Rheumatology E-learning

University of Szeged

Department of Rheumatology and Immunology

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

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

How to differentiate between

proximal and distal weakness?

Proximal weakness

If the patient has difficulty

rising from a chair (hip

muscles) or combing his or

her hair (shoulder girdle)

Distal weakness

If the patient has difficulty

standing on his or her toes

(gastrocnemius/soleus) or

doing fine work with the

hands (intrinsics)

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. creatine-kinase (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’sphenomenon, interstitial lung disease, arthritis) may be present

The spectrum of myositis (inflammatory

myopathy)

Polymyositis (PM)

Dermatomyositis (DM)

Inclusion body myositis (IBM)

Cancer-associated myositis

Juvenile dermatomyositis

Demographics

Idiopathic inflammatory myopathies

Prevalence rates of 1:100.000

Female:Male 2:1

Peak age range in adults is 40-50 years

Polymyositis is rare in childhood,

dermatomyositis is common

Inclusion body myositis: males after the age

of 50

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

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 nervesand distal muscles of the hands are spared

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

Complications

Interstitial lung disease 10% of cases – may be acute alveolitis or chronic progressivefibrosing 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

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

Clinical Manifestations

Skin Findings

Gottron’s

Sign:

Scaly,

symmetric

eruption over

the MCP and

interphalangeal

joints

Dermatomyositis – shawl sign

Dermatomyositis – heliotropic rash

Shawl Sign

Clinical Manifestations

Skin Findings

Mechanic’s Hands:

Roughening and cracking of skin of the tips and lateral aspects of the fingers, resulting in irregular, dirty-appearing lines

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

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

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

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

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 inPM/DM Early involvement of the long finger flexors

Inability to grip the examiners fingers

Foot drop due to peroneus muscle weakness

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 diagnosisand even in the following few years if there is indication

Diagnosis

Criteria proposed by Bohan and Peter in 19751. 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 infiltrateon biopsy

5. Typical skin rash of DM

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 suggestrhabdomyolysis

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 aremistakenly regarded as a sign of liver disease! If ALAT and ASAT are increased, and muscle weakness is present - perform CPK testing instead of unnecessaryhepatic work-up!

Electromyography

EMG findings are not specific for IIM, but help in thedistinction from 1) neuropathic origin, and 2) from non-inflammatory 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

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

Polymyositis: CD8+Tcells, endomysial infiltration

Dermatomyositis: Humoral response B cells, CD4+ T cells; perifascicular/perivascular infiltration

Lymphocytic infiltration with muscle

necrosis

Histology: DM

Skin Biopsy

Direct immunofluorescencestudy 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

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

Autoantibodies in IIM

Classified as

Myositis-associated antibodies (anti-Ro/SSA, anti-U1RNP) – found in other autoimmunediseases 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)

What is anti-synthetase syndrome?

•It is a subcategory of the inflammatory myositisdefined 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 relapsesduring the tapering of corticosteroids – otherimmunosuppressants are required•Worse prognosis

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

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

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

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)