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Idiopathic Inflammatory Myopathies (IIM)

• Chronic inflammation of striated muscle (myositis)

• Characteristic cutaneous features

• Variety of systemic complications

●The characteristic “heliotrope” rash of dermatomyositis was first described in 1875 (Paris).● Eleven years later Wagner coined the term polymyositis (PM) ●Gottron, in 1930, reported on the skin lesions of dermatomyositis .●1975, Bohan and Peter proposed five criteria or the diagnosis of PM and DM that are still used today

Epidemiology Prevalence of DM and PM ~ 1/100,000

• The overall incidence of IIM ranges from 2 to 10 new cases per million persons at risk per year

• The prevalence of IBM in Western Australia is

high

Prevalence of IBM: 5-10/million (in> 50 y/o: 1-3/100,000)

• IIM can occur at any age, includes both childhood and adult peaks.

• The mean age of myositis onset is increased when there is an associated malignancy.

• The overall female-to-male incidence ratio is 2.5:1.

• This ratio is lower(nearly 1:1) in childhood disease and with malignancy.

• (10:1)when there is a coexisting connective tissue disease.

Association with other disorders

• PM-DM occurs in overlap with SSc more than any other CTD.

• Often associated with one of several serum autoantibodes such as anti-U1-RNP, anti-PM-Scl, or anti-U3-RNP.

Environmental factors

• Disease onset is more frequent in the winter and spring months, especially in childhood cases

• Disease relapses were noted most frequently

during summer months, perhaps precipitated by infection or sun exposure.

• DM and PM have occurred in HIV-infected patients

• Myositis occurs in GVHD.

Genetic and Environmental Risk Factors

Genetic

• Reports of familial occurrence

• Higher incidence of other autoimmune disorders in first degree relatives

• HLA DRB1

• DR3 in Anti Jo-1 Ab

Environmental Risk Factors

• Infectious Agents• Drugs• Ultraviolet radiation exposure• Other agents

Genetic factors• (HLA-DRB1*03-DQA1*05-DQB1*02), are

important risk factors (anti-synthetase, antibody-positive patients)

• JDM associated with HLA-DQA1*0501.• Single nucleotide polymorphism have

identified associations in genes outside the MHC area.

• Genes regulating cytokines and their receptors including PTPN22, interleukin (IL)-1,and tumor necrosis factor (TNF)-a appear to play a role in the development and course of both childhood and adult onset myositis.

Idiopathic Inflammatory Myopathies

• Polymyositis (PM)

• Dermatomyositis (DM)

• Inclusion body myositis (IBM)

Clinical manifestations

ماه6-3شروع تدریجی درعرض گرفتاری شدید کمربند شانه ایی ولگنی

درصد مواقع50گرفتاری گردن در عدم گرفتاری چشم وصورت

گرفتاری عضالت دیستال ناشایع استدیسفاژی ودیستونی داریم

در بچه ها و بالغان جوان شروع ممکن است سریعتر و با درد عضالنی همراه باشد

آتروفی در موارد شدید و طول کشیدهگرفتری دیافراگم می تواند باعث نارسایی

تنفسی شود

• Other early findings included pitting edema of the extremities or eyelids as a combined result of hypoalbuminemia

• Capillary leakage, and lack of muscle tone needed to promote central venous return.

• Pharyngeal muscle weakness may contribute to hoarseness, dysphagia, nasal regurgitation of liquids, or aspiration pneumonia.

• Ventilatory muscle weakness may contribute to dyspnea

• Unlike muscle weakness, which is a hallmark of PM-DM, muscle hypertrophy is more characteristic of muscular dystrophy.

• Muscle atrophy and joint

contractures are sequelae of disease damage; they are therefore late findings

Constitutional• Fatigue is a prominent complaint and it

may persist even after adequate treatment of myositis.

• Fever is more commonly observed with JDM, and anti-synthetase syndrome.

• Weight loss may occur in myositis patients, but if persistent and severe, associated malignancy should be considered.

Skin findings in DM

• Gottron papules are scaly, erythematous or violaceous papules, and plaques located over bony prominences, particularly the MTP and proximal and DIP joints of the hands.

• Gottron sign is a macular erythema that occursn in the same distribution. One of these rashes is seen in 60% to 80%of patients with DM.

• Pruritus is common,particularly in the scalp and its presence differentiates DM from SLE, in which pruritus is uncommon.

Gottron's sign

symmetric, roughened, erythematous skin changes over extensor surfaces of MCPs, IPs, elbows, and/or knees

• Heliotrope rash is purplish in color, may be edematous or scaling in nature, and is located in the periorbital area, especially over the upper eyelids

Heliotrope rash

a violaceous eruption on the upper eyelids, sometimes with edema

Shawl sign, V signa diffuse flat erythema in a shawl-like distribution or in a V-shaped pattern over the anterior neck and chest

Erythroderma

a generalized redness (at a variety of other skin sites: malar, forehead)

Periungual abnormalities

erythematous capillary nailbeds with vascular changes (like other CTDs) Abnormal loops with areas of dilatation and dropout

Calcinosis• Soft tissue calcification, which can be

disabling, occurs most commonly in chronic, childhood-onset DM and is less frequent in adult-onset disease.

• Calcinosis may appear in well-controlled myositis but more typically occurs in the setting of chronic, active disease or aftera prolonged delay in the initiation of corticosteroid treatment.

• Calcinosis may be intracutaneous, subcutaneous, fascial, or intramuscular in location, with a predilection for sites of repeated microtrauma (elbows, knees, flexor surfaces of fingers, and buttocks).

• Medical therapy has been disappointing; however,bisphosphonates have led to rapid improvement in some cases,whereas probenecid and infliximab have been beneficial in othersituations.

بالینی تظاهراتریه

• ILD important complication in approximately %10 of cases of DM and PM

• Respiratory failure may result from diaphragmatic and chest wall muscle weakness

• ILD in the inflammatory myopathies often occurs in the context of anti-synthetase antibodies and the anti-synthetase syndrome

• Amyopathic patients remain at risk for fatal ILD, malignancy,or even delayed-onset, full-blown DM.

Antisynthetase (anti-Jo-1) syndrome

• ILD

• Raynaud

• Arthritis

• mechanic's hands

• Pulmonary function testing (PFT) reveals restrictive physiology inmyositis-associated ILD.

• NSIP and the organizing pneumonias represent more favorable histopathology, usual interstitial pneumonitis (UIP) and diffuse alveolar damage (DAD) portend a more ominous course.

• the concomitant finding of anti-Ro/SSA in patients with anti-synthetase autoantibodies may be associated with more severe and progressive ILD.

• Diffuse alveolar hemorrhage with pulmonary capillaritis is uncommon but can be lethal.

• Pneumomediastinum, on the other hand, is increasingly reported.

بالینی تظاهراتمری

• Dysphagia: Weakness of the striated muscle of the upper one-third of the esophagus (and/or the oropharyngeal muscles)

• more common in elderly patients and may underlie the increased incidence of bacterial pneumonia

بالینی تظاهراتقلب

• Heart failure is unusual ↑ CK-MB fraction due to involvement of the

myocardium by the myositis

Reason for ↑CK-MB levels is that the fraction of MB is increased in regenerating muscle

Cardiac troponin I, a more specific and

sensitive marker of cardiac damage

Conduction and ECG abnormality

Joints

• Polyarthralgias or polyarthritis, if they occur, appear early in the disease course.

• The distribution is rheumatoid-like, and the symptoms are relatively mild.

• Joint findings are more common with overlap and the anti-synthetase syndromes but are frequently in childhood Dm.

IBM• سال50گرفتاری باالی • شروع تدریجی وسیرکند• سال قبل از تشخیص6-5بروزعالیم • میتواند غیرقرینه ” دیستال ویا فوکال

باشد• میتواند تغییرات نوروپاتیک داشته باشد• می تواند باعث آتروفی عضله کوادری

سپس شود

Immunopathogenesis

Histologic features:

• muscle fiber necrosis

• degeneration and regeneration

• inflammatory cell infiltration

Muscle Anatomy

Normal Muscle

DM

Cellular infiltrate is predominantly perifascicular and often perivascular

B cells and plasmacytoid dendritic cells

perivascular and perimysial inflammation

perifascicular necrosis in DM

PMcellular infiltrate is found predominantly within the fascicle

cytotoxic CD8+ T cells are dominant

intense interstitial mononuclear infiltrate

with some myocyte degeneration

IBMfilamentous inclusions in electron microscopy

Rimmed vacuoles and eosinophilic muscle

An autoimmune disease

Association with other autoimmune diseases (: Hashimoto's thyroiditis) and collagen vascular diseases (: scleroderma)

Autoantibody response in many patients

Lymphocyte infiltration:

• B cells and plasmacytoid dendritic cells in DM• cytotoxic CD8+ T cells

response to immunosuppressive therapies in some patients

Dermatomyositis

Humoral immune process against vascular endothelium

activation of complement↓

C5b-9 deposition on endothelium↓

capillary necrosis ↓

ischemic muscle injuryperifascicular atrophy

PM and IBM

MHC-1 expression on myocytes

Activation of CD8 T cells and lysis of muscle fibers by release of Perforin granules

Upregulation of cytokines, chemokines and adhesion molecules → ↑transmigration of T cells to muscle

Initial injury ↓

muscle auto antigen release↓

Ag presentation by macrophages to CD4+ TH cells

↓Activated TH cells stimulate

macrophages (IFN-γ)↓

inflammatory mediator release

(: IL-1 and TNF-α)

↑expression of MHC proteins by myocytes

↓Auto-Ag is presented in association with MHC-I molecules on surface of

Myocytes↓

destruction of myocytes byCD8 cytotoxic T cells

Role of non-immune processes

• marked structural changes in muscle fibers in the absence of any inflammatory cells

• lack of correlation between degree of inflammation and degree of muscle weakness

• Some, do not respond to anti-inflammatory therapy

• steroid treatment may eliminate inflammatory cells but may not improve clinical disease

• disease may progress when identifiable inflammation has subsided

Iran Study

Manifestations at onset:

muscle weakness (45%) arthralgia (38%) myalgia (21%) specific rash (25%) fever (16%)

Manifestations during the disease course:

98%: proximal weakness

40-60%: arthralgia, arthritis, Fever, fatigue, weight loss, myalgia, heliotrope rash

20-40%: hair loss, dysphagia, articular rash, eyelids edema,malar rash, pulmonary involvement, Raynaud's phenomenon

<20%: muscular edema, cardiac manifestations, joint deformities, periungual erythema, calcinosis

Diagnosis

clinical laboratory electromyography biopsy

exclusion of other disorders with similar features

Laboratory evaluation

Serum muscle enzyme and Abs

Serum muscle enzymes

↑in most patients

creatine kinase (CK) [early-late, DM/IBM-PM]

lactate dehydrogenase (LDH), Aldolase and aminotransferases

IBM: typically moderate CK↑ (< x10 normal)

Autoantibodies

Present in a majority (~ 80% of PM/DM)

ANA: ↑↑ suggest presence of another CTD

Myositis-specific autoantibodies:

• anti-histidyl-tRNA synthase (: anti-Jo-1) • anti-signal recognition particle (anti SRP)• anti-Mi-2

Electromyography (EMG)

evidence of muscle irritability

classic triad:• Increased insertional activity and spontaneous

fibrillations• Abnormal myopathic motor potential (low amplitude, short–duration polyphasic)• Complex repetitive discharges

Non-specific

Normal in ~ 10%

Tissue biopsies

Biopsy in DM

Skin and/or muscle biopsies may establish the diagnosis

Skin biopsy sufficient to confirm DM if: • typical weakness pattern (symmetric; proximal > distal) +• serum muscle enzymes↑ +• classic cutaneous findings

Muscle biopsy in PM

Even in clinical scenarios highly consistent with PM, muscle biopsy is essential to establishing correct diagnosis and excluding other disorders

Open biopsy is preferred to needle biopsy

Magnetic resonance imaging (MRI)

Useful in:

• identify biopsy site

• longitudinal follow-up (Tx response assessment, flares diagnosis)

Classification Criteria

• 1. Symmetrical weakness Limb-girdle and neck flexors, with or without dysphagia/respiratory sx

• 2. Biopsy

• 3. Elevation of muscle enzymes in serum CK, aldolase, LDH, AST, ALT

• 4. EMG evidence

• 5. Dermatologic features Gottron’s sign, heliotrope rash, shawl sign, etc.

Polymyositis

4 criteria, no rash3 criteria, no rash2 criteria, no rash

Dermatomyositis

Rash + 3 criteriaRash + 2 criteriaRash + 1 criteria

DefiniteProbablePossible

Differential Diagnosis

• Other myopathies

• Neuropathies

• Assosiations (collagen-vascular disease, malignancy)

Malignancy

Can be diagnosed before, with, or after IIM diagnosis

Cancer site in 70% of cases:cervix, lung, ovaries, pancreas, bladder, and stomach

RISK FACTORS:

DM Capillary damage on muscle (especially with trunk cutaneous necrosis) biopsy

Cutaneous leukocytoclastic vasculitis Age >65 y at diagnosis

Evaluation:

• history, physical examination

• Age-appropriate cancer screening tests (: mammography and colonoscopy)

• CT of chest, abdomen and pelvis for high risk patients

Initial therapy

• Prednisone: 1 mg/kg/day (≤ 80 mg/d)

• Severely ill patients→ methylprednisolone pulse

• taper to lowest effective dose over a total of 9 - 12 m

Glucocorticoid-sparing agents

Initiate with GCs

First-line: azathioprine (AZT) or methotrexate (MTX)

Response: importance of muscle strength > muscle enzymes

Taper off GCs before tapering AZT/MTX (careful follow-up for possibility of disease recurrence )

Resistant Disease

Consider several potential scenarios:

• Incorrect original diagnosis

• glucocorticoid-induced myopathy

• Underlying malignancy

Treatment

Rituximab Intravenous immune globulin Tacrolimus CyclosporineMycophenolate mofetil CyclophosphamideCombination therapy TNF inhibitors

General treatment measures

• Early physical therapy and rehabilitation

• Aspiration precautions

• DM may be photosensitive → avoid UV

• Bisphosphonate from the start of treatment

• Sufficient Ca and Vitamin D intake

• high-dose prednisone + immunosuppressive → Pneumocystis jirovecii prophylaxis

Outcome Predictors:

Type of myositis disease severitydelay in diagnosis autoantibody profile

Response to GCs alone: overlap myositis > DM > PM

Antisynthetase Ab: often associated with ILD and a worse prognosis

IBM: more resistance to treatment Progress gradually over a period of years By 15 y, most patients require assistance with basic daily activities