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یکشنبه 3 تیر‌ماه سال 1386
پلی میوزیت ، درماتومیوزیت

369

Polymyositis, Dermatomyositis, and Inclusion Body Myositis

 

The inflammatory myopathies represent the largest group of acquired and potentially treatable causes of skeletal muscle weakness. 3 major groups: polymyositis (PM), dermatomyositis (DM), and inclusion body myositis (IBM).

 

CLINICAL FEATURES

The prevalence of the inflammatory myopathies : 1 in 100,000.

 PM: as a stand-alone entity is a rare disease affecting adults.

 DM : both children & adults, and women > men.

 IBM: m/f =3 (m>f), more common in Caucasians than blacks, persons >50 yrs

 

* پلی میوزیت: بزرگسالان، بالای 18 سال- به تنهایی نادر- همراهی با بیماریهای اتوایمیون سیستمیک- بیماریهای انگلی و باکتریایی -پیومیوزیت- مشابه با میوپاتی ناشی از D-پنی سیلامین ، پروکائینامید - زیدوودین(میتوکوندریایی حاوی رشته های red-ragged) (AZT)- در پلی میوزیت، التهاب اولیه است یعنی انفیلتراسیون Tcell ها درون فاسیکل عضلانی (اندومیزیال) واقع شده است- التهاب اولیه با کمپلکس CD8/MHC-1 بدون واکوئل

 

* درماتومیوزیت: کودکان و بزرگسالان درخانمها بیشتر-بدخیمی تا 15% - تشخیص سریعتر به علت راش- میالژی و تندرنس عضلانی به علت بیماریهای بافت همبند- شبیه سندرم میالژی ائوزینوفیلیک در اثر ال-تریپتوفان - وجود آتروفی پری فاسیکولار مشخصه درماتومیوزیت است حتی در غیاب التهاب!!! التهاب اندومیزیال به طور غالب دور عروقی است و یا در تیغه های بین فاسیکولی و اطراف آن واقع شده تا اینکه درونش باشد-انفیلترای پری فاسیکولار،پری میزیال، پری واسکولار وجود دارد-دخالت ایمنی هومورال

 

* میوزیت جسم انکلوزیونی: بالای 50 سال- در مردان بیشتر (3 برابر)- سیر آهسته طی سالها ارتباط فامیلی(+) - عدم ارتباط با دارو کاهش DTR به علت تحلیل عضلانی- سقوط به علت تحلیل کوادری سپس-درگیری نسبتا زودهنگام عضلات ظریف (دیستال)- درگیری خفیف عضلات صورت- التهاب اولیه با کمپلکس CD8/MHC-1 فیبرهای واکوئله با رسوبات بتا-آمیلوئید فیبرهای سیتوکروم اکسیژناز منفی وجود میتوکندیهای ناهنجار به صورت الیاف red-ragged fibers - علائم میوپاتی مزمن

 

*** در تمام انواع میوپاتیهای التهابی: عضلات چشم، دست نخورده می مانند دیسفاژی(+) ، Head drop (+)، حس نرمال است.

 

Progressive and often symmetric muscle weakness.

Increasing difficulty with everyday tasks requiring the use of proximal muscles, such as getting up from a chair, climbing steps, stepping onto a curb, lifting objects, or combing hair.

 Fine-motor movements (distal muscles), eg. buttoning a shirt, sewing, knitting, or writing, are affected only late in the course of PM and DM, but fairly early in IBM.

 

 Falling is common in IBM because of early involvement of the quadriceps muscle with buckling of the knees.

 Ocular muscles are spared, even in advanced, untreated cases;

If OCULAR muscles are affected, the diagnosis of inflammatory myopathy should be questioned !!!

اگر عضلات چشمی درگیر شوند تشخیص میوپاتی التهابی زیر سؤال می رود!

 

 Facial muscles NL:à in PM and DM/   /but mild facial muscle weakness :à IBM.

 In all forms:à dysphagia +head drop.

 

 Advanced and rarely in acute casesà respiratory muscles affected.

 Severe weaknessà muscle wasting.

Sensation remains normal.

DTR (+) are preserved

DTR (-):in IBM where atrophy of the quadriceps and the distal muscles is common.

Myalgia and muscle tenderness : in DM associated with connective tissue disorders.

 

 Weakness in PM & DM progresses subacutely over a period of weeks or months and rarely acutely;

 by contrast, IBM progresses very slowly, over years, simulating a late-life muscular dystrophy  or slowly progressive motor neuron disorder.

 

SPECIFIC FEATURES (Table 369-1)

 

TABLE 369-1 Features Associated with Inflammatory Myopathies


Characteristic

Polymyositis

Dermatomyositis

Inclusion Body Myositis


Age at onset

>18 yr

Adulthood and childhood

>50 yr

Familial association

No

No

Yes, in some cases

Extramuscular manifestations

Yes

Yes

Yes

Associated conditions

 

 

 

  Connective tissue diseases

Yesa

Scleroderma and mixed connective tissue disease (overlap syndromes)

Yes, in up to 20% of casesa

  Systemic autoimmune diseasesb

Frequent

Infrequent

Infrequent

  Malignancy

No

Yes, in up to 15% of cases

No

  Viruses

Yesc

Unproven

Yesc

  Drugsd

Yes

Yes, rarely

No

  Parasites and bacteriae

Yes

No

No


a SLE, RA, Sjögren's syndrome, SS, MCTD.

b Crohn's disease, vasculitis, sarcoidosis, primary biliary cirrhosis, adult celiac disease, chronic graft-versus-host disease, discoid lupus, ankylosing spondylitis, Behçet's syndrome, myasthenia gravis, acne fulminans, dermatitis herpetiformis, psoriasis, Hashimoto's disease, granulomatous diseases, agammaglobulinemia, monoclonal gammopathy, hypereosinophilic syndrome, Lyme disease, Kawasaki disease, autoimmune thrombocytopenia, hypergammaglobulinemic purpura, hereditary complement deficiency, IgA deficiency.

c HIV (human immunodeficiency virus) and HTLV-I (human T cell lymphotropic virus type I).

d Drugs include penicillamine (dermatomyositis and polymyositis), zidovudine (polymyositis), and contaminated tryptophan (dermatomyositis-like illness). Other myotoxic drugs may cause myopathy but not an inflammatory myopathy (see text for details).

e Parasites (protozoa, cestodes, nematodes), tropical and bacterial myositis (pyomyositis).

Polymyositis

 patients typically delay seeking medical advice for several months. This is in contrast to DM, in which the rash facilitates early recognition.

 PM : is a diagnosis of exclusion!!!

 It is a subacute inflammatory myopathy affecting adults, and rarely children,

 

Who do not have any of the following:

rash,

involvement of the extraocular and facial muscles,

family history of a neuromuscular disease,

history of exposure to myotoxic drugs or toxins,

endocrinopathy,

neurogenic disease,

muscular dystrophy,

biochemical muscle disorder (deficiency of a muscle enzyme), or

IBM as excluded by muscle biopsy analysis.

 

More commonly, PM occurs in association with a systemic autoimmune or connective tissue disease, or with a known viral or bacterial infection.

Drugs, especially D-penicillamine or zidovudine (AZT), may also produce an inflammatory myopathy similar to PM.

داروهای D-پنی سیلامین و زیدوودین (AZT) ممکن است میوپاتی التهابی مشابه پلی میوزیت ایجاد کنند.

 

Dermatomyositis

A characteristic rash accompanying, or more often preceding, muscle weakness.

The rash may consist of a blue-purple discoloration on the upper eyelids with edema (heliotrope rash), a flat red rash on the face and upper trunk, and erythema of the knuckles with a raised violaceous scaly eruption (Gottron rash). The erythematous rash can also occur on other body surfaces, including the knees, elbows, malleoli, neck and anterior chest (often in a V sign), or back and shoulders (shawl sign), and may worsen after sun exposure. In some patients the rash is pruritic, especially on the scalp, chest, and back.

Dilated capillary loops at the base of the fingernails are also characteristic. The cuticles may be irregular, thickened, and distorted, and the lateral and palmar areas of the fingers may become rough and cracked, with irregular, “dirty” horizontal lines, resembling mechanic's hands.

The weakness can be mild, moderate, or severe enough to lead to quadraparesis.

At times, the muscle strength appears normal, hence the term dermatomyositis sine myositis.

 *درماتومیوزیت: راش مشخص- دستهای مکانیک ها- سندرم همپوشانی با اسکلرودرما و بیماریهای مختلط بافت همبند مرتبط با آنتی بادی anti-PM/Scl سندرم ائوزینوفیلی میالژی در اثر ال-تریپتوفان

DM usually occurs alone, but may overlap with scleroderma and mixed connective tissue disease.

 

 Fasciitis and thickening of the skin, similar to that seen in chronic cases of DM, have occurred in patients with the eosinophilia-myalgia syndrome associated with the ingestion of contaminated L-tryptophan.

 

Inclusion Body Myositis

In patients ≥50 years à IBM

It is often misdiagnosed as PM -- suspected when a presumed PM does not respond to therapy.

 

Weakness and atrophy of the distal muscles, especially foot extensors and deep finger flexors, occur in almost all cases of IBM and may be a clue to early diagnosis.

 

Some present with falls because their knees collapse due to early quadriceps weakness.

 

Others present with weakness in the small muscles of the hands, especially finger flexors, and complain of inability to hold objects such as golf clubs or perform tasks such as turning keys or tying knots.

 Dysphagia is common 60% à maybe episodes of choking.

Sensory examination à NL

Mildly diminished vibratory sensation at the ankles àis age-related.

Progression is slow but steady.

In at least 20% of cases, IBM is associated with systemic autoimmune or connective tissue diseases.

 Familial aggregation of typical IBM designated as familial inflammatory IBM.

This disorder is distinct from hereditary inclusion body myopathy (h-IBM), which describes a heterogeneous group of recessive, and less frequently dominant, inherited syndromes; the h-IBMs are noninflammatory myopathies. A subset of h-IBM that spares the quadriceps muscles has emerged as a distinct entity. This disorder, originally described in Iranian Jews and now seen in many ethnic groups, is linked to chromosome 9p1 and results from mutations in the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene.

 

ASSOCIATED CLINICAL FINDINGS

 

Extramuscular Manifestations

These may be present to a varying degree in patients with PM or DM, including:

  • Systemic symptoms, such as fever, malaise, weight loss, arthralgia, and Raynaud's phenomenon, especially when inflammatory myopathy is associated with a connective tissue disorder.
  • Joint contractures, mostly in DM and especially in children.

*جمع شدن مفاصل: اغلب در درماتومیوزیت و به خصوص در کودکان دیده می شود.

  • Dysphagia and gastrointestinal symptoms, due to involvement of oropharyngeal striated muscles and upper esophagus, especially in DM and IBM.

*دیسفاژی و علائم گوارشی: عضلات مخطط دهانی حلقی و فوقانی مری به خصوص در DM و IBM

  • Cardiac disturbances, including AV conduction defects, tachyarrythmias, dilated cardiomyopathy, and a low ejection fraction. CHF and myocarditis may also occur, either from the disease itself or from hypertension associated with long-term use of glucocorticoids.
  • Pulmonary dysfunction, due to weakness of the thoracic muscles, interstitial lung disease, or drug-induced pneumonitis (e.g., from methotrexate), which may cause dyspnea, nonproductive cough, and aspiration pneumonia.

*متوتروکسات: پنومونیت دارویی

  • Interstitial lung disease may precede myopathy or occur early in the disease and develops in up to 10% of patients with PM or DM, most of whom have antibodies to t-RNA synthetases.

*بیماری بینابینی ریه: در 10% پلی میوزیت و درماتومیوزیت.

 

  • Subcutaneous calcifications, in DM.

 

 

Association with Malignancies

The incidence of malignant conditions appears to be specifically increased only in patients with DM and not in PM or IBM.

 

*** افزایش ریسک بدخیمی فقط در DM،  شامل: کنسر تخمدان، سینه، کولون،ملانوما، لنفوم غیرهوجکین.

The most common tumors associated with DM are ovarian cancer, breast cancer, melanoma, colon cancer, and non-Hodgkin lymphoma.

A complete annual physical examination with pelvic, breast (mammogram, if indicated), and rectal examinations (with colonoscopy according to age and family history); urinalysis; complete blood count; blood chemistry tests; and a chest film should suffice in most cases. In Asians, nasopharyngeal cancer is common, and a careful examination of ears, nose, and throat is indicated.

 

Overlap Syndromes

A well-characterized overlap syndrome occurs in patients with DM who also have manifestations of systemic sclerosis or mixed connective tissue disease, such as sclerotic thickening of the dermis, contractures, esophageal hypomotility, microangiopathy, and calcium deposits (Table 369-1).

 

By contrast, signs of RA, SLE, or Sjögren's syndrome are very rare in patients with DM.

 

Overlap syndrome of DM and systemic sclerosis à may have anti-PM/Scl, directed against a nucleolar-protein complex.

 

PATHOGENESIS

Autoimmune etiology

 

Autoantibodies and Immunogenetics

Various autoantibodies found in up to 20%.

The antibodies to cytoplasmic antigens are directed against ribonucleoproteins involved in protein synthesis (anti-synthetases) or translational transport (anti-signal-recognition particles).

 

The antibody directed against the histidyl-transfer RNA synthetase, called anti-Jo-1, accounts for 75% of all the anti-synthetases and is clinically useful because up to 80% of patients with anti-Jo-1 antibodies have interstitial lung disease.

*آنتی سنتتاز: شامل آنتی Jo-1 (75%) است   حدود 80% از بیماران دارای آنتیJo-1 بیماری بینابینی ریه دارند - برخی بیماران دارای anti-Jo-1 دارای فنومن رینود، آرتریت غیراروزیو و مولکول MHC DR3 & DRw52 می باشند.

 

Some patients with the anti-Jo-1 antibody also have Raynaud's phenomenon, nonerosive arthritis, and the MHC molecules DR3 and DRw52.

DR3 (molecular designation DRB1*0301, DQB1*0201) occurs in up to 75% of patients with PM and IBM, whereas in juvenile DM there is an increased frequency of DQA1*0501.

 

Immunopathologic Mechanisms

In DM, humoral immune mechanisms are implicated, resulting in a microangiopathy and muscle ischemia. Endomysial inflammatory infiltrates are composed of B cells located in proximity to CD4 T cells and macrophages; there is a relative absence of lymphocytic invasion of nonnecrotic muscle fibers. Activation of the complement C5b-9 membranolytic attack complex is thought to be a critical early event that triggers release of proinflammatory cytokines.

 

By contrast, in PM and IBM a mechanism of T cell–mediated cytotoxicity is likely. The CD8/MHC-I complex is characteristic of PM and IBM;

*در DM مکانیسمهای ایمنی هومورال دخیل هستند که منجر به میکروآنژیوپاتی و ایسکمی عضلانی می شوند.

*ولی در PM و IBM مکانیسم با واسطه سیتوتوکسیته سلولی احتمالا دخالت دارد، یعنی کمپلکس CD8/MHC-1.

 

The Role of Nonimmune Factors in IBM

In IBM, the presence of vacuoles (almost always in fibers not invaded by T cells) together with β-amyloid deposits within the vacuolated muscle fibers and abnormal mitochondria with cytochrome oxidase–negative fibers suggest that, in addition to the autoimmune component, there is also a degenerative process.

 

Association with Viral Infections and the Role of Retroviruses

Several viruses, including:

 coxsackieviruses, influenza, paramyxoviruses, mumps, cytomegalovirus, and Epstein-Barr virus, have been indirectly associated with myositis.

The best evidence of a viral connection in PM and IBM à retroviruses HIV or (HTLV-1);

 

Long-term therapy with AZTà toxic myopathy,

characterized by fatigue, myalgia, mild muscle weakness, and mild elevation of creatine kinase (CK). AZT-induced myopathy, which generally improves when the drug is discontinued, is a mitochondrial disorder characterized histologically by “ragged-red” fibers. AZT inhibits γ-DNA polymerase, an enzyme found solely in the mitochondrial matrix.

 

DIFFERENTIAL DIAGNOSIS

 

Subacute or Chronic Progressive Muscle Weakness

1-This may be due to denervating conditions : spinal muscular atrophies or amyotrophic lateral sclerosis.

2-The muscular dystrophies  à usually develop over years rather than weeks or months and rarely present after the age of 30.

Doubtful cases (like facioscapulohumeral muscular dystrophy, dysferlin myopathy, and the dystrophinopathies) should always be given an adequate trial of glucocorticoid therapy and be screened for the respective genetic defect. Search for the MHC/CD8 lesion is helpful.

3-Metabolic myopathies, including glycogen storage disease.

4-Endocrine myopathies such as those due to hypercorticosteroidism, hyper- and hypothyroidism, and hyper- and hypoparathyroidism.

5-Muscle wasting in patients with an underlying neoplasm may be due to disuse, cachexia, or rarely to a paraneoplastic neuromyopathy.

6-Diseases of the neuromuscular junction, including myasthenia gravis or the Lambert-Eaton myasthenic syndrome, cause fatiguing weakness that also affects the eye and cranial muscles.

 

Acute Muscle Weakness

1-Acute neuropathy such as Guillain-Barré syndrome,

2-transverse myelitis,

3-a neurotoxin, or

4-a viral infection such as poliomyelitis or West Nile virus.

5-Acute weakness + painful muscle cramps, rhabdomyolysis, and myoglobinuriaà metabolic disorders including a glycogen storage disease.

6-Animal parasites, such as protozoa (toxoplasma, trypanosoma), cestodes (cysticerci), and nematodes (trichinae), may produce a focal or diffuse inflammatory myopathy known as parasitic polymyositis.

7-Staphylococcus aureus, Yersinia, Streptococcus, or other anaerobic bacteria may produce a suppurative myositis, known as tropical polymyositis, or pyomyositis; is now occasionally seen in AIDS patients. Other bacteria, such as Borrelia burgdorferi (Lyme disease) and Legionella pneumophila (Legionnaire's disease) may infrequently cause myositis.

8-Patients with periodic paralysis develop episodes of recurrent painless acute muscle weakness, always beginning in childhood.

9-Chronic alcoholics may develop painful myopathy with myoglobinuria after a bout of heavy drinking or present with a painless, acute hypokalemic myopathy, which is completely reversible with replacement therapy; other times they show an asymptomatic elevation of serum CK and myoglobin. Acute muscle weakness with myoglobinuria may occur with prolonged severe hypokalemia or with hypophosphatemia and hypomagnesemia, often seen in chronic alcoholics and

10-in patients on nasogastric suction receiving parenteral hyperalimentation.

 

 

Macrophagic Myofasciitis

Presents as diffuse myalgias, fatigue, and mild muscle weakness.

Muscle biopsy reveals pronounced infiltration of the connective tissue around the muscle by sheets of periodic acid–Schiff-positive macrophages and occasional CD8 T cells.

The CK or erythrocyte sedimentation rate is variably elevated.

Most patients respond to glucocorticoid therapy, and the overall prognosis seems favorable.

 This disorder been linked to an aluminum-containing substrate used in vaccine preparation.

 

Drug-Induced Myopathies

D-Penicillamine and procainamide à PM myositis

L-tryptophanà DM-like illness.

AZT à mitochondrial myopathy.

 

Cholesterol-lowering agents (clofibrate, lovastatin, simvastatin, or provastatin) esp. + cyclosporine or gemfibrozilà toxic noninflammatory myopathy that is histologically different from DM, PM, or IBM.

 

Amphotericin B, ε-aminocaproic acid, fenfluramine, heroin, and phencyclidine àRhabdomyolysis and myoglobinuria

 

Amiodarone, chloroquine, colchicine, carbimazole, emetine, etretinate, ipecac syrup, chronic laxative or licorice use resulting in hypokalemia, and glucocorticoids or growth hormone administration have also been associated with myopathic muscle weakness.

Some neuromuscular blocking agents such as pancuronium, in combination with glucocorticoids, may cause the acute critical illness myopathy.

 

Pain on Movement and Muscle Tenderness

 

polymyalgia rheumatica  and arthritic disorders of adjacent joints. The muscle biopsy is either normal or discloses type II muscle fiber atrophy.

Patients with fibrositis and fibromyalgia  complain of focal or diffuse muscle tenderness, fatigue, and aching, which is sometimes poorly differentiated from joint pain. The muscle biopsy is usually normal, some response to NSAIDs.

 

Chronic fatigue syndrome, which may follow a viral infection, can present with debilitating fatigue, fever, sore throat, painful lymphadenopathy, myalgia, arthralgia, sleep disorder, and headache. These patients do not have muscle weakness, and the muscle biopsy is normal.

 

 

 

 

DIAGNOSIS

The clinically suspected diagnosis of PM, DM, or IBM is confirmed by examining the serum muscle enzymes, EMG findings, and muscle biopsy (Table 369-2).

TABLE 369-2 Criteria for Diagnosis of Inflammatory Myopathies


 

Polymyositis


 

Criterion

Definite

Probable

Dermatomyositis

Inclusion Body Myositis


Myopathic muscle weaknessa

Yes

Yes

Yesb

Yes; slow onset, early involvement of distal muscles, frequent falls

Electromyographic findings

Myopathic

Myopathic

Myopathic

Myopathic with mixed potentials

Muscle enzymes

Elevated (up to 50-fold)

Elevated (up to 50-fold)

Elevated (up to 50-fold) or normal

Elevated (up to 10-fold) or normal

Muscle biopsy findingsc

“Primary” inflammation with the CD8/MHC-I complex and no vacuoles

Ubiquitous MCH-I expression but minimal inflammation and no vacuolesd

Perifascicular, perimysial, or perivascular infiltrates, perifascicular atrophy

Primary inflammation with CD8/MHC-I complex; vacuolated fibers with β-amyloid deposits; cytochrome oxygenase–negative fibers; signs of chronic myopathye

Rash or calcinosis

Absent

Absent

Presentf

Absent


a Myopathic muscle weakness, affecting proximal muscles more than distal ones and sparing eye and facial muscles, is characterized by a subacute onset (weeks to months) and rapid progression in patients who have no family history of neuromuscular disease, no endocrinopathy, no exposure to myotoxic drugs or toxins, and no biochemical muscle disease (excluded on the basis of muscle-biopsy findings).

b In some cases with the typical rash, the muscle strength is seemingly normal (dermatomyositis sine myositis); these patients often have new onset of easy fatigue and reduced endurance. Careful muscle testing may reveal mild muscle weakness.

c See text for details.

d An adequate trial of prednisone or other immunosuppressive drugs is warranted in probable cases. If, in retrospect, the disease is unresponsive to therapy, another muscle biopsy should be considered to exclude other diseases or possible evolution in inclusion body myositis.

e If the muscle biopsy does not contain vacuolated fibers but shows chronic myopathy with hypertrophic fibers, primary inflammation with the CD8/MHC-I complex and cytochrome oxygenase–negative fibers, the diagnosis is probable inclusion body myositis.

f If rash is absent but muscle biopsy findings are characteristic of dermatomyositis, the diagnosis is probable DM.

 

The most sensitive enzyme is CK, which in active disease can be elevated as much as 50-fold.

Although the CK level usually parallels disease activity, it can be normal in some patients with active IBM or DM, especially when associated with a connective tissue disease. The CK is always elevated in patients with active PM.

Along with the CK, the serum glutamic-oxaloacetic and glutamate pyruvate transaminases, lactate dehydrogenase, and aldolase may be elevated.

Needle EMG shows myopathic potentials characterized by short-duration, low-amplitude polyphasic units on voluntary activation and increased spontaneous activity with fibrillations, complex repetitive discharges, and positive sharp waves.

Mixed potentials (polyphasic units of short and long duration) indicating a chronic process and muscle fiber regeneration are often present in IBM.

These EMG findings are not diagnostic of an inflammatory myopathy but are useful to identify the presence of active or chronic myopathy and to exclude neurogenic disorders.

 

MRI is not routinely used for the diagnosis of PM, DM, or IBM. However, it may guide the location of the muscle biopsy in certain clinical settings.

Muscle biopsy is the definitive test for establishing the diagnosis of inflammatory myopathy and for excluding other neuromuscular diseases. Inflammation is the histologic hallmark for these diseases.

 

In PM the inflammation is primary, a term used to indicate that T cell infiltrates, located primarily within the muscle fascicles (endomysially), surround individual, healthy muscle fibers and result in phagocytosis and necrosis. The MHC-I molecule is ubiquitously expressed on the sarcolemma, even in fibers not invaded by CD8+ cells. The CD8/MHC-I lesion is now fundamental for confirming or establishing the diagnosis and to exclude disorders with secondary, nonspecific, inflammation. When the disease is chronic, connective tissue is increased and may react positively with alkaline phosphatase.

*در پلی میوزیت، التهاب اولیه است یعنی انفیلتراسیون Tcell ها درون فاسیکل عضلانی (اندومیزیال) واقع شده است.

 

In DM the endomysial inflammation is predominantly perivascular or in the interfascicular septae and around, rather than within, the muscle fascicles. The intramuscular blood vessels show endothelial hyperplasia with tubuloreticular profiles, fibrin thrombi, and obliteration of capillaries. The muscle fibers undergo necrosis, degeneration, and phagocytosis, often in groups involving a portion of a muscle fasciculus in a wedgelike shape or at the periphery of the fascicle, due to microinfarcts within the muscle. This results in perifascicular atrophy, characterized by 2 to 10 layers of atrophic fibers at the periphery of the fascicles. The presence of perifascicular atrophy is diagnostic of DM, even in the absence of inflammation!!!

*وجود آتروفی پری فاسیکولار مشخصه درماتومیوزیت است حتی در غیاب التهاب!!! التهاب اندومیزیال به طور غالب دور عروقی است و یا در تیغه های بین فاسیکولی و اطراف آن واقع شده تا اینکه درونش باشد.

 

In IBM, there is endomysial inflammation with T cells invading MHC-I-expressing nonvacuolated muscle fibers; basophilic granular deposits distributed around the edge of slitlike vacuoles (rimmed vacuoles); loss of fibers, replaced by fat and connective tissue, hypertrophic fibers, and angulated or round fibers; eosinophilic cytoplasmic inclusions; abnormal mitochondria characterized by the presence of ragged-red fibers or cytochrome oxidase–negative fibers; amyloid deposits within or next to the vacuoles; and filamentous inclusions seen by electron microscopy in the vicinity of the rimmed vacuoles.

 

 

 

TREATMENT

The goal of therapy is to improve muscle strength ( NOT CK LEVEL!!!), thereby improving function in activities of daily living, and ameliorate the extramuscular manifestations (rash, dysphagia, dyspnea, fever).

هدف از درمان میوپاتی التهابی بهبود قدرت عضلانی است، نه بازگشت سطح CK به حد نرمال!!!

 When strength improves, the serum CK falls concurrently; however, the reverse is not always true.

 

Agents used in the treatment of PM and DM include:

1.     Glucocorticoids.

Oral prednisone(1 mg/kg/d) is the initial treatment of choice;

The efficacy of prednisone is determined by an objective increase in muscle strength and activities of daily living, which almost always occur by the 3rd month of therapy.

کارایی درمان با کورتون توسط افزایش عینی!! در قدرت عضلانی سنجیده می شود.

A feeling of increased energy or a reduction of the CK level without a concomitant increase in muscle strength is not a reliable sign of improvement.

 

If prednisone provides no objective benefit after ~3 months of high-dose therapy, the disease is probably unresponsive to the drug and tapering should be accelerated while the next-in-line immunosuppressive drug is started.

 اگر پس از 3 ماه درمان با کورتون  دوز بالا، بیماری به درمان پاسخ نداد، باید کورتون Taper شود، ضمن اینکه داروی ایمونوساپرسیو شروع می شود.

In general, DM responds better than PM.

به طور کلی درماتومیوزیت پاسخ بهتری به درمان می دهد.

The long-term use of prednisone à steroid myopathy.

Development of new weakness under high dose prednisone therapy :

1-steroid myopathy or

2- disease activity  

In uncertain cases,the prednisone dosage can be adjusted arbitrarily: the cause of the weakness is usually evident in 2 to 8 weeks.

 

2-Other immunosuppressive drugs.

 ~75% of patients ultimately require additional treatment.

 When a patient:

1-fails to respond adequately to glucocorticoids after a 3-month trial,

2-the patient becomes glucocorticoid-resistant,

3-glucocorticoid-related side effects appear,

4-attempts to lower the prednisone dose repeatedly result in a new relapse, or

5-rapidly progressive disease with evolving severe weakness and respiratory failure develops.

 

The following drugs are commonly used:

(1) Azathioprine is well tolerated, has few side effects, and appears to be as effective for long-term therapy as other drugs. The dose is up to 3 mg/kg daily.

(2) Methotrexate: faster onset of action than azathioprine. A rare side effect: pneumonitis!!!

(3) Cyclophosphamide: limited success and significant toxicity.

(4) Chlorambucil.

(5) Cyclosporine.

(6) Mycophenolate mofetil.

 

3-Immunomodulation. In refractory DM, IVIg improved not only strength and rash but also the underlying immunopathology.

The benefit is often short-lived (≤8 weeks); repeated infusions every 6 to 8 weeks are generally required to maintain improvement.

IVIg may beneficial for PM.

Neither plasmapheresis nor leukapheresis appears to be effective in PM and DM.

 

The following sequential empirical approach to the treatment of PM and DM is suggested:

Step 1: high-dose prednisone;

step 2: azathioprine or methotrexate;

step 3: IVIg;

step 4: a trial, with guarded optimism, of one of the following agents, chosen according to the patient's age, degree of disability, tolerance, experience with the drug, and the patient's general health: cyclosporine, chlorambucil, cyclophosphamide, mycophenolate.

 

Patients with interstitial lung disease à aggressive treatment with cyclophosphamide.

 

A patient with presumed PM who has not responded to any form of immunotherapy most likely has: IBM or another disease, usually a metabolic myopathy, a muscular dystrophy, a drug-induced myopathy, or an endocrinopathy. In these cases, a repeat muscle biopsy and a renewed search for another cause of the myopathy is indicated.

 

Calcinosis, a manifestation of DM, is difficult to treat;

IBM is generally resistant to immunosuppressive therapies.

 

PROGNOSIS

The 5-year survival rate for treated patients with PM and DM is ~95% and the 10-year survival 84%; death is usually due to pulmonary, cardiac, or other systemic complications.

Worse prognosis:

Patients severely affected at presentation or

treated after long delays,

those with severe dysphagia or

respiratory difficulties,

older patients, and

those with associated cancer.

 

Better prognosis: DM

 

IBM has the least favorable prognosis of the inflammatory myopathies. Most patients will require the use of an assistive device such as a cane, walker, or wheelchair within 5 to 10 years of onset. In general, the older the age of onset in IBM, the more rapidly progressive is the course.


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