Systemic Therapies

Systemic Corticosteroids

The first-line systemic treatment of muscle disease in patients with Dermatomyositis (DM) is systemic glucocorticoids (e.g., prednisone) with or without immunosuppressants. A high-dose of systemic corticosteroids are maintained until muscle symptoms abate and then are slowly tapered over several months based on response. There is no standardized tapering regimen, though the tapering pace should be slower as the corticosteroid dose decreases, which allows time for a response in case of disease reactivation, reducing the risk of significant clinical worsening. The process may require about six weeks for muscle enzymes to normalize and three months for muscle weakness to improve. Duration of therapy with systemic steroids usually spans between nine and twelve months, though administering high dose glucocorticoids for more than six weeks may lead to glucocorticoid myopathy. Patients should be regularly evaluated for response to treatment.

In patients with severe DM with muscle, lung, or cardiac involvement, intravenous methylprednisolone may be needed including intravenous methylprednisolone pulse doses may be required.

Although corticosteroids are useful, regular long-term use is limited by adverse events such as suppression of adrenal functions, immunosuppression, and osteoporosis. It is essential to use systemic corticosteroids at high doses for the shortest duration possible. Glucocorticoids are a major contributor to impaired bone health in DM patients. Bone-mineral density and vertebral fractures are associated with reduced quality of life and increased disability and pain in patients with DM.

To minimize the need for corticosteroids, other immunosuppressants include azathioprine, methotrexate, mycophenolate, cIVIG, or rituximab is used in monotherapy or combination to control disease activity. This decision is largely based on the extent of disease activity and severity.

Corticosteroid-Sparing Immunosuppressants

Immunosuppressants

Immunosuppressants such as methotrexate, azathioprine, or mycophenolate mofetil are commonly used in conjunction with steroids to minimize the exposure to steroids. There are no head to head clinical trials demonstrating one immunosuppressant is superior to another in terms of efficacy. Thus, a careful assessment of organ involvement is imperative to determine which agent should be used as the first-line immunosuppressant.

Methotrexate

Methotrexate is an antimetabolite with both anti-proliferative and anti-inflammatory properties that is often considered as first-line in patients who do not show satisfactory response to antimalarial therapy for skin disease.

Methotrexate is effective for both cutaneous and muscle disease and may help relieve associated joint symptoms such as inflammatory arthritis. However, methotrexate use is associated with gastrointestinal, hepatic, and hematological (neutropenia, thrombocytopenia) adverse events, as well as rare pulmonary toxicity. Drug-induced lung toxicity can be difficult to differentiate from myositis-ILD. As a result, patient selection for methotrexate is important, and depends on the presence of metabolic syndrome, alcohol consumption, non-alcoholic fatty liver disease, use of hepatotoxic medications, liver and renal function, concomitant pulmonary disease, and family planning.

Azathioprine

Azathioprine can inhibit both deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) synthesis by inhibiting purine synthesis. Azathioprine is especially favored in patients planning to conceive due to its safety profile during pregnancy. It can treat lung disease or ILD, myositis, and skin disease.

Mycophenolate Mofetil (MMF)

Mycophenolate mofetil (MMF) is a lymphocyte-selective immunosuppressive agent that inhibits de novo purine synthesis and has a potent cytostatic effect on lymphocytes. MMF also suppresses antibody formation and inhibits the recruitment of leukocytes into areas of inflammation.

Mycophenolate mofetil can be used to treat cutaneous disease, myositis, and DM-associated interstitial lung disease. It is the preferred treatment option for patients who have pulmonary involvement at presentation or are at increased risk of developing DM-associated lung disease, as it is associated with improvement in pulmonary function and corticosteroid-sparing effects. MMF is generally well tolerated, and is associated with dose-dependent gastrointestinal distress and increased genitourinary symptoms in the first year of therapy. It is also associated with an increased risk of reversible cytopenia, infection, and malignancy.

Calcineurin Inhibitors

The calcineurin inhibitors cyclosporine and tacrolimus are immunosuppressive agents that inhibit T cell activation and proliferation. They are widely used in organ transplantation and treatment of autoimmune conditions. Tacrolimus is largely used for refractory dermatomyositis not responsive to first line immunosuppressants such as methotrexate, azathioprine, or mycophenolate mofetil.

Other more potent immunosuppressive agents such as cyclophosphamide has been used in treatment of DM-associated lung disease, but evidence for use is limited.

Antimalarials

Antimalarials [hydroxychloroquine, chloroquine, and quinacrine] have an anti-inflammatory and photo-protective effect and have been a preferred initial treatment for mild cutaneous DM. Antimalarials have a long history of use and overall tolerability.

If hydroxychloroquine does not provide enough control, combination with quinacrine may have a synergistic effect, though it should never be combined with cyclosporine due to additive ocular toxicity. Hydroxychloroquine and cyclosporine are usually well tolerated but can cause a gastrointestinal upset, hypersensitivity reactions, and blue-gray dyspigmentation. Due to a risk for irreversible retinopathy, patients receiving these agents are required to undergo baseline fundus examination and regular follow-up with ophthalmology.

Biologics and Immunoglobulin Therapy

Biologic drugs can be used for the off-label treatment of DM.

Rituximab

Rituximab is a chimeric monoclonal antibody targeting the CD20 antigen protein on B cells, resulting in B cell depletion. The clinical benefits of rituximab may not become apparent until around two-four months after administration, but the effects typically endure for approximately six to nine months.

Rituximab can be used to treat refractory DM that failed to respond to multiple conventional immunosuppressives, particularly DM-associated extracutaneous manifestations such as interstitial lung disease and refractory myositis. Use of rituximab is limited by risk of infusion related reactions and infections, as well as the high cost of treatment.

Intravenous immunoglobulin (IVIg)

Intravenous immunoglobulin (IVIg) is derived from pooled donor plasma from numerous donors, and is thought to treat DM via neutralization of autoantibodies, downregulation of proinflammatory cytokines, binding of complement, and decreased formation and deposition of the membrane attack complex. A major advantages of IVIG is that administration of exogenous immunoglobulin counteracts any immunosuppression. IVIg is effective for both refractory cutaneous disease and myositis.

The ProDERM (Progress in DERMatomyositis) study was a large, randomized, placebo-controlled trial that established the efficacy, safety and tolerability of IVIg in adult DM patients compared to placebo. The study results led to the approval of IVIg (Octagam® 10%) for treatment of DM in the USA, Canada and most European countries. The recent FDA approval for Octagam® 10% adds to treatment options for DM, with possibility for future alternative formulations.

IVIG is an effective treatment in patients with refractory DM and involvement of esophagus and throat muscles and lungs. It has been reported to have a corticosteroid-sparing effect. IVIg is typically reserved for patients with refractory cutaneous DM who have not responded to or are intolerant of first-line agents.

Intravenous immunoglobulin is generally well tolerated, and most commonly associated with headache. Limitations of IVIG use include cost, difficulty of access, risk of clotting, and long infusion times.

OCTAGAM 10%

This FDA-approved IVIG preparation is specifically indicated for dermatomyositis. Typical dosing is 2 g/kg over 2–5 consecutive days every 4 weeks. OCTAGAM 10% has demonstrated efficacy in improving muscle strength and skin symptoms, with a generally well-tolerated safety profile.

Recommended Dosing

• For chronic TIP: 2 g/kg divided in equal doses given on 2 consecutive days.
• Initial infusion rate: 1.0 mg/kg/min (0.01 mL/kg/min)
• Maintenance infusion rate (if tolerated): up to 12.0 mg/kg/min (Up to 0.12 mL/kg/min)
• For Dermatomyositis: 2 g/kg divided in equal doses given over 2-5 consecutive days every 4 weeks.
• Initial infusion rate: 1.0 mg/kg/min (0.01 mL/kg/min)
• Maintenance infusion rate (if tolerated): up to 4.0 mg/kg/min (Up to 0.04 mL/kg/min)

Subcutaneous Ig (SQIg)

Subcutaneous Ig (SQIg) is an alternative subcutaneous approach to the administration of IVIG in DM patients, which has been shown to be safe and well-tolerated. Advantages of SQIg include the possibility of convenient home treatment, better quality of life, reduced cost, lack of the need for intravenous access, and lower incidence of adverse reactions compared to IVIg. Disadvantages of SQIg is large dose volume and requirement for frequent weekly injections.