Inflammatory Myositis Flashcards
What is the epidemiology of idiopathic inflammatory myositis?
- Female to male ratio: 2:1
- DM bimodal distribution of onset, highest in 2nd and 4th decade
- PM peaks in 4th decade
- IBM typically affects men >50yo
What is the pathophysiology of DM/PM/IBM (muscle biopsy findings)
- DM is typically associated with a mixed B and CD4- positive T-cell perivascular infiltrate, vasculitis with microinfarction and grouping of muscle fibers, and perifascicular muscle atrophy.
- PM infiltrates primarily consist of CD8- positive T cells, involving all layers of muscle fibers with invasion and myophagocytosis.
- The primary target seems to be the vascular endothelium in DM and the myofibrils themselves in PM.
- IBM demonstrates a mild T-cell predominant inflammatory infiltrate (similar to PM), along with the presence of rimmed vacuoles and eosinophilic and basophilic inclusions within muscle fibers. Filamentous tubules seen on electron microscopy are highly specific for IBM.
Characterisitics of anti-synthetase syndrome
Anti-jo positive plus 2 of the following features
- Raynauds
- Mechanics hands
- ILD
- Non erosive inflammatory arthritis
Features of DM vs PM vs IBM
Epidemiology
- DM: bimodal, 2nd + 4th decade, female > male, no familial association
- PM: female > male, <50yo, no familial association
- IBM: male > female, >50yo, familial association
Clinical Presentation
- DM + PM: acute + subacute onset, proximal weakness (deltoids, arm/hip flexors, neck flexors), rapid course. Have systemic features (fever, fatigue, weight loss)
- DM has skin features: helioptrope rash, gottrons papules, shawl sign
- IBM: insidious onset, proximal + distal weakness (difficulty gripping objects), slowly progressive course, nil skin rash. Rarely associated with extra-muscular manifestations.
Diagnostic Findings
- DM + PM: CK >10 times normal, myopathic on EMG
- IBM: CK <10 times noormal, myoneuropathic on EMG
Muscle Biopsy
- DM: microinfarctions, myofibril grouping
- PM: myofibril necrosis
- IBM: rimmed vacuoles, inclusions
Tx
- DM+ PM: good response
- IBM: poor response
What weakness is involved in PM and DM
Proximal weakness especially affecting the deltoids, arm/hip flexors, neck flexors - classic triad of hair/chair/stair - difficulty combing hair, rising from chair and climbing stairs.
What weakness is involved in IBM?
- Proximal and distal weakness
- Normally symmetrical but can be asymmetrical
- Onset insidious and slowly progressive
Cutaneous manifestations of DM
DM is associated with multiple cutaneous manifestations.
- Gottron sign/papules are symmetric erythematous/violaceous macules, patches, or papules located on the extensor surfaces of the metacarpophalangeal joints
- Common rashes include heliotrope rash (edematous lilac discoloration of periorbital tissue) as well as photodistributed rashes such as the shawl sign (upper back) and V sign (neck/upper chest)
- Poikiloderma (mottled pigmentation, epidermal atrophy, and telangiectasia) can occur in both sun-exposed and unexposed areas.
- Gottron sign/papules and heliotrope rash are considered pathognomonic for DM.
- Nail changes such as cuticular hypertrophy or nailfold capillary abnormalities can occur.
- Amyopathic DM refers to classic cutaneous findings occurring in the absence of muscle involvement.
- Mechanic’s hands, characterized by hyperkeratotic fissuring of the palmar and lateral surfaces of the fingers , is seen in both DM and PM
- The skin is generally uninvolved in PM and IBM
Cardiopulmonary and gastrointestinal involvement in IIM.
Cardiopulmonary:
- All of the IIMs can cause chest wall and diaphragm muscle weakness, resulting in shortness of breath and occasionally respiratory failure
- ILD in PM/DM
- Myocarditis, AV block, heart failure in PM/DM
GIT:
- Weakness of the striated muscle of the upper esophagus or oropharynx is common in IIM and can lead lo dysphagia, aspiration, regurgitation. and associated pneumonitis.
Esophageal disease is more common among older patients and those with inclusion body myositis.
ILD in IIM.
ILD is commonly in DM and PM and may precede muscle symptoms.
Often associated with antisynthetase syndrome (anti-jo1) and is associated with poor prognosis.
In which IIM is there a risk of malignancy?
Both DM and PM increases the risk of malignancy, especially DM!
- Breast/pelvic/prostate exam
- Mammography
- Colonoscopy
Cancers associated with DM and PM are similar to those seen in the general population. including adenocarcinomas of the bladder, cervix, lung, ovaries, pancreas, and stomach.
Ovarian cancer risk may be especially increased.
Does the degree of CK rise correlate to disease in DM/PM?
In DM and PM, muscle enzyme elevation is dramatic (usually 10- to 50-fold the upper limit of normal) but may or may not correlate with degree of weakness.
What is amyopathic DM?
Amyopathic DM refers to DM with cutaneous involvement and normal muscle enzyme levels in the absence of muscle manifestations.
What is mixed connective tissue disease?
Usually combination of SLE and cleroderma
Anti-RNP
EMG findings of IIM
The characteristic triad of EMG findings includes short duration small, low-amplitude polyphasic potentials; fibrillation potentials at rest; and bizarre, high frequency, repetitive discharges
What is the gold standard ix for IIM?
Muscle biopsy
• DM: CD4 T cells, microinfarctions, myofibril grouping
Is typically associated with a mixed B and CD4- positive T-cell perivascular infiltrate, vasculitis with microinfarction and grouping of muscle fibers, and perifascicular muscle atrophy.
• PM: CD8 T cells, myofibril necrosis
Infiltrates primarily consist of CD8- positive T cells, involving all layers of muscle fibers with invasion and myophagocytosis.
• The primary target seems to be the vascular endothelium in DM and the myofibrils themselves in PM.
• IBM: rimmed vacuoles, influsions
Demonstrates a mild T-cell predominant inflammatory infiltrate (similar to PM), along with the presence of rimmed vacuoles and eosinophilic and basophilic inclusions within muscle fibers. Filamentous tubules seen on electron microscopy are highly specific for IBM.
Lab findings for IIM?
Elevated CK
Elevated aldolase
Elevated myoglobin, LDH, AST, ALT
Antibodies for IIM
- ANA (non specific)
DM:
- Anti-MI-2- Ab: classic marker of DM, mild disease, associated with good response to steroids
- Anti-MDA-5: severe skin involvement, can present as amyopathic, rapidly progressive ILD - poorest survival of all DM due to ILD, avoid methotrexate (lung toxicity), annual pulmonary function test.
- Anti NXP2: calcinosis, malignancy
- Anti TIF1y: malignancy
- Anti NXP2 and TIF1y have higher risk of malignancy.
Antisynthetase Syndrome
- Anti-Jo-1 ab, PL7, PL12
- ILD, Raynaud’s, Mechanic’s hands, nonerosive inflammatory arthritis
- Often require 2nd line agent.
- Anti jo more common in PM
Myositis Overlap:
- Anti la/ro/U1-RNP - with other conditions like Sjogrens, SLE, sclerderma. MCTD, RA
- Typically responds well to immunotherapy
IBM
- Anti-cN1a
Immune-mediated necrotising myopathy: anti-SRP, may also be seen in DM
Anti-HMGCR. More response to steroids, need 2nd line, ritux early for anti SRP
Features of PMR
- Elderly women
- Fatigue and malaise
- Often rapid onset: symmetric pain in shoulder, pelvic girdle and neck (proximal muscles)
- Morning stiffness > 45min
- Associated with GCA
- Elevated ESR ++
- Norma CK
Features of fibromylagia
- Peak incidence 20-50yo
- Tender points over multiple areas of the body with no signs of inflammation
- Chronic fatigue, sleep disturbances
- Morning stiffness
- Normal ESR/CK
Features of corticosteroid induced myopathy
- History of glucocorticoid intake
- Insidious onset proximal muscle weakness of UL + LL
- Normal ESR, high CK
Features of statin associated myopathy
- History of statin intake
- Fatigue
- muscle pain and weakness
- Normal ESR, high CK
- Associated with HLADRB1*1101
- Usually months on treatment, persist after cessation
- CK usually >10x normal
- Anti HMGCR ab specific - if this is present, it indicates immune mediated necrotising myopathy which needs to be treated with steroids
Treatment for IIM
- First line: steroids and usually a steroid sparing immunosuppressive agent (methotrexate, azathioprine)
- Severe refractory disease
IVIG +/- rituximab - For ILD; plasmapheresis
Complications of IIM
Respiratory failure
Myocarditis
Esphageal disease
Features of inclusion body myositis
- Common in people > 50yo
- Myodegeneration, rimmed vacuoles
- Treatment
- Can have asymmetric muscle weakness
Quadriceps, long finger flexors, ankle flexors
Distal weakness > proximal weakness in UL especially FINGER FLEXORS, FOREARM MUSCLES - Proximal LL pattern - QUADRICEPS atrophy, patient can present with falls (hip extensors/flexors normally fine)
- Can be quite asymmetric, non dominant seems to be more affected than dominant
- IgG anti-CN1A: >90% specificity
- CK <10x normal
- T cell large granular lymphocytic leukemia associated with IBM
Cells, cytokines, target cells, autoantibodies and other involved in DM/PM/ IBM/IMNM (immune mediated necrotising myopathy)
DM: CD4+ cells, type 1 interferon, perifasicular mononuclear cells and atrophy
MDA-5 in amyopathic DM
Anti Jo
Related to malignancy
PM: CD4 + CD8 cells
Diffuse muscle fibre injury
IBM: CD4 + CD8
Type 1 interferon
Nuclear degeneration - rimmed vacuoles
IMNM Macrophages Muscle fibre necrosis with sparse inflammatory infiltrate Anti SRP Anti HMGCR
What does anti-MDA5 mean?
Occurs in DM
Higher risk for ILD including a rapidly progressive presentation with high mortality
Can also occur in amyopathic DM
Antibodies associated with DM
- Anti-Mi-2: classic DM, mild disease
- Anti MDA5: amyopathic DM, ILD, poor prognosis
- Anti-TIF1y, Anti NXP2: severe DM, cancer associated DM
- Anti SAE: DM initially amyopathic
Antibodies associated with PM
Anti-synthetase ab, eg: anti-jo-1, anti Pl-7, 12 as part of antisynthetase syndrome
Antibodies associated with IBM
Anti cN1a
Antibodies associated with IMNM (immune mediated necrotising myopathy)
Anti SRP: necrotising myopathy - severe myopathy, dysphagia
Anti HMGCR: necrotising myopathy, prior statin, can be related to malignancy
Malignancy in DM
- Increased 5-7x in DM, possibly not increased in PM
- Cervical, lung, ovaries, pancreas, bladder and stomach account for ~70%
- usually in first 12 months after diagnosis of myositits
What factors predict outcome and response to therapy?
- DM and overlap more responsive to glucocorticoids
- Worse prognosis: Jo-1, SRP
- Better prognosis: Mi-2, overlap (RNP, PM-Scl, Ku)
What is the leading cause of death in myositis?
Cardiovascular disease is the leading cause of death in myositis
- Accelerated atherosclerosis of coronary arteries
- Myocardial inflammation/myocarditis
Atherosclerosis
- High coronary artery calcification scores in myositis patients
- Increased HTN and diabetes in myositis
- 16x risk of MI
Which antibodies confers a higher risk of myocarditis in IIM?
- Main one would be antiSRP
- Others include MDA5, JO1, SAE, Pl12, Ro
- Antimitochondrial ab
What is the best investigation for diagnosing myocarditis?
- Need baseline troponin, ECG, TTE
- cMRI - the best non-invasive
- Gold standard - endomyocardial biopsy
What leukaemia is associated with inclusion body myositis?
T cell large granular lymphocytic leukaemia
- Clonal expansion of CD8+CD57+ cytotoxic T cells seen in peripheral blood, bone marrow and spleen
- Associated with autoimmune disorders
Associated with IBM
- In IBM clonal expansion of LGL is seen and resembles T-LGLL
- LGL have been detected in muscle and shown to have an aggressive phenotype, with expression of CD57, indicating a neoplastic-like morphology
- May explain resistance to immunosuppressive therapies
Side effects of hydroxychloroquine
QT prolongation Cardiomyopathy Should not be used with drugs with potential to prolong QT Hyperpigmentation Retinopathy/maculopathy
