BOTTOM LINE

IIMs are a heterogenous group of diseases characterized by insidious symmetrical proximal muscle weakness (exception amyopathic DM). Investigations typically reveal high CK and seropositivity for myositis antibodies. Myopathy can be supported by EMG and MRI. Biopsy is typically needed to characterize myopathy, though in patients with classic DM and positive antibodies, a muscle biopsy is often not necessary. Treatment requires steroids and agents like MTX, MMF; necrotizing and severe myopathy including dysphagia and interstitial lung disease may need IVIG with rituximab or cyclophosphamide. Screen all patients for underlying malignancy & ILD at diagnosis. This review will not focus on inclusion body myositis, which is distinct in its clinical presentation and treatment.
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CLINICAL/SEROLOGICAL FRAMEWORK

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CONCEPTUAL FRAMEWORK

As shown above, IIM is a heterogenous family of several distinct diseases, each with particular CLINICAL, SEROLOGICAL, and HISTOLOGICAL characteristics

• Dermatomyositis (DM, amyopathic/hypomyopathic DM, MDA5-myopathy)
• Juvenile myositis (DM >> PM)
• “Polymyositis” (PM)
• Malignancy-associated myositis
• Immune-mediated Necrotizing myositis (IMNM)
• Anti-synthetase syndrome (may sometimes have rashes of dermatomyositis)
• Overlap myositis: occurring with clinical SLE, scleroderma, Sjogren’s, or rheumatoid arthritis
• Inclusion body myositis (IBM)

Recent literature emphasizes that polymyositis is now considered a rare or even contested entity, with many cases reclassified as overlap myositis, antisynthetase syndrome, or immune-mediated necrotizing myopathy

An incomplete conception of myositis: “Polymyositis vs. Dermatomyositis vs. Inclusion Body Myositis (IBM)” (i.e.: if a patient has proximal muscle weakness but no rashes, it must therefore be polymyositis — this is not a necessarily precise deduction).

EPIDEMIOLOGY

Epidemiology is challenging due to changing myositis classification/diagnostics/nomenclature over time; these are rare diseases. Epidemiological data exist historically for Polymyositis (PM), but contemporary literature contests the entity of PM.

• Age
  • DM/PM: Peak incidence 50-60 years-old
    IBM: 70-80 years-old
• Sex
  • Dermatomyositis F > M, 2.75:1.00
    Polymyositis: F>M, 1.55:1.00
    IBM: M>F
• Incidence:
  • 8 (1-29)/1,000,000/year
• Prevalence:
  • 14 (2-14)/100,000
• Risk factors:
  • Genetic
    • Heritability unknown (rare disease, less data)
    • HLA loci associations: HLA-DRB1*03:01, HLA-B*08:01, HLA-DRB1*08:03 (in Japanese patients), HLA-DQA1*01:04 and HLA-DRB1*07 (in Chinese patients), HLA-DQB1 (dermato, Jo-1 myositis), HLA-DRB1*11:01 (HMGCR-myopathy), HLA 8.1 ancestral haplotype
    • Non-HLA Loci associations: PTPN22, STAT4,  TRAF6, UBE2L3, C4, IRF4
  • Environmental
    • Infections: any, especially GI, respiratory, group A strep, and viral (HIV, Hepatitis B or C)
    • Non-infectious: bovine collagen implants (anecdotal), smoking, latitude (more DM closer to equator)

CLINICAL MANIFESTATIONS

— Muscle

• Limbs: insidious subacute (weeks/months) symmetrical weakness (ex: holding objects overhead, climbing stairs); does not usually present acutely, does not onset chronically over years
• Axial: Neck weakness (ex: head drooping forward, cannot lift head off pillow)
• Oropharyngeal: swallowing weakness (12-54%), nasal regurgitation, quiet voice, drooling
• Respiratory: Orthopnea, hypercapnia symptoms, ineffective cough
• Amyopathic/hypomyopathic DM: all the classic dermatomyositis rashes with minimal weakness or CK elevation
• Atrophy can occur late in chronic DM/PM, early in IMNM, more frequently with NXP-2 antibody. Consider steroid myopathy as differential
• IBM:
  • Chronic, asymmetric weakness often affecting finger flexors and quadriceps,

Predominant muscle complaint in myositis is true objective weakness, not pain. Pain may be seen with necrotizing myopathies, but is always accompanied by profound weakness. See differential diagnosis below

— Skin

• Classic DM rashes: Mi2, SAE,  TIF1ɣ, NXP2. ASyS antibodies may also sometimes present with DM rashes. (photographic examples):
  • Heliotrope rash: on/around eyelids
  • Gottrons papules: extensor surfaces of MCP/PIP, elbows, knees, ovoid palatal patch (hard palate)
  • Dilated nailfold capillaries and Raynauds; can develop digital ulcers especially if MDA5+
  • Periungal nailfold erythema with cuticular punctate hemorrhages
  • Psoriasiform rashes on scalp and palms (especially TIF1ɣ antibody)
  • V-sign: anterior chest below neck
  • Shawl sign: Upper back below neck
  • Mechanics hands: cracked skin along lateral/palmar sides of fingers (also seen in other overlap syndromes can, MDA-5, and PMScl antibodies)
  • Holster sign: lateral  thigh
  • No rash: DM sine dermatitis (no/minimal rashes but classic DM on muscle biopsy)
• Calcinosis:
  • Juvenile DM, NXP2 antibody association;  often develops at sites of microtrauma
• Anti-MDA5 DM
  • Palmar papules,  severe Raynaud’s and vasculopathy with digital ischemia
• Overlap
  • Cutaneous findings of overlap systemic lupus and scleroderma  (see related chapters)
  • Associated with Anti-PmScl, RuvBL1/2 , Ro, La, SnRNP, Ku
• Histology
  • Interface dermatitis with dyskeratosis, dermal mucin deposition, perivascular inflammatory infiltrates, and vascular dilatation and/or damage — looks like cutaneous lupus
  • Skin biopsy may be helpful in myositis patients without major muscle involvement
• Other
  • Pruritis

— Lung

• Parenchyma
  • Interstitial lung disease 
    • Prevalence  20–40% in Western cohorts, up to 60–70% in Asian cohorts
    • Especially if MDA5+ or ASyS (anti-Jo-1, -PL7, PL12) More likely to be signficant and rapidly progressive if paired with Anti-Ro52 antibody.
  • Acute: diffuse alveolar hemorrhage (rare), organizing pneumonia
  • Chronic: NSIP (most common). Less common: UIP, LIP, DIP, or RB-ILD
  • MDA5 antibody: associated with rapidly progressive ILD (10-15%)
  • Can precede muscle involvement or be dominant manifestation
• Diaphragm
  • Diaphragmatic weakness (10-20%); more common in IBM
• Mediastinum
  • Pneumomediastinum (rare but well described), especially in MDA5 dermatomyositis
• Vascular
  • Pulmonary arterial hypertension, screen with Echo and PFT.
  • Consider PAH in anti-synthetase and myositis-scleroderma overlap syndromes
  • Pulmonary embolism
• Differential diagnosis
  • GERD/aspiration pneumonia, infection, pulmonary edema, PAH, drug toxicity

ILD is a leading cause of morbidity/mortality. Screen with HRCT at diagnosis and serial screening if high risk clinical-serological subtype

— Cardiac

Prevalence 3-10% Subclinical up to 75%

• Myocardium
  • Cardiomyopathy/CHF, myocarditis.
  • Subclinical diastolic dysfunction and late gadolinium enhancement on cardiac MRI are common
  • Biopsy: inflammatory infiltration &  fibrosis of cardiac muscle similar to skeletal muscle biopsy
• Pericardium
  • Pericardial effusion, pericarditis
• Electrophysiological
  • Dysrhythmias related to infiltration of conduction system

Consider screening all with Echo, ECG (limited sensitivity in asymptomatic patients). Troponin T (sensitive) and troponin I (specific) can detecting subclinical involvement. Cardiac MRI is valuable for further evaluation if abnormalities detected.

— Musculoskeletal

• Arthritis
  • Inflammatory arthritis; esp in anti-synthetase
  • Erosive if RF/CCP positivity (overlap RA)
• Myalgias
  • Particularly if underlying necrotizing myopathy (HMGCR, SRP antibodies), though not exclusive to this subtype
• IBM: high prevalence of dysphagia and muscle atrophy

— Malignancy

Malignancy risk highest within 1 year before and after myositis diagnosis, but high for up to 10 years in some subgroups. Most commonly seen in 3 year window at time of diagnosis.

• 2-7X risk of cancer (except for ASyS and IBM)
• Most common IIM subtype
  • Dermatomyositis, especially anti-TIF1γ and anti-NXP2
  • Not seen in inclusion body myositis or antisynthetase syndrome.
• Most common cancer:
  • Lung, breast, ovarian, colorectal, lymphoma (same types of cancer most common in general population, with geographic variation)
• Increased risk of malignancy
  • Older age (RR 11.19) [mean age of IIM onset in cancer cases was 59 years, compared with 49 years in the non-cancer cases in literature review]
  • Anti-TIF1 gamma (RR 4.66)
  • Anti-Mi-2, -SAE, -NXP2; weaker association than anti-TIF1γ
  • Cutaneous ulceration (RR 2.73)
  • DM subtype (RR 2.21)
  • Dysphagia (RR 2.09)
  • Male sex (RR 1.53)
• Decreased risk of malignancy
  • Clinically amyopathic DM (RR 0.44)
  • Raynaud’s phenomenon (RR 0.61)
  • Interstitial lung disease (RR 0.49)
  • Anti-Jo1 (RR 0.45) or anti-EJ (RR 0.17) positivity
  • Very high serum CK or LDH
• See Cancer Screening below

INVESTIGATIONS

At diagnosis: Basic bloodwork + CK, ANA, MSA/MAA panel, Biopsy skin/muscle, Echo, ECG, PFT, and cancer screen

— Bloodwork

• CBC
  • Typically normal, unless overlap with other systemic disease or other process
• Creatinine, Urinalysis
  • Typically normal, unless overlap with other systemic disease or other process
• ALT, AST, serum aldolase
  • May be elevated due to ALT originating from muscles rather than reflective of liver damage
• CK
  • Mild elevations (<2x ULN): occur in dermatomyositis, overlap myositis, and inclusion body myositis,
  • Very high elevations (>10x ULN, sometimes >50x ULN): IMDM, ASyS

Normal CK does not exclude active disease, especially in amyopathic dermatomyositis and inclusion body myositis. Consider differential diagnosis if <2X or >100X ULN

• ESR, CRP
  • Normal/minimally elevated; more often elevated in IMNM reflecting muscle necrosis—not myositis
    
• ANA
  • Positive in 50-80%; many myositis-associated and myositis-specific antibodies target non-nuclear cytoplasmic antigens
    
• Myositis Specific Antibodies and Myositis Associated Antibodies
  (MSA and MAA)
  • Myositis-specific antibodies (MSA) and myositis-associated antibodies (MAA) may not be commercially available to all, in particular high quality western blot, immunoprecipitation using radio-labeled antigens, or immunodiffusion.
  • Commercial antibody panels may miss certain antibodies; immunoprecipitation is gold standard but not widely available
  • Helps define clinical subsets of IIM, predict organ involvement, and aid management
  • MSA: antibodies specific to IIM; 20-40% of IIM
  • MAA: antibodies which can be seen in other overlap CTD (Ro, La, Sm, RNP, PM-Scl, Ku)
  • MSA or MAA can be seen in >80% of DM, PM, IMNM in some studies
  • Clinical Associations
    • Significant muscle disease: NXP2, SRP, HMGCR
    • Mild muscle disease: SAE, Mi2, MDA5, TIF1ɣ
    • Cancer risk: TIF1ɣ, NXP2, absence of MSA/MAA
    • ILD risk: ASyS, MDA5 is rapidly progressive ILD concomitant presence of anti-Ro52 antibody
    • Treatment refractory: MDA5, SRP, HMGCR— needs aggressive combination therapy
    • Treatment responsive: Jo-1, Mi2
    • Dermatomyositis: anti-Mi2, anti-SAE, and anti-NXP2
    • IBM: anti-cN1A

— Further Diagnostics

• EMG
  • Myopathic findings: Short-duration, low-amplitude, polyphasic motor unit potentials
  • Irritative myopathy: ↑insertional activity, spontaneous discharges (fibrillation potentials and positive sharp waves)
  • Sensitive but not specific for IIM; Can help guide selection of muscle biopsy site on contralateral side of EMG
• MRI
  • Role of MRI in myositis is evolving; may be helpful in guiding biopsy site, help gauge disease activity versus damage, evaluate treatment response, evaluate myositis mimics. MRI thigh or shoulder muscles.
  • Sequences: T1-weighted for damage evaluation, Fat-suppressed T2-weighted and fluid sensitive sequences (STIR, T1RM) for muscle edema.
  • Findings: patchy fascial/subcutaneous edema in DM. Pelvic/adductor muscles edema seen in IMNM more than DM.
  • Sensitivity ~60-80% (higher for DM). Specificity 60-90% (higher for IMNM).
• PFT
  • Baseline PFT as screen for subclinical ILD; especially in ASyS or anti-MDA5 patients
• Echo
  • Baseline echo (ex: cardiomyopathy, echocardiographic signs of pulmonary hypertension)
  • Routine echocardiography and ECG have limited diagnostic value in asymptomatic patients; troponin T/I and cardiac MRI should be considered if cardiac involvement is suspected.
• High-resolution CT chest
  • HRCT chest if symptomatic (cough/dyspnea, crackles on exam, abnormal PFTs)
  • Consider especially if anti-MDA5 or ASyS-associated antibody

—Cancer screening

• Approach
  • All adult IIM patients should participate in country/region specific age/sex appropriate cancer screening programs
  • All adult IIM patients (excluding IBM) should have MSA/MAA testing to help stratify cancer risk
  • Stratify IIM patient based on
    • IIM subtype
    • MSA/MAA
    • Clinical features

—Cancer screening based upon risk

• ≥2 “High risk” factors
  High risk of IIM-related Cancer
  • Screening at diagnosis: Basic and enhanced screening panels
  • Screening at follow up: Basic screening panel at 1, 2 and 3 years after IIM onset
  • Consider: 18F-FDG PET–CT, upper and lower GI endoscopy
• ≥2 “intermediate” or 1 “high risk” factor
  Moderate risk of IIM-related Cancer
  • Screening at diagnosis: Basic and enhanced screening panels
  • Screening at follow up: None
• <2 “intermediate“ & no high risk factors
  Standard risk of IIM-related cancer
  • Screening at diagnosis: Basic screening panel
  • Screening at follow up: None

—Screening panels

• Basic Screening
  • Comprehensive history and physical examination
  • CBC
  • Serum liver function tests
  • Serum ESR and/or plasma viscosity
  • Serum CRP
  • Serum protein electrophoresis
  • Urinalysis
  • Plain chest X-ray radiograph
• Enhanced Screening
  • CT scan of the neck, thorax, abdomen and pelvis
  • Cervical screening^b
  • Mammography^b
  • Prostate-specific antigen^b
  • CA-125
  • Pelvic or transvaginal ultrasonography for ovarian cancer
  • Fecal occult blood^b
• Nasopharyngeal carcinoma
  • Consider nasoendoscopy at time of diagnosis in geographical regions where the risk of nasopharyngeal carcinoma is increased
• (a) Anti-PM-Scl, anti-Ku, anti-RNP, anti-SSA/Ro, anti-SSB/La antibodies
• (b) If not already part of country/region-specific age- and sex-appropriate cancer screening program

— Histopathology

Muscle Biopsy

• Indication
  • Crucial for patients without classic DM rashes, negative antibody panel, and to consider myositis mimics
  • Some might defer muscle biopsy if classic DM rashes, skin biopsy, and positive myositis antibodies
• Target
  • Affected but not end-stage proximal muscle (deltoid, biceps, vastus lateralis, rectus femoris).
  • Contralateral side of EMG testing; MRI may help target biopsy and increase sensitivity.
• Prep
  • Open or large needle (ex Bergstrom needle) biopsy. Small needle biopsy insufficient. Sample 1×1.5cm
  • DO NOT transport in formalin. Place in saline soaked gauze in centre with expertise.
  • Processed for snap frozen and paraffin sections
• Yield
  • Sensitivity >74%, Specificity 77% (in patients with weakness, high CK, myopathic EMG)
• Details (Click to Enlarge)

• Other muscle biopsies
  • Steroid Myopathy: Type 2 muscle fibre atrophy, no degeneration or cellular infiltration
  • Hydroxychloroquine myopathy: Vacuolar myopathy, generally rimmed vacuoles. Usually no cellular infiltration
• Non-specific findings:
  • Endomysial inflammation without myofiber invasion characteristic of PM or without clinical/pathologic features of DM.
  • These patients may have myositis mimic and require periodic re-evaluation for myositis mimics (see differential diagnosis below)**

Skin Biopsy

• Indications
  • May consider skin biopsy rather than muscle if classic DM rashes and positive serology
  • Ambiguous skin findings in absence of clear clinical muscle disease
  • Ddx DM rashes: seborrheic, contact, atopic dermatitis, polymorphous light eruption, lichen planus, psoriasis
• Method
  • Active skin lesion; punch or shave biopsy.
    • Punch better for palmar/plantar, ulcerative, or panniculitis lesions for deeper vasculature and SC fat
    • Shave biopsy may be used for superficial lesions
• Target
  • Biopsy should target an active, non-ulcerated lesion for optimal yield
• Light Microscopy
  • “Interface dermatitis”
    • Lymphocytic infiltrate extending from dermis to basal keratinocyte layer
    • Vacuolar changes in cytoplasm of basal epidermal keratinocytes
    • Dermal mucin
  • Vasculopathy and neutrophilic infiltrate may be seen in anti-MDA5 dermatomyositis
• Immunofluorescence
  • Granular deposition at dermal-epidermal junction of C3, IgG, IgA, IgM
  • Less commonly done, lacks specificity/sensitivity.
  • Requires 2nd sample sent in Michel’s solution
• Differential diagnosis for interface dermatitis
  • Acute cutaneous lupus, subacute cutaneous lupus
  • Drug eruption, including erythema multiforme
  • Lichenoid dermatoses: ex lichen planus

Skin biopsy cannot reliably distinguish dermatomyositis from subacute cutaneous lupus in all cases, and clinicopathologic correlation is essential

Lung Biopsy

• Myositis ILD usually diagnosed based on clinical evaluation and HRCT; Biopsy not routinely required; decision for biopsy is made in conjunction with respirology
• Typical CT pattern is NSIP and NSIP+OP
• Possible indications
  • Atypical clinical course, atypical HRCT pattern
  • Exclude differential: if suspecting malignancy, infection
  • When choice of therapy may depend on histopathologic features
• Method
  • Surgical biopsies or generous cryobiopsies usually needed for diffuse ILD
    • Cryobiopsy is increasingly favored due to lower complication rates and comparable diagnostic yield to surgical biopsy
  • Small biopsies may sometimes be sufficient for focal lesions (bronchoscopic, needle or core biopsy)
• Pathology
  • Myositis related ILD may be consistent with UIP, NSIP, OP, AIP histologic patterns
    
• Bronchoalveolar lavage may be useful to exclude infection in select cases

Histopathology alone cannot definitively distinguish myositis-associated ILD from other connective tissue disease-ILDs or idiopathic forms; multidisciplinary discussion is essential

DIAGNOSIS

Suspect IIM in a patient, most often middle-aged, presenting with insidious symmetrical proximal muscle weakness and elevated CK; or with classic dermatomyositis rashes and/or features of antisynthetase syndrome, even with minimal weakness. CK can be normal in up to 20% of cases. Screen clinically for extra-muscular manifestations, especially interstitial lung disease.  Muscle biopsy is recommended for definitive diagnosis, especially in seronegative or atypical cases, and should be targeted to affected but not end-stage muscle, ideally guided by MRI or EMG. Skin biopsy is appropriate in patients with classic dermatomyositis rashes, especially if muscle involvement is unclear, but may not be necessary if dermatomyostis rashes are clear and obvious. Screen all patients for malignancy (particularly if anti-TIF1γ or anti-NXP2 positive); also order Echo and HRCT to assess cardiac and pulmonary involvement.  Be vigilant for myositis mimics in patients without rashes or without positive serology.

DIFFERENTIAL DIAGNOSIS

— Suggestive of alternate diagnosis to IIM

• Patient profile
  • Family history of muscle weakness or myopathy
  • Lack of systemic manifestations of autoimmune disorders
• Onset
  • Chronic slowly progressive weakness over months-years
  • Acute weakness over hours/days
• Pattern
  • Pain > weakness
  • Distal weakness
  • Asymmetric weakness
  • Presence of facial or extraocular muscle weakness
  • Scapular winging
  • Episodic weakness (ex: after eating, exercise, or illness)
  • Myotonia
  • Dark coloured urine
• Investigations
  • CK <2x or >10x ULN
  • Lack of myositis autoantibodies
  • EMG evidence of myotonia
• Treatment
  • No response to immunosuppression

— Differential diagnoses

• Inflammatory
  • IBM: inclusion body myositis
• Endocrine
  • Hyper/hypothyroidism, steroid myopathy/Cushing’s, hyperparathyroidism
• Toxic
  • Alcohol, colchicine, antimalarials, statins
• Metabolic
  • CPT (Carnitine Palmitoyltransferase II Deficiency): long-chain fatty acids
  • McArdel’s: Glycogen storage disease V
  • Pompe’s disease: Acid maltase deficiency
• Mitochondrial
  • MERRF, MELAS
• Inherited
  • Dystrophinopathy: Becker’s
  • Myotonic dystrophy: Calpainopathy, Dysferlinopathy, Myotonic dystrophy, FSHD
• Congenital
  • ex: nemaline, centronuclear, core myopathies
• Channelopathies
  • ex: periodic paralysis
• Infectious:
  • Especially viral myositis, para-infectious rhabdomyolysis
• Other
  • Sarcoid myopathy
  • Amyloidosis
  • ALS, Spinal muscular atrophy (primarily neurogenic, not myopathic, but can present with weakness)
  • Diabetic Amyotrophy
  • Myasthenia
  • LEMS
  • Rhabdomyolysis

CLASSIFICATION CRITERIA

IIM is a clinical diagnosis. Classification criteria are not meant as diagnostic criteria to diagnose disease in a single specific patient. Classification criteria are a standardized way of recruiting a well-defined homogenous population of patients in research studies in order to ensure comparability across studies of a heterogenous disease.

—ACR/EULAR 2017 Classification Criteria for IIM

• Mathematical formula weighing age, weakness characteristics, rashes, Jo-1 antibody, CK, and muscle biopsy characteristics
• Classification of “Definite” “Probable” and “Possible” IIM
• Available as web calculator: http://www.imm.ki.se/biostatistics/calculators/iim/

TREATMENT

— Non-pharmacologic treatment

• Physiotherapy, exercise therapy
• Speech language pathology, other steps to assess and prevent aspiration risk
• Sun safety for dermatomyositis rashes
• Anti-HMGCR IMNM patients should avoid naturally occurring statins in red yeast rice, Pu-Erh tea, Oyster mushrooms

— Pharmacologic treatment

All patients require steroids typically in combination with steroid sparing immunotherapy. No large consensus guidelines exist. Tapering therapies, particularly tapering steroids, should be individualized and based on clinical response — not the CK alone.

• Steroids
  • If severe myositis (ex profound weakness, dysphagia, rapidly progressive disease)
    • Could Pulse methylprednisolone 1g IV daily x 3 days first
  • Initial dose
    • Prednisone 0.5–1 mg/kg/day (max 80–100 mg/day) x ≤1-2 months
  • Taper: guided by clinical improvement, not CK alone
    • Taper by 20-25% monthly until
    • Prednisone 5-10mg/day within 6 months, then
    • Low dose of prednisone for an extended period, depending on side effects and response
• First Line therapy
  • Methotrexate 20-25mg weekly (consider if joint dominant disease), or
  • Azathioprine 2-3mg/kg/day (consider if lung dominant disease), or
  • Mycophenolate mofetil 1000-1500mg BID (consider if lung dominant disease)
• If ineffective after 3 months
  • Methotrexate/azathioprine combination first line therapy, or
  • Add Mycophenolate 1000-1500mg BID or
  • Add Calcineurin inhibitor (cyclosporine, tacrolimus; less preferred due to toxicities or blood level monitoring)
• Resistant disease
  • Rituximab 1g IV Day 0 and 14, q6 months (especially if IMNM), or
  • Cyclophosphamide 1g IV monthly or 1-2mg/kg PO daily
  • Other therapies described in literature, limited evidence: tocilizumab, tofacitinib, abatacept, anakinra
• IVIG
  • At any point, can add IVIG 1-2g/kg over 2-5 days/month for 3-6 months, then taper

If resistant/recurrent disease, consider re-screening for malignancy or re-consider myositis mimic as a differential diagnosis

— Specific Considerations

• IMNM
  • Necrotizing myopathy often requires aggressive therapy with high-dose steroids with IVIG or rituximab. HMGCR positive patients tend to respond well to IVIG, not as well to rituximab, whereas anti-SRP patients respond well to both
• Dysphagia
  • Consider adding IVIG to steroids and other immunosuppressive agents particularly if airway threatened
• Arthritis
  • Methotrexate 25mg/week
  • Azathioprine 2-3mg/kg PO daily
  • Rituximab 1g IV Day 0 and Day 14, q 6 month
• Skin (DM rashes)
  • First Line
    • Methotrexate 25mg/week
    • Mycophenolate 1000-1500mg BID
  • Second Line
    • IVIG 1-2g/kg over 2-5 consecutive days/month
    • Tacrolimus 2-3mg BID for trough level 10-15ng/mL; when stable ↓dose trough 5-10ng/mL
    • Cyclophosphamide 1g IV monthly or 1-2mg/kg PO daily
    • Rituximab 1g IV Day 0 and Day 14, q 6 month
  • Third Line
    • Tofacitinib 11mg daily — consider earlier in algorithm for anti-MDA5 patients
    • Apremilast 30mg BID
• Calcinosis
  • Difficult to treat, may require surgical excision. Case series of bisphosphonate added to immunosuppression (limited evidence). Tofacitinib may be helpful.
• Malignancy-realted myositis
  • Treat underlying cancer
  • Add corticosteroids and/or IVIG if necessary

Lack of robust randomized controlled trials for most agents. Treatment must be individualized. Inclusion body myositis is generally refractory to immunosuppression and is not addressed in this summary.

— Lung-targeted therapy

IIM related ILD encompasses a spectrum from chronic/indolent disease to rapidly progressive, life-threatening presentations. Prognosis is by ILD subtype, autoantibody profile, and response to therapy. Management should be multidisciplinary and individualized, involving rheumatology, respirology, pathology, radiology, and transplant teams as appropriate

Chronic ILD

First Line

• Prednisone 0.5-1.0mg/kg/d
  • Taper based on clinical response to 7.5-12.5mg/day by ~12 weeks, and 5mg/d by ~15-20 weeks
    PLUS:
  • Mycophenolate mofetil 1.0-1.5g BID
    OR
    Azathioprine 2mg/kg/d
    OR
    Consider: calcineurin inhibitors, JAK inhibitiors

If Progression

• “Inflammatory” CT pattern: Add/switch immunosuppression
  (ex: ground glass, consolidation)
  • Rituximab, tacrolimus, or JAKi
  • Cyclophosphamide
  • Other described therapies: abatacept, tocilizumab
• “Fibrotic” CT pattern: add “anti-fibrotic” if progressive fibrosis
  (ex: traction bronchiectasis, reticular opacities, honeycombing)
  • Nintendanib (consider Pirfenidone, if not tolerated)
  • Nerandolimast
• Lung Transplant
  • Refer early if high risk for evauluation

May add IVIG as adjunctive therapy any time

Rapidly Progressive ILD

First Line

• Methylprednisolone IV pulse, then Prednisone 1mg/kg/d
  AND
• 1 or 2 of
  • RTX, CYC, MMF, CNI, JAKi

Additional Management

• ECMO: evaluate candidacy, as bridge to transplant or recovery
• Lung transplant: evaluate candidacy, if isolated respiratory failure
• Salvage therapy: PLEX, IVIG

— Duration

• Taper per treatment response; taper sequentially based up on clinical response: steroids, IVIG, other immunosuppressants
  • Steroids: taper to  5-10mg/day by 6 months, discontinue steroids by 9-12 months; then
  • Taper IVIG be elongating dosing interval and/or decreasing dose, and also then taper
  • Azathioprine/methotrexate at monthly intervals if still in remission
  • Taper additional immunosuppressants according to disease activity
  • May be difficult to fully taper anti-synthetase patients off therapy

— Adjunctive Therapy

• PJP
  • PJP prophylaxis: Trimethoprim-sulfamethoxazole 1tab DS Monday/Wednesday/Friday
  • May consider initiation if: >20mg/day prednisone with additional DMARD, or if on CYC and RTX
  • Duration: at least 3 months following CYC cessation or  6 months following RTX cessation
• GI
  • Add a PPI if on high dose steroids and if other risk factors for GI ulcer
• Bone
  • Bone density: consider screening for osteoporosis in patients with additional risk factors

PROGNOSIS

• Varies by clinical-serological subtype and presence of extramusclar involvement
• Mortality
  • 10-year survival rate: 20-90% depending on studies in Europe, North America, Japan
  • Mortality ratio: 1.7-2.6
• Main cause of death: Malignancies, cardiovascular disease, lung disease

REFERENCES

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