Paraneoplastic Dermatomyositis

Paraneoplastic dermatomyositis is dermatomyositis (an inflammatory myopathy with a characteristic rash) that occurs together with a malignancy, usually within 3 years before to 3 years after the diagnosis of myositis. Finding the cancer and treating it is as important as treating the myositis, because the disease often improves when the tumour is controlled.

Dermatomyositis has an incidence of about 1 case in 100,000 people each year. About 15% to 30% of adults with dermatomyositis have a cancer, a risk 3 to 8 times that of the general population. Median age at onset is 50 to 60, and women are affected 2 to 3 times more often than men. In Asian populations nasopharyngeal carcinoma is a major association.

Cancer risk is highest with anti-TIF1-gamma and anti-NXP2 antibodies, older age, dysphagia, cutaneous necrosis or ulceration, and absence of interstitial lung disease. Risk is lower with anti-Jo-1, anti-MDA5 and anti-synthetase antibodies. The commonest tumours are ovarian, lung, pancreatic, gastric, colorectal, breast and nasopharyngeal carcinoma, and lymphoma.

Pathophysiology. An immune response to tumour antigens (especially TIF1 and NXP2 proteins expressed by the tumour) cross-reacts with muscle and skin. Type 1 interferon activation drives the skin and capillary injury, with complement mediated microvascular damage in muscle.

Prognosis. Survival is shorter than for dermatomyositis without cancer, and is determined mainly by the tumour. Five year survival is about 50% to 60% in cancer associated disease, against over 85% without cancer.

• Skin: heliotrope rash (violaceous eyelid discolouration with oedema), Gottron papules over the knuckles and Gottron sign over extensor surfaces, shawl sign, V sign, periungual erythema with dilated capillary loops, mechanic's hands, scalp erythema, photosensitive poikiloderma, and ulceration.
• Muscle: symmetric proximal weakness (difficulty rising from a chair, climbing stairs, lifting arms), myalgia, and dysphagia from pharyngeal and oesophageal muscle involvement.
• Calcinosis (more common in juvenile disease), interstitial lung disease, arthralgia and weight loss.
• Amyopathic disease (rash with no weakness) occurs in 10% to 20%.

Red flags.

• Dysphagia with aspiration risk, or respiratory muscle weakness.
• Rapidly progressive breathlessness (interstitial lung disease).
• Skin necrosis or ulceration, which suggests a higher cancer risk.

• Creatine kinase (raised up to 50 times the upper limit, normal in amyopathic disease), aldolase, AST, ALT, LDH, and troponin to exclude myocardial involvement.
• Myositis specific antibody panel: anti-TIF1-gamma, anti-NXP2, anti-Mi-2, anti-SAE, anti-MDA5, anti-Jo-1 and other anti-synthetase antibodies, and ANA.
• Electromyography (myopathic pattern with spontaneous activity), MRI of the thigh muscles (oedema), and muscle biopsy (perifascicular atrophy, perivascular inflammation, capillary loss). Skin biopsy shows interface dermatitis.
• Cancer screening at diagnosis, repeated at least every 6 to 12 months for 3 years: CT of the chest, abdomen and pelvis, FDG-PET-CT, mammography, pelvic ultrasound with CA 125 in women, gastroscopy and colonoscopy, and nasendoscopy for nasopharyngeal carcinoma in at risk populations.
• Pulmonary function tests and high resolution CT for interstitial lung disease, and swallowing assessment.

Differential diagnosis.

• Polymyositis, inclusion body myositis and immune mediated necrotising myopathy
• Statin myopathy, hypothyroid myopathy and inflammatory myopathies from checkpoint inhibitors
• Systemic lupus erythematosus, mixed connective tissue disease and psoriasis
• Muscular dystrophy and glycogen storage disease

Management combines tumour treatment with immunosuppression, and is shared by rheumatology and oncology.

Tumour treatment. Surgery, chemotherapy or radiotherapy for the underlying cancer as early as possible. Myositis and rash improve after tumour control in most patients, and relapse of myositis can signal tumour recurrence.

First line immunosuppression.

• Pulse methylprednisolone for severe weakness, dysphagia or respiratory involvement: methylprednisolone 1 g IV over 1 to 2 hours once daily for 3 to 5 days, then oral prednisolone 1 mg/kg daily (maximum 60 mg daily) tapered over 4 to 8 weeks in line with response; maximum 1 g daily for pulse therapy; monitoring: glucose, blood pressure, potassium, mood, infection, gastric symptoms, bone health; adjustment: give gastric protection, calcium and vitamin D, pneumocystis prophylaxis when over 20 mg prednisolone daily is expected for more than 4 weeks, reduce for psychiatric toxicity
• Oral prednisolone: prednisolone 1 mg/kg orally once daily (maximum 80 mg daily) for 4 to 6 weeks, then tapered by about 10% every 2 weeks to the lowest effective dose over 6 to 12 months; maximum 80 mg daily; monitoring: creatine kinase and muscle strength every 2 to 4 weeks, glucose, blood pressure, potassium, bone density, mood, infection, steroid myopathy (to separate from disease flare); adjustment: add calcium, vitamin D and a bone protective drug when treatment will exceed 3 months, give gastric protection, add pneumocystis prophylaxis when combined with other immunosuppression, move to a steroid sparing drug when the dose cannot fall under 10 mg daily

Steroid sparing and second line therapy.

• Methotrexate (avoid with interstitial lung disease or hepatic and renal impairment): methotrexate 7.5 to 10 mg orally or subcutaneously once weekly, increased by 2.5 to 5 mg every 2 to 4 weeks to 15 to 25 mg once weekly, with folic acid 5 mg orally once weekly on a different day; maximum 25 mg weekly; monitoring: FBC, creatinine and liver tests every 2 weeks for 6 weeks and then every 1 to 3 months, chest symptoms (pneumonitis), mouth ulcers, pregnancy test; adjustment: avoid when creatinine clearance is under 30 mL/min and reduce by 50% at 30 to 60 mL/min, hold for neutrophils under 1.5 x 10^9/L, platelets under 100 x 10^9/L or ALT over 2 times the upper limit, avoid trimethoprim, limit alcohol, use effective contraception and stop 3 months before conception
• Mycophenolate mofetil (preferred with interstitial lung disease): mycophenolate mofetil 500 mg orally twice daily, increased every 2 weeks to 1000 to 1500 mg twice daily; maximum 3 g daily; monitoring: FBC every 2 weeks for 2 months, then monthly for 3 months and then every 3 months, liver tests, creatinine, diarrhoea; adjustment: halve the dose when GFR is under 25 mL/min, hold for neutrophils under 1.5 x 10^9/L, avoid in pregnancy (two forms of contraception are needed), separate from antacids and iron
• Immunoglobulin for refractory weakness, dysphagia or when immunosuppression is hazardous: immunoglobulin (human normal) 2 g/kg IV in total each month, divided over 2 to 5 consecutive days, for 3 to 6 months; maximum 2 g/kg each month; monitoring: creatinine, blood pressure, headache and aseptic meningitis, haemolysis, thromboembolic events, IgA level; adjustment: use a slower rate (start at 0.5 mL/kg/h, maximum 4 mL/kg/h) and a sucrose free product in renal impairment, hydrate beforehand, reduce the rate or avoid in high thrombotic risk, stop if there is no clinical response after 3 cycles
• Rituximab for refractory disease: rituximab 375 mg/m2 IV once weekly for 4 doses (or 1000 mg IV on days 1 and 15), with hydrocortisone 100 mg IV, an antihistamine and paracetamol before each dose; maximum 1000 mg in one dose; monitoring: hepatitis B serology before the first dose, FBC, immunoglobulins, CD19 counts, infusion reactions, infection; adjustment: start the first infusion at 50 mg/h and increase by 50 mg/h every 30 minutes to a maximum of 400 mg/h, give antiviral prophylaxis for hepatitis B core antibody positivity, defer live vaccines, repeat at 6 months if relapse occurs and B cells have returned

Skin disease. Strict photoprotection (broad spectrum sunscreen with SPF 50 and clothing), topical corticosteroids or topical tacrolimus for limited rash, and antimalarial therapy:

• Hydroxychloroquine: hydroxychloroquine 200 mg orally once or twice daily (maximum 5 mg/kg daily of actual body weight) for cutaneous disease; maximum 400 mg daily; monitoring: retinal screening at baseline and yearly after 5 years (earlier with renal impairment or tamoxifen), QTc, glucose, skin reactions; adjustment: reduce by 25% to 50% when eGFR is under 30 mL/min/1.73 m2, avoid with QT-prolonging drugs, stop for visual disturbance or worsening rash

Supportive care. Swallowing assessment and modified diet or enteral feeding for dysphagia, physiotherapy (graded exercise once inflammation is controlled), bone protection on steroids, vaccination, and treatment of interstitial lung disease with specialist input. Pneumocystis prophylaxis is added with combined immunosuppression.

Monitoring. Muscle strength, creatine kinase and skin assessment every 4 to 8 weeks at first. Cancer screening every 6 to 12 months for at least 3 years, and lung function every 6 months.

Referral and escalation.

• Urgent rheumatology and cancer assessment for new dermatomyositis in an adult.
• Emergency admission for aspiration, respiratory failure or rapidly progressive interstitial lung disease.

Special groups.

• Anti-MDA5 disease: aggressive interstitial lung disease needs early combination immunosuppression in a specialist unit.
• Pregnancy: prednisolone and immunoglobulin are acceptable, and methotrexate and mycophenolate are contraindicated.
• Older adults: lower steroid doses and early steroid sparing agents.