Inflammatory myopathies N. Movaffagh MD Rheumatologist

The inflammatory myopathies represent the largest group of acquired and potentially treatable causes of skeletal muscle weakness

They are classified into three major groups: Polymyositis (PM) Dermatomyositis (DM) Inclusion body myositis (IBM)

CLINICAL FEATURES prevalence of the inflammatory myopathies is estimated at 1 in 100000 PM as a stand-alone entity is a rare disease DM affects both children and adults and women more often than men IBM is three times more frequent in men than in women, more common in whites than blacks, and is most likely to affect persons age >50 years

These disorders present as: progressive and symmetric muscle weakness except for IBM

Weakness of proximal muscles, such as difficulty in: getting up from a chair climbing steps stepping onto a curb lifting objects combing hair

Weakness of distal muscles such as difficulty in: buttoning a shirt, sewing, knitting, writing, are affected only late in the course of PM and DM, but fairly early in IBM

Ocular and Facial muscles are unaffected in PM and DM Mild facial muscle weakness is common in IBM Falling is common in IBM because of early involvement of the quadriceps muscle, with buckling of the knees

In all forms of IM : Involvement of pharyngeal and neck-flexor muscles are causing dysphagia or head drop Respiratory muscles (advanced and rarely in acute cases) Severe weakness, if untreated, is almost always associated with muscle wasting

Sensation is normal Tendon reflexes are preserved (but may be absent in severely weakened or atrophied muscles, especially in IBM) Myalgia and muscle tenderness usually early in the disease, and particularly in DM associated with connective tissue disorders

Weakness in PM and DM progresses subacutely period (weeks or months) Weakness in IBM progresses very slowly (years)

HIV and HTLV-1 Drugs include: penicillamine (dermatomyositis and polymyositis) zidovudine (polymyositis) statins (necrotizing, toxic, autoimmune myositis) Protozoa (cestodes , nematodes) Tropical and bacterial myositis (pyomyositis)

Dermatomyositis characteristic rash accompanying, or more often preceding, muscle weakness heliotrope rash: blue-purple discoloration on the upper eyelids with edema Gottron’s sign: erythema of the knuckles with a raised violaceous scaly eruption flat red rash on the face and upper trunk .

Erythematous rash on knees, elbows, malleoli V sign Erythematous rash on neck and anterior chest shawl sign The erythematous rash on back and shoulders may worsen after sun exposure

shawl sign

In some patients, the rash is pruritic, especially on the scalp, chest and back Dilated capillary loops at the base of the fingernails are also characteristic The cuticles may be irregular, thickened, and distorted

lateral and palmar areas of the fingers may become rough and cracked, with irregular, “dirty” horizontal lines, resembling mechanic’s hands.

Mechanic’s hand

The weakness can be mild, moderate, severe enough to lead to quadriparesis

DM sine myositis The muscle strength appears normal but in muscle biopsy significant perivascular and perimysial inflammation is often seen

Polymyositis A subacute inflammatory myopathy There are not any of the following: rash, involvement of the extraocular and facial muscles family history of a neuromuscular disease history of exposure to myotoxic drugs or toxins endocrinopathy neurogenic disease muscular dystrophy biochemical muscle disorder

As an isolated entity, PM is a rare disorder more commonly, PM occurs in association with : Systemic autoimmune Connective tissue disease Known viral or bacterial infection

Inclusion Body Myositis Most common of the IM in patients ≥50 years Weakness and atrophy of the distal muscles especially foot extensors & deep finger flexors (may be a clue to early diagnosis)

Inclusion Body Myositis weakness and atrophy can be : Asymmetric and involve: quadriceps, iliopsoas triceps, biceps, finger flexors

Inclusion Body Myositis Dysphagia is common episodes of choking Normal Sensory examination mildly diminished vibratory sensation at the ankles pattern of distal weakness which superficially resembles motor neuron or peripheral nerve disease Disease progression is slow familial inflammatory IBM

Hereditary-IBM(h-IBM) Non inflammatory myopathies recessive, and less frequently dominant A subset of h-IBM that spares the quadriceps muscles in Iranian Jews and many ethnic groups

ASSOCIATED CLINICAL FINDINGS Extramuscular Manifestations Association with Malignancies Overlap Syndromes

Extramuscular Manifestations 1. Systemic symptoms 2. Joint contractures 3. Dysphagia and gastrointestinal symptoms 4. Cardiac disturbances 5. Pulmonary dysfunction 6. Subcutaneous calcifications 7. Arthralgias, synovitis

Systemic symptoms, such as fever, malaise, weight loss, and Raynaud’s phenomenon 2. Joint contractures, mostly in DM and especially in children Dysphagia and gastrointestinal symptoms, especially in DM and IBM

4. Cardiac disturbances: Atrioventricular conduction defects, Tachyarrhythmias Dilated cardiomyopathy low ejection fraction Congestive heart failure

Pulmonary dysfunction, due to: weakness of thoracic muscles ILD drug-induced pneumonitis (e.g methotrexate)

Arthralgias, synovitis, or deforming arthropathy with subluxation in the interphalangeal joints, which can occur in some patients with DM and PM who have Jo-1 antibodies

Association with Malignancies the incidence of malignant conditions appears to be specifically increased only in patients with DM The most common tumors associated with DM: ovarian cancer breast cancer Melanoma colon cancer non-Hodgkin’s lymphoma

A complete annual physical examination with pelvic ,breast(mammogram, if indicated) rectal examinations (with colonoscopy according to age and family history) urinalysis; complete blood count; blood chemistry tests; and a chest film

In Asians, nasopharyngeal cancer is common Careful examination of ENT is indicated If malignancy is clinically suspected, screening with a whole-body positron emission tomography (PET) scan should be considered

Overlap Syndromes DM with manifestations of systemic sclerosis or mixed connective tissue disease Such as sclerotic thickening of the dermis, contractures, esophageal hypomotility, microangiopathy and calcium deposits

overlap syndrome of DM and systemic sclerosis may have a specific ANA, anti-PM/Scl

PATHOGENESIS various autoantibodies (MHC) genes T cell–mediated myocytotoxicity complement-mediated microangiopathy

Autoantibodies and Immunogenetics antinuclear antibodies antibodies to cytoplasmic antigens ,against ribonucleoproteins(antisynthetases& anti-signal-recognition particles) antisynthetases directed against the histidyl-transfer RNA synthetase( anti-Jo-1)

Immunopathologic Mechanisms in DM In DM, humoral immune mechanisms are implicated, resulting in a microangiopathy and muscle ischemia Bcells ,CD4 T cells, plasmacytoid dendritic cells,and macrophages in Endomysiom Relative absence of lymphocytic invasion of nonnecrotic muscle fibers

DM Activation of the complement C5b-9 membranolytic attack complex(critical early event) release of proinflammatory cytokines and chemokines induces expression of vascular cell adhesion molecule facilitates migration of activated lymphoid cells to the perimysial and endomysial spaces

Immunopathogenesis of DM

DM Reduced numbers of endomysial capillaries, ischemia, The remaining capillaries often have dilated lumens in response to the ischemia perifascicular atrophy reflects the endofascicular hypoperfusion

PM, IBM In PM and IBM, a mechanism of T cell–mediated cytotoxicity CD8 T cells, along with macrophages, initially surround and eventually invade and destroy healthy, non necrotic muscle fibers that express class I MHC The CD8/MHC-I complex is characteristic of PM and IBM

muscle damage in PM and IBM

IBM possibility B cells and the humoral immune system might also play a role in IBM

Expression of cytokines and upregulation of MHC class I by the muscle fibers activation of nuclear factor κB (NF-κB), leading to further cytokine activation

Association with Viral Infections and the Role of Retroviruses Coxsackie viruses, influenza, paramyxoviruses, mumps ,CMV,EBV, have been indirectly associated with myositis The best evidence of a viral connection in PM and IBM is with the retroviruses

Some individuals infected with HIV or with HTLV-1 develop PM or IBM Histologic findings are identical to retroviral-negative PM or IBM

AZT-induced myopathy, which generally improves when the drug is discontinued It is a mitochondrial disorder characterized histologically by “ragged-red” fibers

GLOBAL ISSUES PM more often in Asia and southern Europe IBM North America, northern Europe, Australia Pyomyositis and parasitic myositis tropics

DIFFERENTIAL DIAGNOSIS Subacute or Chronic Progressive Muscle Weakness Acute Muscle Weakness Myo fasciitis (The most common form is eosinophilic Myofasciitis) Hyper acute Necrotizing Fasciitis/Myositis (Flesh-Eating Disease) Drug-Induced Myopathies Necrotizing Autoimmune Myositis

Necrotizing Autoimmune Myositis acute or subacute onset of symmetric muscle weakness CK is typically extremely high interstitial lung disease and cardiomyopathy may be present may develop after a viral infection in association with cancer in patients taking statins muscle biopsy demonstrates necrotic fibers infiltrated by macrophages but only rare, if any, T cell infiltrates. muscle

Necrotizing Autoimmune Myositis Some patients have antibodies against signal recognition particle (SRP) The muscle biopsy demonstrates necrotic fibers infiltrated by macrophages but only rare, if any, T cell Muscle MHC-I expression is only slightly capillaries may be swollen with hyalinization Most patients respond to immunotherapy, but some are resistant.

DIAGNOSIS The clinically suspected diagnosis of PM, DM, IBM is confirmed by : serum muscle enzymes EMG findings muscle biopsy

muscle enzymes The most sensitive enzyme is CK it can be normal in active IBM or DM (especially when associated with a connective tissue disease) CK is always elevated in patients with active PM SGOT, SGPT, LDH, aldolase may be elevated

EMG myopathic potentials characterized by: Short duration & low-amplitude polyphasic units on voluntary activation Increased spontaneous activity with fibrillations complex repetitive discharges positive sharp waves

Mixed potentials (polyphasic units of short and long duration) indicating: chronic process and muscle fiber regeneration are often present in IBM

These EMG findings are not diagnostic of an IM They are useful to identify : 1.presence of active or chronic myopathy 2.exclude neurogenic disorders

Muscle biopsy the most sensitive and specific test for establishing the diagnosis of IM Histologic hallmark: Inflammation

PM In PM the inflammation is primary T cell infiltrates primarily within the muscle fascicles (endomysially) surround individual,healthy muscle fibers and result in phagocytosis and necrosis

Muscle biopsy in PM

The CD8/MHC-I lesion is characteristic and useful to confirm or establish the diagnosis

DM Endomysial inflammation is predominantly perivascular or in the interfascicular septae around muscle fascicles obliteration of capillaries This results in perifascicular atrophydi

perifascicular atrophy is diagnostic of DM even in the absence of inflammation

Muscle biopsy in DM

IBM Primary inflammation with CD8/MHC-I complex vacuolated fibers with β-amyloid deposits cytochrome oxygenase–negative fibers Eosinophilic cytoplasmic inclusions

Muscle biopsy in IBM

TREATMENT The goal of therapy is to improve muscle strength ameliorate the extramuscular manifestations (rash, dysphagia, dyspnea, fever) When strength improves, the serum CK falls discontinue these drugs if, after an adequate trial, there is no objective improvement in muscle strength or not CK levels are reduced

Glucocorticoids A feeling of increased energy or a reduction of the CK level without a concomitant increase in muscle strength is not a reliable sign of improvement in general, DM responds better than PM steroid myopathy In uncertain cases, the prednisone dosage can be steadily increased or decreased as desired the cause of the weakness is usually evident in 2–8 weeks

Azathioprine Methotrexate Mycophenolate mofetil rituximab Cyclosporine has inconsistent and mild benefit Tacrolimus (Fk506) IVIg improved strength and rash ,underlying immunopathology The benefit is(≤8 weeks), and repeated infusions every 6–8 weeks cyclophosphamide