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July - December, 2017 Vol 9 No.2ISSN: 2086–1435

The official journal of Indonesian Rheumatology Association

INDONESIAN JOURNAL OF

RHEUMATOLOGY

A B

IJRIndonesian Journal of RheumatologyThe Official Journal of the Indonesian Rheumatology Association (IRA)

Cover image:A. Pelvic X-Ray Examination showed fracture on left medial side of inferior pubic ramus. B. Lumbal X-Ray Examination showed endplate fracture on right side superior L4

AIMS AND SCOPEIndonesian Journal of Rheumatology is self-focused on rheumatic diseases and connective tissue disorders in forms of original article (extended or concise reports), review articles, editorial, letters, leaders, lesson from memorable cases, book review, and matters arising. Both clinical and laboratory including animal studies are welcome.

EditorYoga I Kasjmir

Associate EditorsAnna ArianeSandra S. LangowLinda Kurniaty Wijaya

Editorial Board / Peer ReviewerJulius Shoenfeld (Slovakia)Rohini Handa (India)Prakash Pispati (india)Chak Sing Lau (Hong Kong)Sandra Navarra (Philippines)Chng Hiok Hee (Singapore)Attiqul Haq (Bangladesh)Andrea Doria (Italy)Kazuhiko Yamamoto (Japan)Tsuneyo Mimori (Japan)Yoshinari Takasaki (Japan)Kusuki Nishioka (Japan)Shumpei Yokota (Japan)Noboyuki Miyasaka (Japan)Azmillah Rosman (Malaysia)Charles Inderjeeth (Australia)Peter Hollingsworth (Australia)David D’Cruz (United Kingdom)Paul Bacon (United Kingdom)Bambang Setiyohadi (Jakarta, Indonesia)C.Singgih Wahono (Malang, Indonesia)Ika Wulan Yuliani (Jakarta, Indonesia)RM Suryo Anggoro (Jakarta, Indonesia)Kusworini Handono (Malang, Indonesia)Rudy Hidayat (Jakarta, Indonesia)Bagus Putu Putra Suryana (malang, Indonesia)

Advisory CommitteeOK Moehad Sjah (Medan, Indonesia)ES Tehupeiory (Makassar, Indonesia)Harry Isbagio (Jakarta, Indonesia)Handono Kalim (Malang, Indonesia)Zuljasri Albar (Jakarta, Indonesia)

Editorial TeamSari Purnama HidayatRatna Dwi Puji Astuti

INSTRUCTION FOR AUTHORSFull instruction is available online athttp://www.reumatologi.or.id. If you do not have any access please contact editorial office.

Copyright© 2016 Indonesian Rheumatology Association. All rights reserved.No part of this publication may be produced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise without the prior permission.

Contents Volume 9 Number 2 | IJR July-December 2017

Editorial3 Editorial NoteYI Kasjmir

Original article4 The Pattern of Joints Involvement in Patients with Rheumatoid Arthritis in

Rheumatology Clinic Dr. Hasan Sadikin General Hospital Bandung Muhammad Kevin Pratama, Nur Atik, Laniyati Hamijoyo

8 Correlation Between Serum Procollagen Type 1 N-Terminal Propeptide Level With Modified Rodnan Skin Score In Systemic Sclerosis Patients.

Vincent, Sumartini Dewi, Rachmat Gunadi Wachjudi

13 Most Frequent Musculoskeletal Manifestation of Systemic Lupus Erythema-tosus Patients in Dr. Hasan Sadikin General Hospital Bandung

Rahadian Nugi Sutrisno, Andri Reza Rahmadi, Nita Novita, Laniyati Hamijoyo

18 Neuropsychiatric Manifestation Screening among Systemic Lupus Erythe-matosus Patients in Hasan Sadikin General Hospital Bandung

Septian Dwi Putra, Mulya Nurmansyah Ardisasmita, Laniyati Hamijoyo

23 Overview of Anemia among Systemic Lupus Erythematosus Patients in Reproductive Age based on Reticulocyte Hemoglobin Equivalent (RET-He) Level and Reticulocyte Count

Ismiana Fatimah Modjaningrat, Amaylia Oehadian, Mohammad Ghozali, Laniyati Hamijoyo

27 Outcome of Pregnancy in Patients with Systemic Lupus Erythematosus Erica Kwan Yue, Coriejati Rita, Laniyati Hamijoyo

CASE REPORT31 Osteomalacia Induced by Renal Tubular Acidosis Type 1 Steven Sutanto Sihombing, Anna Ariane, RM Suryo Anggoro Kusumo Wibowo, Bambang Setyohadi

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July - December, 2017 Vol 9 No.2ISSN: 2086–1435

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RHEUMATOLOGY

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Editorial

Editorial NoteYI Kasjmir

3Indonesian Journal of Rheumatology 2017; Vol 9 No.2

intrauterine growth retardation, intrauterine fetal death, premature deliveries, and other obstetric complication still higher among SLE patients rather than non-SLE population.5 Secondary prevention such as prepare the mothers before their pregnancy, include controlling disease activity and detecting any risk factors, might result in lower morbidity and mortality.

Moreover, we also had an article about the pattern of joint involvement in patients with rheumatoid arthritis, which had written by Pratama MK, et al.6 The last, there was a case report article about osteomalacia in RTA patients reported by Sihombing SS, et al. RTA is a risk factor for osteomalacia, especially proximal RTA or RTA type 2 which is known have association with Fanconi syndrome and bone involvement. In this edition, Sihombing SS, et al, reported Osteomalacia was induced by distal RTA or RTA type 1 in 22-years-old asian woman. This patient suffered prolonged hypokalemia for 4 years before diagnosed as RTA and 5 years after the first onset, patient developed osteomalacia. Learning this case, physicians might have the higher vigilance in making diagnosis of prolonged hypokalemia patients, so that osteomalacia can be prevented.

We never get bored to invite all readers to contribute as the author in our Indonesian Journal of Rheumatology. The next edition will be more special, because we have been registered our journal for the accreditation. Every article will get a cum value. So, do not hesitate to collect your manuscript to our editorial office via email: [email protected]. We accept all type of manuscripts, include original article, case-report, evidence based case report, review article, meta-analysis, etc.

1. Vincent, Dewi S, Wachjudi RG. Correlation Between Serum Procollagen Type 1 N-Terminal Propeptide Level With Modified Rodnan Skin Score In Systemic Sclerosis Patients.

2. Sutrisno RN, Rahmadi AR, Novita N, Hamijoyo L. Most Frequent Musculoskeletal Manifestation of Systemic Lupus Erythematosus Patients in Dr. Hasan Sadikin General Hospital Bandung

3. Putra SD, Ardisasmita MN, Hamijoyo L. Neuropsychiatric Manifestation Screening among Systemic Lupus Erythema-tosus Patients in Hasan Sadikin General Hospital Bandung

4. Modjaningrat IF, Oehadian A, Ghozali M, Hamijoyo L. Over-view of Anemia among Systemic Lupus Erythematosus Pa-tients in Reproductive Age based on Reticulocyte Hemoglo-bin Equivalent (RET-He) Level and Reticulocyte Count

5. Yue EK, Rita C, Hamijoyo L. Outcome of Pregnancy in Patients with Systemic Lupus Erythematosus

6. Pratama MK, Atik N, Hamijoyo L. The Pattern of Joints In-volvement in Patients with Rheumatoid Arthritis in Rheuma-tology Clinic Dr. Hasan Sadikin General Hospital Bandung

7. Sihombing SS, Ariane A, Wibowo RMSAK, Setyohadi B. Case Report : Osteomalacia Induced by Renal Tubular Aci-dosis Type 1

Why does acknowledging rheumatic diseases is im-portant? Rheumatic diseases have been reported not only lowering the patient’s life quality, but also increasing the mortality and morbidity rates. In this edition, we provided articles about the rare rheu-matic diseases, such as systemic sclerosis and osteo-malacia induced renal tubular acidosis (RTA) type 1. Besides there were some articles about the ap-pearances and pregnancy prognosis in patients with Systemic Lupus Erythematosus (SLE) and an article covered joint involvement pattern in rheumatoid ar-thritis patients in Bandung, West Java, Indonesia.

Scleroderma also known as Systemic Sclerosis (SSc) is chronic autoimmune disease involving con-nective tissue. It is caused by the excessive collagen deposition in skin and internal organs. However, it is reported as the third most common disease found Hasan Sadikin Hospital Rheumatology Clinic, and also in the fourth most common diseases in Cipto Mangunkusumo National General Hospital. The evaluation of this disease was conducted using Mod-ified Rodnan Skin Score (MRSS) which is well cor-related with the gold standard assessment, skin bi-opsy. Unfortunately, MRSS examination should be performed by the trained physicians who have high skill and experiences. Research done by Vincent, et al, entitled “Correlation between serum procollagen type 1 N-terminal level with modified rodnan skin score in systemic sclerosis patients”. They revealed that serum procollagen type 1 N-terminal Propeptide (P1NP) may be as a potential biomarker and also be an alternative examination of MRSS examination in evaluation skin fibrosis in SSc patients.1 Whether it can be applied to wider clinical settings, a larger study about it is still need to be performed.

The deeper study about Systemic Lupus Erythematosus (SLE) had been done in Hasan Sadikin Hospital, Bandung, West Java. After the studies about mucocutaneus manifestation, organ system involvements, and memory performance in SLE patients which have been published in the last edition of Indonesian Journal of Rheumatology, Hasan Sadikin Hospital submitted study about musculosceletal manifestations,2 neuropsychiatric manifestations,3 anemia,4 prognosis of pregnancies in SLE patients.5 With higher understanding, physicians may have higher proficiency in managing SLE patients. Whether patients have musculosceletal complains due to higher disease activity of SLE or due to other causes2; whether neuro or psychiatic manifestation related to SLE or the change of environment3; whether the anemia due to chronic SLE disease, iron deficiency, or autoimmune hemolytic anemia due to high SLE disease activity.4 Prognosis of pregnancy may be vary among SLE patients. Although most babies (64.2%) could be delivered normally; spontaneous abortion,

Original Article

4 Indonesian Journal of Rheumatology 2017; Vol 9 No.2

1 Faculty of Medicine, University of Padjajaran, Bandung, Indonesia; 2 Department of Anatomy, Physiology, and Cellular Biology, Faculty of Medicine, University of Padjajara, Bandung, Indonesia;3 Department of Internal Medicine, Faculty of Medicine, University of Padjajaran / Dr. Hasan Sadikin General Hospital, Bandung, Indonesia

Correspondence:Muhammad Kevin Pratama, MDBandung-Sumedang KM.21, Jatinangor, SumedangEmail: [email protected]

The Pattern of Joints Involvement in Patients with Rheumatoid Arthritis in Rheumatology Clinic Dr. Hasan Sadikin General Hospital Bandung

Muhammad Kevin Pratama1, Nur Atik2, Laniyati Hamijoyo3

by symmetric peripheral polyarthritis. RA is the most common form of chronic inflammation involving the joints and often ended in joint damage and physical disability.1 It is one of the chronic inflammatory disease with the highest prevalence of 0.5 - 0.8% among adult population in the world.2 Although there has been evidence that overall RA incidence has been reduced over the past few decades, but its prevalence is not changed.3 According to the data from Indonesia Basic Health Research (Riskesdas) 2007 and from National Socioeconomic Survey (2007), the prevalence of RA in Indonesia was around 0.1% .11

Diagnosis of RA is made based on the signs and symptoms of chronic inflammation, with the laboratorium and radiologic results.4 In 2010, a collaborative effort conducted between the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) revised the 1987 classification criteria for RA.5 It was done in attempt to make a faster diagnosis of RA so patients will get earlier treatment.6,7 Joint damages as the result of uncontrolled RA may decrease the patient’s quality of life.

RA should be diagnosed as soon as possible, followed by early treatment initiation. Early detection of RA will provide a better disease management. Besides, it also could prevent many RA complications, of which the most frequent is joints damage.7 This study aimed to provide a better management of RA by determining the pattern of joint involvement in RA in order to made earlier diagnosis, so that further complication can be prevented.

MethodsThe study was conducted from August to October 2016 at Dr. Hasan Sadikin General Hospital using a descriptive design study. The subjects were all patients who came to Rheumatology Clinic Dr. Hasan Sadikin General Hospital. The inclusion criteria was all patients who has been diagnosed as RA based on ACR / EULAR 2010 criteria. The exclusion criteria were patients with incomplete or

AbstractBackground: Rheumatoid arthritis (RA) is a chronic inflammatory disease with primary manifestation in the joints. Early management of RA will prevent further joint damage. The joint damages, result of uncontrolled disease activity, will decrease patient’s quality of life. RA should be diagnosed earlier and followed by early treatment initiation, in order to prevent further damages. This study aimed to determine the pattern of joint involvement in RA in order to made earlier diagnosis and treatment initiation.Method: This research was conducted using descriptive study design. Data were obtained using interview of RA patients who coming to Rheumatology Clinic of Dr. Hasan Sadikin General Hospital from August 2016 to October 2016. Collected data included number of joints involvement, duration of therapy, and duration of illness after diagnosed according to the criteria of ACR / EULAR 2010.Result: Ninety-seven RA patients were involved in this study. Subjects were dominantly women (87%), the highest age group was 45-49 years old (17.53%), duration of the disease <5 years (90.72%), and duration of therapy > 3 months (86%). Joint that frequently involved at the time when the diagnosis made was first proximal interphalangeal (49.50%), overall findings during the course of RA was the wrist joint (90.72%). There were different tendency of joint involvement between the gender, knee joints occured in 53,84% male subjects, while PIP joints were accounted for 52,38% in female subjects.Conclusion: The first PIP was the most common joint involved in RA patients when the diagnosis made. The wrist joint involvement was dominantly found in overall course of RA. Knee joint involvement was majorly found in male RA patients, whereas female RA patients would suffer mostly from PIP joint involvement.Keywords: involvement pattern, joints, rheumatoid arthritis

IntroductionRheumatoid arthritis (RA) is a chronic inflammatory condition of unknown etiology and characterized

Original Article


missing data and the presence of other autoimmune rheumatic diseases or other joint problems. Minimum samples required in this study were 97 determined based on the categorical descriptive study formula to estimate the proportion of the population.

The data were taken by interviewing subjects, as the primary data, and collecting information from their medical records, as the secondary data. The data were analyzed descriptively by counting the number and the percentage of the joints involvement which has been examined by the Residents of Internal Medicine Department through the standardized examination. The variables in this study were gender, age, occupation, ethnic, duration of therapy, duration of illness, number of overall findings and manifestations when diagnosed as RA.

Data collection have been approved by the Ethic Committee on Health Research of Faculty of Medicine Universitas Padjadjaran and Ethics Committee on Health Research of Dr Hasan Sadikin General Hospital, Bandung. Data was processed using Microsoft Excel 2010 program.

ResultThe number of samples obtained in this study was 97. Most of them were women (87%). Table 1 shows the characteristics of RA patients by their group age. The division of this age group is done to see if the prevalence of RA is not influenced by age, according to the previous study’s results.3 Dominant age group diagnosed with RA is 45-49 years (17,53%).

Table 1. Age Group Characteristic in RA Patients

AgeMen

(n = 13)Women (n=84)

Total, N(%)

15 – 19 0 2 2 (2.06%)20 – 24 1 4 5 (5.15%)25 – 29 1 4 5 (5.15%)30 - 34 3 7 10(10.31%)35 - 39 0 13 13(13.40%)40 - 44 0 13 13(13.40%)45 - 49 2 15 17(17.53%)50 - 54 2 9 11(11.34%)55 - 59 1 10 11(11.34%)60 - 54 1 3 4 (4.12%)65 - 69 0 2 2 (2.06%)70 - 74 2 2 4 (4.12%)≥75 0 0 0

According to the previous studies, RA is one of the autoimmune diseases which are strongly associated with gender, race, and ethnic origin as internal risk factors and environmental exposures as external risk factors.4 The distribution of patients based on characteristics gender, occupation and ethnic origin, are presented on Figure 1.

Figure 1. Occupation Characteristics of Male Subjects

3

ResultThe number of samples obtained in this study was 97. Most of them were women (87%).

Table 1 shows the characteristics of RA patients by their group age. The division of this age group is done to see if the prevalence of RA is not influenced by age, according to the previousstudy’s results.3 Dominant age group diagnosed with RA is 45-49 years (17,53%).

Table 1. Age Group Characteristic in RA Patients

According to the previous studies, RA is one of the autoimmune diseases which arestrongly associated with gender, race, and ethnic origin as internal risk factors and environmental exposures as external risk factors.4 The distribution of patients based on characteristics gender, occupation and ethnic origin, are presented on Figure 1.

Figure 1. Occupation Characteristics of Male Subjects

Age Men(n = 13)

Women(n=84) Total, N(%)

15 – 19 0 2 2 (2.06%)20 – 24 1 4 5 (5.15%)25 – 29 1 4 5 (5.15%)30 - 34 3 7 10(10.31%)35 - 39 0 13 13(13.40%)40 - 44 0 13 13(13.40%)45 - 49 2 15 17(17.53%)50 - 54 2 9 11(11.34%)55 - 59 1 10 11(11.34%)60 - 54 1 3 4 (4.12%)65 - 69 0 2 2 (2.06%)70 - 74 2 2 4 (4.12%)≥75 0 0 0

61.53%15.38%

15.38%

7.69%

Men

Government/ private employee Entrepreneur Student Others

Figure 2. Occupation Characteristics of Female Subjects

4


RA was found commonly in women (84; 87%) than in men patients. Figure 2 shows female subjects in the study, mostly worked as a housewife (61 patients; 72.61%), male subjectsmostly worked as civil servants / private employees (8; 61.53%), and all subjects are mostlySundanese (82; 84.54%).

Figures 3 and 4 show the pattern of joint involvement in patients with RA in Rheumatology clinic of Dr. Hasan Sadikin General Hospital based on joint involvement at the time of diagnosis and overall course of the disease. The highest percentage of joint involvedwhen RA diagnosed in male patients was knee joint (53.84%) and in female patients was proximal interphalangeal joint (52.38%). The joint involvement found in overall course of RA in male subjects was the knees joint (84.61%) and in female patients was the wrist joint (91.67%).Without gender classification, the joint that showed the highest percentage at the time of diagnosis was the proximal interphalanges (49.50%), and the findings during the whole course of RA is wrist joint (90.72%).

Figure 3. Pattern of Joint Involvement at the Time of Diagnosis

15.47%

4.76%

5.95%

72.61%

7.69%

Women

Government/ private employee EntrepreuneurStudent Housewife

0.00%

10.00%

20.00%

30.00%

40.00%

50.00%

60.00%

Men

Women

Total

RA was found commonly in women (84; 87%) than in men patients. Figure 2 shows female subjects in the study, mostly worked as a housewife (61 patients; 72.61%), male subjects mostly worked as civil servants / private employees (8; 61.53%), and all subjects are mostly Sundanese (82; 84.54%).

Figures 3 and 4 show the pattern of joint involvement in patients with RA in Rheumatology clinic of Dr. Hasan Sadikin General Hospital based on joint involvement at the time of diagnosis and overall course of the disease. The highest percentage of joint involved when RA diagnosed in male patients was knee joint (53.84%) and in female patients was proximal interphalangeal joint (52.38%). The joint involvement found in overall course of RA in male subjects was the knees joint (84.61%) and in female patients was the wrist joint (91.67%). Without gender classification, the joint that showed the highest percentage at the time of diagnosis was the proximal interphalanges (49.50%), and the findings during the whole course of RA is wrist joint (90.72%).


4


RA was found commonly in women (84; 87%) than in men patients. Figure 2 shows female subjects in the study, mostly worked as a housewife (61 patients; 72.61%), male subjectsmostly worked as civil servants / private employees (8; 61.53%), and all subjects are mostlySundanese (82; 84.54%).

Figures 3 and 4 show the pattern of joint involvement in patients with RA in Rheumatology clinic of Dr. Hasan Sadikin General Hospital based on joint involvement at the time of diagnosis and overall course of the disease. The highest percentage of joint involvedwhen RA diagnosed in male patients was knee joint (53.84%) and in female patients was proximal interphalangeal joint (52.38%). The joint involvement found in overall course of RA in male subjects was the knees joint (84.61%) and in female patients was the wrist joint (91.67%).Without gender classification, the joint that showed the highest percentage at the time of diagnosis was the proximal interphalanges (49.50%), and the findings during the whole course of RA is wrist joint (90.72%).


15.47%

4.76%

5.95%

72.61%

7.69%

Women

Government/ private employee EntrepreuneurStudent Housewife

0.00%

10.00%

20.00%

30.00%

40.00%

50.00%

60.00%

Men

Women

Total

Original Article


Figure 4. Pattern of Joint Involvement during Overall Course of RA

5

Figure 4. Pattern of Joint Involvement during Overall Course of RA

The results of the study conducted by Monti et al, suggested a correlation between the patient's response to therapy and duration of disease.6 In this study, there were differences in the number of joint manifestations of patients based on the duration of treatment and disease of each patient group. Most patient had received therapy for > 3 months group (55.4%); and had suffered from RA for <5 years group (90.72%). Of the 88 patients who suffered from RA <5 years, 58 patients (65.91%) had ≥ 5 joints involvement, but also had lower percentage than patients suffered from RA for > 5 years (77.78%). Of 83 patients undergone therapy for > 3 months, 53(63.86%) patients had ≥ 5 joints involvement.

Table 2. Duration of Therapy and Illness of The SubjectNumber of joints

involvementDuration of Therapy Duration of Illness

< 3 months > 3 months < 5 years >5 years1 joint 0 (0%) 0 (0%) 0 (0%) 0 (0%)

2 – 4 joints 6 (42.86%) 30 (36.14%) 30 (34.09%) 2 (22.22%)≥ 5 joints 8 (57.14%) 53 (63.86%) 58 (65.91%) 7 (77.78%)

Total 14 (14.43%) 83 (85.57%) 88 (90.72%) 9 (9.28%)

Discussion

This study showed that patients with RA were mostly women. These results are similarwith the joint researches conducted by WHO in several countries included medium-to-lowincome countries group which showed the prevalence of female RA patients was five times higher than male patients.3 It suggested to be related with the important role of estrogen in activating inflammatory response within the pathogenesis of RA.12

0.00%10.00%20.00%30.00%40.00%50.00%60.00%70.00%80.00%90.00%

100.00%

Men

Women

Total

The results of the study conducted by Monti et al, suggested a correlation between the patient’s response to therapy and duration of disease.6 In this study, there were differences in the number of joint manifestations of patients based on the duration of treatment and disease of each patient group. Most patient had received therapy for > 3 months group (55.4%); and had suffered from RA for <5 years group (90.72%). Of the 88 patients who suffered from RA <5 years, 58 patients (65.91%) had ≥ 5 joints involvement, but also had lower percentage than patients suffered from RA for > 5 years (77.78%). Of 83 patients undergone therapy for > 3 months, 53 (63.86%) patients had ≥ 5 joints involvement.

Table 2. Duration of Therapy and Illness of The Subject

Number of joints

involvement

Duration of Therapy Duration of Illness

< 3 months > 3 months < 5 years >5 years

1 joint 0 (0%) 0 (0%) 0 (0%) 0 (0%)

2 – 4 joints 6 (42.86%) 30 (36.14%) 30 (34.09%) 2 (22.22%)

≥ 5 joints 8 (57.14%) 53 (63.86%) 58 (65.91%) 7 (77.78%)

Total 14 (14.43%) 83 (85.57%) 88 (90.72%) 9 (9.28%)

DiscussionThis study showed that patients with RA were mostly women. These results are similar with the joint researches conducted by WHO in several countries included medium-to-low income countries group which showed the prevalence of female RA patients was five times higher than male patients.3 It suggested to be related with the important role of estrogen in activating inflammatory response within the pathogenesis of RA.12

Previous research showed the influence of gender on RA.3 Our results also supported that statement. We found the differences in the joint involvements of each gender. Unfortunately, there have not been any researches explained the role of gender on the difference joints manifestations. Moreover, there have not been any studies discussed the type of job that can be a risk factor for RA, so there is no explanation of the correlation between joint manifestations in RA with the type of occupations of each gender.

According to Iskandar A, et al., the most frequent joint appears in RA of both genders was metacarpofalangeal

(85%).11 This is not consistent with the results of this study, based on the data obtained, regardless the gender of the patient, the joint that showed the highest percentage of occurrence for RA is wrist joint (90.72%), while for the highest percentage occurrence at the time of diagnosis is the proximal interphalangeal joint (52.38%).

More than 5 joints involvement were documented on patients with >3 months duration of therapy, this result was differed from the results of study conducted by Nell et al which showed a lower joint involvement after > 3 month therapy.10 Research conducted by Demourelle et al also found the maximum results of therapy were shown after the therapy at first 3 months of therapy and persisted throughout 3 years of followup.8 The difference results found in this study may be due to the differences of patient adherence to the treatment. Patients who tend to be less alert to the conditions at the onset of RA may have delay the diagnosis, therefore affect the progression of this disease, so patients will suffer the more severe condition, as described in Nagano et al.9

RA is a progressive disease if not treated immediately.12

Schneider, et al. mentioned that duration of illness affects the number of joints involved in the overall course of the disease.3 The finding was accordance with the our data that most patients who suffered >5 years had ≥ 5 joints involvement.

We realized some limitations of this study. Our study cannot determine the correlation of cause and effects in the course of disease. The gender and occupation of RA patients might be related to their joints involvement, however further investigation with proper study design is needed to proved that.

ConclusionThe involvement of joints in patients with rheumatoid arthritis is different and depends on several aspects. Overall patients had PIP joint involvement at the time being diagnosed and wrist joint involvement in overall course of RA. Based on the gender, most male patients had knee joint involvement at the time being diagnosed as RA and at overall course of RA. While RA female patients mostly suffered PIP joint involvement at the time being diagnosed and wrist joint involvement at overall course of RA. Most patients have ≥ 5 joints involvement even they had been treated for >3 months suggested the low compliance of patients. Further studies investigated the correlation of each study parameter is needed.

References1. Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO, et

al. 2010 Rheumatoid Arthritis Classification Criteria. Arthritis Rheum. 2010;62(9):2569–81.

2. Kaneko Y, Takeuchi T. A Paradigm Shift in Rheumatoid Arthritis over the Past Decade. Intern Med. 2014;53:1895–903.

3. Papana A, Meng SJ, Wei YX, Wang W, Ruth M, Page C, et al. Prevalence of rheumatoid arthritis in low – and middle – income countries : A. J Glob Health. 2015;5(1):1–10.

Original Article


4. A. Gibofsky, MD, JD, FACP F. Overview of Epidemiology, Pathophysiology, and Diagnosis of Rheumatoid Arthritis. Am J Manag Care. 2010;18(13):295–302.

5. Kay J, Upchurch KS. ACR / EULAR 2010 rheumatoid arthritis classification criteria. Rheumatology. 2012;51:5–9.

6. Monti S, Montecucco C, Bugatti S, Caporali R. Rheumatoid arthritis treatment : the earlier the better to prevent joint damage. Rheum Musculoskelet Dis. 2015;1(1):1–5.

7. Heidari B. Rheumatoid Arthritis : Early diagnosis and treatment outcomes. Casp J Intern Med. 2011;2(1):161–70.

8. Demoruelle MK, Deane KD. Treatment Strategies in Early Rheumatoid Arthritis and Prevention of Rheumatoid Arthritis. Curr Rheumatol Rep. 2013;14(5):472–80.

9. Nagano J, Sudo N, Nagaoka S, Yukioka M, Kondo M. Life events, emotional responsiveness, and the functional prognosis of patients with rheumatoid arthritis. Biopsychosoc Med. 2015;9(15):1–7.

10. Nell VP, Machold KP, Eberl G, Stamm TA, Uffmann M, Smolen JS. Benefit of very early referral and very early therapy with disease-modifying anti-rheumatic drugs in patients with early rheumatoid arthritis. Rheumatology (Oxford). 2004; 43:906–14.

11. Iskandar A, Wachjudi RG. Diagnosis dan Prinsip Penatalaksanaan Artritis Reumatoid: Himpunan Makalah Lengkap Reumatologi Klinik Bandung. Bandung: Pusat Informasi Ilmiah, Departemen Ilmu Penyakit Dalam, Fakultas Kedokteran UNPAD, RS Dr Hasan Sadikin; 2014: p.309-40

12. Shah A, William E. Rheumatoid Arthritis. In: Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo J, editors. Harrison’s principles of internal medicine. 19th ed. New York: McGraw - Hill Education; 2015, p2136-49

Original Article


1 Department of Internal Medicine,2 Division of RheumatologyFaculty of Medicine Universitas Padjadjaran/ Hasan Sadikin General Hospital Bandung

Corespondence: Vincent, MDemail: vincent.lim.86@ gmail.com

Correlation Between Serum Procollagen Type 1 N-Terminal Propeptide Level With Modified Rodnan Skin Score In Systemic Sclerosis Patients.

Vincent1, Sumartini Dewi2 Rachmat Gunadi Wachjudi2

Clinic data revealed some alterations of disease patterns prior to JKN (Jaminan Kesehatan Nasional, National Health Insurance) enactment in 2014 compared to the period after the JKN enactment. Connective tissue diseases had the largest portion of diseases in 2013 and 2014 at Rheumatology Clinic, the number rose from 51.2% in 2013 to 63.5% in 2014.4,5 Systemic Sclerosis was the third most common disease in our Rheumatology Clinic, the number of the cases rose from 189 patients/year in 2013 to 196 patients/year in 2014. Numerous study reported that survival rate of the disease has not significantly been improved since the last 30 years. While the opposite result was reported by some other studies, such as Steen, et al study reported the increase of 10-year survival rate of systemic sclerosis from 53% in 1970s to 67% in 1990s;6 and Ehai, et al study revealed the improvement of the mortality rate of systemic sclerosis patients for the last 40 years.7,8

Modified Rodnan Skin Score (MRSS) is well correlated with the gold standard assessment, skin biopsy, for skin fibrosis in systemic sclerosis disease. However, performing MRSS assesment requires great skills. Moreover, even though it is well corelated with the gold standard, MRSS is not sensitive to detect the small skin alteration happened within the development of the disease.1,9 Therefore, some biologic markers are necessary used to assist clinicians to examine skin fibrosis because it is reported more objectively, quantitatively, and rapidly in detecting small skin lession in fibrosis skin .10

Procollagen Type-1 Terminal Propeptide (P1NP), degraded product from type-1 collagen synthesis, is one of the potential biological marker. Nevertheless, some studies which has investigated the association between skin fibrosis severity assessed by MRSS with the level of serum P1NP in systemic sclerosis patients, revealed inhomogenous results.11,12,13 Further, there is not any study examining association between concentration of serum P1NP of any disease progressivity, particularly skin fibrosis severity according to

AbstractIntroduction: Systemic Sclerosis (SSc) is a chronic autoimmune disease, characterized by vasculopathy, specific autoimmune, and fibrosis. Assesment of skin fibrosis by modified Rodnan Skin Score (mRSS) can not detect the minimal changes of skin fibrosis within less than 3 months. A biomarker is needed to assess the minimal changes of skin fibrosis progressivity with a more objective, quantitative, and rapid way. Procollagen type-1 N-Terminal Propeptide (P1NP), a degradation product of collagen type-1, may become a potential biomarker for skin fibrosis. This study aims to evaluate the correlation between skin fibrosis by mRSS with P1NP serum in systemic sclerosis.Methods: This was a cross-sectional study performed among systemic sclerosis patients at Rheumatology out-patient clinic, Dr.Hasan Sadikin Hospital Bandung, from May 2016 to July 2016. Skin fibrosis was measured by mRSS. P1NP level was determined by ELISA. Data were analyzed using Rank-Spearman Correlation.Result: There were thirty-seven subjects, with mean age 37 (SD ±7) years old. Most of subjects were fe-male (91.9%). Subjects consisted of 23 (62.2%) limited SSc and 14 (37.8%) diffuse SSc. Six subjects (16.2%) were DMARD naïve. We found median (range) P1NP serum was 43.85 (9.81-127.90) ng/dL, while the median of MRSS was 14 (3-36). There is a moderate correlation between MRSS and P1NP serum (r=0.443, p=0.003)Conclusion: There was a significant correlation between mRSS and P1NP serum in systemic sclerosis patient at Dr. Hasan Sadikin Hospital Bandung. Keywords: systemic sclerosis, P1NP, modified rodnan skin score.

IntroductionSystemic Sclerosis is an autoimmune disease involving many organs with complex pathophysiology and heterogenous clinical features. The exact etiology of systemic sclerosis remains unknown to this day. The disease severity and prognosis are varied among the patients, depending on the involvement of organs in the disease.1-3

Hasan Sadikin General Hospital Rheumatology

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MRSS, has ever been conducted in Indonesia. Therefore, the study is perform to seek any positive correlation between the P1NP level and skin fibrosis severity based on MRSS in systemic sclerosis patients. Hopefully P1NP will be able to be a biologic marker

MethodsSubjectSubject were chosen from Hasan Sadikin General Hosipital’s outpatient clinic and ward who came from may to July 2016 with consecutive random sampling methods. Samples included in this study with criteria: age between 18 to 50 years old4,14,15 and has been diagnosed as Systemic Sclerosis using ACR/EULAR 2013 criteria. Subject were excluded if they have some comorbidities, such as osteoporosis16, hepatic cirrhosis17, bone metastases malignancy disease18, post menopause woman19, and chronic kidney disease20

Subjects were screened for any one of those exclusion criteria: osteoporosis, hepatic cirrhosis, bone metastase, menopausal status, and chronic kidney disease. Osteoporosis were diagnosed if Bone Mineral Densitometry (BMD) T score < -2.5, diagnosed as osteoporosis in medical history, or using moderate dose steroid therapy (≥ 7,5 mg prednisone/day) for more than 3 months with T score <1.5. Hepatic Cirrhosis were diagnosed if there is clinical stigmata of chronic hepatic disease or diagnosed as cirrhosis in medical records. Bone metastasis were assesed by medical record history of malignancy and bone metastases. Menopause status reffered for this study is when mensturation cycle has been stop for 12 months or more. Chronic kidney disease reffered for this study is when estimated Glomerular Filtration Rate (eGFR) < 60 ml/min/1.73m2 counted using The Modification of Diet in Renal Disease (MDRD) or has been diagnosed as chronic kidney disease in medical records.

MRSS ExaminationMRSS examination were done by selected rheumatology consultant. All Hasan Sadikin General Hospital/Padjajaran University rheumatology consultants were included for “interobserver variability agreement” assesment. Physician who has good intraclass correlation coefficient result (>0.7) were selected to be the examinee for our study.

MRSS examination is used to classified skin fibrosis. Skin fibrosis were assesed in 17 area of the skin, each area will be scored from 0 to 3. Score ‘0’ means normal skin, ‘1’ means minimal skin thickening, ‘2’ means moderate skin thickening,’3’ means severe skin thickening where the skin has been fixated with the deeper tissue.

P1NP concentrationThe concentration of serum P1NP were assesed stimultaneously with MRSS examination. Using ELISA sandwich methods. The result were served in ng/mL.

Statistical AnalysisData were analyzed using SPSS version 17.0. Normality of

the quantitative data were test using Shapiro-Wilk test. We used two analysis methods, such as univariate and bivariate analysis methods. Pearson correlation test were used to assess any correlation in normal distribution data and Rank Spearman correlation test were used to assess any correlation in not normal distribution data.

ResultFrom May to July 2016, we found 40 patients fulfilled the inclusion criteria. Three of them were excluded due to osteoporosis which is found during the first assesment. Within thirty seven subjects, there were 14 subjects (37,8%) with diffuse systemic sclerosis and 23 subjects (62,2%) with limited systemic sclerosis. Six subjects (16.2%) were newly diagnosed systemic sclerosis patients who have never gotten methotrexate therapy. The median for disease course were 26 months, ranged from 6 months to 8 years.

Table 1. Subject CharacteristicsCharacteristics Result

Age (years) 37 ± 7 yearsFemale 34 (91,9%)Systemic Sclerosis Type

Limited, N(%) 23 (62,2%)Diffuse, N(%) 14 (37,8%)

Course of Disease (Month) 26 (6 - 96) monthMedication History, N(%)

Methotrexate 31 (83,8%)Steroids 27 (73,0%)Cyclophosphamide 1 (2,7%)CCB 31 (83,8%)Aspirins 29 (78,4%)

Clinical Features of ACR EULAR 2013, N(%) Finger Fibrosis 37 (100%)Finger Oedema 24 (64,9%)Finger Scar 26 (70,3%)Telangiectasia 13(35,1%)Salt and Pepper Appearance 21 (56,8%)Raynaud Phenomenon 33 (89,2%)

MRSS (score) 14 (3 - 31)

CCB: Calcium Channel Blocker

Subjects were diagnosed as sclerosis systemic prior to this study. Among the subjects, 31 subjects (83.8%) had been treated with methotrexate. Steroids were given to 27 (73.0%) subjects with equivalent dose less than 7.5 mg of prednisone a day (mean 5 mg of prednisone). One subject (2.7%) had undergone cyclophosphamide therapy due to lung involvement, while calcium channel blockers were given to 31 (89.2%) subject for treating Raynaud phenomenon.

Finger fibrosis was the most common manifestation, found in all subjects, followed by Raynaud phenomenon (33 subjects or 89.2% of total subjects), finger ulcers or scars (26 subjects or 70.3% of total subjects), finger oedema (24 subjects or 64.9% of total subjects), salt and pepper appearance (21 subjects or

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56.8% of total subjects), and telangiectasia (13 subjects or 35.1% of total subjects).

Table 2 explained the subjects’ laboratory features. All hematologic parameter averages were within normal limits. This examination was also conducted over the entire subjects for detecting any exclusion criteria, such as: hepatic cirrhosis, post-menopause, bone-metastasized malignancies, chronic kidney disease and osteoporosis.

Table 2. Laboratory Features

Characteristics (unit) ResultLaboratory featuresHb (g/dL) 12,9 ± 1,2Leukocytes (/mm3) 8,200 (4,490-19,400)Trombocytes (/mm3) 312,703 ± 91,743ESR (mm/h) 28 (6 - 87)SGOT (U/L) 17 (11 - 59)SGPT (U/L) 13 (5 - 39)Creatinine (mg/dL) 0,65±0,15 Proteinuria, n (%) 0 (0%) P1NP (ng/mL) 43,85(9,81-127,90)

Bivariate analysis was carried out to test the significancy

association of P1NP level and MRSS. The result of rank spearman correlation test was presented in table 3

Table 3. MRSS Bivariate Test Result of Serum P1NPVariable MRSS

R p-value

P1NP (ng/dL) 0,443 0,003*

NB: Rank spearman analysis was used for analysis, the resilf was significant if p <0.05

Bivariate test revealed a significant correlation between skin fibrosis severity assessed by MRSS and serum P1NP level (p<0.05) as shown in Table 3. The correlation was categorized as medium correlation according to Guilford criteria with r ranged from 0.40 to 0.70. The scattered diagram of Correlation Between MRSS and Serum P1NP is presented in Figure 1.

Figure 1 Scatter Diagram Revealing Correlation Between MRSS and Serum P1NP

DiscussionMean age of subjects involved in this study was 37 ±7 years old, explaining that the highest prevalence of systemic sclerosis onset was between third and fourth decade.21,22 The epidemiology of SSc in our studies is dissimilar with Denton, et al study which found the mean age of subjects 48.5 ±11 years old, but it is consistent with Pagalavan, et al study in Malaysia which found the mean age 38.8 years old. The wide difference between the two studies might be happened due to the different race of the subjects involved. The races difference will also contribute to the expression of autoantibody and other genetical factors that influence systemic sclerosis pathophysiology between Caucasians and Asians.23-25 Female constituted for 91.9% of subjects involved in this study. It is concordant with the fact that systemic sclerosis mostly affects women.21,26 A study was conducted by Low, et al. in Asia also revealed 86% of systemic sclerosis patients were women.27

All subjects in this study was diagnosed using first criteria, which was skin thickening at fingers of both hands that expanded proximally to metacarpophalangeal joints. That first criteria was fundamentally similar to major criteria on ACR 1980 which means the inclusion criteria of this study was similar to the two studies mentioned before. Raynaud phenomenon was found in 89.2% of this study’s subjects. The phenomenon is, in fact, common at the early stage of disease.26,28 Other clinical findings such as finger scars or ulcers (70.3% of the subjects) and telangiectasia (35.1% of the subjects) was considerably resemble to ones revealed by Low, et al., with Raynaud phenomenon, finger scars or ulcers, and telangiectasia were found in 80.5%, 70.5%, and 34.5% of the subjects, respectively.29

The median for MRSS in this study was 14, ranged between 3 to 36. There was a significant difference (p=0.005) between the result of MRSS in type diffuse and limited systemic sclerosis. As gold standard examination for assessing fibrosis severity, MRSS could be helpful in measuring the course of disease and skin fibrosis response to therapy. MRSS monitoring, based on disease development conducted in a longitudinal study, revealed the changing score after 3-6 month of therapy administration.30-32 The proximal parts of the body may return to normal during the therapy, except the part which suffered severe fibrosis or atrophy, frequently in the distal part of the finger.33

The median level of P1NP serum was 43.85 (9.8-127.90) ng/ml. Minier, et al. study showed nearly same result, 45.0 (34-65) ng/ml.34 The median level of P1NP serum in our study was higher than the median level of P1NP serum in non SSc patients which presented by Minier, et al study, 33.5 (28.3-44.5) ng/ml.34

Bivariate analysis of skin fibrosis assessed by MRSS yielded a significant correlation with the level of P1NP serum (r=0.443; p=0.003). The result was consider high if we compare it to the result revealed by Denton, et al. (r=0.37; p=0.027). However both studies show a significant correlation (p<0.05) between the two variables.

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Our study supported the fact that P1NP has a role on fibrosis process. P1NP is released to the circulation as a metabolite in collagen syntesis process, a fundamental process of fibrosis.21,35,36 A study conducted by Minier, et al. disclosed a significant correlation between MRSS and P1NP compared to other biologic markers.37 A study carried out by Denton, et al. showed a consistent result with the previous two studies, that P1NP does not only have positive correlation with MRSS (r=037, p=0.027), but also can be used as marker in monitoring the response of therapy.11 P1NP was stated as one of the excellent biologic marker for fibrosis process according to Panticos, et al. They revealed the presence of excessive deposition of type 1 collagen in skin biopsy of systemic sclerosis patients.38

We realized some limitation of our study that could influence the results of our study. First, the limitation number of the samples due to low prevalence of systemic sclerosis in our center. A multicenter study is needed to gather a higher number of subjects. Second, the method used in this study could not be used to describe the real picture regarding to the correlation between P1NP and MRSS.

ConclusionThere was a medium and significant correlation between skin fibrosis severity assessed by MRSS and the concentration of P1NP serum in systemic sclerosis patients. Further study assessing the correlation between skin fibrosis severity based on MRSS and serum P1NP concentration between newly diagnosed patients who never got methotrexate and steroid using a cohort method are needed in order to reveal the correlation of P1NP level in monitoring the therapy response and prove the role of P1NP as a potential marker for SSc’s disease activity.

The measurement of P1NP serum could be considered as a routine examination that would assist clinicians to assess skin fibrosis severity in systemic sclerosis patients.

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Most Frequent Musculoskeletal Manifestation of Systemic Lupus Erythematosus Patients inDr. Hasan Sadikin General Hospital BandungRahadian Nugi Sutrisno1, Andri Reza Rahmadi2, Nita Novita3, Laniyati Hamijoyo2

1 Faculty of Medicine, Universitas Padjadjaran2 Division of Rheumatology, Department of Internal Medicine, Universitas Padjadjaran/Hasan Sadikin General Hospital3 Department of Forensic and Legal Medicine, Universitas Padjadjaran/Hasan Sadikin General Hospital

Corresponding author:Rahadian Nugi Sutrisno, MDEmail: [email protected]

America, the incidence of SLE was reported around 2 to 8 cases per 100.000 people per year. In USA, prevalence of SLE was reported in 51 cases per 100.000 people. In 2010, there were 291 SLE patients registered at Rheumatology Outpatient Department dr. Hasan Sadikin General Hospital Bandung. It was accounted for about 10,5% of all patients registered at Rheumatology Outpatient Clinic. The increase of SLE incidence in the last 40 years is implicated due to the invention of SLE diagnostic tools.1 Prevalence of SLE is six to ten fold higher in female than male. The prevalence was 128,7 cases per 100.000 people and incidence was 9,3 cases per 100.000 people. SLE prevalence was 2,3 fold higher in black people.2

Clinical manifestation of SLE involves joints, skin, kidney, lung, heart, central nervous system, and immune system. The wide clinical spectrum of SLE causes the difficulties in establishing the diagnosis. Further, patient’s chief complaints are seldom specific. If the SLE patients get delayed therapy, disease activity may harm the patients.3

According to 10 years - research study conducted on 1.000 SLE patients in seven countries in Europe, the proper of most common SLE manifestation were athritis (48,1%), malar rash (31,1%), nephropathy (27,9%), and photosensitivity (22,9%).4 About 5 to 10 percent of SLE patient showed muscle enzymes elevation, include creatinine kinase, aminotransferase, aldolase, and lactate dehydrogenase.5 This explained that musculoskeletal manifestation in SLE patients had high occurrance.

The most prevalent musculoskeletal manifestation of SLE was arthritis, that marked by joint pain, effusion, and swollen joint of hand, wrist, and knee.5 Arthritis can significantly decrease patient’s life quality. It make some disablities in daily activity, includes walking, climbing stairs, kneeling, and gripping fingers. The conditions may affect the psychosocial life of SLE patients.6,7 According to the research done at El Menia University Hospital, Egypt, avascular bone necrosis was occured in 15% of SLE patients.8 Several studies performed in Brazil reported, beside arthritis, 2.8% of SLE

AbstractBackground: Systemic Lupus Erythematosus (SLE) is an autoimmune disease with wide range of clinical symptoms. The patients frequently complain musculoskeletal involvement during the active state of the disease. Musculoskeletal manifestation in SLE patients is an important sign in making early diagnosis and monitoring treatment response. This study aims to determine the presentation of musculoskeletal involvement of SLE patients in Dr. Hasan Sadikin General Hospital Bandung.Methods: a descriptive cross-sectional quantitative study done by interviewing SLE patients concerning musculoskeletal manifestation as the primary data and tracking their medical record as the secondary data. Study was conducted between September to November 2016 in Rheumatology Clinic Dr. Hasan Sadikin General Hospital Bandung. Result: Ninety-seven SLE patients, 91 females (93,81%) and 6 males (6,19%), were enrolled in this study with mean age 35.12 (±10.91) years. The three highest proportions of muskuloskeltal manifestations were arthritis of the knee (84,5%), myalgia of upper back (40,2%), and muscle weakness (15,5%). We did not find any Jaccoud’s Arthropathy (JA) and tendinitis manifestation. Osteoporosis were occured in 4 patients (4,12%), whereas gout arthritis, spondytlitis, osteoarthritis, rotator cuff syndrome, and rhupus were only occured in one patient (1,03%), respectively. Conclusion: The common musculoskeletal manifestation in SLE patients were arthritis of knee, myalgia of upper back, and muscle weakness. Only small portion of patients suffered from osteoporosis, gout arthritis, spondytlitis, osteoarthritis, rotator cuff syndrome, and rhupus. Keyword: musculoskeletal manifestation, musculoskletal involment, SLE

BackgroundSystemic Lupus Erythematosus (SLE) is an autoimmune disease that has wide clinical spectrum and organs involvement. The prevalence and incidence of SLE have been increasing in recent year. In Europe, North America, and South

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patients had Jaccoud’s Arthropathy (JA) which marked by fingers and toes deformities,9 and about 95 percent of SLE patients complained general myalgia.10

Despite the high involvement of musculoskeletal, the data of musculoskeletal manifestations in SLE patients in Indonesia has not been documented. This study was designed to identify the musculoskeletal involvements of SLE patients at Dr. Hasan Sadikin General Hospital Bandung, Indonesia.

Methods We used a descriptive cross-sectional study method. The primary data were obtained through interview with SLE patients about symptoms of the musculoskeletal system and the secondary data were obtained from medical records of patients. The study was conducted in Rheumatology Clinic Dr. Hasan Sadikin General Hospital Bandung from September-November 2016. The minimum sample required in our study were 97 patients based on the formula for categorical and descriptive sample measurements that were taken consecutively. Samples included in the study were patients who have been diagnosed with SLE using ACR revised criteria, aged ≥14 years, and registered as an outpatient. Patients whose medical records with incomplete identity and clinical condition reports were excluded in this study. Ethical clearance for this study has been received from the Commission on Health Research Ethics Faculty of Medicine, University of Padjadjaran with number 540 / UN6.C1.3.2 / KEPK / PN / 2016 and licence for this study has been received from Direktorat Jenderal Pelayanan Kesehatan Dr. Hasan Sadikin General Hospital.

All subjects got the explanation about the study and signed a consent form. Patient’s demographic data (name, age, date of birth, occupation, address, and telephone number), duration of lupus, and the location of first diagnosis of SLE were obtained through interview. The interview results were recorded on a case report form (CRF). History of hypertension, trauma, infection, anemia, BMI, dyslipidemia, and definitive diagnosis of the musculoskeletal system were obtained through medical records of patients.

Data were collected and analyzed using Microsoft Excel 2013. Standard deviation for numerical data and percentages for categorical data were calculated

ResultThere were 100 SLE patients met the inclusion criteria. One patient was excluded due to disagreement to join the study, two patients were excluded due to incomplete interview. Ninety-seven patients included as subjects in this study.

Mean age of subjects was 35,12 years (SD 10,103). There were 91 (93,81%) females. The most prevalent group age was between 30-39 years old (34,02%). Among all samples, 63 patients (64,95%) were housewife. Most patients (46,39%) had been diagnosed as SLE for more than 5 years. There were 70 patients (72,16%) lived in Bandung. Demographic data of SLE patients were presented in Table 1.

Table 1. Demographic Data of SLE Patients

Characteristic Data (N=97)

Mean Age (years)Group age (N,%)

≤15 years16 – 19 years20 – 29 years30 – 39 years40 – 49 years50 – 59 years60 – 69 years

Gender (N,%)MaleFemale

BMI (N,%)UnderweightNormalOverweightObese

Occupation (N,%)HousewifeEmployeeEnterpreneurStudentTeacherHealth WorkerHousemaidUnemployment

SLE duration (N,%) <1 year1 – 3 years3 – 5 years>5 yearsNot Identified

Residency (N,%) BandungNon-Bandung

35.12 ± 10.103

1 (1.03%)2 (2.06%)

29 (29.89%)33 (34.02%)24 (24.74%)7 (7.21%)1 (1.03%)

6 ( 6.19% )91 (93.81% )

9 (9.27%)73 (75.25%)11 (11.34%)4 (4.12%)

63 (64.95%)15 (15.46%)7 (7.22%)5 (5.15%)4 (4.12%)1 (1.03%)1 (1.03%)1 (1.03% )

17 (17.52%)16 (16.49%)17 (17.52%)45 (46.39%)2 (2.06%)

70 (72.16%)27 (27.83%)

According to the medical history which is presented in Table 2, 12 patients (12.37%) have hypertension, 73 patients (75.25%) had normal BMI, and four patients were obese. The most frequent of infectious disease from 2015 to 2016 was acute respiratory syndrome accounted for 11 patients (11.34%).

Table 2. Medical History of SLE patients (N=97) Medical History Results

Hypertension (N,%)ObesityTraumaInfectious Disease periode 2015 – 2016 (N,%)

Acute Respiratory SyndromePeriodontitisAsymptomatic BacteriuriaPulpitisDental CariesTuberculosisTinea Corporis GingivitisUrinary Tract InfectionHerpes Zooster

12 (12.37%)4 (4.12%)1 (1.03%)

11 (11.34%)8 (8.24%)8 (8.24%)5 (5.15%)5 (5.15%)4 (4.12%)4 (4.12%)4 (4.12%)3 (3.09%)3 (3.09%)

Original Article


Medical History ResultsGastroenteritis Bronchitis PneumoniaTyphoid FeverCandidiasisImpetigo

HypercholesterolemiaAnemia

3 (3.09%)3 (3.09%)2 (2.06%)1 (1.03%)1 (1.03%)1 (1.03%)6 (6.18%)

23 (23.71%)

Among all samples, 96 patients had musculoskeletal involvement during disease activity and the manifestation were varied. There were 82 patients (84.5%) had knee arthritis, 64 patients (66%) had right fingers arthritis, and 61 patients (62,9%) had left fingers arthritis. Presentation of arthritis in SLE patients are showed in Figure 1.

Figure 1. Arthritis in SLE patients (N=97)

There were 39 (40,2%) patients had myalgia in upper back, 37 (38,1%) patients had myalgia in neck, and 31 (32%) patients had myalgia in lower back. Myalgia manifestation of SLE patients are presented in Figure 2.

In this study, Jaccoud’s Arthropathy and tendinitis were not found. Other musculoskeletal manifestation are presented in Figure 3.

Figure 2. Myalgia in SLE Patients

5





Figure 3. Other Musculoskeletal Manifestation in SLE Patients

9.30% 10.20%

32% 84.50%

62.90% 66%

38.10% 38.10%

51.50% 39.20%

0.00% 10.00% 20.00% 30.00% 40.00% 50.00% 60.00% 70.00% 80.00% 90.00%

Left ToesRight Toes

AnkleKnee

Left FingersRight Fingers

Left WristRight Wrist

ElbowShoulder

16.50%

26.90%

32%

40.20%

7.20%

25.80%

38.10%

0.00% 10.00% 20.00% 30.00% 40.00% 50.00%

Lower Leg

Thigh

Lower Back

Upper Back

Forearm

Arm

Neck

1.03% 4.12%

1.03% 1.03% 1.03% 1.03% 0% 0%

15.50%

0.00% 5.00% 10.00% 15.00% 20.00%

RhupusOsteoporosis

GoutOsteoarthritis

SpondilitisRotator Cuff Syndrome

TendinitisJaccoud's Arthropathy

Muscle Weakness


5






9.30% 10.20%

32% 84.50%

62.90% 66%

38.10% 38.10%

51.50% 39.20%

0.00% 10.00% 20.00% 30.00% 40.00% 50.00% 60.00% 70.00% 80.00% 90.00%

Left ToesRight Toes

AnkleKnee



ElbowShoulder

16.50%

26.90%

32%

40.20%

7.20%

25.80%

38.10%

0.00% 10.00% 20.00% 30.00% 40.00% 50.00%

Lower Leg

Thigh

Lower Back

Upper Back

Forearm

Arm

Neck

1.03% 4.12%

1.03% 1.03% 1.03% 1.03% 0% 0%

15.50%

0.00% 5.00% 10.00% 15.00% 20.00%

RhupusOsteoporosis

GoutOsteoarthritis



Muscle Weakness

DiscussionIn this study, demographic data showed that female’s prevalence was higher than male’s, this is consistent with study done by Julia F. Simard et al., stated the prevalence of SLE in Sweden on 2010, were 144 in females per 100.000 SLE cases a year and only 25 in males per 100.000 SLE cases;11 Also accordance with the epidemiology study of SLE patients in America which is six fold higher in females than males.12 It is suggested due to higher leptin level found in females than in males. Leptin is known could induce autoantibody and inhibit immune regulation.13,14

SLE was more frequently found in patients ranged from 30 to 39 years old. This condition is caused by the higher level of esterogen in reproductive age. Estrogen could cause disregulation of immune system. Therefore, SLE is nine fold more frequent in reproductive-aged females than in males with the same age.15

Infection in SLE was likely caused by the immunosuppressant drugs used for controlling disease activity. Infections may induce the flare in SLE. This is caused by molecular mimicry of immune system stimulates autoimmunity by cross-reactive process of immune system and self-antigen. Infection of Herpes virus, Retrovirus, and RNA virus could induce this reaction. Furthermore, infection caused by Candida albicans, Staphylococcus aureus, Salmonella, and Escherichia coli are more frequent in SLE and cause flare.16 In this study, etiology of infectious diseases are not listed in medical record so the comparison of infectious agents could not be presented.

In our study, we found 82 patients (84,5%) had knee arthritis, 64 patients (66%) had arthritis of right fingers, and 61 patients (62,9%) had arthritis of left fingers. Arthritis may occur in almost all joints of SLE patients. This finding is similar with Smith PP, et al. study17, which stated that in SLE, arthritis could manifest in all joints with knee involvement was the highest proportion. This is nearly similar to article written by Manole Cajacaru et al., that stated arthritis in SLE frequently affect toes, wrist, and knee.18 High level of cytokine is correlated with SLE disease activity level and arthritis manifestation. Cytokine induction resulted from

5






9.30% 10.20%

32% 84.50%

62.90% 66%

38.10% 38.10%

51.50% 39.20%

0.00% 10.00% 20.00% 30.00% 40.00% 50.00% 60.00% 70.00% 80.00% 90.00%

Left ToesRight Toes

AnkleKnee



ElbowShoulder

16.50%

26.90%

32%

40.20%

7.20%

25.80%

38.10%

0.00% 10.00% 20.00% 30.00% 40.00% 50.00%

Lower Leg

Thigh

Lower Back

Upper Back

Forearm

Arm

Neck

1.03% 4.12%

1.03% 1.03% 1.03% 1.03% 0% 0%

15.50%

0.00% 5.00% 10.00% 15.00% 20.00%

RhupusOsteoporosis

GoutOsteoarthritis



Muscle Weakness

Original Article


the deposition of antigen-antibody complex may activate complement system in high filtration area, such as joints and kidneys. 5,19

Myalgia of upper back occured in 40.2% SLE patients, myalgia of neck occured in 38.1% patients, and myalgia of lower back occured in 32% patients. This result concordants with study conducted by A Zoma, which found myalgia in 40-80% of SLE patients during flare state.20 Muscle ache in SLE is related to the activation of complement system by antigen-antibody complex deposition which is similar to patophysiology of arthritis. This complement activation ultimately induces inflammation in muscle tissue.5

Jesscia L, et al. reported myositis were found in 55 SLE patients aged 9 – 21 years old in Southeast America, 31% of 55 myositis patients had proximal muscle weakness and muscle enzyme elevation, such as creatinine kinase, AST, aldolase, and LDH.21 The report is dissimilar with our study result. We only found 15,5% of SLE patients complained muscle weakness. The differences were possibly occured due to the fewer of total sample used in previous study than in our study and the difference of sampling technique used. In the other hand, Joseph Font, et al., study found lower rate of muscle weakness in SLE patients, which were found only in 7% of 600 SLE patients.22 These distinct results are probably due to total samples used in Joseph F,et al study is higher than in our study despite the same level of disease activity.

There were not any Jaccoud’s Arthropathy (JA) cases found in this study. This is inconsistent with previous study done by Thelma L Skare et al., who found 6,17% JA in SLE patients.23 The dissimilarity is probably caused by the difference characteristic of study sample and the amount of samples used between the studies. However, we had same level disease activity among the samples joined in the research. Tendinitis, as a cause of JA, was also not found in our study. This is contradicted with previous study by T.Ogura et al., who concluded that tendinitis was more frequent in SLE than Rheumatoid Arthritis.24 This difference may occur due to the lack of data in medical record and no subjective data regarding tendinitis was obtained.

Osteoporosis were found in 4 (4,12%) SLE patients. The result is consistent with review-article conducted by García-Carrasco M, et a.l that found osteoporosis in 4.0-48.8% SLE patients.25 Osteoporosis in SLE is related to low osteocalcin level, the habits to avoid UV light may influence vitamin-D level. Furthermore, the adverse effect of corticosteroid used for long period may also play roles.25 Our study found only one SLE patient with spondilitis. This conclusion is similar to literature review written by Figen T, et al. that conclude spondilitis as a rare condition among SLE patients. 26

Study done by Tani C. et al27 found 10 (9,7%) of 103 SLE patients with RA, or Rhupus, at Rheumatology Unit of Pisa University Italy. This percentage was slightly higher than our study (1,03%). Despite the same sampling technique, the length of period and amount of sample used in Tani C, et al was wider than our study.

The limitation of the study is the comparison among variables could not be done due to lack of article discusses the same topic, especially in Indonesia. Researcher interpretation to musculoskeletal symptoms could cause bias.

ConclusionsThe most common musculoskeletal manifestations in SLE patients were knee arthritis and myalgia of the upper back muscles. Patients with symptoms of muscle weakness were low compared to other studies. JA manifestation and tendinitis were not found in this study. Osteoporosis was the most common other musculoskeletal manifestation compared to spondylitis, rhupus, osteoarthritis, rotator cuff syndrome, and gout.

Further studies should be conducted on a multi-characteristic of populations in Indonesia with a cohort study design so that the clinical pictures of patients with SLE are more accurate. Longer period of the study is needed to include more subjects.

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pathogenesis and clinical features. Eular On-line Course Rheum Dis. 2012;(1909):476–505.

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4. Cervera R, Khamashta MA, Font J, Sebastiani GD, Gil A, Lavilla P, et al. Morbidity and mortality in systemic lupus erythematosus during a 10-Year period a comparison of early and late manifestations in a cohort of 1.000 patients. Mortality. 2003;82(5): 299–308

5. Navara SV, Torralba TP. The musculoskeletal system and bone metabolism. In : Dubois’ lupus erythematosus and related syndromes, 8th ed. Wallace Daniel J, Hanh Bevra H, editors. Philadelphia: Elsevier Saunders;2013: 333-40

6. Beckerman N, Auerbach C, Blanco Irene. Psychosocial dimension of SLE: implication for the health team. J Multidiscip Healthc. 2011;4:63-72

7. Backman C. Arthritis and pain, psychosocial aspect in the management of arthritis pain. Arthritis Res Ther. 2006;8(6):221.

8. Ghaleb RM, Omar GM, Ibrahim MA. Avascular necrosis of bone in systemic lupus erythematosus. Egypt Rheumatol. 2011;33(1):27–33.

9. Ball EMA, Bell AL. Lupus arthritis-do we have a clinically useful classification?. Rheumatology. 2012;51(5):771–9.

10. Lam NVU, Ghetu M V, Bieniek ML, Luke S. Systemic lupus erythematosus: primary care approach to diagnosis and management. Am Fam Physician. 2016;94(4):284–94.

11. Simard JF, Sjöwall C, Rönnblom L, Jönsen A. Systemic lupus erythematosus prevalence in Sweden in 2010 : what do national registers say ? Arthritis Care Res. 2014;66(11):1710–17.

12. Feldman CH, Hiraki LT, Liu J, Fischer MA, Solomon DH, Winkelmayer WC, et al. Epidemiology and sociodemographics of systemic lupus erythematosus and Lupus nephritis among US adults with medicaid coverage. Arthritis and Rheumatism. 2013;65(3):753–63.

13. Lourenço E V, Liu A, Matarese G, La A. Leptin promotes systemic lupus erythematosus by increasing autoantibody production and inhibiting immune regulation. Proc Natl Acad Sci USA. 2016;113(38):10:637-42.

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14. Wahrenberg H, Hruska K, Reynisdottir S, Arner P, Hellstro L. Mechanisms behind gender differences in circulating leptin levels. J Intern Med. 2000;247(4):457–62.

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16 Perl A, Francis L. Infection in systemic lupus erythematosus: friend or foe. Int J Clin Rheumatol. 2010;5(1):59-74

17. Smith PP, Gordon C. Autoimmunity reviews systemic lupus erythematosus : clinical presentations. Autoimmun Rev. 2010;10(1):43–5.

18. Hospital C, Sciences B. Manifestations of Systemic Lupus Erythematosus. Maedica. 2011;6(4):330-36.

19. Ball EMA, Gibson DS, Bell AL. Plasma IL-6 levels correlate with clinical and ultrasound measures of arthritis in patients with systemic lupus erythematosus. Lupus. 2014;23(1):46-56.

20. Zoma A. Musculoskeletal involvement in systemic lupus erythematosus. Lupus. 2004;13(11):851–3.

21. Record JL, Beukelman T, Cron RQ. High prevalence of myositis in a southeastern United States pediatric systemic lupus erythematosus cohort. Pediatr Rheumatol Online J. 2011;9:201–6.

22. Font J, Cervera R, Ramos-casals M, Garcı M, Herrero C, Olmo J, et al. Clusters of clinical and immunologic features in systemic lupus erythematosus: analysis of 600 patients from a single center. Semin Athritis Rheum. 2004;33(4):217–30.

23. Skare TL, Godoi Ade L, Ferreria Vo. Jaccoud arthropathy in systemic lupus erythematosus : clinical and serological findings. Rev Assoc Med Bras 2012;58(4):489–92.

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25. García-carrasco M, Mendoza-pinto C, Escárcega RO, Jiménez-hernández M, Etchegaray I, Pt M, et al. Osteoporosis in patients with systemic lupus erythematosus. Isr Med Assoc J .2009;11(8):486–91.

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Original Article


Neuropsychiatric Manifestation Screening among Systemic Lupus Erythematosus Patients inHasan Sadikin General Hospital Bandung

Septian Dwi Putra1, Mulya Nurmansyah Ardisasmita2, Laniyati Hamijoyo3

1 Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia2 Department of Public Health, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia 3 Department of Internal Medicine, Faculty of Medicine, Universitas Padjadjaran/Hasan Sadikin General Hospital, Bandung, Indonesia

Corespondence:Septian Dwi Putra, MDFaculty of Medicine, Universitas Padjadjaran, Email: [email protected]

Involvement of organ systems of lupus includes musculoskeletal, hematologic, mucocutaneus, neurologic, cardiopulmonary, renal, and ocular organ systems. One of the most significant manifestation is neurologic symptoms, with or without psychiatric symptoms, widely known as Neuropsychiatric Systemic Lupus Erythematosus (NPSLE).1,5 According to American College of Rheumatology, NPLSE was classified based on central and peripheral nervous manifestation onto 19 case definitions.5 NPSLE is found on 12.2%-94.7% patients prior to the diagnosis, during the diagnosis, following the diagnosis, or even during undetected or quiescent period of disease.4

NPSLE is quite burdensome in terms of quality of life, psychological comorbidity, and even mortality. Lower life quality were found in SLE patients who have NPSLE, includes any neurological, psychological-emotional, or cognitive dysfunction, rather than SLE patients without NPSLE. Besides life quality, the presence of psychological disturbance. like depression or anxiety, were higher among NPSLE patients.6 Mortality rate was also worrisome, as NPSLE patients may have 10-fold higher mortality rate than other SLE patients.7 Further, NPSLE patients also have higher risk of having neurologic complications in the future.8

Despite the alarming burden of NPSLE, diagnosing NPSLE among SLE patients is quite challenging for physician. Such diagnosis should be made by the combination of immunology, neurology, and psychiatric examination.8,9 Fortunately, despite the complex assesment and burden of NPSLE, an adequate treatment can prevent the progression of disease.8,10 Therefore, it is important to encourage physicians in recognizing NPSLE in daily clinical practice.6–10

In Indonesia, especially in Department of Internal Medicine, Hasan Sadikin General Hospital, data regarding the distribution of neuropsychiatric manifestation among SLE patients had not been available yet. Such data were needed for physicians to increase the awareness of NPSLE and to be able to treat them adequately. NPSLE screening

AbstractBackground: Systemic Lupus Erythematosus (SLE) is an autoimmune diseases caused by deposition of immune complex with the involvement of various organ system and certain autoantibodies production. One of the most significant manifestation is neuropsychiatric symptoms, known as NPSLE (Neuropsychiatric Systemic Lupus Erythematosus). This study aims to portray the distribution of neuropsychiatric manifestation of SLE patients using a screening method in Hasan Sadikin General Hospital. Method: An observative, descriptive categoric study, with consecutive sampling were done. Data were collected by spreading the questionnaire to subjects diagnosed as SLE who visiting Hasan Sadikin General Hospital during August-October 2016 and by tracing their medical records. Data analyzed included age, sex, education background, duration of lupus, diagnosis criteria, ongoing therapy, and neuropsychiatric manifestation. Result: Samples volunteered in this study were 97 patients. Of them 94 patients (96.9%) were women and 47 patients (48.5%) were senior high school graduated. Most common diagnosis criteria found was positive ANA test (91.8%). Most necessary ongoing therapy given was methylprednisolone (96.9%). Common neuropsychiatric manifestations were mood disorders (73,2%), headache (57,7%), and mononeuropathy (51,5%).Conclusion: The common psychiatric, central nervous, and peripheral nervous manifestations were mood disorder, headache, and mononeuropathy, respectively. Keywords: Neuropsychiatry, NPSLE Screening, Systhemic Lupus Erythematosus.

IntroductionSystemic Lupus Erythematosus (SLE) or widely known as lupus, is an autoimmune diseases caused by deposition of immune complex with involvement of various organ systems and specific autoantibodies production.1,2 In Asia, prevalence of lupus was estimated around 50 to 100 cases per 100.000 population.3 Female patients has accounted for 76.4%-95.4% of all recorded SLE patients.4

Original Article


could be done using a questionnaire, even though it is not recommended to be used as the sole diagnosis.11 This study aims to portray the distribution of NPSLE manifestation using a NPSLE screening quistionnaire.

MethodStudy was conducted at Rheumatology clinic in dr. Hasan Sadikin General Hospital, by using categoric descriptive study design. Subject of the study were all SLE patients visited Hasan Sadikin General Hospital during August to October 2016. Inclusion criteria were: all SLE patients recorded in medical record of Dr. Hasan Sadikin General Hospital, and routinely underwent follow-up during the period of the study. Patients with incomplete medical record data, lacking desired criteria, and unwilling to be involved in this study would be excluded. Minimum samples needed were 97 samples. Samples were selected by consecutive sampling method, which data collected until the minimum sample obtained.

NPSLE manifestation was screened by questionnaire. Questionnaire used was Mosca and colleague 38-questions 2011 questionnaire, and Kundu and colleague 2012 peripheral nervous sign of SLE.11,12 Questionnaire was translated with double translate method (English-Bahasa Indonesia-English) by certified translator, validated by Cronbach’s Alpha of 0.802 and Pearson correlation value of 0.913 and 0.916, respectively. Questionnaire was then consulted with Department of Neurology, Dr. Hasan Sadikin General Hospital. The questionnaires were filled by patients with supervision to minimize the bias. Questionnaire filling was done in workdays within time period of study until minimum sample obtained.

Secondary data were obtained from medical records, included age, sex, education background, duration of diseases, diagnosis criteria, and ongoing therapy. The collected data were sorted by variables and analyzed.

Ethical clearance were approved prior to data collection. Analysis were conducted in descriptive manner by counting

number and percentage by using Microsoft Office Excel. Variables of this study were age, sex, education background, duration of lupus, diagnosis criteria, ongoing therapy, and neuropsychiatric manifestation. Normality test of numeric variables data (age, age during the establishment of diagnosis, and duration of disease) was done using Saphiro-Wilk test to reveal whether the data is well distributed or not. Data were presented as mean “(± Standard Deviation)” if distributed well, or presented as “median (range)” if not distributed well.

ResultsWithin time period of the study, we were able to obtain minimum sample of 97 patients. Demographic data of the participants of the study were presented in Table 1.

Table 1. Demographic Data

Characteristic (N=97) Results

Age (years) 33 (14-61)*

Women, N(%) 94(96.9)

Age of diagnosis (years) 27 (9-52)*

Duration of Disease (years) 4 (0-20)*

Educational Background, N(%)

Primary School 11(11.3)

Junior High School 20(20.6)

Senior High School 47(48.5)

University 19(19.6)

*: not normally distributed data, presented in median (range)

Duration of SLE were defined as age range since establishment of diagnosis until the time of this study conducted. Among 97 patients, most of participants were women (96.9%) and graduated from senior high school (48.5%).

Table 2. Distribution of SLE Patients According to Diagnosis Criteria and Ongoing Therapy

Distribution of patientsN=97

Frequency N (%)

Diagnosis Criteria

Malar Rash 64 (66,0%)Discoid Rash 37 (38,1%)Photosensitivity 65 (67,0%)Oral Ulcers 40 (41,2%)Arthritis 88 (90,7%)Serositis 23 (23,7%)Renal Disorder 26 (26,8%)Neurology Disorder 10 (10,3%)Hematology Disorder 45 (46,4%)Immunology Disorder 33 (34,0%)Positive ANA Test 89 (91,8%)Ongoing TherapyCyclophosphamide 11 (11,3%)Methylprednisolone 94 (96,9%)Dexamethasone 1 (1,0%)Chloroquine 45 (46,4%)Azatioprin 14 (14,4%)Methotrexate 5 (5,2%)Cyclosporin A 1 (1,0%)Micophenolat Mophetyl 0 (0%)

Distribution of diagnosis criteria met on the first lupus diagnosis establishment were presented in Table 2, with positive ANA test (91.8%) and arthritis (90.7%) as the most common finding. Table 2 also showed ongoing therapy among participants was corticosteroid in form of methylprednisolone (96,3%), while the other therapies were less frequent.

Original Article


Figure 1. Neuropsychiatric Manifestation Distribution Graphic

4

Figure 1 shows the percentage of each neuropsychiatric manifestation among subjects. Headache, cerebrovascular disease, demyleinating syndrome, seizure, chorea, and aseptic meningitis are classified as central nervous system manifestation of NPSLE. Acute convusional state-cognitive dysfunction, mood disorder, anxiety disorder, and psychosis are classified as psychiatry manifestation of NPSLE. Guillain-Barre Syndrome, mononeuropathy, polyneuropathy, cranial neuropathy, plexopathy, and myasthenia gravis are classified as peripheral nervous system manifestation of NPSLE. The least common NPSLE findings was cerebrovascular disease (2.1%), while the most common NPSLE complain is mood disorder(73.2%).

Discussion

Lupus are likely to be occured in productive-aged women,4 same as our study’s results which found 96,9% female participants with median age was 33 (14-61) years old. Thesimilar finding also showed by the study conducted by Chiewthanakul, et al, which found the mean age SLE patients was 35+11.7 years and Kampylafka et al, who found the mean age ofSLE patients was 32+14 years.13,14 Data of current age and age of SLE onset were collected due to fact that disease activity and damage were presented more in older age subjects.15 It shows that high level of disease activity conveyed by the level of interferon-alpha confirmed the conclusion that disease are more common in productive age.16 Median of duration of disease in this study was 4 years, with range between 0-20 years. It is similar with founding conducted by Kampylafka et al, in which means duration of disease suffered by patients was

57.7 2.1

10.3 14.4

7.2 37.1

48.5 73.2

48.5 12.4

30.9 23.7

51.2 39.2

5.2 33

6.2

0 20 40 60 80

HeadacheCerebrovascular Disease

Demyelinating SyndromeSeizure

Movement Disorder - ChoreaAseptic Meningitis

ACS - CD*Mood Disorder

Anxiety DisorderPsychosis

Guillain-Barre SyndromeAutonomic Disorder

MononeuropathyPolyneuropathy

Cranial NeuropathyPlexopathy

Myasthenia Gravis

Percentage (%)

Neu

rop

sych

iatr

ic M

anif

esta

tion

ACS - CD: Acute Confusional State, Cognitive Dysfunction

Figure 1 shows the percentage of each neuropsychiatric manifestation among subjects. Headache, cerebrovascular disease, demyleinating syndrome, seizure, chorea, and aseptic meningitis are classified as central nervous system manifestation of NPSLE. Acute convusional state-cognitive dysfunction, mood disorder, anxiety disorder, and psychosis are classified as psychiatry manifestation of NPSLE. Guillain-Barre Syndrome, mononeuropathy, polyneuropathy, cranial neuropathy, plexopathy, and myasthenia gravis are classified as peripheral nervous system manifestation of NPSLE. The least common NPSLE findings was cerebrovascular disease (2.1%), while the most common NPSLE complain is mood disorder (73.2%).

DiscussionLupus are likely to be occured in productive-aged women,4 same as our study’s results which found 96,9% female participants with median age was 33 (14-61) years old. The similar finding also showed by the study conducted by Chiewthanakul, et al, which found the mean age SLE patients was 35+11.7 years and Kampylafka et al, who found the mean age of SLE patients was 32+14 years.13,14 Data of current age and age of SLE onset were collected due to fact that disease activity and damage were presented more in older age subjects.15 It shows that high level of disease activity conveyed by the level of interferon-alpha confirmed the conclusion that disease are more common in productive age.16 Median of duration of disease in this study was 4 years, with range between 0-20 years. It is similar with founding conducted by Kampylafka et al, in which means duration of disease suffered by patients was 9+7.8 years.13 There are no other NPSLE studies describing educational background of subjects. Educational background depicted person’s perception of illness and often associated with NPSLE, especially cognitive function.17,18

Positive ANA test and arthritis were two most common criteria found in this study, while positive ANA test is the most

common diagnosis criteria with percentage of 96% from all participants. The results were similar with Chiewthanakul, et al study.13

The use of therapy other than methylprednisolone such as cyclophosphamid, azatriopine, chloroquine, and methrotexate was rarely found. It was different compared with Chiewthanakul, et al study which presented wider variation of therapy with proportion of azatriopin, choloroquine, metothrexate, cyclophosphamide, and micophenolate mophetil were as follow 35%, 62%, 17%, 33%, and 32%.13 It might be caused by the subject selection method in our study. We chose respondents in outpatient setting who were relatively in stable condition. Besides, not all drugs were available in Hasan Sadikin General Hospital pharmacy. Current therapy might affect direct or inderectly as secondary cause to NPSLE, by means of secondary infection caused by suppressed immunity or drug adverse effect.8,10

Central nervous system’s manifestations in this study were dominated by headache. The finding is similar with the research conducted by Al-Shareef, et al which revealed headache in 34% subjects;19 and the research conducted by Abdel-Nasser, et al found headache prevalence was as much as 46.9%.20 Headache in SLE could be caused by many pathomechanism, but some studies suggested that headache-related SLE were caused by idiopathic intracranial hypertension.21

Cerebrovascular diseases was the least common finding in this study (2.1%). The result was different with the finding in Al-Shareef, et al study, in which found the incidence of cerebrovascular in 35% subjects.19 The difference is suggested due to the different modalities used in our study. The questionnaire can only confirm the preexisting complaint, but can not detect the cerebrovascular events as the standard examination; while in Al-Shareef, et al study every patients was assessed objectively by standard examination in hospital.19 Despite the difference, detecting cerebrovascular events in SLE patients is important because SLE patients reported having 2.05 fold higher chances to be hospitalized from cerebrovascular events.22

The finding of aseptic meningitis in our study was quite high (37.1%). It is different with the result of study conducted by Al-Shareef et al, which only revealed 1.4% cases among their study subjects.19 The difference might be happened due to over presumptive of aseptic meningitis by the screening from questionnaire. The true diagnosis of aseptic meningitis is needed to be investigated further. Nevertheless, with a high result of aseptic meningitis presumption, physician should be aware of aspetic meningitis as to prevent complication such as neurological deficit and mortality in the future.23

Questionnaires in this study combined manifestations of acute confusional state and cognitive disfunction which has never conducted in any other study. Unseparated rate from both manifestations was 48.5%. In studies conducted by Hanly, et al, Steaup Beekman, et al, and Morrison, et al, percentage of acute confusional state were tent to be low

Original Article


(2.6%-6.9%). Cognitive dysfunction was considerably high in the study conducted by Steup-Beekman, et al, with percentage of 26.5%.24–26 However, mood disorder was neccesary found in study conducted by Hanly, et al, with proportion of 16.5% from overall samples.26 The findings of mood disorders in this study were consistent with the study conducted by Abdel-Nasser, et al, with proportion of mood disorder as much as 59.4% of respondents, while we found 73.2% of respondents.20 Depression, the most common mood disorder in NPSLE, is a main concern for clinician treating SLE patients. Depression is not only a mere clinical manifestation, but also a serious threat to medical adherence, whereas SLE needs a long-term therapy.27

In peripheral nervous manifestations, the prevalence found were comparatively high compared to central nervous manifestation, included Guillan-Barre syndrome, otonomic nervous disorder, mononeuropathy, polyneuropathy, and plexopathy. The founding is different compared to the study perfomed by Hanly, et al and Morrison, et al. They found peripheral nervous system manifestation ranging between 0-24% and 0-7.9%, respectively.26

Distribution of psychiatric disorder among lupus patients may vary, due to numerous factor, such as active autoantibodies and the method of diagnosis.28 We acknowledged our study were tend to be more subjective in making diagnosis because we only used questionnaire for assessing NPSLE manifestation. Exact diagnosis must be established by various supporting modalities, such as electroencephalogram, MRI, CT-scan, mental status examination, comprehensive nervous system examination, and other psychiatric status examination.9,28 Thus, several acquired data were not in line with other studies due to the different of interpretation and patients’ subjectivity. Questionnaire was only describing 17 from 19 neuropsychiatric manifestation according to American College of Rheumatology (ACR) criteria since this questionnaire combined acute confusional state and cognitive disorder; and there were no questions to diagnose probable myelopathy. Uncompleted patients’ medical record were also limiting this study.

ConclusionThe most common psychiatric manifestation was mood disorder. The most common CNS manifestation was headache. The most common peripheral nervous manifestation was mononeuropathy. Neuropsychiatry manifestation screening is recommended to be done routinely to all SLE patients. Further examination is needed when NPSLE manifestation found by the screening, so that optimal therapy could be given to the patients. Screening questionnaire used in this study still have to be tested to be used as a screening modality to detect neuropsychiatric manifestation.

Reference1. Wallace DJ, Hahn BH. Definition and classification of lupus and lupus-

related disorders. In: Yazdany J, Dall’Era M, editors. Dubois’ Lupus Erythematosus and Related Syndromes. 8th ed. Philadelphia: Elsevier Saunders; 2013. p. 1–7.

2. Longo D, Fauci A, Kasper D, et al. Systemic lupus erythematosus. In: Fauci AS, editor. Harrison’s Principle of Internal Medicine. 18th ed. New York: McGraw-Hill; 2011. p. 2724–34.

3. Feng P. Systemic lupus erythematosus: the face of asia. Ann N Y Acad Sci. 2007;1108:114–20.

4. Unterman A, Nolte JES, Boaz M, et al. Neuropsychiatric syndromes in systemic lupus erythematosus: a meta-analysis. Semin Arthritis Rheum. Elsevier; 2011;41:1–11.

5. Liang MH, Corzillius M, Bae SC, et al. The american college of rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes. Arthritis Rheum. 1999;42(4):599–608.

6. Pettersson S, Lövgren M, Eriksson LE, et al. An exploration of patient-reported symptoms in systemic lupus erythematosus and the relationship to health-related quality of life. Scand J Rheumatol. 2012;41:383–90.

7. Zirkzee EJM, Huizinga TWJ, Bollen ELEM, Buchem MA Van, Middelkoop HAM. Mortality in neuropsychiatric systemic lupus erythematosus (NPSLE). Lupus. 2014;23:31–8.

8. Joseph FG, Scolding NJ. Neurolupus. Pract Neurol. 2010;10:4–15. 9. Hanly JG. Diagnosis and management of neuropsychiatric SLE. Nat Rev

Rheumatol. Nature Publishing Group; 2014;15:1–10. 10. Wallace DJ, Hahn BH. Clinical Aspects of the Nervous System. In: West

SG, editor. Dubois’ Lupus Erythematosus and Related Syndromes. 8th ed. Philadelphia: Elsevier Saunders; 2013. p. 368–81.

11. Mosca M, Govoni M, Tomietto P, et al. The development of a simple questionnaire to screen patients with SLE for the presence of neuropsychiatric symptoms in routine clinical practice. Lupus. 2011;20:485–92.

12. Kundu AK, Maity A. Neuropsychiatric lupus. Med Updat. 2012;22:646–52.

13. Kampylafka EI, Alexopoulos H, Kosmidis ML, et al. Incidence and prevalence of major central nervous system involvement in systemic lupus erythematosus : a 3-year prospective study of 370 patients. PLoS One. 2013;8(2):1–8.

14. Chiewthanakul P, Sawanyawisuth K, Foocharoen C, Tiamkao S. Clinical features and predictive factors in neuropsychiatric lupus. Asian Pacific J Allergy Immunol. 2012;30(1):55–60.

15. Lalani S, Pope J, Leon F De, Peschken C. Clinical features and prognosis of late-onset systemic lupus erythematosus: results from the 1000 faces of lupus study. J Rheumatol. 2010;37(1):38–44.

16. Niewold TB, Adler JE, Glenn SB, et al. Age- and sex-related patterns of serum interferon-alpha activity in lupus families. Arthritis Rheum. 2008;58(7):2113–9.

17. Croog SH. Ethnic origins, educational level, and responses to a health questionnaire. Hum Organ. 1961;20(2):65–9.

18. Conti F, Alessandri C, Perricone C, et al. Neurocognitive dysfunction in sys-temic lupus erythematosus: association with antiphospholipid antibod-ies, disease activity and chronic damage. PLoS One. 2012;7(3):1–7.

19. Al-shareef A, Attar SM. Central nervous system manifestation in patients with SLE: a 12-year retrospective chart review at a tertiary center. Kuwait Med J. 2014;46(1):14–20.

20. Abdel-Nasser AM, Ghaleb RM, Mahmoud JA, Khairy W, Mahmoud RM. Association of anti-ribosomal P protein antibodies with neuropsychiatric and other manifestations of systemic lupus erythematosus. Clin Rheumatol. 2008;27:1377–85.

21. Kim J-M, Kwok S, Ju JH, Kim H, Park S. Idiopathic intracranial hypertension as a significant cause of intractable headache in patients with systemic lupus erythematosus : a 15-year experience. Lupus. 2012;21:542–7.

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22. Ward MM. Premature morbidity from cardiovascular and cerebrovascular diseases in women with systemic lupus erythematosus. Arthritis Rheum. 1999;42(2):338–46.

23. Baizabal-Carvallo JF, Delgadillo-Márquez G, García-Ramos G, Estañol B. Clinical characteristics and outcomes of the meningitides in systemic lupus erythematosus. Eur Neurol. 2009;61:143–8.

24. Steup-Beekman GM, Zirkzee EJM, Cohen D, et al. Neuropsychiatric manifestations in patients with systemic lupus erythematosus: epidemiology and radiology pointing to an immune-mediated cause. Ann Rheum Dis. 2013;72(2):1176–9.

25. Morrison E, Carpentier S, Shaw E, Doucette S, Hanly J. Neuropsychiatric systemic lupus erythematosus: association with global disease activity. Lupus. 2014;23(4):370–7.

26. Hanly JG, Urowitz MB, Su L, et al. Prospective analysis of neuropsychiatric events in an international disease inception cohort of patients with systemic lupus erythematosus. Ann Rheum Dis. 2010;69(3):529–35.

27. Julian LJ, Yelin E, Yazdany J, et al. Depression, medication adherence, and service utilization in systemic lupus erythematosus. Arthritis Rheum. 2009;61(2):240–6.

28. Stojanovich L, Zandman-goddard G, Pavlovich S, Sikanich N. Psychiatric manifestations in systemic lupus erythematosus. Autoimmun Rev. 2007;6:421–6.

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AbstractBackground: Anemia is a common manifestation found among patients with Systemic Lupus Erythematosus (SLE). It may be caused by iron-deficiency, autoimmune hemolytic, and chronic inflammation. Each anemia has different therapy approachments. Without adequate management, anemia may lead to poor prognosis. By identifying the etiology of anemia, appropriate management could be conducted. Reticulocyte Hemoglobin Equivalent (RET-He) and reticulocyte count test may distinguish anemia based on its etiology. This study aimed to give scientific portrayed of the proportion of anemia based on its etiology among patients with SLE using RET-He and reticulocyte count. Method: This study involved women diagnosed with SLE underwent outpatient treatment in Rheumatology Clinic, Dr. Hasan Sadikin General Hospital during September-October 2016. Data were collected from blood exam using 35-parameters hematology Sysmex by calculating levels of hemoglobin, RET-He, and reticulocyte count. Results: Seventy four female patients were volunteered as subject in this study with median of age was 29.5 (16-70) years old. Thirty four (46%) of 74 subjects were suffering from anemia and 12 (35%) of them were between 25-34 years old. Proportion of iron-deficiency anemia, autoimmune hemolytic anemia, and chronic inflammatory anemia were 14 ( 41%), 13 (38%), and 7 (21%), respectively.Conclusion: Based on hemoglobin, RET-He, and reticulocyte count, iron-deficiency anemia is the most common anemia among patients with SLE in repoductive age.Keyword: Age, Anemia, Reticulocyte, RET-He, Systemic Lupus Erythematosus (SLE)

IntroductionAnemia is the most common hematology complication among Systemic Lupus Erythematosus (SLE) patients, with prevalence of 59%.1 This complication may raise morbidity and mortality of SLE patients It will reduce patient’s life quality, if it is not treated appropriately.2 Renal failure, serositis,

and seizure are several complication presented in that circumstances.3 It rise the urgency to detect the etiology of anemia among SLE patients. So appropriate treatment would be given according to etiology.

Etiology of anemia among SLE patients may vary such as iron deficiency, autoimmune hemolytic, and chronic inflammatory.4iron deficiency anaemia (IDA Each anemia has different approach to treat. Previous study stated that anemia among SLE were commonly found on particular age range of 15-29 years old,5 thus approach of anemia etiology according to age may assist in managing therapy.

The requirement of iron among reproductive-aged women is also risen due to menstruation and preparation for pregnancy. Pregnant women suffered from anemia have higher level of morbidity and mortality6. Besides, anemia will also affect fetal development.7 Therefore, early detection of anemia among reproductive-aged women is important.

In 2005 similar study to portray proportion of each anemia in patients with SLE was conducted using ferritin as the parameter. Ferritin level in patient with SLE is likely to increase due to inflammation.8 Therefore, the study revealed bias results. Method to detect etiology of anemia by measuring level of hemoglobin in reticulocyte (RET-He) is suggested to be more efficient and cheaper.9 This parameter easily distinguish iron-deficiency anemia accurately with a sensitivity of 93.3% and a specificity of 83.2%.9 On the other side, reticulocyte count may be used as reference to differentiate autoimmune hemolytic anemia,10 thus by combining both parameters, the etiology of anemia among SLE patients may be identified.

In this study, we applied combination of hemoglobin level measurement, RET-He, and reticulocyte count among SLE patients, and try to find each proportion anemia based on its etiology.

MethodThis descriptive study with cross-sectional design and consecutive sampling method had been done

Overview of Anemia among Systemic Lupus Erythematosus Patients in Reproductive Age Women based on Reticulocyte Hemoglobin Equivalent (RET-He) Level and Reticulocyte Count

Ismiana Fatimah Modjaningrat1, Amaylia Oehadian2, Mohammad Ghozali3, Laniyati Hamijoyo2

1 Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia2 Department of Internal Medicine, Faculty of Medicine, Universitas Padjadjaran/ Dr. Hasan Sadikin General Hospital, Bandung, Indonesia3 Department of Biochemistry and Molecular Biology, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia

Corespondence:Ismiana Fatimah Modjaningat, MDJalan Raya Bandung-Sumedang Km. 21, Jatinangor, SumedangEmail: [email protected]

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to 74 women diagnosed with SLE visited Rheumatology Clinic, Dr. Hasan Sadikin General Hospital Bandung during September to October 2016. This study had been approved by hospital ethical committee of Dr. Hasan Sadikin General Hospital.

Systemic Lupus Erythematosus patients with ongoing bleeding include menstruation period or infection and SLE patients who had received packed red cell blood transfusion in the prior three months were excluded from this study. Blood samples were taken at laboratory of Clinical Pathology Dr. Hasan Sadikin General Hospital with patient’s consent. Blood test included hemoglobin level, RET-He level, and reticulocyte count, were performed using Sysmex XN 1000. The machine uses principles of flow cytometry, where blood sample will be converted into a fluorescent-labeled suspension and then inserted into a narrow gap, and was shot by some rays.11

Patients were classified as anemia if hemoglobin level was <12gr/dL. For etiology classification, we referred to RET-He level and reticulocyte count. RET-He level <27.2 pg showed iron deficiency anemia and reticulocyte count >1.5% showed autoimmune hemolytic anemia, while in chronic inflammatory anemia RET-He level ≥27.2 pg and reticulocyte count ≤1.5%.9,10 Results in this study were processed by using software in the computer.

Table 1. Classification of Anemia

Type of Anemia RET-He Reticulocyte Count

Iron Deficiency Anemia <27.2 pg ≤1.5%Chronic Inflammatory Anemia ≥27.2 pg ≤1.5%Autoimmune Hemolytic Anemia ≥27.2 pg >1.5%

ResultsSLE patients most commonly found between 25-34 years old. Thirty four (46%) of 74 subjects were suffered anemia. Subjects’ age were not well-distributed, and it was known that the median was 29.5 (16-70) years old. Characteristic of subjects were presented in table 2.

Table 2. Characteristic of Subjects

Variable Result

Hemoglobin (g/dL) 12.15 (6-16)*Age (years old) 29.5 (16-70)*

15-24, N(%) 19 (26%)25-34, N(%) 29 (39%)35-44, N(%) 17 (23%)45-54, N(%) 8 (11%)55-64, N(%) 0 (0%)65-74, N(%) 1 (1%)

Patients with anemia, N(%) 34 (46%) Hemoglobin (g/dL) 9.95 (5.6-11.5)* RET-He (pg) 26.98 ± 5.37 Jumlah Retikulosit (%) 1.86 (0.34-11.25)

*:Not normally distributed data

There were 3 subjects with RET-He < 27.2 pg and reticulocyte count >1.5% which were included into iron deficiency anemia cases. Proportion of Anemia based on its etiology and the results of the blood tests in non-anemic subjects were presented in table 3.

Table 3. Proportion of Anemic and Non-Anemic SLE Patients

Iron

deficiency anemia(14 patients, 19% *)

Autoimmunehemolytic anemia(13 patients, 18%)

Chronicinflammatory anemia

(7 patients, 9%)

No anemia(40 patients, 54%)

Hb (g/dL) 9.95 (5.7 - 11.7) 9.78 ± 1.57 9.29 ± 1.95 13 (12 - 15.8)

RET-he (pg) 21.74 ± 3.24 31.69 ± 3.10 28.71 ± 1.16 31.2 (24.9 - 38)

Reticulocyte count (%) 1.88 (0.34 - 11.25) 2.02 (1.51 - 10.58) 0.91 ± 0.33 1.68 ± 0.51

Age (years old) 32.86 ± 10.79 28.85 ± 9.48 28.29 ± 8.42 31 (16-70)

15-24 4(28%) 4 (31%) 3(44%) 8 (20%)

25-34 4(28%) 6(46%) 2(28%) 17 (43%)

35-44 3(22%) 3(23%) 2(28%) 9 (22%)

45-54 3(22%) 0 0 5 (12%)

55-64 0 0 0 0

65-74 0 0 0 1(3)

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Discussion Proportion of anemia in this study was not different from previous study in Dr. Hasan Sadikin General Hospital Bandung in 2005, stated that proportion of anemia in SLE patients was 48%.12 It is also in line with study stated that SLE patients had suffered from hematology disorder, 50% of them were anemia.13 Proportion of each anemia in this study were different with last study in Dr. Hasan Sadikin General Hospital Bandung on 2005, in which there were no iron deficiency anemia, 8% of autoimmune hemolysis anemia, and 92% of chronic inflammatory anemia.12 The differences may be caused by different parameter used. In previous study, parameter ferritin were used to portray iron reserved in the body. Unfortunately this parameter is likely to increase in patient with SLE with inflammation so it tends to be misdiagnosed of chronic inflammatory anemia. Therefore in this study, more recent parameters, which are RET-He and reticulocyte count were used.

RET-He or Reticulocyte Hemoglobin Equivalent is a parameter calculating means of hemoglobin level in reticulocyte. It capables to detect iron availability used in erythropoiesis process. Normal limit for RET-He is 27.2 pg, means the amount of iron is available for performing erythropoesis, with sensitivity 93.3% and specificity 83.2%.9

Erythropoiesis process starts from pronormoblast, basophilic normoblast, polychromatophlic normoblast, orthochromatophylic normoblast, reticulocyte, and erythrocyte. During the basophilic normoblast phase, hemoglobin formation is initiated and the process requires iron continuously.10 The process of hemoglobin formation is starting from reticulocyte phase and stop when red blood cells have became matured erythrocytes.10 In case when iron availability is depleted, hemoglobin formation process will disturb. This will lead the lack of hemoglobin level in immature red blood cells.9 Therefore in iron deficiency anemia the RET-He level is decreased.

Level of RET-He among patients with anemia was lowest on patient aged between 45-54 years old, because subjects are not been in reproductive period anymore. Low iron level during menopause is usually caused by iron malabsorption and chronic gastrointestinal bleeding.14

In the study conducted in 2014, RET-He was used as parameter to evaluate anemia in patients with cancer and it was concluded that 32 pg was a cut-off point to eliminate iron deficiency with negative predictive value of 98.5% and 100%.15 Other study in 2013 also used RET-He as a parameter to analyze iron deficiency in geriatric patients and it was concluded that cut off value of 26 pg was able to distinguished iron deficiency anemia with chronic inflammatory anemia with sensitivity of 85% and specificity of 69%.16

Level of reticulocyte in iron deficiency anemia might be normal, which is ranged between 0.5-1.5%.10 In several subjects with low RET-He level and reticulocyte of >1.5% and in non-anemic patients the median of reticulocyte count was high, it might be cause by iron supplementation. Iron supplementation

therapy will raise reticulocyte count quickly.17 In patients with autoimmune hemolytic anemia, level of

RET-He are expectedly to be normal since no iron absorption disturbance happened during erythropoiesis. In autoimmune hemolytic anemia, antibody is not able to distinguish external and self-antigen, thus antibody attacks erythrocyte antigen.10 The destruction of erythrocyte is compensated by the rise of erythropoiesis, marked by the raise of reticulocyte count.10

Chronic inflammatory anemia is caused by a long-term cytokine production. Cytokine IL-1, IL-6, tumor necrosis factor-α (TNF-α), and interferon-gamma (IFN-γ) lead to the reduction of eryhtrocyte age, disturbance on erythroid progenitor cell proliferation, and rising of cellular iron uptake and retention.18 Increasing cytokines will raise hepcidin, thus reduces intestinal iron absorption.18 IL-1 also activates macrophages, leading to the rise of serum iron uptake and iron reserve, but IL-6 affects negatively in iron reserve release to the blood.19 The reduction of erythropoiesis process caused stagnant or even reduced reticulocyte count in patients with chronic inflammatory anemia in this study. Level of RET-He in patients with chronic inflammatory anemia in this study also tended to be normal since iron reserve for erythropoiesis was not depleted. According to study conducted in 2011 among patients with rheumatoid arthritis, it was known that RET-He level among patients with chronic inflammatory anemia were significantly higher compared with patients with iron-deficiency anemia.19

This study revealed that majority SLE patients were reproductive-aged woman and most of them were suffering anemia. Most common type of anemia found was iron-deficiency anemia, followed by autoimmune hemolytic anemia and chronic inflammatory anemia. Most patients suffered from anemia were between 25-34 years old.

General characteristic seen in this study only revealed anemia in women since overall subjects were exclusive to women. Median age of participants was 29.5 years old, a reproductive age. This result was consistent to previous study stated that SLE was commonly found among reproductive-aged women.20 It might be influenced by high estrogen hormones level among reproductive aged women, leading into the raise of immune responses.21

Most patients with anemia and patients with lowest hemoglobin level were aged between 25-34 years old. Anemia on SLE patients in reproductive age may be caused by the SLE itself, or other additional factors such as menstruation, high parity, or low socioeconomic level.22,23

Reproductive-aged women needs more iron intake due to menstrual bleeding and preparation of pregnancy. Women experience the rise of blood volume during pregnancy, around 40-45%, in order to fulfill the needs of angiogenesis in enlarging uterus, the needs of fetal and maternal if venous return disturbance were occurred, and to reserve blood if bleeding was happened during the parturition.24 Iron is vital for fetal brain development especially during the first trimester. Iron deficiency anemia during pregnancy may lead

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into mental growth retardation of the children 7 Iron deficiency anemia during pregnancy also raise the risk of preterm birth.25 Moreover, pregnancy on SLE patients may raise the disease activity.26 Anemia in SLE patients during pregnancy may cause by the progression of disease. However, distinguish it with anemia in normal women during pregnancy is difficult.27 The rise of disease activity may threat maternal and fetal safety which lead to an abortion.20,28 Thus finding the etiology of each anemia is important, so anemia can be treated appropriately.

Lacking of samples limited this study. Minimal samples with 95% interval confidence was 96 patients, while in this study, only 74 patients participated as research subjects, 90% of predicted samples. Other limitation was inability to detect the mixed of chronic inflammatory anemia and iron-deficiency anemia since RET-He parameter was weak to distinguished both type of anemia.28 We did not record the socioeconomic level, parity and other causes of anemia, so we could not concluded any the other factors causing anemia in this study.

We suggest to perform further study with higher number of subjects thus the portray of SLE patients will be more accurate. The use of other parameter such as ferritin, inflammation test, and better therapy documentation given to the patients will also enhance the more accurate results.

ConclusionIt is concluded that almost half of patients with SLE in Dr. Hasan Sadikin General Hospital Bandung year of 2016 was suffering from anemia. Anemia in SLE was more commonly found among patients aged between 25-34 years old. According to the parameter of RET-He and reticulocyte count, iron deficiency anemia is the most common type of anemia found, followed by autoimmune hemolytic anemia and chronic inflammatory anemia. Parameter of RET-He may not able to distinguish etiology of anemia on SLE patients by itself, and needs the addition of other parameters. Reference1. Keeling D., Isenberg D. Haematological manifestations of systemic lupus

erythematosus. Blood Rev. 1993;7(4):199–207.2. Hernandez D M, C CR, C MM, et al. Active haematological manifestations

of systemic lupus erythematosus lupus are associated with a high rate of in-hospital mortality. SAGE J. 2016;45:1–6.

3. Bashal F. Hematological disorders in patients with systemic lupus erythematosus. Open Rheumatol J. 2013;7:87–95.

4. Voulgarelis M, Kokori SI, Ioannidis JP, et al. Anaemia in systemic lupus erythematosus: aetiological profile and the role of erythropoietin. Ann Rheum Dis. 2000;59(3):217–22.

5. Huu C, Le H. The prevalence of anemia and moderate- severe anemia in the us population. Plosone. 2016;11(11):1–14.

6. Allen LH. Anemia and iron deficiency : effects on pregnancy outcome. Am J Clin Nutr. 2000;71:1280–1284.

7. Zeng L, Brouwer D, Kok FJ, Yan H. Effect of iron deficiency anemia in pregnancy on child mental development in rural China. Pediatr Off J Am Acad Pediatr. 2013;131(3):755-763.

8. Olthof AW, Sijens PE, Kreeftenberg HG, et al. Correlation between serum ferritin levels and liver iron concentration determined by MR imaging : impact of hematologic disease and inflammation. Elsevier. 2007;25(3):228–31.

9. Brugnara C, Schiller B, Moran J. Reticulocyte hemoglobin equivalent (ret he) and assessment of iron-deficient states. Clin Lab Haematol. 2006;28(5):303–308.

10. Harmening DM. The red blood cell: struture and function. In: Harmening DM, editor. Clinical hematology and fundamentals od hemostasis. 5th ed. Maryland: F.A. Davis; 2009. 64-81 p.

11. Pedreira CE, Costa ES, Lecrevisse Q, Dongen JJM Van. Overview of clinical flow cytometry data analysis : recent advances and future challenges. Trends Biotechnol. 2013;31(7):415–25.

12. Oehadian A. Hematological problems in lupus erythematosus systemic[Kelainan darah pada lupus eritematosus sistemik].In: Oehadian A. Lupus Erythematosus Systemic Symposium for General [Simposium Lupus Eritematosus Sistemik untuk Awam]; Bandung: 2008, p. 2–6.

13. Janoudi N, Bardisi ES. Haematological manifestations in systemic lupus erythematosus. In: H. Almoallim, editor. Systemic Lupus Erythematosus. 1st ed. Rijeka: In Tech; 2012. 363–382 p.

14. Qamar K, Saboor M, Qudsia F, et al. Malabsorption of iron as cause of iron deficiency anemia in postmenopausal women. Pakistan J Med Sci. 2015;31(2):304–308

15. Peerschke EIB, Pessin MS, Maslak P. Using the hemoglobin content of reticulocytes (ret-he) to evaluate anemia in patients with cancer. Am J Clin Pathol. 2014;142:506–512.

16. Joosten E, Lioen P, Brusselmans C, Indevuyst C, Boeckx N. Analysis of the reticulocyte haemoglobin equivalent a useful test fo the diagnosis of iron deficiency anemia in geriatric patients. Eur J Intern Med. 2013;24(1):63–66.

17. Zhu A, Kaneshiro M, Kaunitz JD. Evaluation and treatment of iron deficiency anemia : a gastroenterological perspective. Dig Dis Sci. 2010;55:548–559.

18. Ana Beatriz Barbosa Torino, Gilberti M de FP, Costa E da, Lima GAF de, Grotto HZW. Evaluation of erythrocyte and reticulocyte parameters as indicative of iron deficiency in patients with anemia of chronic disease. Rev Bras Hematol Hemoter.2015;37(2):77–81

19. Santen S Van, Dongen-lases EC Van, Vegt F De, et al. Hepcidin and hemoglobin content parameters in the diagnosis of iron deficiency in rheumatoid arthritis patients with anemia. Arthritis Rheum. 2011;63(12):3672–3680.

20. Kasjmir YI, Handono K, Wijaya LK, et al. Rekomendasi Perhimpunan Reumatologi Indonesia untuk diagnosis dan pengelolaan lupus eritematosus sistemik. Perhimpunan Reumatologi Indonesia; 2011.

21 Hahn BH. Systemic lupus Erythematosus. In: Harrison T, Resnick W, Wintrobe M,et al, editors. Harrison’s principles of internal medicine.17th ed. Mcgraw-hill; 2008. 2075–2079.

22. K Pala, D Nundar. Prevalence and risk factors of anemia among women of reproductive age in Bursa, Turkey. Indian J Med Res. 2008;128(3):282–286.

23. Cunningham FG, Leveno KJ, Bloom SL, et al. Maternal physiology. In: Twickler D, Wendel G, Dashe J, et al, editors. Williams obstetrics. 23th ed. New York: McGraw-Hill Education; 2010. 107-135 p.

24. Sadeghlan M, Fatourechi A, Lesanpezeshki M, Ahmadnezhad E. Prevalence of Anemia and Correlated Age Women in Rural Areas of Tabas. Journal of Family and Reproductive Health. 2013;7(3):139–144.

25. Banhidy F, Acs N, Puho EH, Czeizel AE. Iron deficiency anemia : pregnancy outcomes with or without iron supplementation. Nutr J. 2011;27:65–72.

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29. Wong C, Chen T, Lee C, Lin C, Chen C. Outcome of pregnancy in patients with systemic lupus erythematosus. Taiwan J Obstet Gynecol. 2006;45(2):120–123.

Original Article


AbstractBackground: Systemic lupus erythematosus (SLE) is an autoimmune disease which involves many different organ systems and immunological abnormalities. SLE mainly affects females in their reproductive age. This study aimed to describe the fetal outcome, neonatal complications, maternal outcome, and obstetrics complication in patients diagnosed with SLE, in order to help the physicians to reduce the fetal loss, improve maternal morbidity, and reduce neonatal or maternal deaths.Method: This research was conducted using descriptive quantitative design. Data were obtained from direct interview noted in a report form and medical records. Subjects were SLE patients who came to Rheumatology Outpatient clinic, Dr. Hasan Sadikin General Hospital, Bandung from September 2016 to November 2016; and fulfilled the inclusion and exclusion criteria. The minimal required sample was 96 subjects. Results: Due to time limitation, only 53 pregnancies from 40 females were managed to be recorded. The median age when being diagnosis of the subjects was 24 (14 - 41) years old. The fetal outcomes showed 64.2% live births, 18.9% spontaneous abortions, 9.4% intrauterine death, 1.8% intrauterine growth retardation, and 9.1% neonatal deaths. Neonatal complications included premature delivery, low birth weight, and growth retardation. Maternal complications during pregnancy included rash, pregnancy-induced hypertension, arthritis, anemia, and thrombocytopenia. Furthermore, obstetric complications included 13.2% pre-eclampsia, 13.2% placenta previa, and 1.8% stroke. There were 2 cases (3.8%) of maternal death happened during the delivery.Conclusion: The most frequent maternal complications during pregnancy were arthritis and rash. Pre-eclampsia and placenta previa were the most frequent obstetric complications which experienced by the pregnant SLE patients. Exclude the live births, the most frequent fetal outcome was spontaneous abortion. The most frequent neonatal complications were preterm delivery and low birth weight. Keywords: pregnancy, systemic lupus erythematosus, fetal outcomes, maternal outcomes

IntroductionSystemic lupus erythematosus (SLE) is a systemic autoimmune disease which characterized by heterogeneous, multi organ system involvement, and the production of the arrays of autoantibodies.1 A 9:1 female-to-male ratio has been reported with peak age of onset between 15 and 40 years old.2 The disease is dominantly affected women in their reproductive years.3 However, women with SLE have the same fertility as the healthy women with the same age.4 In the past, women with SLE were advised not to get pregnant due to poor fetal and maternal outcomes and also due to high tendency of flare-up.5

The relationship of SLE with pregnancy is complex. Female SLE patients would suffer from dilemma of their desire to get pregnant and the difficulties of managing lupus during pregnancy. Study reported women with active lupus at the onset or in the early stages of pregnancy have high rate of pregnancy loss.6 Moreover, there is an increased risk of spontaneous abortions, premature births, intrauterine growth retardation and stillbirth in overall SLE pregnancy.7 Therefore, the outcome of pregnancy become a major concern in most SLE patients.8

The maternal complications faced by the SLE patients during pregnancy include hypertension, lupus flare, lupus nephritis, arthritis, pre-eclampsia, and more severe complications such as eclampsia, HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome, stroke, and maternal death.9 Neonates from an SLE mother has higher risk to develop neonatal lupus erythematosus (NLE) that could result in cardiac, dermatologic, hepatic disorders, and hematologic abnormalities.10 Congenital heart block is also one of the major complications which is occured in 2% of neonates from SLE mother. Congenital heart block is an irreversible condition which causes the scarring of the cardiac tissue and eventually affects the functionality of the heart.11

There is no data about the outcome of pregnancy in patients with SLE in Indonesia and in Dr. Hasan Sadikin Hospital. The objective of our research was to describe the fetal and maternal outcome and complications in pregnancy with SLE in order

Outcome of Pregnancy in Patients withSystemic Lupus Erythematosus

Erica Kwan Yue1, Coriejati Rita2, Laniyati Hamijoyo3

1 Faculty of Medicine, Universitas Padjadjaran; 2 Department of Clinical Pathology, Universitas Padjadjaran/Dr. Hasan Sadikin General Hospital;3 Division of Rheumatology Department of Internal Medicine Faculty of Medicine, Universitas Padjadjaran/Dr. Hasan Sadikin General Hospital

Correspondence:Erica Kwan Yue Bandung-Sumedang KM.21, Jatinangor, SumedangE-mail: [email protected]

Original Article


to help the physicians to reduce the maternal morbidity or mortality and fetal loss.

MethodThis research was conducted using descriptive quantitative design. Data was collected from medical records and noted in a report form. Subjects were female SLE patients visited Outpatient Rheumatology clinic of Dr. Hasan Sadikin Hospital between September 2016 to November 2016. An ethical clearance letter was obtained from the Ethical Clearance Committee of Faculty of Medicine Universitas Padjadjaran before the study proceeded.

The minimum required sample for this study were 96 cases. The inclusion criteria was female SLE patients who had at least one pregnancy at or after she was diagnosed as SLE. SLE was diagnosed with America College of Rheumatology Criteria 2010.12 Patients who were unwilling to follow the study or do not remember the history of their pregnancy were excluded from the study. After the selection, subjects were required to sign an informed consent form regarding the objectives and procedure of the test.

The report form comprised of the questions about the basic information, gestation history, fetal and maternal outcome, and lastly, neonatal and obstetrics complications of the subjects. Data were analyzed descriptively using Microsoft Excel 2012.

ResultsWe only gathered 53 pregnancies cases from 40 female SLE patients were due to time limitation. The characteristics of subjects were presented in Table 1.

Table 1. Characteristics of the subjects.

Characteristics Result

Age of Diagnosis (years) 24 (14-41)*Present Age (years) 31.5 (24-47)*Duration of the disease (years) 6.5 (0-17)*

*not normally distributed data, data presented in median (range)

Table 1 above shows the median age when diagnosis made was 24 years old, demonstrating that SLE mainly affects female in their reproductive years.

Chart 1. Maternal Complications of SLE patients.

3

The report form comprised of the questions about the basic information, gestation history, fetal and maternal outcome, and lastly, neonatal and obstetrics complications of the subjects. Data were analyzed descriptively using Microsoft Excel 2012.

Results

We only gathered 53 pregnancies cases from 40 female SLE patients were due to time limitation. The characteristics of subjects were presented in Table 1.

Table 1. Characteristics of the subjects.Characteristics ResultAge of Diagnosis (years) 24 (14-41)*Present Age (years) 31.5 (24-47)*Duration of the disease (years) 6.5 (0-17)**not normally distributed data, data presented in median (range)

Table 1 above shows the median age when diagnosis made was 24 years old,demonstrating that SLE mainly affects female in their reproductive years.

Chart 1. Maternal Complications of SLE patients.

The results of maternal complications occurred during pregnancy are shown in Chart 1. Arthritis presented to be the highest frequency of maternal complication and followed by rash. Most patients experienced complications during their 2nd pregnancy.

Table 2. Obstetrics Complication and Maternal Outcome of SLE patients.Obstetric Complication, N=40 Result, N (%)

Maternal mortality 2 (3.8%)Stroke 1 (1.8%)Pre-eclampsia 7 (13.2%)

Placenta previa 7 (13.2%)

According to Table 2, 13.2% of the pregnant SLE patients experienced pre-eclampsia and placenta previa during birth. Maternal mortality presented with 2 cases.

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10

15

20

Rash Hypertension Arthritis Anemia Thrombocytopenia

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en

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Maternal Complications

Maternal Complications

1st Pregnancy 2nd Pregnancy 3rd Pregnancy 4th Pregnancy

The results of maternal complications occurred during pregnancy are shown in Chart 1. Arthritis presented to be the highest frequency of maternal complication and followed by rash. Most patients experienced complications during their 2nd pregnancy.

Table 2. Obstetrics Complication and Maternal Outcome of SLE patients.

Obstetric Complication, N=40 Result, N (%)

Maternal mortality 2 (3.8%)Stroke 1 (1.8%)Pre-eclampsia 7 (13.2%)Placenta previa 7 (13.2%)

According to Table 2, 13.2% of the pregnant SLE patients

experienced pre-eclampsia and placenta previa during birth. Maternal mortality presented with 2 cases.

Table 3. Fetal outcomes in SLE pregnancy.

Fetal outcome, N=53 cases Result, N (%)

Live born 34 (64.2%)Spontaneous abortion 10 (18.9%)Intrauterine death 5 (9.4%)IUGR* 1 (1.8%)Neonatal mortality 3 (5.7%)

*IUGR= Intrauterine Growth Retardation

Table 3 recorded the results of fetal outcome and neonatal complications of our study. Based on the table, out of the 53 pregnancies had more than half live births. However, there are still highlight cases of abortion in 18.9%.

Table 4. Neonatal Complications.

Neonatal complication, N=34 cases Result, N (%)

Preterm Delivery 10 (29.4%)

Low Birth Weight 14 (41.2%)

Growth retardation 1 (2.9%)

Neonatal Lupus 0

Congenital Heart Block 0

Table 4 shows that the most frequent neonatal complications were preterm delivery and low birth weight.

Discussion Based on our results, arthritis (35.8%) presented to be the most common flares during the subjects’ pregnancy period, following by rashes (28.3%). Same amount of subjects experienced pre-eclampsia (13.2%) and placenta previa (13.25) when they were giving birth. Overall, the fetal outcome came out well with 34 (64.2%) live births, despite there was 10 (18.9%) cases of spontaneous abortions. The most frequent neonatal complications were preterm delivery (29.4%) and

Original Article


low birth weight (41.2%). Growth retardation was rare, only occurred in one live-birth and there was no Neonatal Lupus Erythematosus (NLE) and Congenital Heart Block (CHB) were recorded. Although pregnancy is not contraindicated for patients with SLE, significant fetal, neonatal and maternal risks still exist.13

In the past, pregnancy of lupus patients had high risks of complication due to the high flare-up rate especially during the late pregnancy or postpartum period. It was also concordance with the increased incidences of fetal loss, spontaneous abortions, preterm delivery and intrauterine death.5,1426 patients Our study and several recent studies had shown an increase morbidity rate in pregnancies of lupus patients compared to healthy women.

A study was conducted by Hee WC in Mackay Memorial Hospital, Taipei, Taiwan with 24 pregnancies in 17 female SLE patients between January 2000 and February 2005,5 revealed 22 (91.6%) live-birth pregnancies, eight (33.3%) preterm delivery,5 two (8.3%) pregnancies were terminated due to loss of fetal heartbeat, three (13.6%) of the neonates had IUGR, and one (4.5%) had stillbirth.5 Pre-eclampsia occurred in three (13.6%) subjects. 5 There is no symptom indicating disease flare-up throughout the pregnancy period, such as malar rash, alopecia, and arthritis.5

A prospective study conducted by Aly Eman in the high-risk pregnancy unit in Department of Obstetrics and Gynecology, Cairo University Hospitals, Egypt included 84 SLE patients for the total 91 pregnancies from October 2010 to January 2015,15 showed complications such as arthritis were experienced by 84 (92%) patients, hypertension in 36 (39%) patients; hematological abnormalities (anemia and thrombocytopenia) were presented in 39 (42%) patients;15 spontaneous abortion occurred in 14 patients (15%), 7 (8%) pregnancies had IUFD, 3 (3%) cases of neonatal death and 77 (76%) live births neonates; 15 Twenty-nine (32%) pregnancies had IUGR, 12 (13%) was recorded with preterm deliveries, 12 (13%) experienced pre-eclampsia during pregnancy and 20 (22%) neonates presented with low birth weight. 15

There was another study conducted by Dey ID at the Korle-bu Teaching Hospital in 2013 in Ghana, West Africa showed that out of 7 pregnancies, there were 4 cases of full term birth and 3 cases were loss births during 16, 24 and 32 weeks of pregnancy.16 Meanwhile, six of these patients complained of arthritis, three had hypertension, four had rash. But no maternal death were reported. 16 Many doctors in Ghana did not have experience managing pregnant SLE patients. Thus, most pregnancies were not planned with the physicians.16 However, these cases provide valuable evidence that normal pregnancy is possible within SLE patients, even in poor resource settings.16

Upon the results, SLE remained stable in most patients during their pregnancy. Most women were able to carry out their pregnancy to term with a mild lupus activity.5 Hence, mothers with active SLE would achieve a higher chance to deliver successful pregnancies if they got optimal care from

obstetricians and physicians.5,17

Every woman with SLE who would like to get pregnant should consult and make plan with their respective physicians in order to decrease the risk of fetal and maternal complications. Patients are suggested to conceive only when the disease is inactive or has been stable for 6 months on appropriate medications.16 Pre-pregnancy counseling and multidisciplinary management can crucially improve the maternal and fetal outcome in lupus pregnancies.16 Throughout the gestational period, patients should cooperate with the physicians for detailed monitoring and antenatal care. Furthermore, some people experienced exacerbations of the disease in the postpartum period. Mother with SLE after pregnancy should be giving a great care and undergo respective management as to decrease or prevent any flares.

Limitation of this study is the time to conduct the research, due to that we only managed to get 53 samples out of 96 minimal required samples. The data only based on the interview, pediatrician and obstetrician were not involved to validate. Furthermore, our results were limited by the incomplete medical record about the manifestations during delivery such as laboratory results.

Conclusion In conclusion, the most frequent maternal complications during pregnancy were arthritis and rash. Pre-eclampsia and placenta previa were the most frequent obstetric complications which experienced by the pregnant SLE patients. Apart from live birth, the most frequent fetal outcome was spontaneous abortion. The most frequent neonatal complications were preterm delivery and low birth weight.

Reference1. Yazdany J, Dall’era M. Definition and classification of lupus and lupus-

related disorder. In: Wallace DJ, Hahn BH, editors. Dubois’ lupus erythematosus and related syndromes, 8th ed. Philadelphia: Saunders Elsevier;2012;(1):1–6.

2. Masi AT, Kaslow RA. Sex effects in systemic lupus erythematosus: a clue to pathogenesis. Arthritis Rheum. 1978;21(4):480–484

3. Witter FR. Management of the high-risk lupus pregnant patient. Rheum Dis Clin North Ame.2007;33(2):253–65.

4. Øtensen M. New insights into sexual functioning and fertility in rheumatic diseases. Best Pract Res Clin Rheumatol.2004;18(2):219–32.

5. Wong CH, Chen TL, Lee CS, Lin CJ, Chen CP. Outcome of pregnancy in patients with systemic lupus erythematosus. Taiwan J Obstet Gynecol. 2006;45(2):120-123

6. Michael LD, Ware B. Reproductive and hormonal aspects of systemic autoimmune diseases. In: Doria A, Pauletto P, editors. Handbook of systemic autoimmune diseases, 2nd ed. Philadelphia: Saunders Elsevier;2006;4:1–183.

7. Kumar A. Indian Guidelines on the Management of Sle. J Indian Rheumatol Assoc. 2002;10: 80–96.

8. Cervera R, Font J, Carmona F, Balasch J. Pregnancy in Systemic Lupus Erythematosus. Postgrad Med J. 2005;77:118–23.

9. Smyth A, Oliveira GHM, Lahr BD, et al. A systematic review and meta-analysis of pregnancy outcomes in patients with systemic lupus erythematosus and lupus nephritis. Clin J Am Soc Nephrol. 2010;5(11): 2060–8.

Original Article


10. Kalim H. Low Birth Weight and Maternal and Neonatal Deaths are Complications of Systemic Lupus Erythematosus in Pregnant Pristane Induced Lupus Mice. Arch Rheumatol. 2015;30(4):85–91.

11. Huang JB, Jian L. Molecular Mechanisms of Congenital Heart Disease. In: Rao PS, editors. Congenital Heart Disease-Selected Aspects, 1st ed. China: Intech; 2009(5): 121–40

12. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997;40(9):1725.

13. Gimovsky ML, Montoro M, Paul RHM. Pregnancy outcome in women with Systemic Lupus Erythematosys. Obstet Gynecol. 1984; 63(5): 686–692

14. Georgiou PE, Politi EN, Katsimbri P, Sakka V, Drosos AA. Outcome of lupus pregnancy: a controlled study. Rheumatology (Oxford). 2000;39(9): 1014–9.

15. Hussein AEA, Mohamed RR, Nabil MA. Pregnancy outcome in patients with systemic lupus erythematosus: A single center study in the High Risk Pregnancy unit. Middle East Fertil Soc J; 2016;21(3): 168–74.

16. Dzifa DI, Jerry C, Harriet K, Michael MK. Outcome of pregnancy in patients with systemic lupus erythematosis at Korle-bu Teaching Hospital. Ghana Med J.2016;50(2):6.

17. Kiss E, Bhattoa HP, Bettembuk P, Balogh A SG. Pregnancy in women with systemic lupus erythematosus. Eur J Obs Gynecol Reprod Biol. 2002;101:129–34.

Case Report


AbstractRenal Tubular Acidosis, a group of disorders characterized by defective renal acid-base regulation, can impair mineralization of bone matrix in adults known as osteomalacia. RTA is classified into 3 major forms, such as proximal RTA or type 2; distal RTA or type 1; and hyperkalemic RTA or type 4. Among all type of RTA, proximal RTA or type 2 is known have association with Fanconi syndrome and bone involvement. However, distal RTA or type 1 can also cause osteomalacia. Hereby we report a case of 22 years old Asian woman who was firstly diagnosed with distal type RTA several years ago then started developing bone involvement recently. She was complaining with low back pain due to fracture on left medial side of inferior pubic ramus and endplate fracture on right side superior L4 and BMD examination showed low mineral density. She was diagnosed with osteomalacia induced by distal type RTA due to the loss of calcium salts from bone and hypophosphatemia. Keywords: Osteomalacia; Renal Tubular Acidosis; Hypokalemia; Hypophosphatemia

Introduction Osteomalacia is the softening of the bones due to defective mineralization of the bone organic matrices. Osteomalacia is caused by inadequate intake or malabsorption of vitamin D and/or vitamin D metabolism disorders such as in chornic renal failure. Osteomalacia can also be caused by long standing hypophosphatemia due to renal phosphate wasting or excessive use of phosphate binders. Patients with osteomalacia may complain of bone pain and have muscle weakness, pigeon chest, spinal curvature and pseudofractures.1,2

Renal Tubular Acidosis (RTA) causes transport defect in the reabsorption of bicarbonate (HCO3-), the excretion of hydrogen ion (H+), or both. The syndromes of RTA are characterized by relatively normal GFR and metabolic acidosis, accompanied by hyperchloremia and normal plasma anion gap.3,4

RTA is classified into 3 major forms are proximal RTA or type 2, distal RTA or type 1, and hyperkalemic RTA or type 4. Proximal RTA is caused by impairment of HCO3- reabsorption in

proximal tubule and characterized by decreasing renal HCO3- threshold; distal RTA is caused by impairment of distal acidification and characterized with inability to lower urinary pH optimally under systemic acidemia condition. In general, HCO3- reabsorption is quantitatively normal in distal RTA. In hyperkalemic RTA (type 4), the acidification defect is caused mainly by impairment of ammoniagenesis and characterized by normal ability to acidify the urine after an acid load associated to subnormal net acid excretion due to very low rates of NH4

+ excretion.3,4 RTA has been identified as a cause of

osteomalacia. Proximal RTA is RTA which associated with Fanconi syndrome and osteomalacia due to hyphophosphatemia and relative 1,25-dihydroxy vitamin D deficiency but rarely rickets and osteomalacia can also be caused by distal RTA.5-11

Herewith, we reported a rare case of osteomalacia induced by distal RTA in 22 years old Asian female. She was diagnosed with distal RTA two years before she complained about bone pain and eventually diagnosed with osteomalacia.

Case ReportA 22 years old female came to rheumatology clinic in Cipto Mangunkusumo National Hospital due to low back pain which has been getting worse since six month ago. She was complaining pain on her back especially when she walks far, climbs up the stairs, and during sexual intercourse. She was diagnosed with Renal Tubular Acidosis Type 1 two years ago although the first time she complained about general weakness and low level of potassium was five years ago.

Five years ago, because of general weakness, she went to nearby hospital and diagnosed as hypokalemia. She had been treated with potassium supplementation and bicarbonate for three years before she admitted to our hospital one years ago due to worsening general weakness and hypokalemia. She was diagnosed with Renal Tubular Acidosis type 1 and was given potassium chloride, potassium citrate and bicarbonate.

Osteomalacia Induced by Renal Tubular Acidosis Type 1

Steven Sutanto Sihombing1, Anna Ariane2, RM Suryo Anggoro Kusumo Wibowo2, Bambang Setyohadi2

1 Internal Medicine Residency Program, Department of Internal Medicine, Faculty of Medicine University of Indonesia, Cipto Mangunkusumo Hospital2 Rheumatology Division, Department of Internal Medicine, Faculty of Medicine University of Indonesia, Cipto Mangunkusumo Hospital

Correspondence:Steven Sutanto Sihombing, MDEmail: [email protected]

Case Report


Table 1. Laboratory Examination Result First Time Admitted to RSCM

Laboratory Examination Result (December 2014)

HbHtWBCPlateletESR Na/K/Cl (mEq/L)Mg (mg/dL)Ca ion (mmol/L)Phosphate (mg/dL)AST/ALT (U/L)Ureum/Creatinin (mg/dL)Urine Na per 24 hours Urine K per 24 hoursUrine Cl per 24 hours

12 g/dL 35%29,790/µL451,000/µL84mm140 / 2,39 / 1101,270,780,817 / 1710 / 1,2131 mEq/24 hrs85 mEq/24 hrs165 mEq/24 hrs

Urine ExaminationColor: YellowWBC: 5-6/hpfRBC: 25-27/hpfCylinder : negativeBacteria : negativeBJ 1.015, pH 7.5Bilirubin : negativeAlbumin : negativeGlucose : negativeKeton : negativeBlood/Hb : +2Nitrite : negativeLeucocyte esterase : negative

ABG : pH 7.108/ pCO2 30.10/ pO2 122.90/ HCO3- 9.6/ BE -18/ SpO2 97%

Hb: Hemoglobin; WBC: White Blood Cells; RBC: Red Blood Cells; ESR: Erythrocyte Sedimentation Rate; AST: aspartate transaminase; ALT: alanine transaminase; ABG: Analysis Blood Gas

Although she was routinely went to our nephrology clinic in Cipto Mangunkusumo National Hospital, she still had recurrent symptoms of generalized weakness and hypokalemia due to lack of potassium citrate available in pharmacies.

From the kidney ultrasonography examination by nephrologist, there was nephroclacinosis bilateral with mutiple cyst in right kidney. She started complaining about low back pain since 6 months ago when she was walking far away, climbing up stairs, bending over and during sexual intercourse with her husband. Due to the worsening of the back pain, she was suggested to do lumbar and pelvic X-ray examination. X-ray photos showed fracture on left medial side of inferior pubic ramus and suspected fracture on right inferior pubic ramus and superior pubic ramus. There is also endplate fracture on right side superior L4 spine.

Figure 1. A. Pelvic X-Ray Examination showed fracture on left medial side of inferior pubic ramus. B. Lumbal X-Ray Examination showed endplate fracture on right side superior L4

She was referred to rheumatology clinic due to suspected bone and mineral disorder. She was examined for alkaline

phosphatase and parathyroid hormone in serum, also calcium and phosphate level in urin. She had low level of calcium and phosphate in urine and high level of intact parathyroid hormone.

Table 2. Laboratory Examination Result From Rheumatology Clinic

Laboratory Examination Result (March 2017)

Alkaline PhosphataseUrin calciumUrin calcium 24 hoursUrin Inorganic Phosphate Urine volumePhosphateUreumCreatinin

358 U/L (high)2.6 mg/dL 45.5 mg/24 hrs (low)0.3 g/24 hrs (low)1750 mL1.4 mg/dL (low)23 mg/dL0.8 mg/dL

ABG : pH 7.317/ pCO2 29.7/ pO2 96.40/ HCO3 15.30/ BE -8.60/ SpO2 97%

ABG: Analysis Blood Gas, BE: Base Excess.

Beside laboratory work up, she was also examined for bone mineral density (BMD). Her BMD examination showed low mineral density with Z score L1-4: -2.2 and Z score radius 33%: -1.5.

Table 3. Bone Mineral Density Examination ResultRegion BMD (g/

cm2)Young-Adult Age-Matched

(%) T-score (%) Z-score

L1 0.757 72 -2.4 79 -1.7L2 0.783 70 -2.8 76 -2.1

L3 0.798 70 -2.8 76 -2.1

L4 0.740 65 -3.3 71 -2.6

L1-L2 0.771 71 -2.6 77 -1.9

L1-L3 0.781 71 -2.7 77 -2.0L1-L4 0.768 69 -2.9 75 -2.2L2-L3 0.791 70 -2.8 76 -2.1L2-L4 0.771 68 -3.0 74 -2.3L3-L4 0.767 68 -3.1 73 -2.4Neck 0.688 75 -1.9 78 -1.6Wards 0.594 68 -2.0 70 -1.8Troch 0.505 67 -2.3 71 -1.8Shaft 0.774 - - - -Total 0.641 67 -2.5 71 -2.1Radius UD 0.293 65 -3.4 65 -3.4Ulna UD 0.226 - - - -Radius 33% 0.716 84 -1.5 84 -1.5Ulna 33% 0.760 - - - -Both UD 0.269 - - - -Both 33% 0.736 - - - -Radius Total 0.535 81 -2.0 81 -2.0Ulna Total 0.521 - - - -Both Total 0.529 - - - -

A B

Case Report


Based on the examination results, she was diagnosed with osteomalacia induced by renal tubular acidosis type 1 and also secondary hyperparathyroidism.

DiscussionRenal Tubular Acidosis type I is caused by impaired distal acidification and is characterized by inability to lower urinary pH maximally (pH <5.5) under the stimulus of systemic acidemia. In general, HCO3- reabsorption is quantitatively normal.3

Soriano, et al. tried to simplify the difference between various type of RTA in a table. From that table we can conclude that our patients fit into distal RTA (type 1) due to decreased plasma K+, positive urinary anion gap (urinary Na plus K level per 24 hours is bigger than urinary chloride level), urine pH > 5.5 and also presence of nephrocalcinosis. Ca excretion usually increased in distal RTA but it was decreased in our case. We need to remember that our patient has already been treated with potassium chloride and bicarbonate for three years before she was admitted to our hospital.3

Table 4. Differential Diagnosis of Various Type of RTA3

Our patient also has bone involvement which is more common in proximal RTA than distal RTA. She had fracture on left medial side of inferior pubic ramus and suspected fracture on right inferior pubic ramus and superior pubic ramus. There is also an endplate fracture on right side superior L4 and low mineral density in BMD examination. According to the International Society for Clinical Densitometry, for premenopausal women Z scores of -2.0 or less are below the expected range for age.12

Distal RTA or RTA type 1 can induced osteomalacia, although not as common as proximal RTA or RTA type 2. In RTA type 1, there is an increased calcium phosphate release from bone as a result of bone buffering in the excess acid condition. Besides, there is also reduction in tubular calcium reabsorption secondary to chronic acidosis. Those will lead to hypercalciuria and alkaline urine which increased deposition of calcium salt in renal parenchyma (nephrocalcinosis) and

also induce calcium phosphate stone formation. Low calcium serum level can increase parathyroid

hormone just like what happened in our patient. The hyperparathyroidism can increased renal phosphate excretion which lead to hypophosphatemia due to the ability of parathyroid hormone in inhibiting proximal renal tubule phosphate transport. Our patient has low level of calcium and phosphate in serum although the excretion in the urine was also decreased. Loss of calcium salts from bone and hypophosphatemia in our patient can result in osteomalacia. The pathogenesis of RTA type 1 is presented in Figure 2.

Figure 2. Pathogenesis Osteomalacia Induced by RTA type 1

ConclusionRTA has been identified to cause osteomalacia in adults. Bone involvement is more common in proximal type RTA (type 2) but distal RTA (type 1) can also cause osteomalacia due to loss of calcium salts from bone and hypophosphatemia.

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Harison’s Manual Of Medicine, 18th Edition. United States: McGraw Hill; 2013

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Case Report


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11. Tahir M, Ansari JK. Osteomalacia Due To Type-1 Renal Tubular Acidosis In A Middle Aged Pakistani Woman. PAFMI. 2009;50(1): 123-125

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8. Yamaguchi S, Maruyama T, Wakino S, et al. A case of severe osteo-malacia caused by Tubulointerstitial nephritis with Fanconi syndrome in asymptomatic primary billiary cirrhosis. BMC Nephrology. 2015;16 : 187

9. Lee JH, Park JH, Ha TS, Han HS. Refractory rickets caused by mild distal renal tubular acidosis. Ann Pediatr Endocrinol Metab. 2013; 18(3): 152-155

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