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Myopathic Disorder


Classification Criteria: 
  • Bohan and Peter in 1975 defined DM and PM based upon the following features; 
    • Symmetric proximal muscle weakness
    • Typical cutaneous eruption of DM (the only feature distinguishing DM from PM
    • Elevated serum muscle enzymes
    • Myopathic changes on electromyography (EMG)
    • Characteristic muscle biopsy abnormalities and
    • the absence of histopathologic signs of other myopathies
  • ACR/EULAR 2017 : derived from data on 976 IIM patients (74 percent adults; 26 percent children) and 624 non-IIM patients with mimicking conditions (82 percent adults; 18 percent children).
    • The EULAR/ACR criteria classify patients as having "definite," "probable," and "possible" disease based on a score and corresponding probability of disease. The ACR/EULAR approach identifies 16 distinct clinical, serologic, and muscle biopsy variables which can be entered into a web-based calculator. With this approach, sensitivity and specificity for correctly identifying cases of probable IIM are 93 and 88 percent, respectively. 


7 Subtypes
  1. DM
  2. Chronic Amyotrophic DM
  3. PM
  4. Overlap syndrome (SSc, SLE, Sjogren Syndrome)
  5. Antisynthetase syndrome
  6. Immune-mediated necrotizing myopathy (HMG CoA Reductase antibody , anti-SRP antibody (Signal recognition particle) 
  7. IBM
Antibodies: RAFIM IS-A SRP Mi(xed with) SAE - Malignancy, IMNM 
S - severe for both SAE and SRP
  1. Antisynthetase antibodies: Anti-Jo-1 (20% of IIM) (directed against histidyl-tRNA synthetase), Anti-PL-12. other ab are:  OJ, EJ, PL-7, PL-12, KS, Zo, and Ha antigens
    • clinical features: Mechanics Hand, Raynaud's, Arthritis, ILD, Fever, RAFIM
  2. Amyotrophic DM related ab: Anti-MDA5 ab;  melanoma differentiation-associated gene 5 (MDA5) - involved in innate immunity - high risk for ILD, and severe skin manifestation and arthritis; ulcerations over the Gottron papules and sign, painful palmar papules and macules, oral ulcerations, and prominent nonscarring alopecia. ISA
  3. Anti-SRP-2 ab (Signal recognition particle - SRP) - can have very high CK (also seen in IMNM)
  4. Anti-Mi-2 - better prognosis (not much weakness)
  5. Juvenile DM associated ab: Anti-NXP-2 antibody - severe severe disease, edema, and calcinosis; In children is not associated with malignancy
  6. Anti-NXP-2 antibody and Anti-TIF-1 gamma - malignancy associated in adults ; Anti-TIF-1 Gamma has characteristic cutaneous phenotype including palmar hyperkeratotic papules, psoriasis-like lesions, and hypopigmented and telangiectatic "red-on-white" patches
  7. Anti-SAE antibody - high prevalence of dysphagia and cutaneous manifestations that precede the development of myopathy; may then go on to develop severe myositis and may have an increased risk for malignancy
  8. IMNM ab:  3-hydroxy-3-methylglutaryl coenzyme A reductase (3HMG-CoAR)


Subtypes of IMNM
  • Three subtypes of IMNMs are recognized
    • Anti-signal recognition particle (anti-SRP) autoantibody IMNM
    • Anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGCR) autoantibody IMNM
    • Anti-HMGCR/SRP-negative IMNM

Histology and pathology: 
Histologically, IMNM is characterized by scattered necrotic and regenerating fibers (often many more regenerating fibers than fibers undergoing necrosis) with relative absence of lymphocyte infiltration and abundance of macrophage infiltration [33]. Anti-HMGCR myopathy is strongly associated with both the class II major histocompatability complex (MHC) allele DRB1*11:01 and exposure to statin drugs, suggesting it results when genetically susceptible individuals upregulate HMGCR, particularly after statin exposure [34]. The pathophysiology of anti-SRP autoantibody IMNM is less understood. The mechanism of myofiber injury for all forms of IMNM is even less clear, speculatively related to autoantibody binding to the surface of myofibers and subsequent complement-mediated cellular injury [34]. Notably, in anti-HMGCR, anti-SRP, and in those IMNM cases with no serum antibodies, muscle biopsies reveal expression of MHC class 1 (MHC1) and membrane attack complex (MAC) deposition on the sarcolemma of non-necrotic fibers, suggesting that muscle destruction might be complement-mediated. Deposition of MHC1 and MAC on the sarcolemma of non-necrotic muscle fibers is not seen in toxic myopathies nor other autoimmune inflammatory myopathies

Necrotizing myopathy occurs with:
  • IMNM - statins 
  • Paraneoplastic syndromes 

Below is from up-to-date: 

The spectrum of statin-associated muscle adverse events (defined by the 2014 National Lipid Association Statin Muscle Safety Task Force: ) 
TermClinical findingsHistopathological findings[1]
Myalgia

Unexplained muscle discomfort often described as "flu-like" symptoms with normal CK level

The spectrum of myalgia complaints includes: 
  • Muscle aches; 
  • Muscle soreness; 
  • Muscle stiffness; 
  • Muscle tenderness; and 
  • Muscle cramps with or shortly after exercise (not nocturnal cramping) 
None
MyopathyMuscle weakness (not attributed to pain and not necessarily associated with elevated CK)Variable findings: 
  • Atrophy 
  • Inflammation 
  • Mitochondrial changes 
MyositisMuscle inflammationT cells > B cells; macrophages
MyonecrosisMuscle enzyme elevations or hyperCKemia 
  • Mild: >3-fold greater than baseline untreated CK levels or normative upper limit that are adjusted for age, race, and sex 
  • Moderate: ≥10-fold greater than untreated baseline CK levels or normative upper limit that are adjusted for age, race, and sex 
  • Severe: ≥50-fold above baseline CK levels or normative upper limit that are adjusted for age, race, and sex 
Non-specific inflammatory cells with secondary macrophage infiltration
Myonecrosis with myoglobinuria (rhabdomyolysis)Increase in serum creatinine ≥0.5 mg/dL (clinical rhabdomyolysis)Non-specific inflammatory cells with secondary macrophage infiltration


Colchicine – Myopathy is an infrequent adverse effect of colchicine treatment , particularly in the setting of renal insufficiency. Multiple mechanisms seem to be involved as the interaction has been reported with a variety of statins, including pravastatin.

Cyclosporine – Cyclosporine is an inhibitor of CYP3A4, CYP2C9, and the hepatocyte membrane efflux transporter organic anion transport protein (OATP), which regulates hepatic uptake of fluvastatinrosuvastatin, and pitavastatin. Coadministration of cyclosporine can increase concentrations of fluvastatin twofold and rosuvastatin and pitavastatin by 3- to 10-fold or more. Cyclosporine has been safely administered with fluvastatin doses of up to 40 mg/day. Rosuvastatin and pitavastatin are dose-limited or contraindicated with cyclosporine, respectively.

Statin-associated IMNM and inflammatory myopathy may represent a pathophysiological spectrum rather than categorical entities [147].
In necrotizing myopathy, scattered necrotic muscle fibers are present. This apparently histologically distinct noninflammatory statin myopathy is characterized by a macrophagocytic infiltrate engulfing necrotic muscle fibers, responds to immune therapy, and is presumably autoimmune. 
Despite the lack of inflammation in the muscle itself, IMNM appears to be due to antibodies to hydroxymethylglutaryl (HMG)-CoA reductase (HMGCR) in regenerating muscle, and possibly other proteins 

The European Neuromuscular Centre (ENMC) has produced a guidance document to assist the clinician in the treatment of these patients [161,162].




Dermatomyositis - Pearls

MOST IMPORTANT THING IN DM IS THAT IT IS A VASCOLOPATHY INVOLVING CAPILLARIES and hence it involves skin and perifasicular muscle involvement. More severe vasculopathy means more severe skin including ulcerative disease and necrotizing muscle involvement 

Normal muscle cells do not express class I major histocompatibility complex (MHC) antigens, but these antigens are strongly expressed on muscle fibers in patients with JDM [68]. MHC class I overexpression is an early event in JDM and may occur in the absence of lymphocytic infiltration and muscle damage.





?Antisynthetase syndrome 
83 yo CM with DM, Antisynthetase syndrome
Diagnosed of DM in July
Had hx of prior lung nodule being f/b Pulmonary
Was also diagnosed with anti-synthetase syndrome

Admitted from summer 2020  for evaluation of 4 month history of progressive BUE and BLE weakness associated with facial rash, dorsal MCP and PIP joint papular rash, and bilateral shoulder pain.  Rash was initially thought to be atopic dermatitis or fungal, therefore, the patient was treated with topical steroids and anti-fungal creams.  When there was no improvement of the rash, the patient was referred to see Dermatology.  Skin biopsies of L zygomatic and R lateral thigh rashes were performed.  Before the pathology returned, the patient experienced worsening shoulder pain and inability to ambulate, therefore was  admitted, he was found to have modestly elevated CK levels (718), elevated aldolase (9.5), positive ANA, positive SSA.  An MRI of his BUE did show evidence of a diffuse myositis.  Additionally, an EMG demonstrated a diffuse myopathic process.  A R biceps biopsy was performed which showed denervation atrophy with chronic reinnervation and mild preferential type 2 atrophy.  In the interim, the skin biopsies have returned as interface dermatitis which can be seen in dermatomyositis.
 
 The patient notes that he has trouble with getting up from the bed and with his raising arms.  He is ambulating with walker.  He also continues to have bilateral upper shoulder pain radiating into elbows .  The rash above his eyebrows and on cheeks is improving with steroid and fungal cream.  He continues to have a rash on his buttocks.  The rash on his fingertips, MCPs and PIPs is improving, though he has developed scabs.
 
Review of systems is significant for weight loss (10 lbs in the past month), chronic fatigue, intermittent constipation, occasional numbness in R 2nd finger.  He otherwise denies any hair loss, f/c, conjunctivitis, dry eyes, dry mouth, mouth ulcers, heart burn, chest pain, SOB, abd pain, n/v, diarrhea, bloody stools, hematuria, arthralgias, joint swelling, AM stiffness, Raynaud's.


June 
CK 408 ESR 25 CRP 0.7 

CK-MB 0.0 - 5.0 ng/mL 7.6  

NUCLEAR AB SCREEN 0.0 - 0.9 AI 2.1 
ANTI DOUBLE STRANDED DNA SCR <=4 International Units/mL 1 Negative: <5 IU/mL 
Equivocal: 5-9 IU/mL 
Positive: >9 IU/mL 
ANTICHROMATIN ANTIBODY IGG 0.0 - 0.9 AI <0.2
RIBOSOMAL P ANTIBODY 0.0 - 0.9 AI <0.2
SSB AB SCREEN 0.0 - 0.9 AI <0.2
CENTROMERE ANTIBODY, IGG 0.0 - 0.9 AI <0.2
SMITH AB SCREEN 0.0 - 0.9 AI <0.2
SCL-70 AB SCREEN 0.0 - 0.9 AI <0.2
SMITH AND RNP ANTIBODY 0.0 - 0.9 AI <0.2
ANTI JO-1 0.0 - 0.9 AI <0.2
SSA AB SCREEN 0.0 - 0.9 AI 2.1 High 
RNP ANTIBODY SCREEN 0.0 - 0.9 AI <0.2
ALDOLASE 1.5 - 8.1 unit/L 9.5  


MRI
Extensive diffuse myositis of LUE, no abscess or fluid
collections identified. Given the presence of rash as noted
in the chart, this may be related to dermatomyositis,
however other etiologies like drug induced myositis cannot
be completed excluded

Mi-2 (nuclear helicase protein) Antibody: Negative 
P155/140 Antibody: Positive       *  (Previous name for TIF-1 -g amma)
TIF-1 gamma (155 kDa) Ab: High Positive       * 
SAE1 (SUMO activating enzyme) Ab: Negative 
MDA5 (CADM-140) Ab: Negative 
NXP-2 (Nuclear matrix protein-2) Ab: Negative 

VITAMIN D, 25-HYDROXY 30.0 - 100.0 ng/mL 8.9  
TPMT ACT 24.0 - 44.0 unit/mL 28.1  
positive Ro52,

Additionally, an EMG demonstrated a diffuse myopathic process.  A R biceps biopsy was performed on 7/1/20 which showed denervation atrophy with chronic reinnervation and mild preferential type 2 atrophy

Discussion

All DM and PM patients exhibit the cardinal feature of symmetric proximal muscle weakness other than a subset referred to as clinically amyopathic DM 

Muscle weakness — over 90 percent of patients with PM present with proximal muscle weakness (deltoids, hip flexors, neck flexors) of insidious or subacute nature (acute onset is occasionally reported) however, in DM, cutaneous manifestations often precede or accompany weakness, which is found at presentation in only 50 to 60 percent of patients . Mild myalgias and muscle tenderness occur in 25 to 50 percent of cases. Patients may notice joint pain and swelling, and they occasionally mistakenly ascribe weakness to the joint involvement. Pain is mild, if present, and stiffness is not a prominent complaint.

Skin findings in dermatomyositis — Patients frequently present with some of these features, but not all.

Characteristic findings — Gottron papules and the heliotrope eruption are pathognomonic features of DM.

           Gottron sign, photodistributed erythema, poikiloderma, nailfold changes, scalp involvement, and calcinosis cutis are also characteristic and useful in distinguishing DM from PM.

Gottron papules – Gottron papules are erythematous to violaceous papules that occur symmetrically over bony prominences, particularly the extensor (dorsal) aspects of the metacarpophalangeal (MCP) and interphalangeal (IP) joints. In addition, these lesions may involve the skin between the MCP and IP joints, particularly when the eruption is prominent. Sites such as the elbows and knees may also be affected.

Gottron papules often have associated scale and may ulcerate. When scaling is present, the lesions may mimic psoriasis or lichen planus.

Gottron sign – erythematous to violaceous macules, patches, or papules on the extensor surfaces of joints of the hands, elbows, knees, or ankles

Heliotrope eruption  erythematous to violaceous eruption on the periorbital skin, sometimes accompanied by eyelid edema, which, at times, may be quite marked

Facial erythema – Patients may have midfacial erythema that can mimic the malar erythema seen in systemic lupus erythematosus (SLE) but involves the nasolabial folds (rather than the classic nasolabial sparing seen in the malar rash of SLE)

Photodistributed poikiloderma (including the shawl and V-signs) – Poikiloderma refers to skin that demonstrates both hyperpigmentation and hypopigmentation, as well as telangiectasias and epidermal atrophy. In DM, patients may demonstrate poikiloderma in any photo-exposed site; however, classic areas of involvement are the upper back (shawl sign)  and the V of the neck and upper chest (V-sign). The poikiloderma in DM often presents with a violaceous hue but may be more erythematous in patients with lighter skin.

Early in the course of cutaneous disease, these areas may demonstrate only erythema rather than well-developed poikiloderma The erythema may be macular (nonpalpable) or papular. The cutaneous eruption of DM is often associated with significant pruritus, which may assist in distinguishing its photo-exacerbated eruption from that of SLE.

Holster sign –  poikiloderma or erythematous rash on the lateral aspects of the thighs, referred to as the "Holster sign" . It is unclear why this cutaneous manifestation occurs on this classically photo-protected site.

Nailfold abnormalities – Multiple nailfold capillary changes are often seen in DM. Abnormal capillary nailbed loops with alternating areas of dilatation and dropout, as well as periungual erythema, are common. In addition, cuticular hypertrophy, sometimes termed "ragged cuticles," is also characteristic and may be associated with hemorrhagic infarcts within the hypertrophic area . The degree of cuticular involvement is thought to reflect ongoing cutaneous disease activity, representing active vasculopathy

Psoriasiform changes in scalp – The scalp involvement in DM typically includes poikilodermatous changes and prominent scaling. These changes often mimic seborrheic dermatitis or psoriasis. Scalp involvement may result in severe burning, pruritus, and/or sleep disturbance. In addition, severe scalp pruritus may occur in patients without clinically evident psoriasiform changes.

Calcinosis cutis – The deposition of calcium within the skin occurs more commonly in juvenile DM than in adult DM. Calcinosis cutis, which is very challenging to treat, may be seen in a variety of conditions, including systemic sclerosis (SSc, scleroderma), particularly the limited form of cutaneous SSc known as CREST syndrome (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia); SLE (rarely); and overlap connective tissue disorders. It may be more common in patients with DM with the anti-MJ/anti-NXP-2 autoantibody

Generalized erythroderma – Rarely, including areas that are less exposed to ultraviolet light.

Rare findings — Rarely reported cutaneous findings in patients with DM have included panniculitis, cutaneous vasculitis, porcelain white atrophic scars (ie, Degos disease-like lesions), vesicle and bullae formation, ichthyosis, follicular hyperkeratosis, malakoplakia, papular mucinosis, and flagellate erythema. Diffuse nonpitting edema is another rare manifestation of DM and may be a marker of more aggressive disease

Interstitial lung disease — ILD occurs in at least 10 percent of cases of DM and PM, most often in association with anti-Jo-1 or another antisynthetase antibody. In DM, it can be observed in patients with either classic or amyopathic disease. A rapidly progressive ILD associated with pulmonary failure and death is most commonly a feature of anti-MDA5 DM.

In addition to ILD, respiratory insufficiency in the immune-mediated myopathies may result from diaphragmatic and chest wall muscle weakness. These issues are discussed in detail separately. (See "Interstitial lung disease in dermatomyositis and polymyositis: Clinical manifestations and diagnosis".)

Esophageal involvement — Dysphagia is the most commonly reported gastrointestinal symptom, with studies reporting a wide range in prevalence [25]. Weakness of the striated muscle of the upper one-third of the esophagus and/or the oropharyngeal muscles contribute to dysphagia, nasal regurgitation, and/or aspiration [26]. Esophageal involvement is more common in older patients and may underlie the increased incidence of bacterial pneumonia [27].

Cardiac involvement — Cardiac involvement with histologic evidence of myocarditis is well described in DM and PM, and subclinical manifestations are frequent, including conduction abnormalities and arrhythmia detected by electrocardiographic studies. Symptomatic cardiac disease, such as congestive heart failure, is less common. However, patients with DM and PM are also at increased risk for myocardial infarction (MI) . A large, retrospective, population-based study found a nearly three- and fourfold increased risk of MI among 350 and 424 patients with incident DM and PM, respectively, as compared with those without an inflammatory myopathy, after controlling for relevant risk factors such as age, sex, glucocorticoids, and nonsteroidal antiinflammatory drugs (NSAIDs).

Laboratory findings

Elevated levels of muscle enzymes.

Autoantibodies, including antinuclear antibodies, in up to 80 percent of patients with DM and PM ; myositis-specific autoantibodies in at least 30 to 40 percent of patients; and myositis-associated autoantibodies, especially in patients with overlap syndromes.

The erythrocyte sedimentation rate (ESR) is often normal or is only mildly elevated, even in patients with active muscle disease [39].

Muscle enzymes — Creatine kinase (CK), lactate dehydrogenase (LDH), aldolase, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) 

At some point in the course of the disease, almost all patients with DM and PM, except those with CADM, have an elevation in at least one muscle enzyme; most have elevations in all enzymes. In a review of 153 patients with DM or PM, normal results were found for CK in 5 percent, for aldolase in 4 percent, for LDH in 9 percent, and for the aminotransferases in 15 to 17 percent [10]. However, these data may underestimate the frequency of normal CK concentrations because the Bohan and Peter criteria employed in that study included muscle enzyme elevation as a disease criterion. Additionally, the study was performed before many autoantibody tests and magnetic resonance imaging (MRI) studies were available to facilitate the diagnosis. 

Creatine kinase – The level of serum CK can vary widely. In untreated patients with active muscle disease, it is usually more than 10-fold the upper limit of normal (ie, at least 2000 to 3000 international units/L). In severe cases, the serum CK concentration may be elevated more than 50-fold or even 100-fold (ie, up to 10,000 to 20,000 international units/L), and higher levels are sometimes seen.

There is no clear correlation with CK and severity of weakness, though the level is useful to follow during treatment. In some cases, there may be elevations in serum muscle enzymes without discernible muscle weakness. This is particularly observed in patients with early disease.

The occurrence of muscle weakness with relatively normal enzyme levels is much more likely to occur in DM than PM. Persistently low serum muscle enzyme levels in the setting of obvious muscle weakness may also occur in patients with advanced disease and significant loss of muscle mass. In these groups of patients, assessments other than enzyme levels can be beneficial, including muscle MRI, typically performed on the bilateral thighs with a myositis protocol. Other patients with no clinical muscle involvement, as in CADM, will also have normal enzyme levels.

Aldolase – Aldolase is another glycolytic pathway enzyme that is found in all tissues but predominantly in skeletal muscle, liver, and brain. While increased aldolase levels are not as specific or sensitive for muscle disease as CK levels, aldolase concentrations are occasionally elevated in patients with myositis, particularly with prominent perimysial pathology, who have normal CK levels [40].

CK-MB – Patients with myositis may also have an elevated serum creatine kinase-myocardial band (CK-MB) fraction. This may occur in the absence of myocarditis, which is usually attributed to increased expression in regenerating skeletal muscle affected by the inflammatory disease or, less often, to involvement of the myocardium by the myositis. MI may be suspected in these patients, who may require additional testing. Measurement of cardiac troponin I may be helpful in patients in whom it may be difficult clinically to determine whether elevations in CK or other muscle enzymes are due to cardiac rather than skeletal muscle disease. Increased levels of cardiac troponin I appear relatively specific for myocardial injury, unlike elevations of total CK, CK-MB, and other muscle enzymes or of cardiac troponin T, all of which may be seen both in skeletal muscle inflammatory myopathy and in cardiac disease [34,39,41-43]. (See 'Cardiac involvement' above and "Troponin testing: Clinical use".)

Myositis-associated autoantibodies — Myositis-associated autoantibodies are those found in patients with other systemic rheumatic diseases that can be associated with myositis. A more detailed discussion of myositis-associated autoantibodies is presented separately.

The detection of anti-Ro, anti-La, anti-Sm, or anti-ribonucleoprotein (RNP) autoantibodies in a patient with myositis suggests a diagnosis of myositis associated or overlapping with another systemic rheumatic disease [33]. Anti-Ro52 autoantibodies are more common in patients with antisynthetase antibodies, whereas anti-Ro60 and anti-La may be seen in a smaller number of such patients and in those with other myositis-specific autoantibodies. The presence of anti-Ro52 autoantibodies in patients with DM appears to be a risk factor for ILD

In general, anti-Ro, anti-La, and anti-U1 RNP can be seen in some patients who also have myositis-specific autoantibodies, but myositis-specific autoantibodies tend to be mutually exclusive with each other. High titers of anti-RNP antibodies are associated with mixed connective tissue disease, an overlap syndrome of myositis with features of SSc and SLE 

Anti-PM-Scl and anti-Ku autoantibodies have been identified in patients with overlapping features of myositis and SSc [37]. Many patients with these antibodies, however, do not have myositis [48]. 

SOCIETY GUIDELINE LINKS

Muscle biopsy — DM and PM can be distinguished from each other and other forms of myopathy by their histopathologic findings. Particular attention should be given to the techniques used for the biopsy of muscle tissue. (See 'Muscle histopathology' below and 'Muscle biopsy technique' below.)

Muscle histopathology — The histologic features of both DM and PM include muscle fiber necrosis, degeneration, regeneration, and an inflammatory cell infiltrate. Certain characteristic findings in these two different diseases help to distinguish the disorders from each other and reflect their distinct pathophysiologic pathways [8]. (See 'DM muscle pathology' below and 'PM muscle pathology' below and "Pathogenesis of inflammatory myopathies".)

DM muscle pathology — DM is characterized histopathologically by the following [5]:

There is evidence of injury to capillaries and perifascicular myofibers (picture 1). Perifascicular atrophy and fibrosis are characteristic but may not be found in some patients biopsied early in the course of their illness. Abnormal muscle fibers are usually grouped in one portion of the fascicle, suggestive of microinfarction mediated by blood vessel dysfunction [9].

The predominant inflammatory infiltrate is in the perimysial region and includes CD4+ cells, many of which (30 to 90 percent) are plasmacytoid dendritic cells rather than T cells, and it also includes macrophages and B cells. Unlike PM and inclusion body myositis (IBM), invasion of nonnecrotic fibers is not prominent.

Overexpression of type I interferon-inducible genes and proteins, especially in the perifascicular region, is present, and gene expression profiling has demonstrated increased expression of various genes that are induced by interferon-alpha and interferon-beta [10,11].

The terminal complement C5b–9 membrane attack complex is detectable in vessel walls before the appearance of inflammatory cell infiltration in DM but not in PM (picture 2) [9]. It is not known if the vasculopathy is mediated purely by complement or if the deposition of complement proteins and other immune complexes associated with this diagnosis is secondary to other pathophysiologic events [12,13].

PM muscle pathology — PM is characterized histopathologically by the following [5]:

The cellular infiltrate is predominantly within the fascicle, with inflammatory cells invading individual muscle fibers (picture 3) [14]. In contrast to DM, abnormal necrotic and regenerating muscle fibers are scattered throughout the fascicle and are not limited to one portion. Muscle fiber size is variable. There are no signs of vasculopathy or immune complex deposition.

Myofiber injury appears to be mediated directly by CD8+ cytotoxic T lymphocytes that surround and invade myofibers. Macrophages and myeloid dendritic cells are usually present, and, in some patients, plasma cells are also seen. The inflammatory infiltrate can involve non-necrotic muscle fibers, but this finding is not always present. Perivascular, perimysial, or endomysial inflammation is typically present, but these findings are nonspecific and can occur in muscular dystrophies, metabolic myopathies following rhabdomyolysis, and IBM [5].

There is enhanced expression of class I major histocompatibility complex antigens by the muscle fibers [15].

In patients with autoimmune necrotizing myopathy, which is sometimes classified with PM, scattered necrotic muscle fibers are present. There are few inflammatory cells, and, when present, they are localized to necrotic muscle fibers. Sometimes, inflammatory cells are found around small blood vessels, and thickened basement membranes are seen. Unlike DM, these patients do not exhibit perifascicular atrophy.

MSA and histopathology — Patients with myositis-specific antibodies (MSA) may differ histopathologically from those lacking these antibodies, and there is histopathological variation according to the particular MSA that are present [16-19]. For example, perimysial connective tissue fragmentation and inflammation, with myopathic changes in nearby perifascicular regions but with little endomysial or perivascular change, may be seen in patients with anti-Jo-1 antibodies [17]. Anti-Jo-1 antibody-positive patients may thus exhibit the perifascicular atrophy typical of DM but not the characteristic capillary pathology. (See "Clinical manifestations of dermatomyositis and polymyositis in adults".)

By contrast, patients with anti-signal recognition particle (SRP) antibodies have the capillary pathology but not the perifascicular atrophy. Patients with anti-SRP antibodies are reported to have less intramuscular inflammation than do other patients with DM or PM. (See "Clinical manifestations of dermatomyositis and polymyositis in adults".)

Muscle biopsy technique — The biopsy should be obtained from a muscle that is weak on physical examination but is not atrophied. The usual muscle targets for biopsy are the quadriceps or the deltoid. Biopsying the muscle contralateral to one shown to be abnormal by electromyography (EMG) increases the likelihood of a diagnostic biopsy. We avoid muscles with severe weakness, marked atrophy, or recent EMG testing. In addition, biopsy of the calf muscles is discouraged because of the frequency of artifactual findings in biopsies from that region.

If physical examination and EMG fail to identify an appropriate muscle for biopsy, magnetic resonance imaging (MRI) may be useful. MRI may reveal areas of increased T2 signal in muscles that can then be selected for biopsy. Targeted study of the most accessible muscles (eg, deltoid, biceps, quadriceps) by MRI is one approach, but whole-body imaging is another option 

We generally prefer an open biopsy to a closed-needle biopsy, because larger specimens can be obtained and because muscle fiber orientation is better preserved. Muscle biopsy via a small incision using local anesthesia and a sharp-jawed surgical instrument (conchotome) may also yield a diagnostically adequate specimen with a low complication rate. The efficacy of this technique was evaluated in a report in which 149 muscle biopsies were obtained from 122 patients [21]. Only four biopsies (2.7 percent) failed to provide an adequate sample for histologic analysis. Eighty-three percent of patients who met clinical criteria for definite or probable DM or PM had biopsies that revealed myositis.

Proper processing of the muscle biopsy is essential. Once obtained, the muscle tissue should be preserved appropriately for later testing. Some tissue should be fixed for routine light and electron microscopy, and some tissue should be frozen in isopentane cooled in liquid nitrogen for biochemical assays. Important biochemical assays include:

Testing for metabolic myopathies due to defects in carbohydrate, lipid, or purine metabolism

Immunohistologic assays for mutant proteins including:

Dystrophin for Duchenne/Becker dystrophy

Merosin for congenital muscular dystrophy

Sarcoglycan for limb-girdle muscular dystrophy

The experience of the laboratory in processing muscle biopsy specimens correlates highly with the usefulness of diagnostic information obtained from the procedure. The team performing and processing the biopsy should be provided with detailed clinical information. The clinician requesting the biopsy should communicate directly with the surgeon and pathologist prior to the procedure. An example of detailed instructions for handling of muscle biopsy specimens is available [22].

Skin biopsy — In patients with DM, characteristic findings may also be seen on skin biopsy, although these findings are very similar on light microscopy to changes that can be seen in systemic lupus erythematosus. 

Skin histopathology — On light microscopy, DM skin lesions usually demonstrate mild atrophy of the epidermis with vacuolar changes in the basal keratinocyte layer, as well as a perivascular lymphocytic infiltrate in the dermis [23]. This is referred to as interface dermatitis. In addition, patients with DM frequently have increased dermal mucin.

Lesions of DM are difficult to distinguish histologically from those of systemic lupus erythematosus (SLE), requiring careful clinical examination of the skin for confirmation of the diagnosis [23]. This is particularly important in patients with amyopathic DM who often present after being misdiagnosed as having LE; the distinction must be made based upon clinical rather than histopathologic features. Findings that are more common in DM than LE include a predominance of CD4+ and chemokine receptor CXCR3-positive cells, as well as increased endothelial cell expression of the interferon-inducible MxA protein [24].

Direct immunofluorescence may reveal deposition of complement proteins and immunoglobulin at the dermal-epidermal junction that is generally not distinguishable on light microscopy from systemic lupus erythematosus. However, in DM, deposition of immunoglobulin, but not of complement, is less common than in lupus. Deposits of the membrane attack complex are found along the dermal-epidermal junction and within the walls of dermal blood vessels [25].

Skin biopsy technique — Skin biopsy techniques are described in detail separately. A 4 mm punch biopsy is usually sufficient to obtain an adequate tissue sample for histological examination on light microscopy with hematoxylin and eosin staining. Immunofluorescent studies are generally not required, but some experts also perform these studies. 

Electromyography — Characteristic abnormalities on EMG can support a diagnosis of inflammatory myopathy. However, such changes are not diagnostic of DM or PM, with similar findings occurring in various infectious, toxic, or metabolic myopathies. Certain technical considerations are important in the evaluation of patients with suspected inflammatory myopathy by EMG.

EMG findings — EMG is most helpful in distinguishing myopathic causes of weakness from neuropathic disorders, such as amyotrophic lateral sclerosis, peripheral polyneuropathy, or myasthenia gravis. It also helps identify the muscle group that is likely to provide useful information on biopsy. The biopsy is done on the side contralateral to that on which the EMG is performed to avoid needle-related artifact, given the usually symmetrical muscle involvement

The EMG may show evidence of increased membrane irritability with the following abnormalities, although these changes are not always present in patients with inflammatory myopathy:

Increased insertional activity and spontaneous fibrillations

Abnormal myopathic low-amplitude, short-duration polyphasic motor unit potential

Complex repetitive discharges

In addition, an early finding in myopathy is that of early recruitment, an increased number of motor units firing rapidly in order to produce a low level of contraction. The findings of abnormal spontaneous activity such as insertional activity, fibrillation potentials, and complex repetitive discharges can be seen in a wide range of myogenic processes but are much more frequently seen in inflammatory myopathies.

A normal EMG is unusual in a patient with otherwise typical DM or PM, occurring in one study in 16 of 153 patients (11 percent) [26].

Findings are not always generalized, and highly localized disease, although atypical, sometimes occurs in DM and PM.

EMG technical considerations — Because involvement is typically bilateral and symmetrical, we perform a unilateral EMG study to detect changes suggestive of an active inflammatory myopathy. We perform the biopsy, when indicated, in the contralateral muscle group to avoid needle-related artifact. (See "Overview of electromyography".)

In patients who are having blood drawn for muscle enzyme testing, it should be drawn prior to performing the EMG, because samples obtained soon after (within 24 to 36 hours) may be elevated due to the trauma associated with needle insertion into the muscle. Additionally, the electromyographer should sample multiple sites, if initial sites are unremarkable, before concluding that there are no myopathic changes, because muscle involvement may not be generalized. (See "Muscle enzymes in the evaluation of neuromuscular diseases".)

MRI — MRI of skeletal muscles is a non-invasive sensitive modality for evaluating patients with myopathy [27]. MRI can demonstrate areas of muscle inflammation, edema with active myositis, fibrosis, and calcification. Unlike muscle biopsy, MRI can assess large areas of muscle, thereby avoiding problems with sampling error (image 1). It is, however, nonspecific and may not distinguish the changes of inflammatory myopathy from those that occur in rhabdomyolysis, muscular dystrophy, or metabolic myopathy.

Ultrasound — Musculoskeletal ultrasound with power Doppler is another noninvasive technique that can be used to assess the presence of myopathy. With inflammatory myopathies, muscle becomes hypoechoic, reflecting loss of normal muscle definition due to edema and fatty tissue infiltration. Hypervascular changes on power Doppler are seen in active early disease. While these changes are not specific for inflammatory myopathies, ultrasound can be an alternative to MRI in helping to establish the presence of muscle disease or in helping to locate an appropriate site for muscle biopsy. While it is less expensive and less time-consuming than MRI, it is operator-dependent, requiring an experienced ultrasonographer [28].

DIAGNOSIS


IBM
77yo AAM with IBM. Previously on MTX, now on AZA 150 mg daily and Prednisone 5 mg daily. It was deemed unlikely that the patient was going to benefit from the immunosuppression, and had wanted to try in the past.

CK: 500-800 on 5 mg steroid; 1100 in 2017; CK high noted as far as in 2009

Electromyography in IBM —  EMG in IBM typically reveals an "irritable myopathy" with increased insertional activity, fibrillations, positive waves, and early recruitment of short-duration, small-amplitude polyphasic motor unit action potentials (MUAPs). Fasciculations are not observed. These findings strongly suggest a diagnosis of inflammatory myopathy. In some muscles, EMG may show reduced recruitment and a mixture of short and long duration, small- and large-amplitude polyphasic MUAPs. This mixed pattern of myopathic and "neurogenic"-appearing units is more typical of IBM than polymyositis or dermatomyositis. 

Nerve conduction studies are usually normal, but may show a concomitant peripheral neuropathy in some cases.

EMG in our patient is indicative of a diffuse myopathic process.  Although polymyositis cannot be completely ruled out, the clinical pattern is more c/w sporadic IBM.

The motor conduction in the left ulnar nerve showed normal latency, slowed velocities (greater in the segment over the elbow), with normal amplitudes. The motor conductions in the left tibial and both peroneal nerves showed normal latencies and velocities with reduced amplitudesThe sensory conductions in the left sural and radial nerves showed borderline slow latencies with reduced amplitudes; that of the left superficial peroneal nerve was absent.

On needle electrode examination, there were patchy fibrillation potentials present in several muscles tested. The motor unit potentials were rapidly recruited for level of effort and were variably reduced in duration and main spike size with variable increase in complexity in the proximal muscles. There were enlarged motor unit potentials present in the FDI.

Patient has evidence for an axonal polyneuropathy and a focal ulnar neuropathy at the left elbow.

Muscle biopsy — We biopsy muscles that are only moderately weak (4 or 4+ on MRC scale) and prefer biceps or quadriceps muscles. MRI and EMG may be useful in guiding the selection of a muscle for biopsy, as the diagnostic yield for biopsy is low in muscles with extensive atrophy and/or fatty replacement. However, in some cases, the muscle biopsy in IBM is nonspecific and the diagnosis depends on a combination of clinical findings and a biopsy consistent with IBM.

The histologic features on muscle biopsy associated with IBM include:

Mononuclear cell infiltration of non-necrotic muscle fibers. The infiltrate is predominantly CD8+ T lymphocytes and macrophages. Major histocompatibility complex (MHC)-I is upregulated on immunostaining. These are histologic features of an inflammatory myopathy and are also seen in polymyositis .

Sarcoplasmic "rimmed" vacuoles that are red-rimmed on modified trichrome stain and blue-rimmed on H&E.

Myofiber degeneration, regeneration, and necrosis may be seen. Variability of fiber size with scattered atrophic fibers is common.

Abundant "COX [cytochrome oxidase]-negative" fibers suggestive of mitochondrial abnormalities is common.

●On electron microscopy, the inclusions are shown to consist of 15 to 18 nm tubulofilaments that are not present in other inflammatory myopathies. These inclusions can be seen in the sarcoplasm and within myonuclei.

●Amyloid deposits in vacuolated fibers identified by Congo red staining are occasionally observed.

●Immunostaining for p62 and TDP-43 labeled characteristic protein aggregates. These inclusions are much more common than amyloid, and the presence of fibers on biopsy that contain these protein aggregates increases diagnostic certainty for IBM].

The commonly used Griggs criteria require the presence of rimmed vacuoles, mononuclear inflammatory cells invading non-necrotic muscle fibers, and the presence of either amyloid deposits or tubulofilaments by electron microscopy for pathologically definite IBM is highly specific when all three components are present, but lacks sensitivity and is rarely used clinically

Muscle biopsy report: This biopsy demonstrates alterations consistent with a chronic inflammatory myopathy, including increased fiber size variabilitymany rounded atrophic fibers, increased internal nucleation, occasional necrotic and regenerating fibers, many rimmed calculated fibers, mildly to moderately increased endomysial connective tissue in several fascicles, multiple mononuclear inflammatory aggregates in the endomysial, a few nonnecrotic fibers undergoing early invasion by inflammatory cells, numerous fibers exhibiting altered in terms mild fibrillar cytoarchitecture, increased ragged red fibers, many cytochrome C oxidase negatively staining fibers, and a few atrophic fibers with metachromatically staining cytoplasmic amyloid deposits. In the appropriate clinical setting, these changes are diagnostic of sporadic inclusion body myositis.

The second constellation of alterations is more in keeping with a milder, chronic neurogenic process characterized by denervation atrophy and reinnervation, including many atrophic angular fibers of all histochemical fiber types, several areas of small group atrophy, mild fiber type grouping, several targetoid fibers, and many esterase positive denervated fibers.  Of note, neurogenic changes of this nature are commonly seen in sporadic inclusion body myositis.

Diagnosis: Skeletal muscle, 1 sporadic inclusion body myositis, denervation atrophy with reinnervation

Differentiation between inclusion body myositis and polymyositis

 Inclusion body myositisPolymyositis
SexMale > femaleFemale > male
AgeUncommon before 50Common before 50
OnsetInsidiousAcute or subacute
CourseSlowly progressiveMore rapid
Distribution of weaknessUsually asymmetric finger flexor and proximal leg weaknessProximal, symmetric
Creatine kinaseNormal or <10x normalOften >10x normal
EMGMyopathic or mixed myopathic and neurogenicMyopathic
Muscle biopsyInflammation, rimmed vacuoles, inclusionsInflammation, fiber necrosis
Response to therapyGenerally poorExpecte


Muscle enzymes are typically mildly elevated early in the disease, but may normalize with disease progression. Creatine kinase (CK) levels are usually less than 10 times normal. An elevation of CK greater than 15 times the upper limit of normal suggests an alternative diagnosis. Glucocorticoids may dramatically reduce serum CK levels in IBM, and a normalization of serum CK in the absence of an improvement of weakness is common in IBM

CK: 500-800 on 5 mg steroid; 1100 in 2017; CK high noted as far as in 2009

Measures of the acute phase response, such as the erythrocyte sedimentation rate (ESR) or the C-reactive protein (CRP), are usually normal.

ESR and CRP was normal

Myositis-specific autoantibodies are typically absent in patients with IBM. Testing for autoantibodies directed against cytoplasmic 5'-nucleotidase 1A (cN1A) may be helpful for distinguishing IBM from other forms of myositis. A study evaluated the diagnostic performance of immunoglobulin M (IgM), IgA, and IgG anti-cN1A serum antibodies detected by enzyme-linked immunosorbent assay (ELISA) in 205 patients with muscle disease, 50 of whom had IBM [22]. A combination assay of all three autoantibody levels resulted in a sensitivity and specificity of 76 and 91 percent, respectively. However, anti-cN1A antibodies are also detected in about 20 percent of patients with SLE and Sjögren's syndrome in the absence of muscle disease [23,24]. Laboratory testing is commercially available, and we recommend testing in diagnostically challenging cases

Not tested 

Dysphagia due to involvement of the cricopharyngeal muscle occurs in about one-third to one-half of patients

Myalgias may accompany the weakness but are usually mild

Symptoms of associated conditions should be reviewed since as many as 15 percent of IBM patients have underlying autoimmune disorders such as systemic lupus erythematosus (SLE), Sjögren's syndrome, systemic sclerosis (scleroderma), Hashimoto thyroiditis, variable immunoglobulin deficiency, sarcoidosis, and idiopathic thrombocytopenia purpura

As some hereditary myopathies such as Limb-Girdle Muscular Dystrophy and hereditary IBM may have proximal and distal weakness as well as rimmed vacuoles and/or inflammation on muscle biopsy and may be misdiagnosed as IBM

The diagnosis of IBM should be considered in patients over the age of 40 who present with progressive muscle weakness, even in the absence of an elevated serum creatine kinase (CK). If patients have proximal leg weakness and distal arm and/or leg weakness on exam, referral to a neurologist and muscle biopsy should be performed at a center with the ability to appropriately process and interpret the biopsy.

We also ask about exposure to a variety of prescription and illicit drugs that may cause myopathy, myositis, neuropathy, or other disorders that cause muscle weakness. Among the drug exposures that should be specifically sought are antimalarial drugs (eg, chloroquinehydroxychloroquine), colchicine, glucocorticoids, cholesterol-lowering drugs (eg, HMG-CoA reductase inhibitors [statins]), alcohol, and cocaine. 

However, unlike other inflammatory myopathies such as polymyositis or dermatomyositis, IBM is not associated with myocarditis, interstitial lung disease, or an increased risk of malignancy.

Physical examination — The physical examination helps to determine the distribution of muscle weakness and atrophy. Findings of quadriceps (ie, knee extensor) and forearm flexor (ie, wrist and finger flexor) muscle weakness and wasting are clinical hallmarks of IBM [18]. Many patients also have significant hip flexion weakness and are typically unable to stand from a chair without pushing off with their arms. With severe quadriceps weakness, patients may walk with the leg hyperextended (genu recurvatum). To detect subtle weakness of distal finger flexion (typically the earliest exam finding), the clinician should isolate and specifically examine flexion at the distal interphalangeal (DIP) joint. Other muscles that are commonly affected are orbicularis oculi (leading to weakness with eye closure), triceps (weakness with arm extension), and tibialis anterior (leading to foot drop) [19].

While many patients with IBM present with symmetric and proximal muscle weakness suggestive of polymyositis, the finding of more distal, asymmetric involvement with finger and wrist flexor weakness greater than deltoid weakness and knee extensor weakness greater than hip flexor weakness would be more typical of IBM.

The purpose of laboratory testing is primarily to exclude an alternative diagnosis that could lead to weakness and to look for associated conditions. Laboratory tests that may be useful in the evaluation of weakness include serum electrolytes, calcium, magnesium, phosphate, creatine kinase, aldolase, lactate dehydrogenase, serum aminotransferases, and thyroid-stimulating hormone (see "Approach to the patient with muscle weakness", section on 'Laboratory studies'). An elevated alkaline phosphatase level should prompt evaluation for Paget disease, which can be seen in hereditary IBM. (See "Clinical manifestations and diagnosis of Paget disease of bone".)

There is an association of IBM with some autoimmune diseases, such as Sjögren's syndrome and sarcoidosis, as well as with some lymphoproliferative disorders such as T cell large granular lymphocytic leukemia [26]. In addition, IBM has been observed in patients with chronic viral infections such as HIV and Hepatitis C [27,28]. As such, screening laboratory testing for antinuclear antibodies (ANA), anti-Ro(SSA), anti-La(SSB), serum immunofixation, human immunodeficiency virus (HIV), and hepatitis C should also be obtained.


Magnetic resonance imaging — Magnetic resonance imaging (MRI) is often performed in patients with suspected myositis. While there are no findings on MRI studies that are diagnostic for IBM, there are some disease-specific patterns of muscle involvement that may support the diagnosis and help distinguish IBM from polymyositis [31-33]. For example, MRI of the thigh typically shows edema, atrophy, and fatty replacement of the anterior compartment with relative sparing of the medial and posterior compartments.


DDx

Polymyositis

Hereditable myopathies

Hereditary inclusion body myositis (hIBM

Multisystem proteinopathy (MSP

Muscular dystrophy

Drug-induced myopathies Vacuolar changes are also present in drug-induced myopathy due to colchicine and chloroquine.

Amyotrophic lateral sclerosis

Treatment

Pathophysiology

Muscle immune cell infiltration — IBM muscle is abundantly infiltrated by T cells, myeloid dendritic cells, macrophages, plasmablasts, and plasma cells. Lymphocytes invade non-necrotic muscle fibers

Highly differentiated effector cytotoxic T cells — The predominant infiltration of IBM muscle fascicles by CD8+ cytotoxic T cells has been recognized since the 1980s [40]. The cytotoxic capacity of these cells, as indicated by expression of granzyme B and perforin, was noted in the 1990s [48]. Since then, these T cells have been further characterized as highly differentiated cytotoxic T cells identified by loss of CD28, loss of CD62L, or overexpression of CD244, CD57, and killer cell lectin like receptor G1 (KLRG1)


IBM autoantibodies — An important role for antigen-driven antibody production comes from microarray studies of gene expression within muscle biopsy samples showing that the most abundant transcripts in IBM muscle were derived from immunoglobulin genes [10,11,46]. These plasma cells show evidence of antigen-driven affinity maturation and clonal expansion [47]. An autoantibody directed against cytosolic 5'-nucleotidase 1A (cN1A) has been detected in at least half of patients with IBM studied, and strong reactivity of the antibody has relatively high specificity for IBM, compared with other muscle diseases


The reference above: Up-to-date



Case 37-2021: A 60-Year-Old Man with Fevers, Fatigue, Arthralgias, a Mouth Ulcer, and a Rash

Clinical reasoning discussion: 

The most common rheumatic diseases associated with anti-Ro antibodies are Sjögren’s syndrome and systemic lupus erythematosus. Less common diseases associated with anti-Ro antibodies are inflammatory myositis, mixed connective-tissue disease, and primary biliary cholangitis.

Sjögren’s syndrome typically affects women in their sixth decade and is characterized by an insidious onset of symptoms, including dry eyes and mouth.Extraglandular features may include nonspe- cific constitutional symptoms, pain, and neu- ropathy. The myositis, rapidly progressive lung disease, and mucocutaneous lesions observed in this patient would be atypical of Sjögren’s syndrome, especially in the absence of dry eyes and mouth.

SLE: he had a tongue ulcer, as opposed to the buccal mucosal ulcers often seen in patients with lupus. 

Rheumatic Diseases Associated with Myositis

In one approach to the evaluation of a patient with myositis, the first step is to characterize the distribution of muscle involvement as sym- metric or asymmetric. Pyomyositis and diabetic muscle infarction tend to have an asymmetric distribution, whereas rheumatic diseases tend to be associated with symmetric myositis. The ex- ception is inclusion-body myositis, which tends to be asymmetric.

In patients with symmetric myositis, such as this patient, the next step in the evaluation is to characterize the distribution as primarily proximal or distal. With rheumatic diseases, except for inclusion-body myositis, proximal rather than distal muscles tend to be involved. Endocrinopathies, such as hypothyroidism, can also cause symmetric proximal myopathy,

No IBM based on the distribution of weakness, No PM as has skin findings, no IMNM as not  treated with statins and did not have features of necrotizing myositis on MRI. Not antisynthetase as has RIFAM and ulcerative and nodular skin lesions would not be expected fea- tures of antisynthetase syndrome;

DM possible but worth considering other Rheum disease as has no classic DM rash 

Other Rheum disease with Myositis 

Adult-onset Still’s disease, sarcoidosis, and vasculitis can all be associated with myositis. However, myositis, lung disease, and the presence of anti-Ro antibodies are not typical manifestations of adult-onset Still’s disease, and the character- istic evanescent rash was absent in this patient. Polyarteritis nodosa is a consideration in this patient because he had a history of hepatitis B, on the basis of the positive test for hepatitis B virus core antibodies. Patients with polyarteritis nodosa often have myalgias, but myositis is less common, and the lung disease observed in this patient would be an unusual feature of polyarteritis nodosa. Immune complex vasculitis, such as IgA or cryoglobulinemic vasculitis, is an unlikely di- agnosis in this case, given the normal C3 and C4 levels. Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis is also unlikely, given that an ANCA test was negative. Some patients with limited forms of ANCA-associated vasculitis (e.g., disease limited to the head and neck) may have a negative ANCA test, but this patient did not have other, more typical features of the disease.Finally, Behçet’s disease can be associated with oral ulcers, but lung disease and the presence of anti-Ro antibodies are not con- sistent with this diagnosis. 

Can the results of the skin biopsies help to guide us toward the most likely diagnosis? The biopsy specimens did not show features sugges- tive of small- or medium-vessel vasculitis. There were no granulomas, which would be suggestive of sarcoidosis. There was evidence of interface dermatitis, which is typically associated with ei- ther lupus or dermatomyositis. Because lupus is unlikely to explain this patient’s presentation, I will revisit dermatomyositis as a possible diagnosis.

Another approach to the evaluation of this patient with idiopathic inflammatory myopathy is to consider the phenotypes of myositis associated with various myositis-specific antibodies.10 Some myositis-specific antibodies (anti–transcrip- tional intermediary factor 1γ [anti–TIF-1γ] anti- bodies, anti–Mi-2 antibodies, anti–small ubiqui- tin-like modifier–activating enzyme [anti-SAE] antibodies, and anti–nuclear matrix protein 2 [anti–NXP-2] antibodies) are associated with dermatomyositis with typical cutaneous mani- festations, but these manifestations were not present in this patient. Another type (anti–histi- dyl–transfer RNA synthetase [anti–Jo-1] antibod- ies) is associated with antisynthetase syndrome, but the patient did not have the typical features of this condition, such as inflammatory arthritis or Raynaud’s phenomenon. Additional myositis- specific antibodies (anti–3-hydroxy-3-methylglu- taryl–coenzyme A reductase [anti–HMG-CoA reductase] antibodies and anti–signal recogni- tion particle [anti-SRP] antibodies) are associated withnecrotizingmyositis,whichwasalsoabsent in this case.

Anti–melanoma differentiation-associated protein 5 (anti–MDA-5) antibodies are associated with dermatomyositis with unique cutaneous features, especially skin ulcerations and nodular lesions, along with rapidly progressive interstitial lung disease and subtle myopathy; indeed, many cases of anti–MDA-5 dermatomyositis are amyopathic. Cutaneous ulcerations overlying the metacarpophalangeal and interphalangeal joints, elbows, and nail folds are seen in up to 85% of patients with anti–MDA-5 dermatomyositis, often with lateral digital hyperkeratosis, which was observed in this patient.11,12 Approximately 50% of cases are associated with oral ulcers, often on the tongue. The arthralgias, fever, presence of anti-Ro antibodies, abnormal results on liver-function tests, and elevated ferritin level seen in this patient are common in patients with anti– MDA-5 dermatomyositis.

Biopsy diagnosis.

The biopsy specimen from the left deltoid showed variation in the size and shape of muscle fibers, with scattered angulated and atrophic fibers. The atrophic fibers had a prefer- ential distribution in the perifascicular areas (Fig. 3). There was no evidence of inflammation, vasculitis, or necrotic or regenerating fibers. Im- munohistochemical staining of the biopsy spec- imen for inflammatory markers showed only sparse CD3-positive T cells and scattered CD68- positive perivascular macrophages. Immunohis- tochemical staining for complement (C5b-9) was negative for deposits in capillary walls. Electron microscopic examination revealed multiple endothelial cells that contained tubuloreticular inclusions.

Despite the absence of inflammation and active injury to myocytes, the presence of perifascicular atrophy and endothelial inclusions in the muscle, in combination with the dermatopatho- logical findings, is consistent with the diagnosis of DM


Further discussion; What is MDA-5 ab and Anti-RO ab. 

An enzyme-linked immu- nosorbent assay (ELISA) was used to detect myositis-associated autoantibodies. The patient’s serum contained antibodies directed against MDA-5 and Ro-52 (Fig. 4). Both of these proteins have important roles in innate cellular immunity. MDA-5 is a cytoplasmic protein that is able to sense double-stranded viral RNA and subsequently contributes to antiviral immunity by up-regu- lating interferon-stimulated genes.1Ro-52 is an E3 ubiquitin ligase that binds to viruses that have been coated with antibodies and causes degradation of capsid proteins. Loss of the viral capsid proteins leads to the premature release of viral nucleic acids, which may then be sensed by proteins such as MDA-5.15 The potential roles of MDA-5 and Ro-52 in the pathogenesis of dermatomyositis are unknown.

A recent study showed the prevalence of false positive results associated with some commercially available assays that are used to detect myositis-associated autoantibodies.16 Therefore, indirect immunofluorescence and HEp-2 cell substrate were used to confirm the presence of autoantibodies against MDA-5 and Ro-52 in the patient’s serum. HEp-2 cells do not express MDA-5 and express very low levels of Ro-52, which explains the low titer of ANA in this patient. To increase the levels of these autoanti- gens in the HEp-2 cell substrate, HEp-2 cells were transiently transfected by plasmids encod- ing green fluorescent protein (GFP) fused to MDA-5 or Ro-52. The cells were subsequently fixed, permeabilized, and stained with the pa- tient’s serum. Antibodies in the patient’s serum stained only the cells that expressed GFP–MDA-5 or GFP–Ro-52 (Fig. 4). Taken together, the re- sults of the ELISA and the indirect immunofluo- rescence assay confirmed the presence of anti– MDA-5 and anti–Ro-52 antibodies in this patient.


Some patients with anti–MDA-5 dermatomyosi- tis have rapidly progressive interstitial lung dis- ease, and this patient had several risk factors for rapid progression, including the high ferri- tin level, presence of anti–Ro-52 antibodies, and Asian ethnic background.

Limited data from case and historical control analyses showed that combination therapy with high-dose glucocorticoids, tacrolimus, and intra- venous cyclophosphamide was associated with a 6-month survival rate of 89% in the treatment group, as compared with a rate of 33% in historical controls who received these therapies in a sequential addition.19  On the basis of these data, we initiated these three immunosuppres- sive drugs, in addition to intravenous immune globulin, on hospital day 14. Despite this treatment, the patient’s condi- tion continued to worsen, and he required oxy- gen therapy through a high-flow nasal cannula. On hospital day 28, the patient began to receive mechanical ventilation. Treatment with tofacitinib, an oral inhibitor of Janus kinase 1 and 3, was initiated as salvage therapy on hospital day 34.20 However, the next day, renal failure occurred. Hemodialysis with venovenous extracor- poreal membrane oxygenation as a bridge to lung transplantation was considered. Eventually, comfort care was pursued, and patient died 





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