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Sree Chitra Tirunal Institute for Medical sciences and Technology

Trivandrum -695011

PROJECT REPORT

Name Dr. Ramesha.K.N

Program DM Neurology

Month & year of submission October 2006

CERTIFICATE

I, Dr. Ramesha .K .N, hereby declare that I have actually carried out the project under report

Place: Trivandrum Date: 12.10.2006

Signature =·

Dr. Ramesha.K.N

Forwarded, he has carried out the project under report

Signature~~/ ~ Dr. Abraham ~uruvilla

Associate Professor Department ofNeurology SCTIMST, Trivandrum

PROJECT REPORT

CLINICAL, ELECTOPHYSIOLOGICAL AND HISTOPATHOLOGICAL CORRELATIONS IN INFLAMMATORY MUSCLE DISEASE

Name Dr. Ramesha.K.N

Program DM Neurology

Month & year of submission October 2006

ACKNOWLEDGEMENT

I wish to express my heartfelt gratitude towards my teacher, Dr Abraham Kuruvilla, Associateprofessor of Neurology, who has been my thesis guide. He has carefully guided me through out the study, without which I might not have been able to accomplish the goal.

I express my sincere gratitude to Dr. K.Radhakrishnan, Professor and Head of the department of Neurology in taking keen interest in the study.

I am very grateful to Dr. Muralidharan Nair, Professor, department of Neurology for his constant guidance.

I am also thankful to staff members of the medical record department, who provided necessary help in data collection.

I am thankful to Dr Sarma, statistician, in helping me for carrying out the statistics part. · Most importantly, I thank all my patients in sincerely participating in the study, without co-operation of whom, this study would never have been possible

CONTENTS

1. INTRODUCTION

2. REVIEW OF LITERATURE

3. AIMS AND OBJECTIVE

4. PATIENTS AND METHODS

5. RESULTS

6. DISCUSSION

7. CONCLUSION

8. REFERENCES

9. APPENDIX

INTRODUCTION

The inflammatory myopathies are simply those disorders in which the primary pathological process is inflammation within muscle. In most, the main clinicai consequence is weakness, much less frequently pain. This definition thus excludes myopathies with secondary inflammation in muscle, such as some of the muscular dystrophies, and conditions in which the inflammatory process is in associated tissues rather than muscle itself, such as polymyalgia rheumatica. These latter conditions are particularly important as they may be misdiagnosed and mistreated as being forms of myositis. ·

The inflammatory myopathies are rare. No accurate figures for incidence or prevalence are available but if one takes the two most common conditions, dermatomyositis and inclusion body myositis, their combined annual incidence IS

probably less than 200 new cases per annum in the UK (population ~60 million).

In perhaps 70% of cases, the diagnosis and management are straightforward and successful· With respect to drug treatment there is an absolute dearth of randomised controlled trials and the best advice that can be offered is based on "expert opinion". Multicentre trials are desperately needed

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Classification of the inflammatory myopathies

• Idiopathic

-dermatomyositis (DM) - polymyositis (PM) - inclusion body myositis (IBM)

• Associated with connective tissue diseases

-systemic lupus erythematosus - mixed connective tissue disease - scleroderma -Sjogren's syndrome -rheumatoid arthritis

• Infective

- viral (Coxsackie, influenza, HIV, HTL V I) -parasitic -bacterial -fungal

• Miscellaneous

- eosinophilic myositis -associated with vasculitis -granulomatous (for example, sarcoid) - orbital myositis - graft v host disease · - macrophagic myofasciitis

Dermatomyositis (DM) is the most common form of classical inflammatory myopathy. Isolated polymyositis (PM) is rare, but a frequent misdiagnosis. But PM is relatively frequently associated with various manifestations of connective tissue disease, a situation for which many use the term "overlap syndrome". Some argue that there is a difference between "overlap" and "association" but in truth we are currently ignorant of the true relationship between these various conditions. Debate continues as to whether inclusion body myositis (IBM) is a primary inflammatory myopathy, or whether the inflammatory changes are a secondary phenomenon. One of the strongest arguments in favour of the latter is that IBM responds poorly, ·if at all, to immunosuppressant/anti­inflammatory treatments. IBM is often initially wrongly diagnosed and treated as PM, usually because. of failure to appreciate the specific clinical and pathological features of the condition.

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PATHOGENESIS

For a long time, DM and PM were considered to be essentially identical disorders, differing only by the presence or absence of skin involvement. There is now overwhelming evidence that they are fundamentally different disorders in term of pathogenesis . It is likely that in the future their differing pathogeneses will lead to specific immunomodulatory treatments for each disorder, but that is not so at present and treatment, as for other autoimmune disorders, takes the form of a "blruiderbuss" approach to immunosuppression

DM is a humorally mediated autoimmune disorder. Complement dependent attack leads to destruction of capillaries in muscle and other tissues. In muscle, the resulting microangiopathy leads to the characteristic pathological features of infarction and perifascicular atrophy. Whether it is deposition of circulating immune complexes or the binding of an antibody to an endothelial antigen which triggers this lytic complement pathway is unknown.

PM is caused by a cell mediated immune phenomenon. Autoinvasive CDS+ T cells, recognising an unknown muscle antigen, invade non-necrotic muscle fibres expressing class 1 major histocompatibility complex antigen (MHC-1) and lead to their destruction.

In IBM, although there is some similarity with the immunocytological findings seen in PM, there is evidence that the fundamental pathological process is different and that at least some of the inflammatory and immune changes seen in IBM may be epiphenomena. Similarities have been drawn between the pathological findings in muscle in IBM and those in the brain in Alzheimer's disease, but again whether these are primary or secondary phenomena has yet to be determined.

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CLINICAL FEATURES

Many inherited myopathies (for example, the muscular dystrophies) are characterised by highly selective involvement of specific muscles, with physically adjacent muscles showing notably different degrees of involvement . Selectivity, which is a powerful diagnostic tool for the appropriately experienced clinician, is not a feature of DM or PM, but is evident in many cases ofiBM.

In DM and PM, as in so many acquired myopathies (for example, endocrine and drug induced myopathies), the characteristic feature is generalised proximal muscle wasting and weakness, with the pelvic girdle musculature nearly always being more severely affected than the shoulder girdle muscles (presentation with shoulder girdle weakness is unusual). The typical symptoms include difficulty climbing stairs and rising from a low chair, and difficulty with tasks at and above shoulder height such as self grooming and lifting objects onto shelves. Distal weakness is a late feature and is never as severe as proximal weakness

In contrast, IBM often shows remarkably selective muscle involvement, with the most characteristic pattern being wasting and weakness of quadriceps (and it is almost certainly the most common cause of what used to be called "isolated quadriceps myopathy") and of the long finger flexors. The clinical consequences are falling, caused by the knees giving way, and weakness of grip. In other words, the most fundamental functions of the lower and upper limbs, respectively, are compromised and the disease can cause profound functional disability.

In addition to these general observations about the pattern of muscle involvement,

each disease also has additional clinical characteristics and associations.

Dermatomyositis

DM can affect all ages but the disease in children differs somewhat from that in adults; general misery rather than obvious weakness may be the presenting feature,

· subcutaneous calcification is more common, the face may be flushed without the more specific characteristics of the rash seen in adults, and the bowel may be involved. In adults the disease usually presents subacutely with symptoms evolving over several weeks, but less commonly the onset can be very acute· with widespread muscle and subcutaneous oedema. Patients with severe disease may develop respiratory failure. Dysphagia, with risk of aspiration, is also common in severe disease.

About 20% of cases, more in the older population, are associated with an underlying malignancy and, as with other paraneoplastic disorders, the neoplasm may not

9

reveal itself until some considerable time (possibly 2-3 years) after first presentation. Unlike, for example, Lambert-Eaton myasthenic syndrome, there is not a close association with one particular site or type of tumour.

Skin rash is evident in most patients and is often the first symptom. It may be absent throughout , the diagnosis then resting on the characteristic muscle biopsy findings in DM, be fleeting and rather non-specific (for example, facial or chest erythema), or be difficult to see in dark skinned individuals (and note that the incidence of D M is higher in those of Afro-Caribbean origin). Dermatologists may see DM without apparent muscle weakness , but in most of those patients muscle biopsy will show characteristic abnormalities.

The rash has many similarities with that seen in systemic lupus erythematosus, and indeed there are pathological features in common including the presence of undulating tubules in capillary endothelial cells. Both show photosensitivity. The typical cutaneous features of DM include erythema over the light exposed cheeks (malar distribution), upper anterior chest (V sign), upper posterior chest (shawl sign), and knuckles. The eyelids may be oedematous and show purple (heliotrope) discolouration, but this is a less constant feature than the less specific erythema and the hand signs. As well as erythema there may be a scaly eruption (Gottron's sign) over the knuckles, but the phalanges are spared. Dilated capillaries may be seen at the base of the fingernails. A dry, cracked, appearance to the hands is referred to as "mechanic's hands"; it is often, but not invariably, associated with the presence of anti-synthetase antibodies, including anti-Jo-1.

Interstitial lung disease is seen in about 10%, and is occasionally the presenting problem. Here . there is a strong association with the presence of anti-synthetase antibodies, particularly anti-Jo-1. It may potentially be confused with methotrexate induced pneumonitis when that drug is used to treat the myositis. Myocarditis and conduction abnormalities may be seen, particularly in severe acute disease. Morbidity and mortality in DM relate mainly to interstitial lung disease, myocardial involvement, and the complications of respiratory failure secondrur to respiratory muscle weakness.

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Polymyositis

Evolution of weakness is slower than in DM, typically over months, but generally faster than in IBM. Dysphagia and facial weakness are uncommon. It is a disease of adult life. It is uncertain whether PM is associated with malignancy, but if it is the link is less strong than for DM, and on current evidence extensive searching for an underlying malignancy is not ·justified. The uncertainty is because earlier studies used obsolete criteria to distinguish between PM and DM.

PM is never associated with the cutaneous features of DM. As in DM, interstitial lung disease is associated with anti-Jo-1 and other myositis specific antibodies. Myocardial involvement may occur.

Pure" PM is rare, but as noted below PM may be associated with other manifestations of connective tissue disease. A diagnosis of PM is frequently made in error . "Treatment resistant" PM is usually the result of an incorrect diagnosis, most often IBM, and indeed many patients with IBM have finally been correctly diagnosed only after failure to respond to immunosuppression. Failure to diagnose IBM at the outset is typically due to not appreciating the specific pattern of muscle weakness, in particular missing ·finger flexion weakness, and failing to appreciate the specific pathological features, notably rimmed vacuoles and filamentous inclusions. Muscular dystrophy may . be mistaken for PM, most often when the duration of symptoms appears to be short. The pattern of weakness may be very helpful in making a distinction. Secondary inflammatory infiltrates may cause pathological confusion, especially in dysferlinopathy and facioscapulohumeral muscular dystrophy.

Diseases commonly misdiagnosed as polymyositis

• Inclusion body myositis • Dermatomyositis sine dermatitis • Muscular dystrophy

-limb-girdle muscular dystrophy type 2B ( dysferlinopathy) -Becker (especially when adult onset)

• Endocrinopathy • Drug induced myopathy • Metabolic myopathies

- acid maltase deficiency -McArdle's deficiency (myophosphorylase deficiency)

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• Neurogenic disorders

- late onset spinal muscular atrophy - motor neurone disease - "Fatigue" syndromes

Finally, the diagnosis of PM is often wrongly made in the rather common situation of a patient with pain, symptomatic but not objective weakness, and modest elevation of the SCK. Muscle biopsy may show minor "abnormalities" which are wrongly taken to confirm the diagnosis of PM. Steroids may offer a brief honeymoon period of improvement. Looking at such patients more carefully, one notes that their pain is not entirely in the muscles, but also affects their joints and sometimes their skin and bones. What they describe as weakness is more a difficulty in sustaining effort. Initial examination may suggest weakness, but with encouragement and functional tests such as rising from a squat it becomes apparent that there is no true weakness. Most laboratories quote an upper normal concentration of SCK that is too low. Values are higher in men than women, and in blacks than whites. A normal male undertaking modest physical activity may have concentrations as high as 600 IU/1. Somebody undertaking more vigorous exercise, and particularly if black, may have values up to 1000 lUll. The difficulty, of course, is knowing whether a concentration of, say, 450 IU/1 in somebody complaining of muscle pain is relevant or not. Patients with this type· of problem should never be put on steroids without a muscle biopsy. But they are, and when their symptoms continue and they then have a biopsy it may be impossible to interpret the findings. The correct diagnosis in this rather common group of patients may prove to be elusive.

Inclusion body myositis

This is the most common acquired myopathy in those over 50 years of age. It is substantially more common in men, an unusual feature for an autoimmune disease and another factor that has cast some doubt as to whether it is a true primary inflammatory myopathy. Infrequently, it can present as early as the third decade. Familial instances have been recorded. It is more correctly designated as sporadic IBM to distinguish it from the much rarer inherited IBM. This includes dominant and recessive forms, which share clinical and pathological features with sporadic IBM, with the notable exception of absence of inflammatory infiltrates.

The major clinical features of IBM have already been discussed, but it merits repetition to emphasise that the presence of distal weakness that is as severe or more pronounced than the proximal weakness in the same limb is highly characteristic. This is usually most evident for the finger flexors, but ankle dorsiflexion weakness may also be pronounced. Another feature of ffiM, but not PM or DM, is asymmetric muscle involvement, sometimes pronounced. Mild facial weakness may be seen even when limb weakness is relatively mild (rare in DM and PM), and dysphagia can be an early or late

feature.

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The rate of progression is typically slower than in PM. Elderly patients frequently cannot easily date the onset of the problem, as they attribute early symptoms to the normal effects of aging. Substantial quadriceps wasting and weakness is frequently evident on first presentation. A major practical problem is falling caused by an inability to lock the knees.

Myositis specific antibodies are much less frequent in IBM compared with DM and PM. Similarly, associated conditions are less frequent, but there are reports of IBM in

association with Sjogren's syndrome, hepatitis C, HTL V -1 infection, and sarcoidosis.

Overlap/associated syndromes

Rather than trying to define specific associations ("splitting"), on the basis of our current somewhat limited knowledge, it is perhaps best to simply note that patients with myositis may also be found to have features of other connective tissue disorders ("lumping"). Many of these associations have been described above. DM may be associated with features of scleroderma (often with circulating anti-PM-Scl antibodies) and mixed connective tissue disease. PM is associated with many systemic autoimmune diseases and indeed isolated PM is rare. DM and PM may be associated with non-specific symptoms such as fever and arthralgia, and with Raynaud's phenomenon. These various phenomena, together with interstitial lung disease, when associated with anti-synthetase antibodies, form the main components of the anti-synthetase syndrome. In such patients, the myositic component may be slight and initially overlooked. Finally, to avoid diagnostic confusion, it is worth noting that DM is often associated with the presence of anti-nuclear antibodies (ANA), often at substantial titre, but without other clinical features or specific immunological findings associated with SLE. On the other hand, patients with SLE may have an associated myositis

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DIAGNOSIS

Skilled clinical assessment, taking into account all of the factors already discussed, is arguably the most powerful diagnostic tool, but laboratory confirmation of the diagnosis is required in most cases. The "gold standard" is muscle biopsy. Electromyography, estimation of SCK, and detection of myositis specific antibodies may be helpful. Arguably, a patient with all of the classical clinical features of DM, elevation of the SCK, and typical neurophysiological changes does not need a confirmatory muscle biopsy, but overall few cases of suspected myositis should escape biopsy. If management difficulties arise, there is often regret if a biopsy was not performed before initiation of treatment

Serum Creatinine kinase

Despite its lack of specificity this is an extremely useful test in both diagnosis and management. In the vast majority of patients with DM or PM the concentration is elevated, typically to several thousand IU/l. It tends to be higher in those with acute onset and substantial weakness, and lower in those with more chronic disease, but there is considerable variability. For unexplained reasons, the SCK occasionally remains stubbornly normal. Most patients with IBM have an increased SCK, .but typically rather lower than in DM and PM, often around 1000 IU/l. In all of these diseases there may be

substantial fluctuation from day to day, even without treatment.

Classical EMG findings in Acute IMD

1. Increased insertional activity with CRDs 2. Fibrillations & positive sharp waves 3. Small polyphasics short duration MUPs 4. Most striking and constant finding: Early recruitment: full interference with

slight volitional effort.

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Muscle biopsy

Pathological feature Dermatomyositis Polymyositis Inclusion body myositis

Inflammatory infiltrates Perivascular Endomysia! Endomysial

T cells > B cells - + + B cells > T cells + - -Partial invasion of fibres - ++ ++ Micro infarcts ++ - -Scattered necrotic fibres - +- +-Perifascicular atrophy ++ - -Zonal myofibrillar loss + - -Rimmed vacuoles - - ++ 15 nm filaments - - ++ MHC-1 expression + ++ ++

Table I: Major muscle biopsy findings

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MANAGEMENT

DM and PM will be considered together, IBM separately. With respect to drug treatment, and also to some extent to general management issues, it must be reiterated that there is little guidance from the literature in the form of randomised controlled trials and that much of what is presented here is based on personal experience and "expert opinion".

Dermatomyositis and polymyositis

Although their drug management will be considered together, there are two issues specific to the management of DM. Firstly, except in children, the possibility of an associated malignancy must be excluded, particularly in the older patient and those with a higher risk of malignancy (for example, smoker, strong family history, other predisposing illness). Where appropriate, examination should include breast, vaginal, and rectal examination. Imaging should include the chest, abdomen, and pelvis. More detailed investigations may be suggested by the history-for example, colonoscopy in somebody with altered bowel habit. Reassessment is necessary for 1-2 years. Secondly, although the skin rash is likely to respond to systemic immunosuppressant therapy, there are situations when topical treatment may also be of value-for example, for a· severe local skin eruption. Furthermore, the rash is photosensitive and a sun blocking cream can be very effective in reducing cutaneous manifestations.

Corticosteroids are the mainstay of treatment. Unanswered questions relate to the specific preparation and dosage regimens, the selection, use, and timing of introduction of other immunosuppressant drugs ("steroid sparing agents"), and the place for intravenous immunoglobulin treatment

Corticosteroids The vast majority of pa.tients respond to steroids. Failure to respond is most often

caused by inadequate initial dosage or duration of treatment, less often to lack of compliance because of worry about side effects. A few patients appear to be truly resistant, but respond to other immunosuppressant regimens. Experience suggests that early aggressive treatment tends to be associated with a faster response and better outcome, so all but the most indolent cases are given intravenous methylprednisolone 500 mg daily for five days, followed by oral prednisolone 1 mg/kg body weight per day, given as a single morning dose. Once the SCK has returned to normal and the patient is improving, the dosage is reduced by 5 mg on alternate days, so that after 1-2 months the patient will be on 1 mg/kg body weight on alternate days. Thereafter, the dose is slowly reduced, depending on clinical response and SCK (see below), to determine the minimal maintenance dose.

Open studies have suggested that other steroid regimens might offer a better benefit/side effect ratio, but none has been proven in an appropriate randomised

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controlled trial. These have included pulsed high dose oral and intravenous regimens, and the use of dexamethasone rather than prednisolone .

. Immunosuppressants

There is enough evidence from the literature and personal experience to leave no doubt that such drugs can be effective. There is currently inadequate data to suggest that any one drug is superior to another, and choice is largely determined by personal experience, often from using the drug to treat other diseases. Thus, rheumatologists and dermatologists tend to use methotrexate (up to 30 mg weekly), as they have experience of its use in arthritis and psoriasis respectively, whereas many neurologists favour azathioprine (2.5 mg/kg body weight per day), having gained experience of its use in myasthenia gravis and immune neuropathies. Methotrexate can cause a pneumonitis, and possibly this could be confused with the interstitial lung disease associated with myositis. Cyclosporin (up to 5 mg/kg body weight per day) has been advocated for use in childhood DM, but is also used in the adult form of the disease. Mycophenolate mofetil (2 g daily) is currently in vogue. Cyclophosphamide has been given as intravenous pulses (up to 1 g/m2 body surface area) and as oral treatment (up to 2 mg/kg body weight per day). There is some evidence to suggest that it is particularly helpful in the treatment of associated interstitial lung disease.

A further question relates to the timing of the introduction of these drugs. It is often suggested that they be used if the patient fails to respond adequately to prednisolone, has serious side effects from prednisolone, or the required maintenance dose of steroids is unacceptably high. The practical problem is that it may take many months, possibly of continuing deterioration, before the patient can be identified as falling into one of these categories. The various immunosuppressant drugs listed above are all slower to act than prednisolone. Azathioprine is probably the slowest--experience from myasthenia gravis shows that it takes 9-12 months to become effective. All of the other drugs probably work faster than this, but even so probably take many months to exert their maximal effect. Because of these issues, and paralleling our experience in myasthenia gravis, it is reasonable to start an immunosuppressant drug (our choice is azathioprine) at the same time as prednisolone, in the expectation that it will eventually allow a lower maintenance dose of prednisolone. This hypothesis has yet to be proven in a randomised controlled trial.

Intravenous immunoglobulin

There have been enough studies to conclude that intravenous immunoglobulin is effective in both DM and PM, but not sufficient data to define its exact position versus steroids and immunosuppressant drugs. At present its use is probably best reserved for those with disease that is resistant to steroid and immunosuppressant drug treatment.

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Monitoring response

This involves elements of art as well as science. The aim is to taper the prednisolone to find the minimum dose required to hold the disease in remission, which in some patients on an additioni:ll immunosuppressant drug may be zero. Although it is often emphasised that one should treat the patient, not the blood test, a rising SCK is a cause for concern and may herald recurrence. On the other hand, recurrence, with increasing weakness, can occur with no increase in SCK. Steroid induced myopathy is a theoretical concern, but appears to be rare on an alternate day dosage regime. As with many other autoimmune diseases, the disease may be held in pharmacological remission, but "cure" is more elusive. In our experience, long term drug-free remission is more common in DM than PM.

Inclusion body myositis

Most patients with typical IBM do not have a useful response to steroids, immunosuppressant drugs, or intravenous immunoglobulin. If after informed discussion they are keen to attempt drug treatment, then I would use an 18-24 month trial of prednisolone and azathioprine (or methotrexate) as outlined above. The prednisolone would be tapered until the SCK started to rise. Treatment would only continue if there was unequivocal benefit. The potential side. effects should not be underestimated and in the ·last year we have seen death from cytomegalovirus pneumonia, and salmonella infection in an artificial hip.

Atypical cases make me more inclined to propose a trial of treatment, but as yet the evidence base for doing 'this is lacking. Features might include onset in early adult life, pronounced inflammatory infiltrates on biopsy, exceptionally high SCK, and associated immune disorders

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AGE DISTRIBUTION

• < 18yrs |»18-50Yre •>50yrs

Fig 1: Pie chart showing age distribution: total 84 cases

SEX DISTRIBUTION

I Male I Female

Fig 2: Pie chart showing sex distribution: total 84 cases

w

Number

50 40 30 20 10 0

With pain without pain

Fig 3: Picture showing the comparison of number of cases with pain /tenderness Vs without pain: total 84 cases

W

So'

60

50

40

30

20

10

0

I Ambulant without supprt

I Ambulant with support

Fig 4:Chart showing the comparison of number of patients who were ambulant without support Vs with support

I 80 1 60

"5 40 20

E 3

0 2

Neck musce weakness

1 1 Yes No

Fig 5: Chart showing neck muscle weakness: total 84 cases

Fig 6: Pie chart showing distribution of patients with bulbar weakness

2 40 S 30 ° 20 1 10 § o

Deep tendon reflexes

r ~ i Normal Sluggish Absent

Grading Brisk

Fig 7: Picture showing status of deep tendon reflexes in 84 patients with inflammatory muscle disease

Total leucocyte count

[Elevated I Normal

Fig 8: Pie chart showing status of total leukocyte counts in 84 patients with inflammatory muscle disease

SGOPT/SGPT

\m Elevated i • Normal {•Not done

Fig 9: Picture showing status of serum SGOT / SGPT enzymes in 84 patients with inflammatory muscle disease

- 6 0 S 50 S 40 2 E

30 20 10 0

Erythrocyte sedimentation rate

Elevated Normal

Fig 10: Picture showing status of erythrocyte sedimentation rate in 84 patients with inflammatory muscle disease

—

I 50

| 4 0

£ 30 1-E 10 3 Z 0

>1000 u <1000U

Values in units /

Normal

Fig 11: Picture showing status of serum creatinine phosphokinase value in 84 patients with inflammatory muscle disease

BIMD • Neurogenic • Normal • Not done • Inconclusive • Alternate

Fig 12: Pie chart showing the distribution of biopsy findings: 84 cases

EMG

• Myopathic • Neurogenic • Normal • Inconclusive • Not done

Fig 13: Pie chart showing status of electromyography findings in 84 patients with inflammatory muscle disease

Others i . >

Neurogenic

1—' IMD 1 - | j

Myopathic 1 Myopathic i i i

20 40 60 80 100

Fig 14: Bar chart showing distribution of EMG changes: total 84 cases (Note: group 'others * include two patients with inconclusive EMG

& one each where EMG was either normal or not done)

• PM • DM • IBM • Neoplasia • overlap • alternate • inconclusive

Fig 15: Pie chart showing the distribution of final diagnosis: total 84 cases

Fig 16: Chart showing number of patients with and without relapse during the follow up of 72 patents when steroids /immunomodulatory were tapered off

w

w

15yrs

11-14yrs

7-10yrs

4-6yrs

1-3yrs

»

1

1

) 10 15 20

Fig 17: Bar chart showing duration of follow up of 72 patients (in years)

Fig 18: Pie chart showing final outcome in 72 patients (Note: Excellent: asymptomatic, incomplete: partial recovery.

Poor: expired: 8 and worsened: 3)

Picturel9: Light microscopy: Histopathology of inclusion body myositis

Picture 20: Light microscopy: Histopathology of polymyositis

IBM PM DM Age at onset >50 adults All ages Sex M F F Family history Rare No No Ass.with No slight yes malignancy Connective tissue 15% yes yes disorder Weakness P=D P>D P>D Rash No No Yes CPK 10 50 times 50 times Response to Rx poor variable Good Biopsy Rimmed vacuoles EM inflammation ' PV inflammation

Amyloid deposits Muscle fiber invasion Complement deposits Tubulofilaments CD8+ T cells .

CD4+ and B cells

Table II: Comparison of major types of inflammatory muscle disease

Ten important points to ponder

1. Pain and discomfort are rarely prominent in myositis 2. The normal upper limit for serum creatine kinase is higher than we usually think 3. Failure io appreciate points 1 and 2 leads to many patients being wrongly

diagnosed, and treated, as having polymyositis 4. Pure polymyositis is a rare condition 5. Inflammatory infiltrates in a muscle biopsy may be a secondary phenomenon and

failure to appreciate this is a common reason for wrong diagnosis and inappropriate treatment

6. Absence of inflammatory infiltrates in a biopsy does not exclude myositis 7. Despite their clinical similarities, dermatomyositis and polymyositis are

fundamentally different disorders in terms of pathogenesis 8. Inclusion body myositis, the most common acquired myopathy over the age of 50

years, is frequently misdiagnosed as polymyositis. Whether it is a true "myositis" remains hotly debated ,

9. Dermatomyositis may be a paraneoplastic disorder, particularly in the elderly 10. Long term morbidity and mortality relate to interstitial lung disease, myocardial

involvement, and associated malignancy

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AIMS AND OBJECTIVES OF THE STUDY

1. To study the clinical, electrophysilogical & histopathlogical profile and their correlations in inflammatory muscle disease

2. To study the overall response rate to treatment and relapse rate with drug tapering

3. To assess the predictive factors which can determine the overall outcome

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MATERIALS & METHODS

All consecutive cases of inflammatory muscle disease treated in the department of Neurology, Sree Chitra Tirunal Institute for Medical sciences and Technology, Trivandrum from 1984 to April 2004 were reviewed. Similarly those cases with clinical diagnosis inflammatory muscle disease admitted and treated from Aprii 2004 to July 2005 were prospectively recruited . The cases were followed up for minimum of one year to maximum of 15 years from the date of diagnosis of the illness. CflSeS with definite alternate diagnosis at any time during follow up were excluded from the study. Analysis was made of the features at presentation and during the course of the illness, and of prognostic factors bearing upon the disability, response to treatment and mortality

A systematic chart review was done to collect the demographic data, clinical features, investigations including serum enzyme assay; electromyography & muscle biopsy findings, treatment details & complication during the hospital stay .In the retrospective group, clinical and investigations details were collected from the case sheets of respective patients from the medical record department .In prospective group, same w~re noted before discharge. Patents were followed up initially at three months intervals till the end of first year after the diagnosis, then yearly till five years, then at 1oth and fifteen years after the diagnosis wherever possible. During each follow up, clinical features, serum CPK value & ESR was noted along with response to treatment

Diagnosis of inflammatory muscle disease was done according to diagnostic criteria: Bohan &Peter (1975)

1. Symmetric weakness of limb-girdle muscles and anterior neck flexors progressing over weeks to months

2. Biopsy findings-necrosis of fiber types, phagocytes, regeneration, perifascicular atrophy, inflammation

3. Elevation of serum muscle enzymes

4.Electromyographic evidence of myopathic motor units, fibrillations, positive waves, insertional irritability

5. Heliotropic eyelid I periorbital rash; erythematous dermatitis over hand joints, knees, elbows, face, neck, upper torso, (Gottron's sign)

Definite PM-four of first four criteria (three or four with rash for definite DM)

Probable PM-three of first four criteria (two of four with rash for probable DM)

Possible PM-two of first four cnteria (one of four with nish for possible DM)

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Diagnostic Criteria for Inclusion Body Myositis

I. Characteristic features-inclusion criteria

A. Clinical features

1. Duration of illness > 6 months

2. Age of onset> 30 years old

3. Muscle weakness must affect proximal and distal muscles of arms and legs and patient must exhibit at least one of the following features:

a. Finger flexor weakness

b. Wrist flexor> wrist extensor weakness

c. Quadriceps muscle weakness (grade 4 MRC)

B. Laboratory features

1. Serum creatinine kinase < 12 times normal

2. Muscle biopsy

a. Inflammatory myopathy characterized by mononuclear cell invasion of nonnecrotic muscle fibers

b. Vacuolated muscle fibers

c. Either

ii. Intracellular amyloid deposits (must use fluorescent method of identification before excluding the presence of amyloid) or

ii. 15- to 18-nm tubulofilaments by electron microscopy

A. Definite IBM : Patients exhibit all muscle biopsy features. No clinical or laboratory features are mandatory if muscle biopsy features are diagnostic.

B. Possible IBM: If the muscle shows only inflammation (invasion of nonnecrotic muscle fibers by mononuclear cells) without other pathological features of IBM, then a diagnosis of possible inclusion body myositis can be given if the patient exhibits the characteristic clinical (Al,2,3) and laboratory (Bl) features

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RESULTS

Total 85 cases were collected in the retrospective group from from1984 to April 2004 but 6 of them were excluded as biopsy and nerve conduction study unequivocally showed alternate diagnosis like muscle dystrophies and acute inflammatory demyelinating polyradiculoneuropathies .. The prospective group included 5 cases recruited from April 2004 to July 2005. Hence Study totally included 84 cases of inflammatory muscle diseases. Definite inflammatory muscle disease was seen in 62 % of cases, probable in 23% cases & possible in remaining 15% cases.

A) Clinical features: 1) Age: Maximum patients Were in the age group of 18 to 50 years of age. Mean age was

32.5 years. Pediatric age group constituted 24% only.

Age group Frequencies (percentages) < 18 years 24 18-50 years 62.5 >50 years 135

Table III: Age group distribution

2) Sex: Females constituted 64.5 % .In the pediatric age group, there was no significant difference in male to female ration (M: F: 1: 14) 3) Type of presentation: 2~% had presentation. less than three month after the onset of symptoms. 4) Muscle pain /tenderness: 48% patients had muscle pain. Half of them had tenderness on examination. Remaining 52 % patients had neither muscle tenderness nor pain. 5) Muscle weakness: Grading of muscle weakness was done according to standard MRC grading system .It was further subdivided for prognostication, as no weakness if power was 5/5., as mild when power was 3-4/5 and severe if it was less than 3/5.

u r b Jpper 1m proxima we akn ess: Grading of muscle weakness Frequencies in percentages Severe 29.6 Mild 65.7 No weakness 4.8

Upper limb distal weakness:

Grading of muscle weakness Frequencies in percentages Severe 6 Mild 51.3 No weakness 42.7

Table IV: Grading & frequency of upper limb weakness

23

L r b . al akn ower 1m prox1m we ess: Grading of muscle weakness Frequencies in percentages Severe 35.2 Mild 62.4 No weakness 1.4

Lower limb distal weakness: Grading of muscle weakness Frequencies in percentages Severe 3.6 Mild 34.7 No weakness 61.7

Table V: Grading & frequency of lower limb weakness

5) Ambulation: 57.1% of patients were ambulatory without support at the time of initial evaluation here. Trunk weakness was seen in 65 out of total 84 cases 6) Type of weakness: Symmetrical weakness was seen in 94% cases. Asymmetrical weakness was seen in only two cases & both had inclusion body myositis. 7) Fasciculation's were seen in only 3 patients out of total 84 cases. Significant muscle wasting was seen only in 24 patients. All were symptomatic for more than 8 months prior to presentation. 8) Neck & bulbar muscle weakness: 76.2% and 36.9% of patients had neck muscle and bulbar muscle weakness respectively at the time of initial evaluation here. More than half of the patients with dysphagia had dermatomyositis. Extra ocular muscle abnormality & ptosis were seen only in one patient. Mild degree if bifacial weakness was seen in 20 patients.

9) Deep tendon reflexes:

Grading Number of cases out of total 84cases Normal 33 Sluggish 29 Absent 13 Brisk 9

Table VI: Grading of deep tendon reflexes with their frequency

24

B) Investigations:

1) Haemogram: Anemia was seen in 5 cases only out of total 84 cases. Leucocytosis was seen in 37.9% .ESR was raised in 35.7%. SGOT /SGPT were raised in 56%

2) CPK values: Mean CPK seen was 3200 lUlL in the cases with value more than 1 ,OOOIU/L. Highest CPK was 25,000 IU IL.

Grading Frequencies in percentages Normal 11.9 < 1000 UIL 34.7 > 1 OOOunits/L 53.4

Table VII: Grading of raise in serum CPK level with their frequency

3) Electromyography: Findings were suggestive of myopathy in 78 cases .Out of 78 cases 56 cases had

classical inflammatory myopathy findings. Yield of Para spinal EMG were very low. It was inconclusive in 2 cases, normal in one & changes of neurogenic aetiology in 2 cases. Neuropathy was seen in total 8 cases .Two were with polymyositis & six were with overlap syndrome

5) Muscle Biopsy findings:

Biopsy findings: Inflammatory disease Neurogenic changes Not done Normal

Inconclusive

Alternate diagnosis

Frequencies out of 84 cases muscle 64

5 9 3

2

1

Table VIII: Biopsy findings with their frequency

Classical perifascicular atrophy was seen in less than half of the cases with DM .Out of three patients who showed normal biopsy findings, two became asymptomatic with treatment & one did not improve . Two had received steroids before biopsy for more than 4weeks duration before biopsy. Among patients with neurogenic changes in the biopsy, three-showed excellent improvement, one improved partially & remaining one patient became bed bound in spite of treatment for long time. Repeat muscle biopsy during the follow up of one patient, who did not show response to treatment was confirmed to have limb girdle muscular dystrophy.

25

Final diagnosis:

Diagnosis Frequencies in percentages Polytny_ositis 51.2 Dermatomyositis 20.2 Inclusion body myositis 2.4 Neoplasia related 1.2 Overlap 23.8 Alternate diagnosis 1.2

Table IX: Frequencies of individual diagnosis

In the dermatomyositis group, 80% had classical cutaneous manifestations like Gottron's scaly rashes & heliotrope eyelid rashes. In the remaining 20% diagnosis was contributed by· histopathology. Classical histopathology was seen only in 40% dermatomyositis cases with typical cutaneous lesions. In the category of overlap syndrome, out of 20 cases, 13 had polyarthritis, five had systemic lupus erythematosis, three had systemic sclerosis and two had multiple connective tissue disorder. Six patients had myoneuropathy. Four patients nerve biopsy also showed vasculitis.

This study included only one patient with IMD associated with malignancy .He had carcinoma of lung with superior vena cava obstruction before presentation .He made significant improvement in muscle power with treatment. But he succumbed to malignancy in few months period

Treatment: Prednisolone was used in the range of 0.75 to lmg /kg/day in single dose in majority of patients. Prednisolone was used alone in 83%, Azathioprine alone in 1 0.4%, Azathioprine & steroids together were used as initial treatment in 6.6 %. Azathioprine was used in 19 patients either initially or during the course of illness due to poor response to steroid or due to steroid induced complications. In four patients it was used in view of relapse as soon as steroids were tapered off. Steroid was started tapering by the end of three months & sixth month respectively in 57% & 32% patients. Mean treatment duration was two years six months.

Out of six patients who had respiratory compromise, intravenous immunoglobulin and plasma exchange were used in two patients and intravenous methylprednisolone was used in four patients. Only two patients survived in this group.

Methotrexate was used in three patients during follow up .It was used as adjunctive in one. In other two patients it was introduced either due to failure of steroid or due to adverse effect for Azathioprine & steroid . Two of them showed good improvement and one of them showed worsening in muscle power.

26

Complications related to drugs: Azathioprine induced hepatitis was seen in three cases & leucopoenia in two cases. Both impreved with discontinuation of the drug. Steroid induced necrosis of bilateral head of femur was seen in 2 cases . One patients improved with replacement of head of femur surgery. Steroid induced systemic hypertension & diabetes mellitus was seen in 20 patients, but in most it was reversible with discontinuation of drug . Two patients had steroid induced psychosis

Cause of death: Eight patients expired out of total of 84 cases. Cause of death was directly related to illness in only six patients. Causes were aspiration pneumonia and septicemia related to bulbar weakness in spite of artificial ventilation in four, arrhythmia in two. Two patients had interstitial lung disease. None died due to the complications of treatment. Remaining one patient had cancer associated delayed death & one had probable co-morbid ischemic heart disease.

Final out come in 84 cases: Out of two patients with inclusion body myositis, one patient made partial recovery with oral steroid. Another patient lost follow up.

Grading Improved Partial recovery Worsened Asymptomatic Expired

No final follow up

Alternate diagnosis

Table X: Final outcome

Frequencies in percentages 4.4 14.4 3.8 54.8 9.5

11.9

1.2

Relapse rate: was seen in 19 patients during the study .In 12 patients there was increase in serum CPK value earlier than clinical worsening while tapering steroids

Follow up: Final follow up was available in total 72 patients only. Mean follow up period was 7.8 years. During follow up, CPK started improving along with clinical improvement in majority of patients (38 out of 46 patients)

Follow up in duration (years) 1-3 4-6 7-10 11-14 15

Number of patients 14 16 19 14 9

Table XI: Follow up of 72 patients

27

Prognostic factors: There was no statistically significant correlation between any of the clinical or lab investigation parameters with the final outcome. However there was positive trend for good prognosis with early age of onset, early presentation & ambulation at the time of evaluation.

Age group Excellent out Average Poor outcome P value come outcome

< 18 years 70.6 23.5 5.9 0.1 19-50years 66.7 20. 13.3 >50 years 44.4 22.2 33.3

Type Excellent out Average Poor outcome P value come outcome

Acute 88.2 0 11.8 0.09 Chronic 57.4 27.8 14.8

Type Excellent out Average Poor outcome P value come outcome

Ambulant 75.6 17.1 7.3 0.01 without support Ambulant with 50.0 26.7 23.3 support

Table XII: Prognostic factors & statistical significance

Here statistical significance was not attained in spite of significant p value as number in some of the categories were less than required in view of small sample size.

28

1 :.<

DISCUSSION

This study totally included 84 cases. However one case was proved to be dystrophy with repeat muscle biopsy during follow up. Final follow up is available in 72 cases. Twelve cases lost follow up.

Definite inflammatory muscle disease were seen in 62% of cases, probable in 23% cases & possible in remaining 15% cases out of total 84 cases. This is comparable to the results from similar studies. Scola RH et al showed similar results in his study of 102 cases. He divided patients into four groups: definite PM (24 cases), probable PM (19 cases), definite DM (34 cases) and mild-early DM (25 cases). In another study, eighty­five percent met the suggested criteria of Bohan and Peter (1975) for definite or probable disease, while 15 percent had possible disease out oftota127 cases (Hoffman GS 1983)

A) Clinical features:

1) Age & Sex:

Maximum patients were in the age group of 18 to 50 years of age. Mean age was 32.5 years. Pediatric age group constituted 24% only. Females constituted 64.5 %. In the pediatric age group, there was no significant difference in sex ratio (M: F: 1: 14).

DeVere R etal (1975) in his study of IMD consisting of 118 cases found following results: The female to male ratio was 1.4:1. Though cases were seen in all age groups, the largest number was in the sixth decade .In another study consisting of 75 patients from Singapore; there were 35 PM and 40 DM cases with a median age at diagnosis of 50.7 years (SD: 16.7) and significantly more females in the PM group (p < 0.05) (Koh ET et all993).

The study done from Kashmir, Shah P A et al found in 1999' that mean age at presentation was 24 years with 62.5% cases presenting in fourth decade out of 24 cases. Male: Female ratio was 1: 1.4. Another study conduced in Madras, consisting of 87 cases showed the mean age of onset in years was 33.26 in adult polymyositis, 35.03 in adult dermatomyositis, · 7.4 in juvenile dermatomyositis, 42 in malignancy-associated dermatomyositis arid 25.51 in the overlap group (Parkodi Ret al2002)

2) Severity of muscle weakness: In this study severe proximal muscle weakness was seen in 29% & 35% in upper &

lower limb respectively .6% of shoulder mus~les & 1.4% pelvic girdle muscles were normal. 76.2% and 36.9%· of patients had neck muscle and bulbar muscle weakness respectively at t;he time of initial evaluation here. More than half of the patients with dysphagia had dermatomyositis

Hoffman GS et al (1983), in his study of27 cases with IMD, found that 26 percent were severely weak and 59 percent moderately weak in limb girdle power .In another study following results were noted: Twenty-six (87%) patients had weakness in the pelvic girdle, 25 (83%) in the shoulder girdle, and 7 (23%) in the neck muscles out of30

29

cases. Other common symptoms included dyspnoea on exertion and dysphagia, each present in 13 (43%) patients (Uthman I et al 1996). Chwalinska et al in his study of 50 patients showed dysphagia was more frequent in DM patients (54.5%) than in PM (17.6%).

3) Other clinical features: 57.1% of patents were ambulatory without support at the time of initial evaluation here. Trunk weakness was seen in 65 out of total 84 cases. 48% patients had muscle pain. Half of them had muscle tenderness on examination. Remaining 52 % patients had neither muscle tenderness nor pain. Symmetrical weakness was seen in 94% cases. Asymmetrical weakness was seen in only two cases and both had inclusion body myositis. Significant muscle wasting was seen only in 24 patients. Mild degree ifbifacial weakness was seen in 20 patients.

B) Investigations:

1) Haemogram: Anemia was seen in only 5 cases only out of total 84 cases. Leucocytosis was seen in 37.9% .ESR was raised in 35.7%. DeVere Ret al found raised sedimentation rate in 55% of cases out of 118 cases.

2) CPK vaiues: Mean CPK seen was 3200 IU/L in the cases with value more than 1 ,OOOIU/L. Highest CPK was 25,000 IU /L. %. DeVere Ret al found serum creatinine kinase activity raised in 64% of cases. He did not find any correlation between the extent of abnormalities in ESR & CPK level with the degree of weakness or disability in his study of 118 cases Creatinine phosphokinase (CPK) values were consistently elevated in 81.25 percent of 132 cases studied from PGI, Chandigarh (Thussu A et al, 1993) .In another study, the serum creatine kinase (CK) level was between 171 and 1,000 U/L in 13 (43%) patients and between 1,001 and 6,000 U/L in 13 (43%) patients (Uthman I et al1996)

3) Electromyography:

In this study classical findings of inflammatory myopathy were seeri in 2/3rd of cases. Patients who had normal & neurogenic EMG had no significant bearing on prognosis compared to those with classical EMG findings.

Bohan et al (1977) in his study of 122 patients with definite /probable dermatomyositis /polymyositis found low amplitude, short duration polyphasics in 89%, increased insertional activity, fibrillations & positive sharp waves in 74%, complex repetitive discharges in 36% and normal EMG in 11%. %. In another study, DeVere Ret al found electromyography was characteristic of polymyositis in 45% of cases, and normal in only 11%. 4) Muscle Biopsy findings: ,

In this study muscle biopsy was positive in 64 out of 84 patients. Classical perifascicular atrophy was seen in less than half of the cases with DM .Out of three patients who showed normal biopsy findings, two became asymptomatic with treatment

30

& one did not improve .Two had received steroids before biopsy for more than 4weeks duration before biopsy. Among patients with neurogenic changes in the biopsy, three­showed excellent improvement, one improved partially & remaining one patient became bed bound in spite of treatment for long time. Repeat muscle biopsy during the follow up of one patient, who did not show response to treatment was confirmed to have limb girdle muscular dystrophy.

DeVere R et al found 65% of muscle biopsies had changes with inflammatory infiltration virtually diagnostic of polymyositis out of 118 cases. 17% of cases had a normal muscle biopsy. In another study consisting of 75 patients from Singapore, positive EMG and muscle biopsy was seen in 79.4% and 76.4% respectively (Koh ET et al1993)

The study done from Kashmir, Shah PA et al found myopathic features in electromyography in 74.3% cases. Muscle biopsy revealed features of inflammatory myopathy in 22 (91 %) cases out of 24 cases.

C) final diagnosis

Diagnosis Frequencies Serratrice G et al (1986) Tymms KE et al 1985: in percentages Out of 135 cases Out of 105 cases

Polymyositis 51.2 56 +16 69 Dermatomyositis 20.2 34+9 36 Inclusion body 2.4 Nil myositis Neoplasia related 1.2 6 8 Overlap 23.8 14 43 Alternate 1.2 Nil diagnosis

Table XIII: Comparison of final diagnosis of the current study with similar other studies

Note: in Tymms et al group, patients with neoplasia related and overlap syndrome were derived from PM & DM group.

In the dermatomyositis group, 80% had classical cutaneous manifestations like Gottron's scaly rashes & heliotrope eyelid rashes. In the remaining 20% diagnosis was contributed by histopathology. Classical histopathology was seen only in 40% dermatomyositis cases wiili typical cutaneous lesions. In the category of overlap syndrome, out of 20 cases, 13 had polyarthritis, five had systemic lupus erythematosis, three had systemic sclerosis and two had multiple connective tissue disorder. Six patients had myoneuropathy. Four patients nerve biopsy also showed vasculitis. Four patients had calcinosis cutis. This study included only one patient with IMD associated with malignancy.

In a study from Canada consisting of 30 French Canadians, idiopathic inflammatory myopathy (IIM) were 8 (27%) primary polymyositis- 9 (30%) primary dermatomyositis,

31

5 (17%) liM with neoplasia (lymphoma, breast, esophageal, colonic, and skin cancer) and 8 (27%) liM with a connective tissue disease (4 with systemic sclerosis, 2 with mixed connective tissue disease, and 2 with rheumatoid arthritis) ( Uthman I et al 1996) Gottron's papules and the · heliotrope rash were the most common skin lesions documented in 11 (37%) and 10 (33%) patients, respectively. (Uthman I et al1996)

Systemic lupus erythematosis was the commonest associated connective tissue disease)(Koh ET et al1993) .In another study Chwalinska et found 11.8% of PM patients and 15.1% of DM patient's with deposition of calcium salts in subcutaneous tissue out of total 50 patients. Signs ofvasculitis were found in 39.4% ofDM cases and 17.6% ofPM cases. Rios G et al found interstitial fibrosis in only 2 patients out of 50 cases. One was in juvenile DM category and second one was in PM category

D) Treatment:

Prednisolone was used alone in 83%, Azathioprine alone in 1 0.4%, Azathioprine & steroids together were used as initial treatment in 6.6 %in this study .. Azathioprine was used in 19 patients either initially or during the course of illness due to poor response to steroid or due to steroid induced complications. Steroid was started tapering by the end of three rnonths & sixth month respectively in 57 % & 32% patients along with clinical improvement.. Mean treatment duration was two years six months.

Out of six patients who had respiratory compromise, intravenous immunoglobulin and plasma exchange were used in 2 patients and intravenous methylprednisolone was used in 4 patients in this study. Only two patients survived in this group. Methotrexate was used in three patients during follow up .It was used as adjunctive in one. In other two patients it was introduced either due to failure of steroid or due to adverse effect for Azathioprine & steroid ·.Two of them showed good improvement and one of them showed worsening in muscle power. Out of two patients with inclusion body myositis in this study, one patient made partial recovery with oral steroid. Another patient lost follow up.

Hoffinan GS et al (1983), in his study of27 cases with IMD, found that within three months, 64 percent had little to no weakness. In another study, twenty eight (93%) patients received corticosteroid therapy, and 8 (27%) patients responded to prednisone alone. Thirteen (43%) patients were treated with methotrexate, and 9 (69%) responded) (Uthman I et al1996)

Cause of death: Eight patients expired out of total of 84 cases. Cause of death was directly related to illness in only six patients. Causes were aspiration pneumonia and septicemia related to bulbar weakness in spite of artificial ventilation in four, arrhythmia in two. Two patients had interstitial lung disease. None died due to the complications of treatment. Remaining one patient had cancer associated delayed death & one had probable co morbid ischemic heart disease.

32

Death occurred in 10 out of 87 patients (seven with dermatomyositis predominantly due to respiratory involvement and three with overlap). (Parkodi R et al 2002) .In another study, the overall mortality rate was 26.7% with infection and malignancy as the main causes of death (Koh ET et al 1993). In one study consisting of 50 patients with 25 years follow up, cardiovascular changes were disclosed in 82.3% of PM and 69.7% ofDM patients. Radiological signs of interstitial pulmonary fibrosis were noted more frequently in DM (36%) than in PM (23%). (Chwalinska et al1990)

E) Final outcome in 84 cases:

Grading Frequencies Marie! et al (2001): 77 cases In percentages In percentages

Improving 4.4 Partial recovery 14.4 43 Worsened 3.8 17 Asymptomatic 54.8 40 Expired 9.5 22

No final follow up 11.9

Keily et al (2003) 78 cases In percentages

32 5 51 12

Table XIV: Comparison of final out come of the current study with the similar studies

In a study of 30 cases, Uthrnan E et al in 1996 found following results: The mean follow-up was 62 months: 23 (77%) had their disease controlled, 3 (10%) patients were lost to follow-up, and 4 (13%) died (no death occurred because of IIM or its treatment). Therapy was discontinued because of remission in 5 (17%) patients. Cumulative survival rates at 2, 5, and 10 years were 89%, 89%, and 85%, respectively

H Lilley et al in his analysis of 77 patients with idiopathic inflammatory myopathy found that partial ( 4 7%) or full (31%) recovery in most cases with no recovery of strength (9%) and death (11%) :ruos Get al found twenty-six patients (51%) achieving complete remission out of 50 cases. ·

Relapse rate:

Totally 19 patents had relapse in this study .In 12 patients there was increase in serum CPK value earlier than clinical worsening while tapering steroids. In another study consisting 77 cases, short term recurrences of PM/DM (during tapering of therapy) occurred in 36 patients and long term recurrences (after discontinuation of therapy) in 9 patients. (Marie! et al 2001)

33

Follow up:

Mean follow up period was 7.8 years is available in 78 patients. During follow up, CPK started improving along with clinical improvement in majority of patients (3 8 out of 46 patients).

F) Prognostic factors:

There was no statistically significant correlation between any pf the clinical or investigation parameters with the final outcome. However there was positive trend for good prognosis with early age of onset, early presentation ( less than three months ) and ambulation at the time of evaluation.

H Lilley et al in his analysis of 77 patients with idiopathic inflammatory myopathy found that routine statistical tests do not differentiate useful prognostic indices. Hence polymyositis disability score was devised in. an attempt to gain some prognostic information. He found that onset before the age of 50 and duration of symptoms of less than 12 months prior to presentation were favourable prognostic features, and treatment with regimes other than steroid therapy alone a ·probable favourable indicator. Level of creatine kinase (CK) at presentation and histopathological separation of dermatomyositis or polymyositis failed to alter prognosis. In another study, Tymms KE et al, in his study of 105 cases, found outcome was worse in older patients and in those where weakness exceeded 4 months before diagnosis

Airio et al (2006) in his study to determine prognostic factors in one hundred and seventy-six patients with PM and 72 patients with DM found that except for age in both groups and the delay in diagnosis in the PM group, no other individual factor reached significance as a predictor of death. However, cancer had a hazard ratio (HR) of 2.16 for death (95% CI: 0.95-4.50) in the DM group and 1.99 (95% CI: 1.01-3.94) in the PM group. In another study consisting 77 cases, factors associated with PM/DM remission were younger age and shorter duration of clinical manifestations prior to therapy initiation. Variables associated with poor outcome ofPM/DM were older age, pulmonary and esophageal involvement, and cancer. (Marie! et al 2001)

34

CONCLUSION

1. Clinical, elctrophysiological and histopathological correlation was seen 62% cases.

2. Majority of the cases were poly myositis (51%) followed by dermatomyositis & overlap syndrome with other connective tissue disorders (20% each)

3. Female sex constituted roughly 2/3rd of cases. Predominant age group affected was between 3rd to 5th decades.

4. Roughly half of the patients had subjective pain and l/41h had muscle tenderness. Majority of the patients with muscle tenderness had dermatomyositis.

5. Predominantly affected muscle group were limb girdle musculature .70% patients had neck muscle weakness & l/3r~ had bulbar weakness

6. Serum creatinine phosphokinase was elevated in majority of cases and elevation more than 1000 lUlL occurred in just more than half of cases .It was normal in only 11 % cases.

7. Classical electromyography & biopsy findings were seen only in 2/3rd cases.

8. Majority of the patients tolerated oral steroids well. Mean follow up period was 7.8 years.

9.2/3rd of cases had excellent outcome out of 72 cases where final follow up was available. 50% remained asymptomatic for more than 2 years in spite of stopping all drugs .20% had partial improvement with treatment.

10. Relapse rate was 25% and half of them had relapsed due to premature with drawl of the drug.

ll.There was no statistically significant correlation between any of the clinical or investigation parameters with the final outcome. However there was positive trend for good prognosis with early age of onset, early presentation & ambulation at the time of evaluation.

35

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14:591-6. ' 19. Hoffman G.S Presentation, treatment, and prognosis of idiopathic inflammatory muscle disease in a rural hospital. American journal of medicine 1983, Sept, 75(3) 433-8 20. Holden DJ et al Clinical and serologic features of patients with polymyositis or dermatomyositis. Can Med Assoc J. 1985 Mar 15;132(6):649-53. 2l..Koh ET at al ,Adult onset polymyositis/dermatomyositis: clinical and laboratory features and treatment response in 75 patients.Ann Rheum Dis. 1993 Dec;52(12):857-61.

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21. Marie I et al Polymyositis and dermatomyositis: short term and longterm outcome, and predictive factors of prognosis. J Rheumatol. 2001 Oct;28(10):2230-7. 22. Marie I et al Influence of age on characteristics of polymyositis an~ dermatomyositis in adults. Medicine (Baltimore). 1999 May;78(3):139-47. 23. Marin Jet al. Polymyositis in childhood, Rev Neurology 1999 Apr 1-15; 28(7): 718-2 24Mastaglia FL. Treatment of autoimmune inflammatory myopathies. Curr Opin Neurol 2000; 13:507-9 25. Pautas E et al. Features of polymyositis and dermatomyositis in the elderly: a case­control study. Clin Exp Rheumatol. 2000 Mar-Apr;18(2):241-4. 26. P. D. W. Kiely et al. Presentation and management of idiopathic inflammatory

muscle disease: four case reports and commentary from a series of 78 patients Rheumatology 2003; 42: 575-582 27.Peng A, Koffman BM, Malley JD, et al. Disease progression in sporadic inclusion body myositis: observations in 78 patients. Neurology, 2000; 55:296-8 28. Plotz PH et al Current concepts in the idiopathic inflammatory myopathies: polymyositis, dermatomyositis, and related disorders. Ann Internal Medicine 1989 Jull5; Ill (2): 143-57 29. Porkodi R at al, Clinical spectrum of inflammatory myositis in South India--a ten year study. J Assoc Physicians India. 2002 Oct;50: 1255-8. 30. Prasad Ml et al Idiopathic inflammatory myopathy: clinicopathological observations in the Indian population. Br J Rheumatol. 1992 Dec;31(12):835-9 3l.Rios et al Retrospective review of the clinical manifestations and outcomes in Puerto Ricans with idiopathic inflammatory myopathies, Journal of clinical Rheumatology, 2005 Jun; 11(3): 153-6 32. Riddoch D et al Prognosis in adult polymyositis. Journals of neurological sciences 1975 Sep; 26(1): 71-80 33.Scola R H et al Diagnosis of dermatomyositis and polymyositis: a study of 102 cases.

Arq Neuropsiquiatr. 2000 Sep;58(3B):789-99. 34. Serratrice G at al. 135 cases of polymyositis Rev Neurology (Paris), 1986,142 (12): 906-17 35. Sparsa A et al, Routine vs extensive malignancy search for adult dermatomyositis and polymyositis: a study of 40 patients. Arch Dermatol. 2002 Jul; 138(7):885-90. 36. Tymss K E et al Dermatopolymyositis and other connective tissue diseases: a review of 105 cases. Journal of Rheumatology 1985 Dec; 12(6): 1140-8. 37. Uthman I et al Distinctive features of idiopathic inflammatory myopathies in French Canadians. Seminar articles Rheumatology 1996 Aug; 26(1): 447-58 38 .. VanderMeulen MF at al ,Polymyositis: an overdiagnosed entity. Neurology. 2003 Aug 12;61(3):316-21.

37

Clinical, electrophysiological and histopathological correlation in inflammatory muscle disease.

1.0 Demographic details 1.1 Name of the patient 1.2 Hospital number

Proforma

1.3 Age 1. Less than 18 years 2. 18- 50 years 3. >50 years 1.4 Sex (M=1; F=2) 1.5 IP/OP (IP= 1; OP=2) 1.6 If IP date of admission

2.0 Clinical details 2.1 Clinical presentation 1. Acute(< 1 month) 2. Chronic(> 1 month) 2.2 Type ofweak:ness 1. Symmetrical2. Asymmetrical 2.3 Muscle pain/tenderness 1 Yes 2.No 2.4 Muscle fasciculations 1 Yes 2.No 2.5 Muscle wasting 1 Yes 2.No 2.6 Upper limbs: Proximal!. 0-3 /5 2. 3-4/5 3. 5/5

Distal 1. 0-3/5 2. 3-4/5 3. 5/5 2. 7, Lower limbs: Proximal 1. 0-3 /5 2. 3-4/5 3. 5/5

Distal 1. 0-3 /5 2. 3-4/5 3. 5/5 2.8 Ambulatory without support 1 Yes 2 .No 2.9 Neck muscle weakness 1. Yes 2. No 2.10 Extra ocular movement !.Affected 2. Not affected 2.11 Ptosisl. Yes 2. No 2.12 Facial weakness 1. Yes 2. No 2.13 Trunk weakness 1. Yes 2. No 2.14 Bulbar symptoms 1. Yes 2. No 2.15 Deep tendon reflexes- 1.Normal2. Sluggish 3. Absent 4. Brisk

5. Exaggerated. 2.16 Neuropathy -1. Yes 2. No 2.17 Other systems 1. Normal 2. Abnormal 2.18 If abnormal describe

38

2.19 Associated copnective disorders 1. Yes 2. No 2.20 If yes

specif)r: .................................................................... .

2.21 Malignancy!. Yes 2. No 2.22 If yes

specify': .......................................................... ~ ........... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3.0 Investigations 3.1 Anaemia 1. Yes 2.No 3.2 Leucocytosis 1. Yes 2.No 3.3 ESR 1. Normal 2.Raised 3.4 Liver enzymes 1. Normal 2. Raised 3.5 CPK 1. Normal2. Raised 3.6 CPK values: ............................................ .. 3.7 LDH values ........................ .. 3.8 EMG 1. Done 2. Not done. 3.9 If done 1. Suggestive of

2.Neurogenic EMG 3.Normal

3.10 Biopsy 1. Done 2. Not done ... 3.11 If done 1. Suggestive

myopathy

of IMD

..................................................................................

2. Neurogenic aetiology 3. Normal

4.0 Final diagnosis 4.1 Polymyositis 2. Dermatomyositis 3. Inclusion body myositis

4.Neoplasia related 5. Overlap syndrome.6 Alternative diagnosis

5.0 Treatment 5.1 Prednisolone ........................................................ . 5.2 Immunomodulatory therapy: 1.Yes 2- No 5.3 If yes give details... Immunoglobulins/PLEX/

Immunosuppressants ..................................................... .

39

5.4 Not treated

6.0Follow-up: 3 months 6.1 Prednisolone continuing same dose /tapered I stopped /hiked

up ................................................ . 6.2Muscle weakness 1. Improved 2.stationary 3.worsened

4.Asymptomatic 6.3 Ambulatory without support 1 .Yes 2. No 6.4 Bulbar symptoms 1. Improved 2.stationary 3.worsened 6.5 CPK 1. Improved 2.stationary 3.worsened 6.6 ESR.1 Improved 2.stationary 3.worsened 6. 7If worsened alternative management

Specify' ........................................................•............

6.8If worsened, alternative , diagnosis Specify' .................................................................... .

7.0 Follow-up: 6 months 7.1 Prednisolone continuing same dose /tapered I stopped /hiked

up ................................................. . 7.2 Muscle weakness 1. Improved 2.stationary 3.worsened

4 Asymptomatic ' 7.3 Ambulatory without support 1 .Yes 2. No 7.4 Bulbar symptoms 1. Improved 2·.stationary 3. worsened 7.5 CPKl. Improved 2.stationary 3.worsened 7.6 ESR.l Improved 2.stationary 3.worsened 7. 7If worsened alternative management

Specify' .................................................................... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ,'~ ................... .

7 .8If worsened alternative diagnosis. Specify' .................................................................... .

40

8.0 Follow-up: 12 months 8.1Prednisolone continuing same dose /tapered I stopped /hiked

up ................................................ . 8.2 Muscle weakness 1. Improved 2.stationary 3.worsened

4 .Asymptomatic 8.3 Ambulatory without support 1 .Yes 2. No 8.4 Bulbar symptoms 1. Improved 2.stationary 3.worsened 8.5 CPKl. Improved 2.stationary 3.worsened 8.6 ESR.l. Improved 2.stationary 3.worsened 8. 7 If worsened alternative management

Specify .................................................................... .

8.8If worsened alternative diagnosis Specify .................................................................... .

9.0Follow-up: 24 months 9.1 Prednisolone continuing same dose /tapered I stopped /hiked

up ................................................ . 9.2 Muscle weakness 1. Improved 2.stationary 3.worsened 9.3Ambulatory without support 1 .Yes 2. No 9.4 Bulbar sympt0ms 1. Improved 2.stationary 3.worsened 9.5 CPKl. Improved 2.stationary 3.worsened 9.6 ESR.l. Improved 2.stationary 3.worsened 9. 7 If worsened alternative · management

Specify .................................................................... .

9.8If worsened alternative diagnosis. Specify .................................................................... .

10.0 Follow-up: 36 months 10.1 Prednisolone continuing same dose /tapered I stopped /hiked

up ................................................ . 10.2 Muscle weakness 1. Improved 2.stationary 3.worsened 10.3 Ambulatory without support 1 .Yes 2. No 10.4 Bulbar symptoms 1. Improved 2.stationary 3.worsened 10.5 CPKI. Improved 2.stationary 3.worsened

41

1 0.6 ESR.1. Improved 2 .stationary 3. worsened 10.7 If worsened alternative management

Specify .................................................................... .

10.8 If worsened alternative diagnosis. Specify .................................................................... .

11.0 Follow-up: 48 months 11.1 Prednisolone continuing same dose /tapered I stopped /hiked

up ................................................ . 11.2 Muscle weakness 1. Improved 2.stationary 3.worsened 11.3 Ambulatory without support 1 .Yes 2. No 11.4 Bulbar symptoms 1. Improved 2.stationary 3.worsened 11.5 CPKl. Improved 2.stationary 3.worsened 11.6 ESR.1. Improved 2.stationary 3.worsened 11.7 If worsened alternative management

Spec1ty .................................................................... .

11.8 If worsened alternative diagnosis. Specify .................................................................... . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

12.0 12.0 Follow-up: 60 months 12.1 Prednisolone continuing same dose /tapered I stopped /hiked

up ................................................ . 12.2 Muscle weakness 1. Improved 2.stationary 3.worsened 12.3 Ambulatory without support 1 .Yes 2. No 12.4 Bulbar symptoms 1. Improved 2.stationary 3.worsened 12.5 CPKl. Improved 2.stationary 3.worsened 12.6 ESR.1. Improved 2.stationary 3. worsened 12.7 If worsened alternative management

Specify .................................................................... .

12.8 If worsened alternative diagnosis. Specify .................................................................... .

42

' /

13.0 13.0 Follow-up: 10 years 13.1 Prednisolone continuing same dose /tapered I· stopped /hiked

up ................................................. . 13.2 Muscle weakness 1. Improved 2.stationary 3.worsened 13.3 Ambulatory without support 1 .Yes 2. No 13.4 Bulbar symptoms 1. Improved 2.stationary 3.worsened 13.5 CPKI. Improved 2.stationary 3.worsened 13.6 ESR.1. Improved 2.stationary 3.worsened 13.7 If worsened alternative management

SpecifY' ..............................•...................................... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . " ..................... . 13.8 If worsened alternative diagnosis.

SpecifY' .................................................................... .

14.0 Follow-up: 15 years 14.1 Prednisolone continuing same dose /tapered I stopped /hiked

up ................................................ . 14.2 Muscle weakness 1. Improved 2.stationary 3.worsened

4 .Asymptomatic 14.3 Ambulatory without support 1 .Yes 2. No 14.4 Bulbar symptoms 1. Improved 2.stationary 3.worsened 14.5 CPKI. Improved 2.stationary 3:worsened 14.6 ESR.1. Improved 2.stationary 3.worsened 14.7 If worsened alternative management

SpecifY' .................................................................... .

14.8 If worsened alternative diagnosis. . SpecifY' .................................................................... .

43