6% of cases, followed by osteoporosis in 1.6% of cases, 2 patients (0.4%) were having primary hypertrophic osteoarthropathy (HOAP) onewith complete expression and one with incomplete form of primary HOAP. Mean age was 37.97 years with female preponderance.

Table-6: Pattern of metabolic bone disease

© JIMI � JULY 2017 � VOL. 11 34


Table-7: Pattern of Infection related joint diseases

S.N. Infec�on related joint diseases

Number and percentage Male Female Mean age In years

1. Post viral arthralgia 34 (6.8%) 09(1.8%) 25(5%) 40.05

2. Post viral arthri�s 09 (1.8%) 2(0.4%) 7(1.4%) 44 3. Hepa��s B related

arthri�s 01 (0.2%) 1(0.2%) 0 36

Total 44 (8.8%) 12(2.4%) 32(6.4%) 40.76 years

Among Infection related joint diseases post viral arthralgia seen in 6.8% of cases and Post viral arthritis were seen in 1.8% of cases due to the Chikungunya and chikungunya like viral epidemic seen in August-October 2016 in India. One case (0.2%) of Hepatitis B related arthritis was also seen. Mean age was 40.76 years with overall female preponderance. We did not find any cases of infective arthritis like septic or tubercular arthritis.

Table-8: Pattern of co morbidities found in the study patients

S.N. Co morbidi�es Number and percentage (n-500)


1. Hypertension (HTN) 38 (7.6%) 9(1.8%) 29(5.8%) 57.26

2. Anemia 35(7%) 6(1.2%) 29(5.8%) 41.26

3. Hypothyroidism 30(6%) 6(1.2%) 24(4.8%) 44.03 4. Diabetes (DM) 28(5.6%) 9(1.8%) 19(3.8%) 54.25

5. Obesity 13(2.6%) 5(1%) 8(1.6%) 56.69

6. Dyslipidemia 122.4%) 3(0.6%) 9(1.8%) 51.91

7. Vitamin B12 deficiency 12(2.4%) 3(0.6%) 9(1.8%) 40.08

8. Metabolic syndrome 11(2.2%) 5(1%) 6(1.2%) 46.81

9. Respiratory Problem like COPD/BA/ILD 08(1.6%) 5(1%) 3(0.6%) 53.75

Total 187(37.4%) 51(10.2%)

136(27.2%)

49.44 years

Medical co morbidities were present in 37.4% of cases. Hypertension (HTN) was most common in 7.6% of cases, followed by anaemia in 7% cases, then hypothyroidism in 6% cases, diabetes in 5.6% of cases obesity in 2.6% cases, Dyslipidaemia in 2.4% cases ,vitamin B 12 deficiency in 2.4% cases, metabolic syndrome in 2.2% cases respiratory diseases like Chronic obstructive pulmonary diseases (COPD) ,Bronchial Asthma(BA) ,interstitial lung diseases (ILD) in 1.6% cases. Combining all cardio metabolic risk factors like HTN, DM, Obesity, Dyslipidaemia and metabolic syndrome, constituted 20.4% cases.

© JIMI � JULY 2017 � VOL. 11 35


Table-9: Pattern of various awareness parameters

Ques�onnaire about Rheumatology branch

S.N. Ques�ons asked from pa�ents Response YES

Response NO

1. Have you heard about Rheumatology specialty? What type of pa�ents rheumatologists see? (Joint, mul�system, autoimmune problems)

71 (14.2%) 429

2. What is difference from orthopedics? 97 (19.4%) 403 3. What are the causes of Rheumatological disorders?

(Gene�c, Autoimmune, environmental)

43(8.6%) 457

4. Who are more affected with Rheumatological problems? (Age/Sex/Habits) 56(11.2%) 444 5. Tell at least 3 Rheumatological problems? 41(8.2%) 459 TOTAL AWARENESS-n-2500 308(12.32%) 2192(87.6

8%) Ques�onnaire about Non steroidal an�-inflammatory drugs (NSAIDs) available over the counter (OTC) 1. What do you know about OTC painkillers/NSAID’s (oral, injectable, local)? 137(27.4%) 363 2. Name at least 3 OTC NSAID’s you know or you have used? 118(23.6%) 382 3. Tell at least 3 condi�ons Where you should uses NSAID’s/painkiller? 156(31.2%) 344 4. Tell at least 3 Side effects of NSAID’s/painkiller? 87(17.4%) 413 5.

Tell at least 2 alterna�ve

painkillers

other than NSAIDs?

36(7.2%)

464

TOTAL AWARENESS N-2500

534(21.36%)

1966(78.64%)

Ques�onnaire about calcium

1.

Tell at least 3

benefits of Calcium for

health?

259(51.8%)

241

2.

Tell at least 3

dietary

sources of Calcium?

351(70.2%)

149

3.

Tell Name of at

least 3

OTC calcium products you have know

or you have used?

67(13.4%)

433

4.

Tell about the Effects of Calcium deficiency?

233(44.6%)

267

5.

Tell about the causes of calcium deficiency in our body?

153(30.6%)

347

TOTAL AWARENESS

N-2500

1063(42.52

%)

1437(57.4

8%) Ques�onnaire about vitamin D

1.

Tell at least 2 benefits of vitamin D in health? How do you come to know about it?

169(33.8%)

331

2.

Tell at least 3 sources of Vitamin

D? (Diet,

environment,

other)

107(21.4%)

393

3.

Tell at least 2 the symptoms of vitamin D deficiency?

72(14.4%

428

4.

Who needs more vitamin D? (Age/sex/ other)

201(40.2%)

299

5.

Tell at least 2 causes of vitamin D

deficiency?

43(8.6%)

457

TOTAL AWARENESS

N 2500

592(23.68%)

1908 (78.72%)

Among all parameters, awareness about calcium was maximum (42.52%), followed by awareness for vitamin D (23.68%), NSAIDs awareness (21.36%) and least for rheumatology branch (12.32%) this is after we have distributed the rheumatology branch information pamphlets about our clinic before start of the clinic.

DISCUSSION:

In the present study, most commonly occurring rheumatological disease groups in order of frequency are-inammatory diseases (39%) while in the study of Boulos et al4 inammatory diseases were in >50% of patients, in study by Miedema et al5 in 50.5% of patients, these differences can possibly be explained by different inclusion criteria in their study .In present study among inammatory arthritis rheumatoid arthritis (RA) was

most common in 22 .4% of cases with female preponderance and mean age 42.68 years, which is similar to study of Ranwa et al6 (RA 35.67%), Miedema et (RA was 2 6 . 5 % ) a n d Z i n k e t a l 7 ( R A 5 1 % ) . Spondyloarthritidies(SpA) was found in 9% of cases which is comparable to studies by Vanhoof et al8 (SpA-7% in new cases ) and Miedema et (AS was 5.1% ,PsA was 3.6%) but different from study by Oguntona et al9 where

© JIMI � JULY 2017 � VOL. 11 36


SpA was seen in only 0.8% cases. Connective tissue diseases (CTD) was seen in 3.4%of cases of which, SLE was most common in 1% of cases which is higher than study by J Vanhoof et al 0.4% but lower than the study by Oguntona et al (2.1%), from India AN Malaviya10 showed very low prevalence of lupus i.e.14-60 per 1000000 in general population. Sjogren's syndrome, systemic sclerosis and vasculitis (Granulomatosis with polyangiitis (GPA) each were seen in 0.4 % cases in our study population which is lower than Oguntona et al (1.3%). However Dutch study by Miedema et al reported CTD in 8.1%of cases . This may be due to ethnical differences .

Osteoarthritis was most common Degenerative disease in 22.8% of patients which is comparable to study by Miedema et al (degenerative diseases 18%) but much lower than the data reported by J Vanhoof et al (45%) , Oguntona et al(45.8%), Ranwa B L et al(51.4%).

Soft tissue rheumatism (15% of all study population) is defined by non-articular or periarticular problems in which pathology are outside the synovial lining e.g. bursae, muscles, tendons etc. Fibromyalgia was most commonly seen in 5.4% cases, followed by non specific aches and pains in 4% of cases which is similar to Indian study by by Ranwa et al (fibromyalgia in 9% cases, ill defined aches and pain in 4.2% cases) and much lower than study by Miedema et al (28%), study by Oguntona et al (34.3%) and J Vanhoof et al (51%).

Metabolic bone diseases accounts for 13.6% of total patients in our study of which vitamin D deficiency was in 11.6% (8% patients having Vitamin D deficiency only and 3.6% patients with Osteomalacia) which contradict with reports by Ritu G11 who showed the prevalence of vitamin D deficiency is 70-100% in general population of Indian subcontinent, this can be explained by the fact that our patients being hospital based and might have taken calcium and vitamin D supplementation.

Among Infection related arthritis (8.8 %) post viral arthralgia (6.8%) and post viral arthritis (2%) were seen mostly due to the Chikungunya and chikungunya like viral epidemic seen in August-September 2016 in India12. We did not find any cases of infective arthritis like septic or tubercular arthritis.

Among co-morbidities, a very high association of cardio-metabolic risk factors seen in 20.4% of cases, with hypertension and diabetes in predominance followed by hypothyroidism in 6% of cases. This indicates

Among all parameters awareness about calcium was maximum (42.52%), followed by awareness for vitamin D (23.68%), NSAIDs awareness (21.36%) and least for rheumatology branch (12.32%) this is after we have distributed the rheumatology branch information pamphlets about our clinic before start of the clinic. So awareness/ information about the rheumatology branch was very poor among the patients and also about the commonly used medicines in rheumatology. W.Sulaiman et al14 from Malaysia reported 45.8% patients not aware of any NSAIDs side effect status in a established rheumatologic clinic, Current report by Durga et al15 .highlighted this problem also. There is a marked imbalance between number of rheumatologist and the concerned disease burden at present scenario15. Despite rheumatologic disorders affecting 18.5%-23.9% of the population, rheumatology in India is still in its infancy. Therefore, there is a dare need of increasing awareness, training programmes for doctors in this developing field of medicine.

CONCLUSION: This study provides an estimate of the pattern of rheumatic diseases in a tertiary institution with a newly started rheumatology clinic in Ghaziabad. It can serve as a base-line research on which future researchers could build on as similar studies from India are scarcely available. A community study will however be more appropriate to determine the actual prevalence of rheumatic diseases in the community. We conclude that inammatory joint diseases are most common in a specialised rheumatology clinic, followed by degenerative joint and spine diseases, soft tissue rheumatism, and metabolic bone diseases. Cardio metabolic risk factors are predominately associated with rheumatological patients and therefore we suggest that proactive screening of these factors should be routinely done for prevention of complications. Patients need more and more public awareness programme to increase their knowledge towards the rheumatology branch and commonly used medicines .Training programmes for physicians should be stated in rheumatology at each institution .CONFLICT OF INTEREST: NoneCORRESPONDENCE AUTHOR: Dr. Rakesh Kumar Jagdish, Assistant Professor Medicine and In-charge Rheumatology Clinic, Santosh Medical College and Hospital, Ghaziabad,UP. Email: [email protected],9718090045.

© JIMI � JULY 2017 � VOL. 11 37


Rheumatological patients are at high risk of cardiacproblem due to accumulation of risk factors and also chronic inammation leads to endothelial dysfunction and accelerated atherosclerosis13. Also high association of hypothyroidism in these patients can add to dyslipidemia.

S.A. Oguntona, A.S. Edunjobi and A. O. Olatunde, Prevalence of rheumatic diseases in a rheumatology outpatient practice of a tertiary hospital. International Research Journal of Medicine and Biomedical Sciences Vol.1 (2),pp. 11-18, April 2016.

Malaviya AN, Singh RR, Singh YN, Kapoor SK, Kumar A (1993). Prevalence of systemic lupus erythematosus in India. Lupus 1993Apr2( 2) 115-8.

Ritu G and Ajay Gupta. Vitamin D Deficiency in India: Prevalence, Causalities and Interventions. Nutrients 2014, 6, P 729-775.

National guidelines for clinical management of chikungunya, 2016,Directrate of vector bone diseases control programme, DGHS, Ministry of health and family welfare, Govt of India, chapter 1, Page1.

Murdaca G, et al. Endothelial dysfunction in rheumatic autoimmune diseases. Atherosclerosis. 2012 Oct; 224 (2) :309-17. doi: 10.1016.

Wahinuddin Sulaiman, Ong Ping Seung, Rosli Ismail. Patient's Knowledge and Perception Towards the use of Non-steroidal Anti- Inammatory Drugs in Rheumatology Clinic Northern Malaysia. Oman Medical Journal (2012) Vol. 27, No. 6: 505-508.

Durga Prasanna Misra, Vikas Agarwal,and Vir Singh Negi. Rheumatology in India: A Bird's Eye View on Organization, Epidemiology, Training Programs and Publications. 2016.31.7.1013. J Korean Med Sci 2016; 31: 1013-1019.

Jacobson L, et al. The commonest rheumatic complaints of over six weeks duration in a twelve months period in a defined Swedish population: Prevalence and relationship. Scand J Rheumatology. 1989;18:353-360.

Dequeker J. Undergraduate education in rheumatology. XVI Annual Conference of Indian Rheumatology Association Scientific Proceedings, IRACON-2000.

Vikas Aggarwal Prevalence of Rheumatic Diseases in India, JK SCIENCE.Vol. 5 No, 2, April-June 2003,P 48-49.

Boulos P, Fitzcharles MA, Cohan M, Starr M. A community rheumatology practice offers an educational experience comparable to that of a university tertiary care center. J Rheumatol 2000;27:2903–5.

Miedema HS, van der Linden SM, Rasker JJ, Valkenburg HA. National database of patients visiting rheumatologists in the Netherlands : the standard diagnosis register of rheumatic diseases. A report and preliminary analysis. Br J Rheumatol 1998;37:555–61.

Ranwa BL et al.prevalence of rheumatic diseases in urban bikaner population in western rajasthan: A WHO-ILAR COPCORD STUDY. International Journal of Basic and Applied Medical Sciences. 2012 Vol. 2 (1) January-April, pp.138-145.

Zink A, Listing J, Klindworth C, Zeidler H, for the German Collaborative Arthritis Centres. The national database of the German Collaborative Arthritis Centres: I. Structure, aims and patients. Ann Rheum Dis 2001;60:199–206.

J Vanhoof, K Declerck, P Geusens.Prevalence of rheumatic diseases in a rheumatological outpatient practice. Ann Rheum Dis 2002;61:453–455.

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Role Of Pulmonary Rehabilitation In Cases OfPulmonary Impairment After Tuberculosis

Review Article

1 2Antriksh Srivastava , Vinisha Chandra ,3 4 5

Mohan Bandhu Gupta , Gajendra Vikram Singh , Santosh Kumar

Introduction:

Pulmonary rehabilitation for patients with chronic lung diseases is well established as a means of enhancing standard pharmacologic and other therapies in controlling and alleviating symptoms and optimizing

[1 ,2 ,3 ]functional capacity . The primary goal of any rehabilitation program is to restore the patient to the highest possible level of independent function. This goal is accomplished by helping patients and significant others learn more about the underlying disease, treatment options, and coping strategies. Patients are encouraged to participate actively in providing their own health care, become more independent in daily activities, and be less dependent on health professionals and expensive medical resources. Rather than addressing solely reversal of the disease process, rehabilitation focuses on improving disability from disease.

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1-Senior Resident, Department of Respiratory Medicine, School of Medical Sciences & Research, Greater Noida.2-Senior Resident, Department of Medicine, School of Medical Sciences & Research, Greater Noida.3-Professor, Department of Respiratory Medicine, School of Medical Sciences & Research, Greater Noida.4-Associate Professor, Department of TB & Respiratory Diseases, S. N. Medical College, Agra5-Associate Professor & HOD, Department of TB & Respiratory Diseases, S. N. Medical College, Agra

Background: Pulmonary rehabilitation is as such a well- established intervention in alleviating the quality of life of patients suffering from chronic lung diseases. Pulmonary TB in itself is an infectious disease with a very good outcome with treatment. But the sequelae of TB in the form of structural changes in the lung parenchyma make the post TB quality of life equivalent to that of a chronic lung disease. Thus it would be prudent to provide these patients with a pulmonary rehabilitation.

Abstract

Objective: To study the role of pulmonary rehabilitation in patients of pulmonary impairment after tuberculosis (PIAT).

Materials and Methods: From January 2015 to October 2016, i.e., over the time period of 1 year & 10 months, we evaluated the effect of pulmonary rehabilitation on 66 clinically diagnosed cases of pulmonary impairment after tuberculosis (PIAT) as confirmed by spirometry (FEV1/FVC < 0.7) in terms oung function, nutritional status, exercising capacity, exercise tolerance and quality of life.

Results: It was found that in patients of PIAT, pulmonary rehabilitation significantly improved the exercise tolerance, exercising capacity and quality of life but there was no significant improvement in lung function and nutritional status.

Conclusion: Pulmonary rehabilitation is a new hope for patients with PIAT. It is an effective adjunct to standard medical treatment that reduces dyspnoea and increases activities of daily living, exercise tolerance, exercising capacity and provides better quality of life.

Keywords: PIAT, pulmonary rehabilitation

In the context of chronic lung diseases, it is worth mentioning that pulmonary TB survivors frequently experience structural4 and functional lung sequels that

The new ATS/ERS definition of pulmonary rehabilitation is: “Pulmonary rehabilitation is a comprehensive intervention based on a thorough patient assessment followed by patient-tailored therapies which include, but are not limited to, exercise training, education and behaviour change, designed to improve the physical and

vary in severity that have recently been more completely [4]described . Pulmonary tuberculosis (TB) can cause

parenchymal destruction by up-regulation of several [5]proteases and dysregulation of protease control . The

histopathological abnormalities after treatment for pulmonary TB include fibrosis, bronchiectasis, and bronchial stenosis, all of which can cause pulmonary

[6,7]function abnormalities . Patients with Pulmonary Tuberculosis (PTB) often develop impairment in pulmonary function due to anatomical changes secondary to the illness. Thus, pulmonary rehabilitation can also aid patients of healed pulmonary TB like any other chronic lung disease.c

psychological condition of people with chronic respiratory disease and to promote the long-term

[8]adherence to health-enhancing behaviors . Pulmonary rehabilitation is an established intervention for the management of obstructive pulmonary diseases. Indeed, the delivery of rehabilitation has become routine care for individuals with moderate to severe disease.

The role of pulmonary rehabilitation has been studied extensively in COPD patients and also for other chronic lung diseases but it has never been studied in patients of pulmonary impairment after Tuberculosis (PIAT) in this country. Present study was done to evaluate the same.

Materials And MethodsFrom January 2015 to October 2016, i.e., over the time period of 1 year &10 months, we evaluated the effect of pulmonary rehabilitation on 66 clinically diagnosed cases of pulmonary impairment after tuberculosis (PIAT) as confirmed by spirometry (FEV1/FVC < 0.7). Patients presenting to Department of T.B. & Chest Diseases, Agra of any age who were stable and interested in participating in our study irrespective of their "smoking status" and having none of exclusion criteria, were enrolled into the study. Participants gave written informed consent, and patient anonymity was preserved using ethical committee approved protocols.

The role of pulmonary rehabilitation was assessed in terms of lung function, exercising capacity and tolerance, nutritional status and quality of life. Patients excluded from the study were those withFEV1/FVC> 0.7 or with other significant comorbidities such as cor-pulmonale, diabetes mellitus, COPD, bronchial asthma or pulmonary impairment not as a result of TB.

Various tools were used for calculation of parameters as described below:

Lung function was assessed by PFT using P.K. Morgan's Spiro 232 pulmonary system in the department of TB & Respiratory Medicine at S. N. Medical College, Agra.Exercising capacity was measured using the 6-minute walk test distance.Exercise tolerance was measured using the modified Borg's scale (RPE scale).Nutritional status was measured by using weight, BMI and mid-arm circumference (MAC). Quality of life was measured using the validated Hindi version of the Saint George's Respiratory Questionnaire.

a)

b)

c)

d)

e)

The study was a hospital-based, randomised, case control study. All the patients were subjected to a baseline assessment at the time of first contact. After the baseline assessment of all patients enrolled for this study, randomly selected patients were put in the case and control group. Those in the case group were explained the various aspects of pulmonary rehabilitation program in the Department of TB & Chest Diseases, SNMC, Agra. This group beside comprehensive pulmonary rehabilitation services, was also on standard medical treatment. The control group was also treated with standard medical management but not the pulmonary rehabilitation program.

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The components of the pulmonary rehabilitation program were:

(A) Education: The patients were told about their disease and were taught specific means to deal with issues if any.

(B) Breathing Retaining Techniques: Breathing techniques such as diaphragmatic and pursed-lip breathing were taught to help the patients to relieve and control breathlessness, improve their ventilatory pattern (i.e. slower respiratory rate and increased tidal volume), prevent dynamic airway compression, improve respiratory synchrony of the abdominal and thoracic musculature and improve gas exchange.

Exercise for Bronchial Hygiene: As secretion retention can interfere with ventilation and diffusion of O2 and CO2, an individualized program of secretion removal technique was taught to the patients of rehabilitation group in form of:

(C)

Adequate hydration and steam inhalationCoughing, postural drainage, chest vibration and percussion.

Brisk walkingStair climbingCyclingStretching and relaxation exercisesHalf and full squatArm ergometry

progressive feelings of hopelessness and an inability to cope with chronic, progressive disease.The patients were kept in follow up on a weekly basis, and on every visit were asked about their experience with the exercises and the benefits they get if any. We were in regular touch with the patients also via telephonic calls, if any patient had any confusion. The duration of rehabilitation program was 10 weeks.

OBSERVATIONSTable 1 summarises all the observations over the entire duration of the study.

Table 1

Sr. No.

Parameter

Cases

Controls

p-value

Pre-Rehab

Post-Rehab

Pre-Rehab

Post-Rehab

1

Weight (Kg)

50.97 ± 10.95

50.97 ± 10.95

50.57 ± 9.57

50.57 ± 9.57

0.59

2

BMI (Kg/m2)

20.83 ± 5.42

20.83 ± 5.42

20.5 ± 3.86

20.5 ± 3.86

0.68

Sr. No.

Parameter

Cases

Controls

p-value

Pre-Rehab

Post-Rehab

Pre-Rehab

Post-Rehab

3

MAC (cm)

14 ± 1

14 ± 1

14 ± 1.15

14 ± 1.15

0.867

4

FEV1 (Litres)

1.21 ± 0.4

1.23 ± 0.4

1.17 ± 0.39

1.19 ± 0.38

0.72

5

FVC (Litres)

1.77 ± 0.32

1.81 ± 0.31

1.97 ± 0.48

2.07 ± 0.56

0.006

6

FEV1/FVC(%)

67 ± 13.39

66.88 ± 13.37

58.14 ± 7.53

57.29 ± 9.57

1

7 RPE score Pre

6-MWT 5.25 ±

0.84 3.25 ±

0.84

5.39 ± 0.88

5 ± 0.86

0

8 RPE score Post

6-MWT 5.91 ± 0.73

3.56 ± 0.84 6.25 ± 0.89 5.75 ± 0.7 0

9

6-MWT distance (m)

369.63 ± 29.59

479.25 ± 33.24

360.89 ± 28.76

416.79 ± 32.34 0.01

10

SGRQ score

15.51 ± 2.46

14.3 ± 2.32

16.61 ± 1.96

16.49 ± 1.81

0

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(D) Exercise: Various simple to perform exercises were taught to the patients like:

The program was tailored to the individual's physical abilities, interests, resources and environment. The patients were motivated and encouraged to incorporate these exercises into daily activities they enjoyed like gardening etc.

(E) Psychosocial support: It was provided as an integral part of the program with a goal to help patients combat

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RESULTS:

Keeping in view the small sample size of the study, it was concluded that in patients of PIAT, when pulmonary rehabilitation was given along with standard medical treatment and it was compared to standard medical treatment alone, following results were obtained:

There was no significant improvement in lung function.There was no significant improvement in nutritional status.However, there was significant improvement found in exercise tolerance and exercising capacity of the patients.The quality of life was found to be significantly improved.

DISCUSSION:Patients with Pulmonary Tuberculosis (PTB) often develop impairment in pulmonary function due to anatomical changes secondary to the i l lness . Histopathologic findings resulting from tuberculosis include the formation of caseating granuloma, tissue

[9]liquefaction, and cavity formation . When these occur in the lung, many survivors experience permanent anatomic changes. These result in pulmonary sequelae that are characterized by bronchial and parenchymal structural changes, including broncho-vascular distortion, bronchiectasis, emphysematous changes, and fibrotic b a n d s . T h e s e c h a n g e s c a u s e s y m p t o m s l i k e breathlessness, cough with expectoration, recurrent infections and chest pain, and thus deteriorate the quality of life of the patients.

Thus it would be prudent to say thatthe great inammatory component causes major injuries that trigger fibroblastic reaction, fibrosis and chest wall retraction, compromising pulmonary expansion, which translates into a clinically and functionally moderate

[10]restrictive pattern and dyspnea during exercise .As healed pulmonary TB behaves as a chronic lung disease affecting airways, pulmonary rehabilitation is aimed to overcome these airway limitations. The patients are encouraged to assume responsibility for their own care and become partners with their physician in providing the

[11]care . Breathing exercises are taught to improve ventilatory pattern. The aim is to slow expiration and maintain positive airway pressure to “stent the airways

[11]open” and prevent collapse . Various methods of bronchial hygiene are taught to remove secretions like adequate hydration and steam inhalation although of

[12,13] questionable benefit .Physical exercises are a major part of pulmonary rehabilitation, providing both physical

[12 ,13]and psychological benefits .Also psychological support is given to the patients to help combat progressive feelings of hopelessness and an inability to cope with

[14,15]chronic, progressive disease.

Various studies have been done previously to study the role of pulmonary rehabilitation in numerous chronic lung diseases like COPD, ILD, Tuberculosis and lung cancer and found conicting results. The present study aimed to evaluate the role of pulmonary rehabilitation in

[16]PIAT. In a previous study by Mir Shad Ali et al (2014),he found that pulmonary rehabilitation brought about a significant change in pulmonary function in COPD.

[17]However, Oh EG (2003)in chronic lung diseases, Osamu [18] [19]Nishiyama et al (2008)in IPF and Donna de Grass et al

(2014)in pulmonary TB patients did not find any significant improvement. Likewise, we also did not find any significant improvement in lung function conferred by pulmonary rehabilitation in patients of PIAT.

CONCLUSION:The patients of pulmonary TB continue to suffer from the various sequelae of the disease even after taking complete treatment. These post tubercular limitations are a source of permanent distress and social withdrawal for the patients. Pulmonary rehabilitation is an effective adjunct to standard medical treatment for management of these patients. When given along with standard medical treatment, i t can be assumed that pulmonary rehabilitation will reduce the need for frequent hospital admissions and rescue medications. It can increase the exercising capacity of patients of PIAT so that they can have less limitations on their daily activities.

In conclusion, pulmonary rehabilitation is a new hope for patients with PIAT. It is a treatment that reduces dyspnoea and increases activities of daily living, exercise tolerance, exercising capacity and provides better quality of life.

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The aforementioned authors in their same studies also reported that pulmonary rehabilitation brought about a significant improvement in the exercise tolerance, exercising capacity and the quality of life of their respective patients. Similar results were found in our study where pulmonary rehabilitation significantly alleviated the exercise tolerance, exercising capacity and quality of life of patients of PIAT.

[20]Neil J Greening et al (2014)in his study on role of pulmonary rehabilitation COPD patients did not find any improvement in nutritional status similar to that observed in our study.

Thus if instituted in a well-organized and proper, patient oriented manner, pulmonary rehabilitation can reduce the utilization of health care resources by patients of PIAT and give them a better life, most of which they can live independently.

Financial Support And Sponsorship: NilConicts Of Interest: Nil

ReferencesAmerican association of cardiovascular and pulmonary rehabilitation. Guidelines for pulmonary rehabilitation programs. 4th ed. Champaign, IL: Human Kinetics; 2011.

American thoracic society, European respiratory society. ATS/ERS statement on pulmonary rehabilitation. Am J RespirCrit Care Med. 2006; 173: 1390-1413.

Ries AL, Bauldoff GS, Carlin BW, et al. Pulmonary rehabilitation: joint ACCP/AACVPR evidence based clinical practice guidelines. Chest. 2007; 131 (suppl5): 4S-42S.

Pasipanodya et al. BMC Public Health 2010, 10:259.

Dheda K, Booth H, Huggett JF, Johnson MA, Zumla A, Rook GA. Lung remodeling in pulmonary tuberculosis. J Infect Dis. 2005;192:1201–9, doi:10.1086/444545.

Curtis JK. The significance of bronchiectasis associated with pulmonary tuberculosis. Am J Med. 1957;22:894–903, doi: 10.1016/0002 9343(57)90025-6.

Rosenzweig DY, Stead WW. The role of tuberculosis and other forms of bronchopulmonary necrosis in the pathogenesis of bronchiectasis. Am Rev Respir Dis. 1966;93:769–85.

S p r u i t m a e t a l ; A n o f fi c i a l A m e r i c a n T h o r a c i c Society/European Respiratory Society statement: key concepts and advances inpulmonary rehabilitation. Am J RespirCrit Care Med. 2014 Jun 15;189(12):1570.

Sodeman, WA, Sodeman, TM Pathologic physiology: mechanisms of disease. 7th ed.1985,467 WB Saunders. Philadelphia: PA: American Thoracic Society. Treatment of tuberculosis. MMWR Morb Moral Wkly Rep2003;52,1-77.

Esther Cecilia Wilches, Julián Andrés Rivera, Ricardo Mosquera, Liliana Loaiza, LucelyObando, Psicol.Pulmonary rehabilitation in multi-drug resistant tuberculosis (TB MDR): a case report. Colomb Med. 2009; 40: 436-41.

Ries AL, Bullock PJ, Larsen CA, et al. Shortness of breath: A guide to better living and breathing. 6th ed. St. Louis, MO: Mosby; 2001.

Gosselink R. Breathing techniques in patients with chronic obstructive pulmonary disease(COPD). ChronRespir Dis. 2004: 1(3): 163-172.

Jones AP, Rowe BH. Bronchopulmonary hygiene physical therapy for chronic obstructive pulmonary disease and bronchiectasis. Cochrane database Syst Rev. 2000;2; CD000045.

O'Shea SD, Taylor NF, Paratz JD. Progressive resistance exercise improves muscle strength and may improve elements of performance of daily activities for people with COPD: a systematic review. Chest 2009; 136:1269-1283.

Emery CF, Huffman MJ, Busby AK. Behavioural medicine in pulmonary rehabilitation: psychological, cognitive and social factors. In: Hodgkin JE, Celli BR, Connors GL, eds. Pulmonary rehabilitation: Guidelines to success. St. Louis MO: Mosby; 2009:269-284.

Mir Shad Ali, Deepak Talwar and S.K. Jain. The Effect of a Short-Term Pulmonary Rehabilitation on Exercise Capacity and Quality of Life in Patients Hospitalized with Acute Exacerbation of Chronic Obstructive Pulmonary Disease. Indian J Chest Dis Allied Sci 2014; 56: 13-19.

Oh EG. The effects of home-based pulmonary rehabilitation in patients withchronic lung disease. Int J Nurs Stud. 2003 Nov;40(8):873-9.

Osamu Nishiyama, Yasuhiro Kondoh, Tomoki Kimura, Keisuke Kato, Kensuke Kataoka, Tomoya Ogawa, Fumiko Watanabe, Shinichi Arizono, Koichi Nishimura and Hiroyuki Taniguchi. Effects of pulmonary rehabilitation in patients with idiopathic pulmonary fibrosis. Respirology (2008) 13, 394–399.

Donna de Grass, ShamilaManie, and SeyiLadeleAmosun. Effectiveness of a home-based pulmonary rehabilitation programme in pulmonary function and health related quality of life for patients with pulmonary tuberculosis: a pilot study. Afr Health Sci. 2014 Dec; 14(4): 866–872.

Neil J Greening et al:An early rehabilitation intervention to enhance recovery during hospital admission for an exacerbation of chronic respiratory disease: randomised controlled trial. BMJ 2014; 349.

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1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

1-Professor, Department Of Internal Medicine, King George Medical University, Lucknow2,3,4-Senior Resident, Department Of Internal Medicine, King George Medical University, Lucknow

Metformin - Marching Beyond Diabetes

Review Article

1 2 3Arvind Kumar Mishra , Rohit Anand, Shilpa , Rohin

Introduction

During the last 10 years Type 2 Diabetes Mellitus has become a major health issue reaching epidemic

[1,2]proportions . The prevalence of type 2 diabetes mellitus (DM) is increasing rapidly worldwide, with a prediction

[3]of more than 380 million people to be affected by 2025 . Patients have a considerably increased risk of vascular disease, which may affect both large arteries (macrovascular,i.e. cerebrovascular, coronary and peripheral arterial disease), and small arteries (microvascular disease, i.e. retinopathy, neuropathy and

[ 4 , 5 ]nephropathy). Overall, these chronic vascular complications lead to increased morbidity and

[4,6]mortality. In an effort to optimize glycemic control and also to reduce the burden of diabetic complications, several classes of oral hypoglycemic agents have been developed. Biguanides represent one of the oldest classes of oral hypoglycemic agents used in the management of

[7]type 2 diabetes mellitus. Phenformin was the first biguanide to be marketed in the 1950's, while buformin

[7-9]and metformin soon followed.

Discovery of Metformin

The discovery of metformin began with the synthesis of galegine-like compounds derived from Gallega officinalis, a plant traditionally employed in Europe as a

[10]drug for diabetes treatment for centuries . In 1950, Stern et al. discovered the clinical usefulness of metformin while working in Paris. They observed that the dose–response of metformin was related to its glucose lowering capacity and that metformin toxicity also

[10]displayed a wide security margin .The other two biguanide agents, phenformin and buformin, were soon withdrawn from widespread clinical use due to their toxicity, especially lactic acidosis. However, five decades were needed to promote metformin from a minor product to the 'gold standard' in the treatment of type 2 DM, with a wide safety profile.

particularly after meals, and has an antilipolytic effect that lowers serum free fatty acid concentrations, thereby

[11,15,16]reducing substrate availability for gluconeogenesis . As a result of the improvement in glycemic control, serum

[17,18]insulin concentrations decline slightly . Metformin has also been shown to decrease food intake and body weight [19,20]. Metformin suppresses gluconeogenesis by inhibiting a specific mitochondrial isoform of glycerophosphate dehydrogenase (mGPD), an enzyme responsible for converting glycerophosphate to dihydroxyacetone phosphate, thereby preventing glycerol from contributing

[21,22]to the gluconeogenic pathway . In addition, inhibition of mGPD leads to accumulation of cytoplasmic NADH and a decrease in the conversion of lactate to pyruvate, limiting lactate contributions to hepatic gluconeogenesis. Excess glycerol and lactate are released into the plasma. Metformin also activates the enzyme AMP-activated protein kinase (AMPK) in hepatocytes, which appears to be the mechanism by which metformin lowers serum lipid

[23 -25 ]concentrations . AMPK-dependent inhibitory phosphorylation of acetyl-CoA carboxylases Acc1 and Acc2 suppresses lipogenesis and lowers cellular fatty acid

[26,27]synthesis in liver and muscle . Metformin also works through the Peutz-Jeghers protein, LKB1, to regulate

[28]AMPK . LKB1 is a tumor suppressor, and activation of AMPK through LKB1 may play a role in inhibiting cell

[29]growth .

Pharmacokinetic Profile & Metabolism[30] Metformin is absorbed by the small intestine. Its oral

bioavailability ranges between 40% and 60%, and gastrointestinal absorption is virtually complete after 6

[31–33] hours of oral administration. A negative correlation has been described between oral dose and drug

[31,32]absorption. Following absorption, metformin is rapidly distributed, without binding to plasma proteins. In contrast to phenformin, metformin does not undergo

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Metformin And Antihyperglycemic ActionMetformin's major effect is to decrease hepatic glucose

[11-14]output by inhibiting gluconeogenesis . In addition, metformin increases insulin-mediated glucose utilization in peripheral tissues (such as muscle and liver), particularly after meals, and has an antilipolytic effect that

Dosage

Treatment is usually begun with 500 mg once daily dosing with the evening meal and, if tolerated, add a second 500 mg dose with breakfast. The dose can be increased slowly

[27](one tablet every one to two weeks) as necessary . The usual effective dose is 1500 to 2000 mg/day; the maximum recommended dose of 2500 mg/day provides only marginally better glycemic control and is often not tolerated due to gastrointestinal side effects. The therapeutic goal is the control of fasting blood sugar & HBA1C at lowest possible dose.

Sustained-release Formulations vs Immediate Release FormulationsMaximum concentrations are reached more slowly with extended release formulations compared with immediate release metformin, although both provide similar exposure at a given total daily dose. Extended release Metformin is as effective as immediate-release Metformin. Tolerability is generally comparable although gastro-intestinal side effects seem to be better tolerated.

Metformin And Safety ProfileGastrointestinal side effects, i.e. diarrhea, nausea, bloating and metallic taste in the palate are not uncommon when treatment with metformin is started, affecting 1%-30% of patients. Increasing the dose gradually, most side affects may be diminished. There is clear relationship between the dosage and effect of metformin, so the most effective dosage of metformin observed in studies (36) was 2000 mg/day. Increasing the metformin dosage from 2000 to 3000 mg/day only reduced fasting blood glucose levels by further 5%, raising the incidence of gastrointestinal side effects. The risk of hypoglycemia was low, almost the same as in the placebo group (37). Lactic acidosis is the most dangerous side effect, fortunately rare, with an incidence of 0-0.084 cases/1000 patient years (38). To

minimize the risk of lactic acidosis, contraindications should be observed, i.e. impaired renal function (limit value of creatinine clearance 60 mL/min), severe liver disease, pancreatitis, alcoholism, hypoxic states, respiratory insufficiency, severe cardiac insufficiency (NYHA III/IV), cardiovascular shock, metabolic acidosis, diabetic ketoacidosis, consumptive diseases, low serum level of vitamin B12, preoperative, perioperative and postoperative states, radiological procedures using contrast, advanced age, and calorie restrictions (<1000 cal per day) (39).

IndicationIn the absence of specific contraindications, metformin is considered initial pharmacologic therapy for most patients with type 2 diabetes because of glycemic efficacy, absence of weight gain and hypoglycemia, general

[40-42]tolerability, and favorable cost . It is preffered in patients who are obese,hypertensive or have prominent dyslipidaemia. Current guidelines from the American Diabetes Association/European Association for the Study of Diabetes(ADA/EASD) and the American Association of Clinical Endocrinologists/American College of Endocrinology(AACE/ACE) recommend early initiation of metformin as a first-line drug for monotherapy and combination therapy for patients with T2DM. This recommendation is based primarily on metformin's glucose-lowering effects, relatively low cost, and generally low level of side effects, including the absence of

[43,44]weight gain . Metformin's first-line position was strengthened by the United Kingdom Prospective Diabetes Study (UKPDS)observation that the metformin-treated group had risk reductions of 32% (p = 0.002) for any diabetes-related endpoint, 42% for diabetes-related death (p = 0.017), and 36% for all-cause mortality (p = 0.011) compared with the control group. The UKPDS demonstrated that metformin is as effective as sulfonylurea in controlling blood glucose levels of obese

[45]patients with type 2 diabetes mellitus . Metformin has been also been shown to be effective in normal weight

[46]patients . It can be initiated at the time of diabetes diagnosis, along with consultation for lifestyle intervention. For patients with glycated hemoglobin (A1C) near target (<7.5 percent), a three- to six-month trial of lifestyle modification before initiating metformin is reasonable. After a successful initial response to metformin, the majority of patients who fail to maintain glycemic targets and require the addition of a second oral or an injectable agent. For patients who fail initial therapy, there are a number of agents that are available and can be used in combination with metformin

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liver metabolism and is excreted unchanged by the [31,32]kidneys. Mean plasma half-life following oral

[31,33]administration ranges between 4 and 8.7 hours. Plasma half-life is significantly prolonged in patients with renal impairment and shows a close relationship to

[31,33]creatinine clearance. Metformin has no clinically relevant interactions with other drugs, because it is not metabolized and does not inhibit the metabolism of other

[ 3 1 , 3 4 ]drugs, it is exccreted unchanged in urine. . Gastrointestinal absorption is the rate limiting step of metformin disposition because the rate of metformin absorption is slower than its rate of plasma elimination. More metformin is absorbed at a lower dose than at a higher dose. Thus, an inverse relationship is observed between the amount of Metformin ingested (from 0.25 to 2.0g) and its bioavailibility (from 86 to 42%), suggesting

[35]the involvement of active and saturable process.

Metformin in combination therapy

Combinations of metformin and insulin secretagogue can reduce HbA1c between 1.5% to 2.2% in patients sub-

[47]optimally controlled by diet and exercise . The optimal

second-line drug when metformin monotherapy fails is not clear. All noninsulin antidiabetic drugs when added to maximal metformin therapy are associated with similar HbA1c reduction but with varying degrees of weight gain and hypoglycemia risk. A meta-analysis of 27 randomized trials showed that thiazolidinediones, sulfonylureas, and glinides were associated with weight gain; glucagon-like peptide-1 analogs, glucosidase inhibitors, and dipeptidyl peptidase-4 inhibitors were associated with weight loss or no weight change. Sulfonylureas and glinides were associated with higher rates of hypoglycemia than with placebo. When combined with metformin, sulfonylureas and alphaglucosidase inhibitors show a similar efficacy on

[48]HbA1c .

Metformin and pre-diabetes

Metformin and hypoglycemia

In their systematic review, Gillies et al. found that lifestyle and pharmacological interventions reduced the rate of progression to type 2 diabetes in people with IGT and that these interventions seem to be as effective as

[49]pharmacological treatment. .The best evidence for a potential role for metformin in the prevention of type 2 diabetes comes from The Diabetes Prevention Program (DPP) trial. Lifestyle intervention and metformin reduced diabetes incidence by 58% and 31%, respectively, when

[50]compared with placebo . At the end of the DPP study, patients were observed for a one to two week wash out period. Diabetes incidence increased from 25.2 to 30.6% in the metformin group and from 33.4 to 36.7% in the placebo group. Even after including the wash out period in the overall analysis, metformin still significantly decreased diabetes incidence (risk ratio 0.75, p = 0.005) compared

[51]with placebo . These data suggest that, at least in the short-term, metformin may help delay the onset of diabetes. The benefits of metformin were primarily observed in patients <60 years old (RR 0.66) and in

[50]patients with a BMI greater than 35 kg/m2 (RR 0.47)

Use In Diabetes Of The YoungMetformin is an effective drug in type 2 young population , The benefits of reduction in insulin resistance without hypoglycemia and with weight loss are the key to its use as first line treatment. There are studies and trials backing the use of metformin and giving strong evidence of its efficacy in the young population. GDM patients can also be prescribed metformin as an alternate to insulin therapy. Further follow up studies are required for finding the effects of Metformin in the offsprings.Type 1 DM, LADA and MODY patients may also be prescribed metformin as an adjunct therapy who are obese or have signs of insulin resistance such as acanthosis nigricans. The beneficial role of metformin in young patients with type 2 diabetes has been demonstrated in a randomized, controlled trial which showed a significant decrease in

fasting blood glucose, HbA1c, weight, and total cholesterol. There is some evidence that suggests improvement in metabolic control of poorly controlled adolescents with type 1 diabetes when metformin is added to insulin therapy. Metformin has been shown to reduce insulin dose requirement (5.7–10.1 U/day), HbA1c (0.6–0.9%), weight(1.7–6.0 kg), and total cholesterol

[52](0.3–0.41 mmol/l) .

The risk of hypoglycemia was low, almost the same as in [53]the placebo group . It reduces insulin resistance,but does

not promote insulin secretion from β-cells, and thus it is not associated with increased risk of hypoglycemia. Hypoglycemia has been reported in combination.

[54]regimens , likely due to metformin potentiating other therapeutic agents.

Hypoglycemia may also occur in the following cicumstances – Concomitant glucose lowering drug use, ethanol consumption, strenous exercise, elderly/debilitated.

Metformin and lactic acidosisLactic acidosis is the most dangerous side effect,with

[55-57]mortality rate up to 50% but fortunately rare, with an [58]incidence of 0-0.084 cases/1000 patient years . To

minimize the risk of lactic acidosis, contraindications should be observed, i.e. impaired renal function (limit value of creatinine clearance 60 mL/min), severe liver disease, pancreatitis, alcoholism, hypoxic states, respiratory insufficiency, severe cardiac insufficiency (NYHA III/IV), cardiovascular shock, metabolic acidosis, diabetic ketoacidosis, consumptive diseases, low serum level of vitamin B12, preoperative, perioperative and postoperative states, radiological procedures using contrast, advanced age.Metformin should be avoided in these conditions.

Metformin and B12 deficiencyAbout 7-10%% of patients who are prescribed metformin have evidence of reduced vitamin B12 absorption due to calcium-dependent ileal membrane antagonism, an effect

[59]that can be reversed with supplemental calcium . This vitamin B12 deficiency is rarely associated with

[60]megaloblastic anemia . A multicentric study reported a mean decrease of 19% and 5% in vitamin B12 and folate

[61]concentration, respectively . Vitamin B12 deficiency has been related with dose and duration of metformin use and occurs more frequently among patients that use it for

[62]more than 3 years and in higher doses .

Metformin and pregnancyMetformin is known to cross the placenta and concerns regarding potential adverse effects on both the mother

[63]and the fetus have limited its use in pregnancy . The

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use of metformin during pregnancy is still a matter of controversy.Metformin has been classified as US FDA class B drug.The Metformin in Gestational Diabetes (MiG) trial, found no significant difference in the composite fetal outcome (composite of neonatal hypoglycemia, respiratory distress, need for phototherapy, birth trauma, 5-minute Apgar score <7, or prematurity) between metformin and insulin. Women assigned to metformin had more preterm births and less weight gain compared to those in the

[64]insulin group . Another randomized trial also found [65]similar results . However Ease of its use, acceptability by

the patients, significantly less maternal weight gain and less maternal hypoglycemia, as evident from these studies, appears a lot encouraging. Moreover, two years follow up of offspring in MIG-TOFU, also reassures no anticipated harm and in fact suggests its beneficial effects in offspring.

Metformin and nursing mothers

Metformin is excreted into milk and may reach levels similar to those of plasma.Not many studies are available so far and the potential for hypoglycemia in infants cannot be ruled out.

Metformin and pcos

PCOS includes several cardiometabolic risk factors associated withinsulin resistance, such as abdominal obesity,hypertension, hyperinsulinemia, low HDL ,cholesterol , hypertriglyceridemia and impaired

(66-68)fibrinolysis,resembling the metabolic syndrome . A metaanalysis of studies comparing metformin with placebo or no treatment in women with PCOS showed that metformin significantly reduced fasting plasma glucose, systolic and diastolic blood pressure, LDL cholesterol and fasting insulin, although total cholesterol, HDL cholesterol or triglycerides did not change

(69)significantly . A Cochrane meta-analysis of trials that compared metformin with the oral contraceptive pill showed significant improvement in fasting insulin and tr ig lycer ides with metformin, but no overal l

(70)improvement in fasting glucose .Besides, both meta-analyses revealed that metformin s i g n i fi c a n t l y r e d u c e d s e r u m T e s t o s t e r o n e , androstenedione and dehydroepiandrostenedione sulfate. Many guidelines suggest the use of metformin as initial pharmacological therapy for most womenwith

(71)PCOS, particularly when overweight or obese , or in addition to clomifene in clomifene-resistant anovulatory

(72)women . Although metformin crosses the placenta, observational studies to date suggest that metformin does

(73-75)not adversely affect fetal or neonatal development . Metformin used during pregnancy decreased the risk of

(76,77)gestational diabetes in women with PCOS . The

mechanisms of metformin effects in PCOS pertain to its central and peripheral action. At the central level, the possible effect is reduction in serum LH level. At the peripheral level , metformin decreases hepatic gluconeogenesis, increases the synthesis of sex hormone-binding globulin (SHBG), consecutively decreasing free androgen levels. Metformin also increases insulin sensitivity in peripheral tissues, reduces free fatty acid oxidation, and reduces ovarian and adrenal secretion of androgens. Pleiotropic actionsof metformin are mediated by the AMPK pathway. Experimental data show the effect of metformin on the expression of some genes involved in

(78)glucose metabolism . In a study conducted by Heard MJ et al. to assess pregnancy outcomes in patients with pcos metformin was started at 500mg bid for 6 weeks and increased to 500mg tid if no ovulation occured, Clomiphene citrate 50 mg added if no ovulatory response after 6 weeks. It was observed 40% patients resumed spontaneous menses with metformin alone 31% required Clomiphine citrate (50 mg) in conjunction with metformin therapy 67% of combination therapy had evidence of ovulation with overall 42% conceiving with a median time of 3 months for conception. Metformin administration during pregnancy also reduced 1st trimester pregnancy losses in women with Polycystic ovarian syndrome.

Metformin and IVFMetformin reduces hyperinsulinemia and suppresses the excessive ovarian production of androgens as a consequence metformin improves assisted Reproductive Technology outcomes- pregnancy and live birth rates.

Metformin and weight lossIn those who are obese, metformin promotes modest weight reduction or at least weight

[79]stabilization . This is in contrast to the weight gain often [79]associated with insulin or sulfonylurea treatment . In

one large study, for example, patients treated with glyburide gained an average of 1.6 kg, whereas those

[80]receiving metformin lost 2.9 kg . In a trial comparing metformin with along-acting glucagon-like peptide-1 (GLP-1)-receptor agonist, weight loss at 52 weeks was similar in the twogroups (-2.29 and -2.22 kg for

[81]dulaglutide 1.5 mg and metformin, respectively) . The mechanisms by which metformin contributes to weight loss may be explained through the reduction in gastrointestinal absorption of carbohydrates and insulin resistance , reduction of leptin and ghrelin levels after glucose overload , and by induction of a lipolitic and anoretic effect by acting on glucagon–like peptide 1 . In another study comparing metformin, exercise & combination of the two in adults with impaired glucose tolerance. Metformin and metformin plus exercise decreased body weight more than exercise alone. Metformin alone also decreased caloric intake but not percent body fat or central body fat.

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Metformin and NAFLD

The management of NASH includes lifestyle intervention with gradual weight loss , fibrates to control hypertriglyceridemia, gastrointestinal lipase inhibitor, orlistat, and agents that improve insulin sensitivity

(82)(metformin and thiazolidinedione) . In randomized studies comparing metformin plus diet versus diet, plasma glucose, body mass index, plasma insulin and plasma cholesterol improved significantly in both groups, while plasma C-peptide and insulin resistance index improved significantly only on metformin plus diet

(83)treatment . Another study compared metformin with vitamin E in patients with NAFLD and found significant improvement in metabolic parameters in the metformin

(84)group .

Metformin and CKD

Metformin is itself not nephrotoxic and Since it is excreted unchanged through renal route,presence of renal failure can lead to toxic levels.Renal dysfunction is the most common risk factor associated with lactic acidosis. Some authors have suggested discontinuing its use when serum creatinine is above 1.5 mg/dL in men and 1.4 mg/dL in

[85]women while others suggested a cut-off of 2.2 mg/dL and continuous use even in the case of ischaemic cardiopathy, chronicobstructive pulmonary disease, or

[86]cardiac failure . As serum creatinine can underestimate renal dysfunction, particularly in elderly patients and women, the use of estimated GFR (eGFR) has been advocated. The recommended eGFR thresholds are generally consistent with the National Institute for Health and Clinical Excellence guidelines in the U.K. and those endorsed by the Canadian Diabetes Association and the Australian Diabetes Society. Metformin may be continued or initiated with an eGFR of 60 mL/min per 1.73 m2 but renal function should be monitored closely (every 3–6 months). The dose of metformin should be reviewed and reduced (e.g. by 50% or to half-maximal dose) in those with an eGFR of 45 mL/min per 1.73 m2, and renal function should be monitored closely (every 3 months). Metformin should not be initiated in patients at this eGFR [87]. The drug should be stopped once eGFR falls to 30 mL/min per 1.73 m2. Metformin also should not be prescribed to patients above 80 years of age as renal functions are not certain.

Metformin and cardiovascular effects

Metformin does not have adverse cardiovascular effects, and it appears to decrease cardiovascular events in certain populations.In the United Kingdom Prospective Diabetes Study (UKPDS), obese patients who were assigned initially to receive metformin rather than sulfonylurea or insulin therapy had a decreased risk of the aggregate diabetes-related endpoint (endpoints included both

macrovascular and microvascular complications) and all-[88]cause mortality . During the post-interventional

observation period of the UKPDS, reductions in the risk of macrovascular complications were maintained in the metformin group.In another trial, 390 patients treated with insulin were randomly assigned to metformin versus

[89]placebo . After four years, mean A1C (7.5 versus 7.9 percent) and body weight (85 versus 90 kg) were significantly lower in the metformin group. In addition, there was a decrease in the risk of the secondary macrovascular endpoint, which was a composite of 13 vascular events including myocardial infarction(MI), heart failure, stroke, amputation, and sudden death. In a subsequent meta-analysis of 170 trials and 25 observational studies evaluating the effects of oral or injectable diabetes medications as monotherapy and in combination with other oral agents or insulin on cardiovascular mortality, intermediate outcomes (A1C, body weight, lipid profiles), and adverse events, metformin was associated with lower long-term cardiovascular mortality compared with sulfonylurea

[ 9 0 ]monotherapy. The possible cardio-protective mechanism is attributed to reduced high fat induced apoptosis ,enhancement of NO production improving endothelial function ,attenuation of fibrosis by inhibition of TGF-B1 and overall activation of AMPK decreases the severity of the failing heart. Besides the above mentioned benefits, metformin has other potential antiatherothrombotic actions that prevent cardiovascular accidents. Treatment with metformin improves endothelial function by decreasing circulating levels of sVCAM-1 and E-selectin, which are markers of endothelial activation ; reduces circulating levels of plasminogen activator inhibitor-1 ; improves other hemostatic parameters, decreasing Factor XIII activity and reducing the levels of Factor VII, a powerful endogenous promoter of coagulation . Metformin reduces circulating C reactive protein level ; inhibits activation of the pro-inammatory nuclear transcription factor, NFkappaB, secondary to an increase in the activity of the enzyme AMP-kinase (AMPK), which has been proposed as a cellular mechanism for the antiinammatory effects of metformin . Metformin also decreases oxidative stress, inhibits lipid peroxidation of LDL and HDL, and the production of the superoxide free radical (O2-) in platelets.

Metformin and tuberculosis

World health organisation estimated that patients with diabetes are 2-3 times higher risk of tuberculosis than the general population. To determine the protective effects of metformin against tuberculosis in diabetic patients, a case control study was conducted over 8 months by Braz et al. and it was concluded that poor diabetic control among

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diabetics is a risk factor for TB occurence and protective effect of metformin against TB was 3.9 fold in diabetics. Hence incorporation of metformin in standard clinical care would offer a therapeutic benefit of prevention of tuberculosis.

Metformin and cancer

Observational data suggest that use of metformin decreases cancer incidence[91-93]. In meta-analyses of predominantly case-control and cohort studies in patients with type 2 diabetes,use of metformin compared with nonuse or with use of other diabetes treatment was associated with a reduced risk of

[94,95]all cancers (relative risk [RR] 0.61, 95% CI 0.54-0.70) , [95-98]colorectal cancer (RR 0.64,95% CI 0.54-0.76) , and lower

[94,96]cancer mortality (RR 0.66, 95% CI 0.49-0.88) . possible mechanism by which metformin may decrease cancer incidence is regulation of AMP-activated protein kinase

[99](AMPK) through LKB1 . LKB1 is a tumor suppressor, and activation of AMPK through LKB1 may play a role in inhibiting cell growth. Studies in C. elegans have suggested that inactivation of mTORC1 with subsequent inhibition of growth through induction of ACAD10 may

[99]explain the anti-cancer effects of metformin .After the discovery that metformin, several clinical studies followed that attempted to test the hypothesis that metformin use is potentially associated with an improvement in cancer incidence and survival. Breast cancer has been extensively studied as a potential therapeutic target for metformin. Metformin was able not only to inhibit cell growth but also to induce cell death in vitro and in vivo in triple-negative (ER/PR/Her-2 neu) breast cancer cells. This profound effect of metformin in this specific subtype of cancer is interesting, especially if one considers that triple-negative breast cancer is more common in more obese and diabetic women. In pancreatic cancer cells, metformin was able to induce apoptosis, by activation of the caspase pathway, and to reduce epidermal growth factor receptor (EGFR) and phosphorylated meteghan activated protein kinase (P-MAPK) levels.Other authors have examined whether metformin use is associated with better outcomes after chemotherapy in various types of cancer. Jiralespong et al. identified approximately 155 diabetic and 2,374 nondiabetic patients with breast cancer and showed that diabetic patients receiving metformin and neoadjuvant taxane chemotherapy have a higher pathologic complete remission rate than do diabetics not receiving metformin. Margel et al. assessed the relation between duration of metformin therapy after prostate cancer diagnosis and

[100]mortality in patients with diabetes . The data were obtained from several databases in Ontario (Canada). In the cohort consisting of 3,837 patients, they noted that the

onger duration of metformin treatment after diagnosis of prostate cancer was associated with a significant decrease not only in the risk of cancer-specific but also in all-cause mortality.However, at this point, several unanswered questions remain. If more evidence supporting an anticancer effect that is independent of the anti hypoglycemic effect emerges from basic research and current clinical trials, then further research should be undertaken to explore the major mechanisms responsible for this

Metfromin & Anti Aging

To date no long-term longitudinal survival/mortality studies have been performed in healthy patients subjected to metformin therapy. A 10-year-long randomized clinical trial of metformin therapy in T2D overweight/obese patients (UKPDSO) shows long-term beneficial effects on health and survival reducing cardiac and all-cause mortality of patients on metformin compared with usual care. Indeed, the benefits of metformin on host metabolism have been observed even after cessation of treatment, the so-called “legacy effect”. However, the molecular mechanisms by which metformin promotes these longterm positive effects on mortality , independent of glycaemic control, remain unknown.

Metformin and alzhiemer's :A potential new therapy

Animal studies have found that metformin helps neurogenesis and enhances hippocampus, a studies show metformin helps reduce risk, other studies show antidiabetic medications like insulin are linked to increased risk of having dementia. Animal studies show that metformin recruits endogenous neural stem cells and also promotes the genesis of new neurons. Metformin, however, needs to have been used for a longer period before a drastic reduction in neurodegenerative disease and its neuroprotective nature is seen. A cohort study of type 2 diabetes patients who are 55 years and above and being managed on a monotherapy antidiabetic drug of either metformin, sulfonylurea (SU), thiazolidinedione (TZD) or insulin were observed in a period of 5 years. In the course of 5 years, dementia was identified in 9.9% of the patients. Comparing those taking metformin to those taking sulfonylurea, there was a 20% reduction in dementia in those taking metformin. The hazard ratio 0.79%, a 95% confidence interval of 0.65-0.95. For TZD, metformin had a 23% reduction in having dementia as compared to TZD with hazard ratio of 0.77, 95% confidence interval of 0.66-0.90. Whereas those on SU as compared to metformin had a 24% increased risk for dementia with a hazard ratio of 1.24, 95% confidence interval of 1.1-1.4.TZD had an 18% increased risk, hazard ratio of 1.18, 95% confidence interval of 1.1-1.4. Insulin had

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the highest risk of 28% with hazard ratio of 1.28, 95% confidence interval of 1.1-1.6. These findings proved that metformin use has neuroprotective benefits while insulin has an increased risk of one having dementia. A spatial learning maze test performed on mice showed those given metformin (200mg/kg) were significantly better to be able to learn the location of a submerged platform as compared to those given a sterile saline solution. Other studies have also proposed that metformin could stimulate neurogenesis from human neural stem cells. Metformin is known to cross the blood-brain barrier, and has pleiotropic effects. It is known to have other possible preventive roles in cancer and heart disease. From all these various studies, one can conclude that metformin does have a therapeutic potential for mild cognitive impairment and dementia, however large scale prospective cohort studies are required to approve the connection between metformin use and the risk of neurodegenerative diseases.

Metformin and HIV

There is now evidence that metformin may be effective in reducing insulin resistance and abdominal fat in HIV-infected people on HAART. Studies have reported that metformin reduced insulin resistance, reduced triglyceride levels and improved abdominal fat

[101]distribution . There is also evidence from randomised, controlled studies which suggests metformin is an effective treatment for insulin resistance and diabetes, and related metabolic and body fat disorders, seen in HIV-infected people on treatment. For instance, a team from Boston conducted a randomised, controlled study of metformin in 26 HIV-infected individuals with fat redistribution, high insulin levels and/or abnormal glucose tolerance. After three months, insulin levels, weight and blood pressure fell significantly in those treated with metformin compared to controls. The treated group also experienced a reduction in waist size and

[102]reduced visceral abdominal fat . The British HIV Association guidelines also recommend metformin for treatment of insulin resistance associated with HIV.

Conclusions

In recent years, metformin has become the first-line therapy for patients with type 2 diabetes. Thus far, metformin is the only antidiabetic agent which has shown reduced macrovascular outcomes which is likely explained by its effects beyond glycemic control. It has also been employed as an adjunct to l ifestyle modifications in pre-diabetes, gestational diabetes and other insulin-resistant states. It has also recently gained attention as a potential treatment of other diseases such as obesity, polycystic ovary syndrome, nonalcoholic steatohepatitis and HIV lipodystrophy . Further,

Metformin has shown definitive protective and even curative properties in many neoplastic diseases particularly breast cancer. Neuroprotection and Alzheimer's are other areas, metformin is showing promising results. As metformin is being reported to be beneficial in variety of unrelated situations, it is interesting to observe what this molecule is having in its store to be revealed in times to come.

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Umpierrez G, Tofé Povedano S, Pérez Manghi F, et al. Efficacy and safety of dulaglutide monotherapy versus metformin in type 2 diabetes in a randomized controlled trial (AWARD-3). Diabetes Care 2014;37:2168.Medina J, Fernandez-Salazar LI, Garcia-Buey L,Moreno-Otero R. Approach to the pathogenesisand treatment of nonalcoholic steatohepatitis.Diabetes Care 2004;27:2057-2066.Uygun A, Kadayifci A, Isik AT, Ozgurtas T, DeveciS, Tuzun A, et al. Metformin in the treatment of patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2004;19:537-544.Bugianesi E, Gentilcore E, Manini R, Natale S,Vanni E, Villanova N, et al. A randomizedcontrolled trial of metformin versus vitamin E orprescriptive diet in nonalcoholic fatty liver disease. Am J Gastroenterol 2005;100:1082-1090.Zheng Z, Chen H, Li J, Li T, Zheng B, Zheng Y, Jin H, He Y, Gu Q, Xun X:Sirtuin 1-mediated cellular metabolic memory of high glucose via the LKB1/AMPK/ROS pathway and therapeutic effects of metformin. Diabetes2012, 61(1):217–228.Rachmani R, Slavachevski I, Levi Z, Zadok B, Kedar Y, Ravid M: Metformin in patients with type 2 diabetes mellitus: reconsideration of traditional contraindications. Eur J Intern Med 2002, 13:428–433Lipska KJ, Bailey CJ, Inzucchi SE: Use of metformin in the setting of mild-to-moderate renal insufficiency. Diabetes Care 2011, 34(6):1431–1437.Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352:854.

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Case Report

Unusual Presentation Of Aortic Dissection1 2

Dr. Rohit Bhagat , Dr. Amitesh Aggarwal

Case Report: We report a case of 60 year old female patient who had a sudden episode of restlessness, chest pain and paraplegia and on computed tomography was found to have an ascending aortic aneurysm with aortic dissection - Stanford type A. Why Should an Emergency Physician be aware of this? The importance of including

Keywords: Aortic dissection, paraplegia, Stanford type A,

Case Report60 year old previously healthy lady presented to the emergency room following the development of sudden restlessness, anterior central chest pain associated with sweating and sudden onset of bilateral lower limb weakness about 6 hours earlier. There was no history of loss of consciousness, bladder and bowel incontinence. She had no past history of any significant illness such as diabetes mellitus or hypertension. She had been a chronic smoker for the about 10 years but had quit smoking since last 2 years. In the emergency room the patient was found to be conscious, oriented, restless and afebrile. The blood pressure was 164/100 mm Hg systolic mm Hg, pulse rate of 56/min with respiratory rate of 18/min. on general physical examination she appeared not to have any abnormality. On systemic examination cardiovascular: heart sounds were distant with no added sounds. Allperipheral pulses were present. Chest examination revealed normal breath sounds. Her abdomen was soft, non tender, and there was no organomegaly. Nervous system examination of upper limbs was normal while power in the lower limbs was 0/5 and deep tendon


Background: Aortic dissection is defined as separation of the layers within the aortic wall. Tears in the intimal layer result in the propagation of dissection (proximally or distally) secondary to blood entering the intima-media space. Acute dissection of the aorta can be life-threatening. Neurologic complications like paraplegia are rarely seen as a presenting manifestation of aortic dissection.

Abstract

1-Associate Professor, Department of MedicineUniversity College of Medical Sciences Delhi 110095 INDIA, 2- Professor, Department of Medicine University College of Medical Sciences Delhi 110095 INDIA

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reexes were absent. Plantar reex was bilaterally mute. There was complete loss of sensations below T8 level. The skin of the lower limbs was normal and there were no ischemic changes. Initial emergency investigations showed a Hemoglobin of 11.2 g/dl; TLC 4300/mm3; Platelets 203; blood urea 23 mg/dl; serum creatinine 34;

RBS 100mg/dl; Sodium 143; Potassium 4.2mg/dl. X-ray chest showed no cardiomegaly. ECG was suggestive of sinus bradycardia with ST elevation in V2 and T wave inversion in V3-V6. Lumber spine x rays didn't show any pathology. NCCT head didn't show any abnormality. Computed tomograpghy (CT) of chest showed- dilated ascending, arch and descending thoracic aorta with intimal ap In its lumen extending from sinus valsalva to the bifurcation having intimal tear at proximal ascending aorta; Ascending arotic aneurysm with aortic dissection- Stanford type A. She was treated supportively with blood pressure control and later transferred to CTVS for emergency operation for aortic dissection repair.

DiscussionAortic dissection is uncommon. It accounts for approximately 1 in 10,000 hospital admissions. The mortality rate is as high as 80% without aggressive treatment. The pathology in aortic dissection is a circumferential transverse tear of the intima. The tear often begins along the right lateral wall of the ascending aorta. Hypertension is considered the most important contributory factor. The typical presentation is a severe painful tearing or ripping sensation. The painful area is usually located in the substernal, interscapular or mid-back area. Other signs and symptoms include cardiovascular collapse, acute myocardial infarction, heart failure, cardiac tamponade, oliguria, syncope, and

[1]cool mottled extremities .Several classification of arotic dissection has been proposed. The two most important classifications which

The differential diagnosis of paraplegia includes spinal cord injury, tumor, infection, disc herniation, decompression illness, multiple sclerosis, and abdominal

[1]aortic occlusion . The diagnosis of abdominal aortic occlusion in acute paraplegia is missed in up to 50% of cases. CT scan with contrast is a convenient diagnostic tool but angiography remains the gold s tandard. Transesophageal echography can be done when the above

[3]tools cannot be used . Neurologic sequelae of aortic dissection occur in as many as one third of patients. These sequelae fall into 3 categories: cerebral ischemia, ischemic

[1]peripheral neuropathy and spinal cord ischemia . When the ascending aorta is involved, cerebral ischemia may result. Cerebral ischemia may present as a stroke or

Images

Fig1: thrombus seen in arch of arota


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are are DeBakey classification and Stanford Classification. DeBakey Classification type I, in which an intimal tear occurs in the ascending aorta but involves descending aorta as well; Type II, dissection is limited to ascending aorta; Type III, intimal tear is limited to descending aorta with distal propagation of dissection. Stanford classification Type A; dissection involves ascending aortaand Type B; dissection is limited to arch of aorta and

[2]descending arota .

encephalopathy. When the iliac arteries are involved, a painful peripheral neuropathy may result. Paraplegia with or without sensory loss is a rare phenomenon. It occurs in about 2% to 8% of patients. It results from dissection of the descending aorta. The clinical picture of motor loss without complete loss of sensation is known as anterior artery syndrome. The artery of Adamkiewicz branches from the posterior aspect of the aorta andsupplies the anterior aspect of the spinal cord. When this artery is involved by the aortic dissection, most areas of the spinal cord receive additional blood ow from the collateral ow. In the thoracic spinal cord, there is a “watershed” area which is especially prone to ischemia [4]. Lesions of the ascending aorta (type I, type II or type A) have an unfavorable outcome and surgery is usually needed. Patients with Type III or type B dissections may b e g i v e n m e d i c a l m a n a g e m e n t fi r s t . From this case, we stress the importance of considering aortic dissection in the differential diagnosis of acute paraplegia. The cause can be either acute abdominal aorta occlusion or acute spinal cord ischemia due to dissection of the abdominal aorta.

Fig2: thrombus seen at origin of arota Fig3: thrombus involving both Ascending

and descending arota.

References

Inamasu J, Hori S, Yokoyama M, Funabiki T, Aoki K, Aikawa N: Paraplegia caused by painless acute aortic dissection. Spinal cord 2000; 38:702-704.

Harrison Principles of Internal Medicine; 19th edition; Cardiovasular system; Diseases of Arota; 1640-1641

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Hammer JPM: Aortic dissection: Role of echocardiography. Imaging Decisions MRI 2002; 1:9-15.

Weinberg L, Harry WR, Marshall RJ: Post-operative paraplegia following spiral cord infarction. Acta Anaesthesiol Scand 2002; 46:469-472.

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4.

ABSTRACT

Case Report

Rifampicin Induced ThrombocytopeniaAnamikaVerma, Nikhil Gupta, Rajendra Prasad

Thrombocytopenia is a potentially life threatening adverse effect seen with anti-tubercular drugs. We report a case of 23 year old male with pulmonary tuberculosis, who was on Isoniazid , rifampicin , pyrazinamide and ethambutol in standard doses. He presented to us with erythematous rashes and epistaxis. On evaluation, he had thrombocytopenia which was found to be rifampicin-induced. Anti Tubercular drugs was restarted without rifampicin and there were no further bleeding episodes. Though, rifampicin is well tolerated, but on rare occasions it can cause thrombocytopenia. This case is being reported because of its rare occurrence and documentation.

Key words :Rifampicin,Thrombocytopenia

IntroductionTuberculosis is a chronic granulomatous infection and has been the cause of mortality and morbidity for many years. Treatment of this disease creates problem due to its long duration and compliance issues. One of the most important factors causing low compliance is the adverse effects of the drugs. Some of them are self-limiting, but some require treatment cessation. Rifampicin is an essential component of the treatment regimen for tuberculosis and is well tolerated. Apart from minor side effects like abdominal discomfort, nausea, vomiting and hepatitis, rarely it can cause life threatening acute renal failure or thrombocytopenia1. Rifampicin induced thrombocytopenia was first reported in 1970. It is reversible if timely detection is made and is characterized by rapid destruction of platelets whenever the drug is taken by a susceptible person. The discovery of isolated thrombocytopenia in a patient taking several medications presents a challenging clinical problem 2. Laboratory confirmation of drug induced thrombocytopenia at time of initial presentation is not possible because tests for drug dependent anti-platelet antibodies are not available in common laboratories 3. The diagnosis of drug induced thrombocytopenia can be supported only by resolution of thrombocytopenia after discontinuation of therapy with the suspected drug.

Case ReportA 23 year old male weighing 48 kg presented to the Department of TB and Chest of Era's Lucknow Medical College and hospital with complaints of generalized rashes and epistaxis for 2 weeks.He was on I s o n i a z i d ( 3 0 0 m g ) , R i f a m p i c i n ( 4 5 0 m g ) , Pyrazinamide(1200mg) and Ethambutol (800mg) daily for 1 month which was started by a private practitioner on radiological basis.His sputum was negative for acid fast baci l l i .Detai led c l inical examination revealed erythematous non blanching non palpable purpuric spots all over the body.Consultation from Dermatology department was taken where suspicion was made for drug induced thrombocytopenic purpura .All Anti tubercular drugs were stopped immediately. His initial reports at the time of presentation showed Hb -1 2 . 2 g m / d l , T o t a l L e u c o c y t e C o u n t - 1 0 5 0 0 /cumm,Dif ferent ia l Leucocyte Count showed Neutrophil-74%,Lymphocyte-21%,Eosinophil-5 %and platelet count was -40,000/cumm. His Bleeding Time 2' 10", Clotting Time 5' 30" and INR 1.27.Dengue markers and ANA were negative.Epistaxis was managed conservatively.He was put on Levooxacin (750mg) ,inj streptomycin( 0.75gm) once daily and challenged with 400 mg of ethambutol ,the full dose of which was achieved in 3 days after frequent monitoring of the platelets,this was followed by 50 mg of isoniazid and the full dose was achieved in 3 days, finally 500 mg of pyrazinamide was added and the dose was escalated to full dose in 5 days under frequent monitoring of platelet count. Rifampicin was not given as it was the offending drug.Therashes regressed after 3weeks .The blood parameters after 3 weeks showed Hb -12.2 gm/dl,TLC-10500/cumm,DLC- lymphocyte-20%,neutophil -72%,eosinophil -6%

1-Assistant Prof., Department Of Pulmonary Medicine.Era's Lucknow Medical College And Hospital, Lucknow, 2-Assistant Prof., Department Of General Medicine. Dr Ram Manohar Lohiya Institute Of Medical Sciences, Lucknow. 3-Prof., Department Of Pulmonary Medicine.Era's Lucknow Medical College And Hospital, Lucknow.

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DiscussionThe causes of thrombocytopenia include viral infections, immune disorders, collagen vascular diseases, lymphoproliferative disorders and drugs4 . Drug induced thrombocytopenia can be caused by quinidine, sulphonamides, chemotherapeutic agents, penicillin, barbiturates , heparin, digoxin and estrogen . Thrombocytopenia attributed to rifampicin, is rare but has been reported in the treatment of pulmonary tuberculosis 5-8. Adverse reactions to rifampicin like cutaneous syndrome, abdominal syndrome, a u like syndrome, respiratory syndrome, purpura, and elevated serum transaminase relatively more common with intermittent

9regimens Ferguson reported thrombocytopenic purpura even with daily rifampicin 10 Incidence of Thrombocytopenic purpura(TCP )occurred from the 1st to the 14th month of

3therapy on rifampicin . Most workers agree that continuous treatment with rifampicin results in neutralization of any of the antibodies formed, the antigen--antibody complex being continuously removed without causing allergic reaction. Discontinuation of treatment allows a sufficient quantity of antibody to be built up during the drug-free interval so that when rifampicin is re-administered, an intense reaction occurs. In vitro tests, for identifying circulating antibodies are not easy to perform. No single test (complement fixation test, immuno injury test) detects all the cases of drug-induced TCP. Direct binding assays for IgG or complement on the platelet surface are very useful .According to WHO-Uppsala Monitoring Center Causality Categories, the association of rifampicin as the cause of Adverse Drug Reaction is “Probable / likely”11. High degree of suspicion is necessary to diagnose drug induced thrombocytopenia in patients of pulmonary tuberculosis as other causes such as hemorrhagic fever and Idiopathic Thrombocytopenic purpura are more common . Our patients had thrombocytopenia on daily regimen containing Rifampicin which was started 1 month before. This is consistent with a case reported by F e r g u s o n i n w h i c h t h e p a t i e n t d e v e l o p e d

10thrombocytopenia on daily rifampicin therapy . If purpura occurs during treatment, the drug must be

12 stopped at once and should never be given again.Thrombocytopenia can occur with all primary anti-tubercular drugs. In case of Isoniazid,it occurs as

1 2hematological reaction . There are reports of 1 3 1 4E t h a m b u t o l a n d P y r a z i n a m i d e i n d u c e d

thrombocytopenia which is caused by immunological mechanism.Rarely Streptomycin can also cause drug induced thrombocytopenia. Rifampicin binds non-covalently to membrane glycoprotein to form compound

3epitope for which antibodies are specific . In some cases of Rifampicin induced thrombocytopenia, the drug dependent antibody has been shown to bind specifically

15to human Glycoprotein IX (L64-D135) . While restarting anti-tubercular therapy in a patient suspected to having drug induced thrombocytopenia it is prudent to start three drugs not given previously including one parentral agents and two oral agent that are safe. Corticosteroids is

1 6of no use in drug induced thrombocytopenia . Plasmapheresis can be helpful in some cases. Offending drug should not be reused as only minute quantity of drug

17is needed to set up subsequent immune reaction It has b e e n r e c o m m e n d e d t h a t r i f a m p i c i n - i n d u c e d thrombocytopenia is an absolute contraindication to

18further therapy with rifampicin . However, Bhasin and 19co-workers has suggested that rechallenges should be

done before finally withdrawing rifampicin.

ConclusionRifampicin induced thrombocytopenia on daily regime is a rare but life threatening complication of anti tuberculardrugs.Clinicians should be aware of this entity as timely intervention can save the life of the patIent.

ReferenecesV. V. BanuRekha et al. Rifampicin induced thrombocytopenia. Case report Lung India 2005; 22: 122–4.

Lori D Wazny , Robert E Ariano .Evaluation & management of drug induced thrombocytopenia in the acutely ill patients Pharmacotherapy. 2000; 20: 292-307.

George JN1, Raskob GE, Shah SR, Rizvi MA, Hamilton SA, Osborne S et al Drug induced thrombocytopenia a systematic review of published case reports. Ann InternMed 1998; 129: 886-90

Robbins, Kumar, Cotran. Diseases of Red cells and Bleeding disorders. In: Robbins Pathological basis of diseases. 4th edn. W.B.Saunders Co.; 1989; 657-702. Prasad R, and Muker jee PK. Rifampicin induced thrombocytopenia. Indian J Tuberc 1989; 36: 44-5.

Sharma TN, Gupta PR, Purohit SD, Jain BL, Durlabji P and Koolwal S. Thrombocytopenic purpura induced by daily administration rifampicin. Indian J Tuberc 1985; 32: 199-200.

Cheng-Huei Lee and Ching-Jyh Lee. Thrombocytopenia. A rare but potentially serious side effects of Initial daily and interrupted use of rifampicin. Chest 1989; 96: 202-3.

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monocyte-02% and platelet - 90,000/cumm.No further rashes appeared and his final blood report after 4 weeks showed Hb-12 gm/dl, TLC-11000 cells/cubic mm and platelet count was 4 00,000/cumm. Based on the WHO-Uppsala Monitoring Centre Criteria, the causality of rifampicin induced thrombocytopenia is probable.

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U ZuzarteCherylann, DurgaLawande and Bagga AS. Rifampicin induced thrombocytopenia. Indian J Tuberc 1995; 42: 173-5.

Bassi L, Perna G, Silvestri LG. Antibodies against rifampicin in patients with tuberculosis after discontinuation of daily treatment. Am Rev Respir Dis. 1976;114:1189–90. Ferguson GC. Rifampicin and thrombocytopenia. Br Med J. 1971;3:638. Edwards IR, Biriell C. Harmonisation in pharmacovigilance. Drug Saf. 1994;10:93–102

Drugs used in chemotherapy. In: Modern drug treatment of tuberculosis. Ist Indian edition 1992. Ed N.W Horne PP 1-17 oxford university press

P r a s a d R , M u k e r j i P K . E t h a m b u t o l i n d u c e d thrombocytopenia. Tubercle 1989; 70: 211-2.

Jain VK, Vardhar H, Prakash OM. Pyrazinamide induced thrombocytopenia, Tubercle 1988; 69:217-18

Chong BH, Zohra A, Shen MJ, Kroll H; Drug induced thrombocytopenia: mapping of the binding site of the Rifampicin dependent antibody on GPIX: Journal ofThrombosis and Haemostasis. 2005; 3 :Supplement-1

Pedersen-Bjergaard, Andersen M, Hansen PB. Drug induced thrombocytopenia: clinical data on 309 cases and the effect of corticosteroid therapy. Eur J ClinPharmacol 1997; 52: 183-9

Handin RI: Disorders of the platelet and vessel wall. In Harrison's Principles of Internal Med. Vol. 2, 12th Ed. McGraw Hill, Inc., 1501

Poole G,StradlingP,WorrledgeS.Potentially serious side effcts of high dose twice –weekly rifampicin .Br Med J 1971;3:343-7.

BhasinDK, SarodeR, PuriS, MarwahaN, SinghK. Can rifampicin be started in patients with rifampicin –induced thrombocytopenia ? Tubercle 1991;72:306-71

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ABSTRACT

Case Report

Cryptococcal Meningitis in an Immunocompetent Patient1 2 3 4Saurabh Sharma , Ravi Kant , Balram ji Omar , Priyanka Gupta

Cryptococcal Meningitis (CM) is a rare infection in immunocompetent patients. It is a kind of central nervous system infection caused by encapsulated yeast-like fungus Cryptococcus. Prognosis in immunocompetent patients is generally considered good. Suspicion to diagnosis begins with clinical symptoms that can be non-specific such as fever, cough, and headache.Since the outcome of the disease can be fatal a high index of suspicion, rapid diagnosis and initiation of the specific antifungal therapy is key to treatment. We present a case of cryptococcal infection in a non-HIV-infected person.

KEYWORDS: Cryptococcus, Immunocompetent Patient,HIV.

IntroductionCryptococcal meningitis is a potentially fatal fungal infection of the central nervous system and is caused by

[1]the encapsulated yeast Cryptococcus neoformans . It is a defining opportunistic infection in patients with H I V / A I D S . I t i s n o t u n c o m m o n i n o t h e r immunocompromised patients as those with lymphomas, (e.g.Hodgkin's Lymphoma), sarcoidosis, liver cirrhosis, organ transplantation and patients on long term

[2]corticosteroid therapy . Cryptococcal meningitis is generally considered rare in immunocompetent patients; therefore, specific treatment is not implemented until the organism is identified or a cryptococcal antigen is

[ 3 ]detected . Amphoter ic in B , uconazole , and amphotericin B in combination with ucytosine have been used in the treatment of cryptococcal meningitis with and without coexisting HIV infection, with significant improvements in the management of cryptococcal

[4]meningitis . We report a rare case of Cryptococcus neoformans as the cause of meningi t is in an immunocompetent adult male.

CASE REPORT

A 50-year-old male, resident of Rishikesh, Uttarakhand, India, who was labourer by occupation, presented to themedical emergency with complaints of headache for 20 days associated with multiple episodes of vomiting, and altered sensorium for 1 day. Headache waspresent throughout the day with increasing severity for last 10 days. Patient had altered sensorium for which hewas taken to the hospital. The history revealed that he was a bird lover and there are around 50 domesticated pigeons

on the roof of his home. He had no history ofdiabetes, hypertension, loss of consciousness, seizure, ear discharge or earache, no focal neurological deficit, chronic cough, head trauma, and malignancy.

On examination, vital signs were stable andpatient was afebrile. He was conscious butdisoriented. Higher mental functions could not beassessed. Neck rigidity and Kernig's sign were present. Pupillary responses werebilaterally sluggish. Bilateral planters were not elicitable and all deep tendon reexes were diminished. Sensory and motor system examination was normal. At the time of admission patient had no focal neurological or cranial nerve deficit.After 2 days of admission he developed right sided facial palsy [Figure 1& 2].Examination of cardiac,respiratory, gastrointestinal and genitourinary systemrevealed no abnormality.Chest X ray and electrocardiogram (ECG)were normal. NCCT scan of head was normal.The patient was tested as non-reactive for HIVantibodies. Her blood and urine cultures weresterile and sputum culture did not yield any significantpathogen. Laboratory investigations revealed total leukocyte count (9970/mm cu.) with 87% neutrophils and 7% lymphocytes. Serum electrolytes,renal function tests and liver function tests were withinnormal limits.Lumbar Puncture was performed and CSF was sent to the laboratory for examination. The cerebrospinal uid (CSF) examination revealed 05 cells,(Lymphocytes 100%), with protein of 43 mg/dl and glucose of 36 mg/dl (corresponding blood glucose was 136 mg/dl). CSF

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1-Senior Resident, Department of Medicine AIIMS Rishikesh, 2-Associate Prof., Department of Medicine AIIMSRishikesh, 3-Additional Professor, Department of Medicine AIIMS Rishikesh, 4-Microbiology, Department ofMedicine AIIMS Rishikesh

adenosine deaminase (ADA) level was 1u/L. No microorganisms weredetected on Gram and Ziehl-Neelsen (Z-N) stains.Gram stain of CSF showed Budding yeast cells [ Figure 3] andgram stain from Blood agar plate showed round, narrow base budding yeast cells[Figure4]. On India ink preparation, round budding and encapsulated yeast cells morphology resembling Cryptococcus species were seen [Figure 5]. The urease test of this isolate was positive [ Figure 6]. Treatment was started with Amphotericin B at0.75 mg/kg per day as an intravenous infusion alongwith intravenous uids and mannitol. Serumelectrolytes and renal functions were monitored on a daily basis. After two days of treatment, the patientdeveloped aspiration pneumonia, after which he wasput on ventilatory support. The condition of the patientdeteriorated and later expired due torespiratory failure.

Figure 1: Right facial nerve palsy

Figure 2 : Right facial nerve palsy

Figure 3: Gram stain of CSF showing Budding yeast cells

Figure 4: Shows Gram positive, Round,Narrow baseBudding Yeast cells with Gram positive granular

inclusions from Blood agar plate.

Figure 5: Clear halo representing capsule around yeastcells in India Ink stain

Figure 6: Positive Urease test

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Cryptococcus Neoformans is usually isolated from soil contaminated with Pigeon excreta and also from the ower and bark of eucalyptus trees [6]. Inhalation of this encapsulated yeast leads to a short lived and silent pulmonary infection in immunocompetent patients [7]. In our patient there was a history of exposure to avian dr ippings and no h i s tory was sugges t ive o f immunocompromised conditions. The patient was non reactive to HIV antibody with no underlying lung disorder and X-ray Chest findings were normal.The onset of disease is insidious with a subacute or chronic course in 'non-AIDS' patients. Symptoms of meningitis may begin months-to-years before clinical diagnosis. Our patient had subacute presentation with a history of headache over a duration of 20 days. The radiological findings of CNS are usually normal in HIV positive cryptococcal meningitis patients whereas in case of HIV negative patients, hydrocephalus, cerebral infarct, edema etc, can be seen in CT/MRI of the brain. However, none of these findings are pathognomonic for cryptococcal meningitis [8].The mortality of cryptococcal infected non- HIV patients can vary from 0 to 47% [9]. Alteration in mental status is among one of the poor prognostic factors reported by Dismukes, Diamond and Bennett, and Saag [10]. As the patient in this case report also presented late in the disease with altered mental status, this might be responsible for the fatal course. Other poor prognostic factors are (i) steroid usage which could not be withdrawn or with a daily required use of >20 mg prednisolone, (ii) lymphoreticular malignancy, (iii) cryptococcus growth from sites other than CSF, (iv) elevated CSF pressure >20 cmH2O, (v) hypoglycorrhachia (abnormally low CSF glucose level) before treatment (CSF glucose < 40 mg/dl), (vi) CSF cell count < 20/mm3 before treatment, (vii) negative cryptococcal latex agglutination test, (viii) cryptococcal latex agglutination test titer>1 : 10000, (xi) CSF cryptococcal latex agglutination test titer>1 : 8 after full course of treatment, (x) positive India ink stain after 4 weeks of treatment, and (xi) hypoglycorrhachia after 4 weeks of treatment.In India, treatment of cryptococcal meningitis is done with amphoter ic in B a lone or with ucytos ine (5-uorocytosine) as induction therapy followed by uconazole maintenance therapy [11]. Due to its unavailability and high cost, ucytosine is not used in our s

Discussion

ConclusionsAlthough rare, meningitis caused by C. neoformans can occur in immunocompetent individuals. This case illustrates the importance of broadening the differential when previously healthy patients present with symptoms of meningitis. Cryptococcal meningitis should be considered when there is history suggestive of exposure to avian drippings. Delay in confirming this diagnosis and subsequent treatment is associated with high mortality rates.

ReferencesChayakulkeeree M, Perfect JR. Cryptococcosis. Diagnosis and treatment of human mycoses. 2008:255-76.Goldman, J.D., E.M. Vollmer and A.M. Luks, 2010. Cryptococcosis in the immunocompetent patient. Respiratory Care, 55: 1499-503.Satpute MG, Telang NV et al. Prevalence of Cryptococcal meningitis at a tertiary care center in western India. J MED Microbiol, 2006. Pandit L, Agrawal A, Shenoy S, Kamath G (2006) Cryptococcal Meningitis and Pulmonary cryptococossis in a non-HIV Infected Patient. Eur J Gen Med 3: 80-82.Chowdhary A, Randhawa HS, Prakash A, Meis JF. Environmental prevalence of Cryptococcus neoformans and Cryptococcus gattii in India: an update. Critical reviews in microbiology. 2012 Feb 1;38(1):1-6.Baddley JW, Perfect JR, Oster RA, Larsen RA, Pankey GA, Henderson H, Haas DW, Kauffman CA, Patel R, Zaas AK, Pappas PG. Pulmonary cryptococcosis in patients without HIV infection: factors associated with disseminated disease. European journal of clinical microbiology & infectious diseases. 2008 Oct 1;27(10):937-43.Chen S, Chen X, Zhang Z, Li Quan Kuang S, Luo X; MRI findings of cerebral cryptococcosis in immunocompetent patients.Journal of Medical Imaging and Radiation Oncology, 2011; 55: 2–57.Shih CC, Chen YC, Chang SC, Luh KT, Hsieh WC; Cryptococcal meningitis in non HIV infected patients. QJM, 2000; 93(4): 245-251.Diamond RD, Bennett JE; Prognostic factors in cryptococcal meningitis: a study in 111 cases. Ann Intern Med., 1974; 80(2):176–181.11. Datta K, Jain N, Sethi S, Rattan A, Casadevall A, Banerjee U; Fluconazole and itraconazole susceptibility of clinical isolates ofCryptococcus neoformans at a tertiary care centre in India: a need for care. J Antimicrob Chemother., 2003; 52(4): 683–686.

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etup. Despite all the measures taken, such as intravenous infusion of amphotericin B, mannitol and intravenous uids along with ventilator support, our patient could not survive and died of respiratory failure. He might have survived if an early diagnosis could be made before the development of CNS complications.


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