Rheumatology E-learning. University of Szeged Department of Rheumatology and Immunology

Transcription

1 Rheumatology E-learning University of Szeged Department of Rheumatology and Immunology

2 Introduction Idiopathic inflammatory myopathies (IIM) are a group of systemic diseases characterized by an immune mediated attack on skeletal muscle Characterized by Proximal muscle weakness Nonsuppurative inflammation of skeletal muscle Accompanied by extramuscular manifestations

3 Is it a myopathy or neuropathy? Both muscle diseases and nerve diseases may present with weakness or pain. Neuropathic processes tend to be: Asymmetrical Distal > proximal Usually accompanied by sensory abnormalities (paraesthesia, hypaesthesia) Myopathic processes tend to be: Symmetrical Proximal > distal

4 How to differentiate between proximal and distal weakness? Proximal weakness Distal weakness If the patient has difficulty rising from a chair (hip muscles) or combing his or her hair (shoulder girdle) If the patient has difficulty standing on his or her toes (gastrocnemius/soleus) or doing fine work with the hands (intrinsics)

5 Is it a myopathy or myositis? Both may present with weakness or pain. Myopathy: E.g. familial muscular dystrophies, hypothyreosis, statin adverse effect, etc. Usually less rapidly progressive Family history may be positive No laboratory signs of muscle cell destruction (e.g. creatinekinase (CK), lactate dehydrogenase (LDH) elevation Myositis: Usually rapidly progressive (severe symptoms within a few days to several weeks) CK and LDH are markedly elevated Other autoimmune phenomena (dermatitis, Raynaud s phenomenon, interstitial lung disease, arthritis) may be present

6 The spectrum of myositis (inflammatory myopathy) Polymyositis (PM) Dermatomyositis (DM) Inclusion body myositis (IBM) Cancer-associated myositis Juvenile dermatomyositis

7 Demographics Idiopathic inflammatory myopathies Prevalence rates of 1: Female:Male 2:1 Peak age range in adults is years Polymyositis is rare in childhood, dermatomyositis is common Inclusion body myositis: males after the age of 50

8 Immunopathogenesis DM: Complement mediated vasculopathy cellular infiltrate is located in the perifascicular regions and is often perivascular PM: Directed T cell muscle injury cellular infiltrate is found predominantly within the fascicle, where there are increased numbers of cytoxic T-cells

9 Clinical Features PM/DM are typically of subacute onset Characterized by Initially myalgia/soreness Progressive, symmetric and usually painless proximal muscle weakness Weakness is most severe in the pelvic girdle and shoulder girdle Facial muscles innervated by the cranial nerves and distal muscles of the hands are spared

10 Major symptoms of muscle weakness Difficulty raising the head when supine Weakness of neck flexors with difficulty holding the head up dropped head Difficulty arising from the lying position patients become bedridden Difficulty lifting carrying, placing items on a shelf Difficulty climbing stairs Impaired ability to arise from a seat knee extensors more affected than flexors The gait will be swaying

11 Complications Interstitial lung disease 10% of cases may be acute alveolitis or chronic progressive fibrosing alveolitis respiratory failure may also result from diaphragmatic and chest muscle weakness both can result in rapid respiratory failure and death Esophageal disease weakness of the striated muscle of the upper 1/3 of the esophagus and/or oropharyngeal muscles can lead to nasal regurgitation, dysphagia leads to increased incidence of bacterial pneumonia, aspiration, death or malnutrition Myocarditis Malignancy see cancer-associated myositis

12 Cutaneous manifestations of DM Rash usually present on sun exposed parts Gottron s papules Symmetric, palpable, heaped up appearing erythematous eruptions overlying the MCP/IP joints of the fingers Heliotrope rash Violaceous/erythematous discoloration of the upper eyelids with peri-orbital edema V sign or shawl sign macular erythema over lower neck and upper chest in a V distribution anteriorly

13

14 Clinical Manifestations Skin Findings Gottron s Sign: Scaly, symmetric eruption over the MCP and interphalangeal joints

15 Dermatomyositis shawl sign

16 Dermatomyositis heliotropic rash

17 Shawl Sign

18 Clinical Manifestations Skin Findings Mechanic s Hands: Roughening and cracking of skin of the tips and lateral aspects of the fingers, resulting in irregular, dirtyappearing lines

19 Articular manifestations Arthralgia in 25% of patients Morning stiffness is common Non-deforming symmetrical arthritis of hands, wrist, feet and ankles Occurs early in the disease and responds to treatment of the underlying muscle disease

20 Interstitial Lung Disease Screening for ILD should be included in the initial investigation of PM/DM patients Chest X-Ray Pulmonary function test Restrictive ventilatory defect with decreased diffusion capacity High-resolution lung CT Broncho-alveolar lavage and lung biopsy if rarely indicated

21 Interstitial Lung Disease Histological correlation of HRCT findings Ground glass pattern prominent interstitial infiltration by inflammatory cells without major distortion of the alveolar architecture Indicates progressive interstitial lung disease Reticular opacities fibrosis in association with gross distortion of alveolar structures Indicates non progression of lung disease

22

23 Interstitial Lung Disease Clinical manifestations Asymptomatic Cough Dyspnea on exertion Bibasilar inspiratory crepitations Dispnea at rest Respiratory failure ILD is considered to be a major risk factor for premature death in patients with myositis

24 Inclusion Body Myositis Recognized as the most common acquired muscle disease in those older than 50 yrs of age Muscle weakness develops insidiously Asymmetric pattern of muscle involvement Weakness and atrophy are first observed in the quadriceps muscles Frequent falls But distal muscles are more often involved than in PM/DM Early involvement of the long finger flexors Inability to grip the examiners fingers Foot drop due to peroneus muscle weakness

25 DM/PM and Malignancy Cancer-associated myositis There is a six-fold increase in the risk of malignancy in DM and two-fold increase risk in PM Factors that increase the probability of an associated malignancy Patients over the age of 50yrs Refractory disease Acute onset of disease and recurrence of disease Elevated ESR Female sex In every patient, especially in those with high risk, cancer screening must be performed at diagnosis and even in the following few years if there is indication

26 Diagnosis Criteria proposed by Bohan and Peter in Symmetric proximal muscle weakness by physical exam 2. Elevation of serum skeletal muscle enzymes CPK, Aldolase, AST, ALT, LDH 3. EMG triad short, small, polyphasic motor unit action potentials Fibrillations positive sharp waves and insertional irritability bizarre high frequency repetitive discharges 4. Muscle degeneration, regeneration, necrosis, phagocytosis and interstitial mononuclear infiltrate on biopsy 5. Typical skin rash of DM

27 Muscle Enzymes Muscle enzymes are elevated ASAT, ALAT, LDH, CPK CPK most sensitive and best measure of muscle injury CPK can be elevated as much as 50 fold in PM/DM CPK elevation more than 100 fold should call the diagnosis into question, and would rather suggest rhabdomyolysis Rising CPK level may be the first indication of disease reactivation, even before muscle weakness develops ALAT and ASAT also increase in many cases, they are mistakenly regarded as a sign of liver disease! If ALAT and ASAT are increased, and muscle weakness is present - perform CPK testing instead of unnecessary hepatic work-up!

28 Electromyography EMG findings are not specific for IIM, but help in the distinction from 1) neuropathic origin, and 2) from noninflammatory myopathies 1) Myopathic motor unit action potentials Polyphasic Short duration Low amplitude 2) Evidence of increased membrane irritability Positive sharp waves Fibrillation potentials Complex repetitive discharges

29 Muscle Biopsy Definitive diagnostic procedure and should be performed prior to treatment Open biopsy is preferable to needle biopsy Site of biopsy Vastus lateralis, biceps brachii or deltoid muscle Avoid atrophic muscles or muscle on which EMG has been performed Tissue obtained should be sent for Conventional light microscopy Immunohistochemical studies dystrophies Electron microscopy Due to patchy nature of histological changes the biopsy may be normal or inconclusive Close collaboration between clinician and pathologist

30 Dermatomyositis: Humoral response B cells, CD4+ T cells; perifascicular/perivascular infiltration Polymyositis: CD8+Tcells, endomysial infiltration

31 Lymphocytic infiltration with muscle necrosis

32 Histology: DM Skin Biopsy Direct immunofluorescence study of a skin lesion from a patient with dermatomyositis Intense staining of immunoglobulins along the dermal-epidermal junction Biopsy was taken from a dermatomyositis patient with the cutaneous finding of flagellate erythema

33 Inclusion body myositis - pathology Key features of IBM Congo red positive amyloid deposits Rimmed vacuoles EM whorled membranous material and tubulofilamentous inclusions The inflammatory cells invade non-vacuolated fibers, while the vacuolated fibers are not invaded by T cells. Two independent processes Primary T cell driven immune process identical to PM Degenerative process in which B-amyloid and related proteins participate in vacuolar degeneration

34 Autoantibodies in IIM Classified as Myositis-associated antibodies (anti-ro/ssa, anti-u1rnp) found in other autoimmune diseases too Myositis-specific antibodies Myositis specific antibodies Anti-synthetase antibodies: autoantibodies to aminoacyl-trna synthetases (e.g. anti-jo1) Anti-Mi-2 ( anti helicase ) Anti SRP ( signal recognition particle)

35 What is anti-synthetase syndrome? It is a subcategory of the inflammatory myositis defined by the presence of autoantibodies to aminoacyl-trna synthetases (20%). Specific clinical manifestations: ILD, arthritis, Raynaud's phenomenon, fever, and mechanic s hands. Steroid-dependent disease frequent relapses during the tapering of corticosteroids other immunosuppressants are required Worse prognosis

36 Differential Diagnosis Muscular dystrophies Limb-girdle muscular dystrophy Dysferlinopathy ( Miyoshi myopathy) Dystrophinapathy Duchene muscular dystrophy Metabolic myopathies Lipid and glycogen storage disorders Mitochondrial myopathies Endocrine myopathies Hypo/Hyperthyroidism Cushing syndrome Hypo/Hyperparathyroidism Acromegaly Drug induced myositis D-penicillamine, Quinidine, Procainamide, IFN alpha, IL-2 HMG CoA reductase inhibitors noninflammatory, necrotizing myopathy

37

38 Therapy Treatment of IIM has traditionally relied upon the use of corticosteroids and immunosuppressive agents Treatment causes generalized immunosuppression and is not organ or antigen specific

39 Corticosteroids Remains the first line treatment of choice 60% to 70% response rate Starting dose oral prednisone 1mg/kg for 4 to 6 weeks then taper by 5 mg per week Combination with a steroid sparing agent such as methotrexate/azathioprine is associated with a lower relapse rate and a better long term outcome Pulse IV methylprednisolone Patients with severe myositis ILD GI angiopathy

40 Steroid resistant disease 20%-30% of cases response is slow or incomplete Methotrexate and azathioprine have both been shown to be effective Combination of Methotrexate and Azathioprine have a synergistic effect For the more difficult cases Intravenous immunoglobulin Cyclophosphamide Mycophenolate Mofetil Rituximab (anti-cd20 B-cell depleting antibody)