Dermatomyositis (overview) M33.-

Rare, acquired, systemic, antibody- or immune complex-mediated group of autoimmune diseases with immunological reactions against vascular and muscle fiber proteins and diagnostically groundbreaking inflammatory skin manifestations. Furthermore, there are inflammatory atrophying vascular connective tissue reactions as well as segmental necroses of the striated musculature, which manifest themselves in a clinically usually clearly prominent muscle weakness.

Dermatomyositis, like other autoimmune myositides with other "collagenoses", can also occur as overlap syn dromes and, in association with malignant tumors, as a paraneoplastic syndrome(dermatomyositis, malignoma-associated).

Clinically, a distinction is made (with frequencies):

• Adult polymyositis (PM- without skin symptoms) 30% - is not seen dermatologically.
• Adult typical dermatomyositis (DM - idiopathic dermatomyositis)/25%.
• Dermatomyositis associated withmalignancy (CAM) /10%.
• Dermatomyositis associated withcollagenoses (CTM - as part of an overlap syndrome/overlap group)/30%
• Amyopathic dermatomyositis (ADM) (in adults and children)
• Juvenile dermatomyositis (with vasculitis)/5%.

• Incidence (juvenile dermatomyositis): 0.2/100,000 inhabitants/year.
• Incidence (adult dermatomyositis): 0.6-1.0/100,000 inhabitants/year.
• African-Americans are more frequently affected than Caucasians.

Together with polymyositis and inclusion body myositis, dermatomyositis belongs to the group of inflammatory myopathies. Environmental factors, especially sun exposure, can lead to an exacerbation of dermatomyositis.

• Genetic predispositions
  • exist for all idiopathic myositis in haplotypes HLA-B8, HLA DRB 03; HLA-A68 and HLA-DR3 for classic and juvenile dermatomyositis. For drug-associated dermatomyositis, HLA-B 08 and HLA-DR4 haplotypes were detected. No HLA associations are known for amyopahtic dermatomyositis.
• Infections:
  • Aetiologically significant is the formation of antibodies against muscle antigens (AK against nuclear Mi-2 antigen, antisynthetase AK). Viral infections ( picornaviruses or coxsackieviruses) are discussed as a trigger mechanism. Antibodies to viral surface antigens may have structural similarity to nuclear antigens and induce antibody formation. In children, bacterial foci may also cause antibody formation.
• A humoral immune mechanism has been described:
  • In this case, deposition of C5b-9 complement complexes on the endothelium of the skin and skeletal muscle occurs. For both polymyositis and dermatoymositis, there is an increased frequency of haplotypes with DR3, up to 75%. Dermatomyositis symptoms have been observed in congenital immunodeficiencies ("X-linked immunodeficency"/C9 defects), as well as in AIDS and HTLV-1 associated T-cell lymphomas (see below lymphoma, cutaneous T-cell lymphoma).
• Medications:
  • Less common is drug induction, e.g., by D-penicillamine, procainamide, NSAIDs, simvastatin, antimalarials; interferon alpha, allopurinol.
• Dermatomyositis as cutaneous paraneoplasia:
  • In 18-32% of pat.; mostly pat. > 50 years): Clustering in individual families. The relative risk of malignancy development is 2.4 times to 3.8 times higher than in the average population. The risk of tumor development is highest in the first year of diagnosis and decreases continuously in the following years. The most common tumors are ovarian carcinomas, gastrointestinal carcinomas, lung and breast carcinomas, prostate carcinomas, and non-Hodgkin lymphomas. In Asians, nasopharyngeal carcinomas are the most common. In juvenile dermatomyositis, the tumor association is absent.

• In the adult form there is gynecotropia: women are affected about 1.5-2 times more often than men. In adult dermatomyositis there are 2 peaks in frequency, 35-44 LJ and 55-60 LJ.
• No sex preference in childhood (this statement is not found in other studies, here: F:M=6:1). First manifestation of juvenile dermatomyositis: Mostly 7-8th LJ.

General: General fatigue with muscle weakness and muscle soreness. Patients can perform their normal activities (e.g., climbing stairs, combing hair) with difficulty or not at all.

Note: Patient appears tired at consultation, leans on chair when standing up, hand clasp is feeble, gait sluggish, voice quiet to broken.

Integument (often initial sign of dermatomyositis: skin manifestations precede muscle weakness in 1/3 of cases).

Initial stage: Initially, areal facial swellings with conspicuous eyelid edema, heliotrope, red to blue-violet, areactive but also pruritic or painful erythema and/or plaques that appear butterfly-shaped over the cheeks, expose a perioral zone, and heliotrope the neckline. Less common are blurred, patchy satin-red erythema on the back. Specifically, the following phenomena are described:

• Gottron's sign: Diagnostically significant are satin-red, streaky erythema and papules on the extensor sides of the fingers (= Gottron's sign in about 70% of patients).
• Nail fold hyperkeratosis: (the attempt to push back the nail fold is very painful = Keining sign) with mega and tufted capillaries, elongated and torqued capillaries possibly with hemorrhages (capillary microscopy).
• Heliotropic erythema:wine-red diffuse erythema is visibleespeciallyin the sun-exposed areas of the skin (face, eyelids, décolleté).
• Perioral pallor: characteristic is the absence of erythema in the perioral region (thus the perioral region appears pale: perioral pallor).
• V sign: confluent macular erythema spreading in a V shape over the lower anterior neck and upper chest region (appearances are often associated with anti-Mi-2 autoantibody).
• Shawl sign: confluent areal erythema localized like a scarf tied around it.
• Holster sign: red or red-purple, planar erythema localized to the lateral thighs or hips in the shape of a worn gun holster.

Late stage: Variegated (poikilodermic) skin appearance due to brown-red discoloration of the lesions with sunken atrophic areas, sometimes also coarse sclerotic plaques with calcification processes (especially in children and adolescents). Often the skin changes are combined with diffuse effluvium .

• Mechanic hands: hyperkeratotic cracked skin on the palmar and lateral aspect of the fingers.

Muscles: Increasing, symmetrical, painful (muscle soreness) muscle weakness, especially of proximal limb segments. Calcifications of the muscles are possible, rather rare in adults, up to 40% in children and adolescents (see below Dermatomyositis, juvenile).

Skeletal system: Arthralgias and arthritides occur in about 25% of patients with inflammatory muscle diseases. Partly type of symmetrical polyarthritis, also as oligo- or monarthritis. Rarely mutilating arthritis (DD: antisynthetase syndrome; see overlap syndrome below). Further: Severe osteoporosis, more extensive calcification of soft tissues (tendons, muscles, aponeuroses), and significant joint deformities (joint space is preserved!).

Lung: Lung involvement (primary interstitial pneumonitis) in 15-30% of patients.

Vessels: Concomitant Raynaud's phenomenon or scleroderma-like edema (hands) suggest overlap syndrome. This symptomatology is rarely associated with malignant tumor.

Adipose tissue: Rare but clinically established manifestation of dermatomyositis with indurated, painful nodules or plaques on the abdomen, buttocks, and arms. Ulceration and lipodystrophy may occur.

Mucous membranes: ulcers of the oral mucosa in 10% to 20%.

Internal organs: involvement of heart, intestine and kidneys. Dysphagia due to weakness of oropharyngeal muscles. Associated: bronchopneumonia (aspiration due to dysphagia), hepato-splenomegaly, nephritis, tenderness of large nerve trunks, mental changes, focal retinitis peripapillosa, cotton-wool exudate, small streaky hemorrhages in the nerve fiber layer, papilledema, rarely episcleritis and scleritis.

• Serum: CK i.S. (especially MM type) increased up to 50-fold, aldolase, GOT, GPT, LDH increased. Creatinine excretion increased in 24h urine during the relapse.
• Antibodies have an increasingly important role. A distinction is made between myositis associated antibodies (MAA) and myositis specific antibodies (MSA). Detection of antinuclear antibodies (ANA) in about 33% of cases is possible. An important indicator for dermatomyositis are antibodies against MI-2. Furthermore the following antibody profile is possible:

• Blood count: Lymphopenia, often marked eosinophilia, leukocytosis with left shift also occurs.
• ESR: Moderate to moderate acceleration.
• Serum electrophoresis: increase in alpha 2- and gamma-globulin.
• Urine: creatinine and creatinineuria. Proteinuria in the episode, myoglobinuria.

Integument: Uncharacteristic interface dermatitis of varying severity, possibly with mild acanthosis or even atrophy with degeneration of basal keratinocytes.

Electron microscopy: Tubulovesicular inclusions in the vascular endothelium.

Muscle: Segmental muscle fiber necrosis, loss of transverse striation, eosinophilic granular necrosis, interstitial mononuclear infiltrate, possible vascular senescence with intimal hypertrophy and fibrin deposition in the small arterioles. Relative decrease in CD4 T cells and lymphocytes.

Adipose tissue: Mixed septal/lobular panniculitis with doming infiltrate of lymphocytes, plasma cells, and focal membranocystic adipose tissue necrosis. Lymphocytic vasculitis may occur.

Clinic

Histology and immunohistology from skin biopsies and muscle biopsies

Electromyogram: short polyphasic potentials, fibrillations

Creatine excretion in 24-hour urine

ANA low-titer positive in majority of patients

Myositis-associated AK are (in contrast to polymyositis) rather rare in dermatomyositis (Jo-1-AK, Mi-2-AK). In patients with AK against aminoacyl-t-RNA synthetases, SRP or Mi-2, myositis is the primary cause of the disease. The Jo-1-AK is of greatest clinical importance (see antisynthetase syndrome below).

To diagnose "polymyositis", at least 3 of the following criteria should be positive:

• Muscle enzymes (creatinine kinase)
• EMG
• muscle biopsy.

In many cases, the tentative diagnosis must be made on the basis of clinical symptoms alone, since other parameters appear inconsistently.

Systemic lupus erythematosus (usually acute onset, absence of Gottron's sign; classic serology).

Acute contact allergic eczema of the face (extensive "contact-related" eczema, possibly weeping (dermatoymositis never weeping), severe itching, no general complaints!)

Mixed connective tissue disease (serological clarification)

Rosacea erythematosa (skin changes are quite similar at first sight. Accompanying follicular papules or pustules exclude DM. Mostly nutritive or emotionally triggered flushing phenomena. Never general complaints!)

Dermatomyositis-like skin signs in infection by B. burgdorferi, in T-cell lymphoma, atopic eczema (serological and histological clarification of the underlying disease).

Trichinosis and cysticercosis (myalgias, fatigue, urticarial, often esosinophilic exanthema; marked blood eosinophilia. Eosinophilia would be unusual in dermatomyositis).

Myositides of other etiologies (e.g., in the setting of a hypereosinophilia syndrome, no dermatologic component)

Thyrotoxic myopathy and muscular dystrophies (neurologic workup; lacks the seminal dermatologic phenomena of dermatomyositis).

Tumor exclusion (esp. ovary, lung, pancreas, colon, non-Hodgkin lymphoma) at least 1 time/year.

Exclusion of bacterial foci, remediation if necessary.

In acute phases of disease, bed rest and general roborative measures.

Due to long-term glucocorticoid treatment, recommendations such as low-salt diet and fluid restriction and, if necessary, substitution of calcium and vit. D (vigantolettes 1000 1tbl./day) should be carried out in case of incipient osteoporosis.

Accompanying physiotherapeutic exercises or physical measures to improve muscle function are recommended.

Photoprotective measures are necessary in all variants of dermatomyositis.

Glucocorticoids such as prednisolone (e.g. Decortin H) in a dosage of (at least) 1.0-2.0 mg/kg bw/day. In highly acute courses, steroid pulse therapy can initially be administered at a dosage of 1 g/day for 3-5 days. Continuation depending on clinical symptoms with prednisolone at a dosage of 1.0-2.0 mg/kg bw/day. Fluorinated glucocorticoids (e.g., dexamethasone, triamcinolone) should be avoided because of their potential to cause myopathy.

Early combination therapy with azathioprine (Imurek) 1.0-3.0 mg/kg bw/day is recommended to save glucocorticoids. Slow dose reduction of glucocorticoids (e.g., by 5-10 mg/day every 2-4 weeks) depending on clinical findings until a maintenance dose (10-15 mg/day) is reached, which usually must be maintained for months to years. The dose may need to be increased again if clinical findings worsen. Progress controls and activity determinations are performed by determination of muscle enzymes (creatine kinase, aldolase, lactate dehydrogenase) in addition to clinical findings. An attempt at cessation can only be attempted after several months of freedom from symptoms (normalization of serum creatine kinase levels). Prior determination of thiopurine methyltransferase (TPMT) may be performed to assess genetic mismetabolism. Contraindications: Combination with allopuriol!

Methotrexate (MTX) is an alternative to azathioprine. Start with 7.5-10.0 mg/week p.o. or i.v., increasing in weekly increments of 2.5 mg up to a maintenance dose of 25 mg/week Cave! No i.m. injections, because of increase of muscle enzymes no follow-up is possible!

Alternative: Cyclophosphamide (e.g. Endoxan) 100-150 mg/day; described also as shock therapy in a dosage of 0.5-1.0 ^g/m2 KO/month i.v.

Alternatively (case reports only): Ciclosporin A (Sandimmune) 3.0-5.0 mg/kg bw/day divided into two doses.

Alternative (case reports only): Mycophenolate mofetil (CellCept) 2.0 g/day p.o. Similar effect to azathioprine (antipurine metabolite) with a start-up time of about 3 months.

Alternative: high-dose immunoglobulins (IVIG) in doses of 0.5-1.0 g/kg bw/day i.v. for 3 days (repeated every 4 weeks) especially in refractory active dermatomyositis patients. Intravenous immunoglobulin therapy ( IVIG therapy) has also proven effective in juvenile forms of dermatomyositis. Caution. Very high therapy costs!

Alternatively, in case of insufficient response to glucocorticoids and IVIG, initiation of therapy with Rituximab (Mabthera) 100-375 ^mg/m2 KO i.v. 4 times weekly. Clear evidence for the success of this therapy is missing so far.

Alternative: In severe, therapy-resistant cases, plasmapheresis remains as ultima ratio; confirmed results are still pending.

In current clinical trials: Eculizumab (anti-complement C5), Tocilizumab (anti-interleukin-6), Anakinra (anti-IL-1 receptor, see also interleukin-1), Gevokizumab (anti-interleukin-1beta), anti-interleukin-17 (see interleukin-17).

Unpredictable development of the course. The duration of the disease varies (months to decades). In smaller cohorts, the 5-year survival rate was 95% and the 10-year survival rate was 84%. 50-75% of patients treated with immunosuppressants show significant improvement in clinical outcome. Older age and association with malignancy are associated with poor prognosis.

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