Dermatomyositis requires a second-line treatment

Dermatomyositis (DM) is a rare autoimmune disease characterized by varying degrees of skin disease and proximal muscle inflammation. At least a fifth of patients have clinically amyopathic DM so present with skin disease without muscular weakness or evidence of myositis.

The skin symptoms of DM are often the most debilitating and the most challenging to treat and can significantly impair quality of life, but there is a lack of strong evidence for the use of most agents and little knowledge about the longitudinal course of the disease.

A study published in the December issue of “International Journal of Women's Dermatology” finds that second-line agents need to be incorporated into treatment for moderate to severe dermatomyositis, which is otherwise very difficult to treat.

“The results show that management of cutaneous DM often requires second-line agents because anti-malarial medications alone are insufficient to treat most patients with skin-only disease,” researchers wrote.

THE STUDY

A group of researchers at the University of Pennsylvania, Philadelphia assessed the impact of care delivered using a treatment algorithm to determine systemic treatment for 41 patients with skin only DM - those with clinically amyopathic DM and no lung involvement - seen at a center between July 2009 and April 2013.ⁱ

Anti-malarial medication is first line therapy for DM where skin symptoms predominate, and most were initiated on hydroxychloroquine (HCQ) ≤6.5 mg/kg/day for 8 weeks. Quinacrine 100 mg/day was added if a trial of HCQ was ineffective, and chloroquine ≤3.5mg/kg/day was used instead of HCQ in patients in whom HCQ was ineffective or who had experienced a reaction to it previously.

A second line agent such as methotrexate (MTX), mycophenolate mofetil (MMF), or azathioprine (AZA) was added if symptoms progressed despite use of antimalarial agents, and if adequate control was not achieved within another 8 weeks, patients were switched to another cytotoxic agent. Use of IVIg, at 2 g/kg administered over two to five days each month, was considered in patients who still did not respond, followed by oral calcineurin inhibitors.

Systemic corticosteroid medications were not used routinely but a course of medium-to-high dose corticosteroid medications was used to provide relief in cases of severe disease. Topical agents such as corticosteroid or immunomodulator medications were commonly used by participants.

Twenty-three of the patients (56.1%) received antimalarial medications alone and 18 patients (43.9%) received second- or third-line agents (cytotoxic drugs or IVIg treatment in combination with antimalarial medications).

Ten patients used HCQ alone (24.4%), 22.0% used HCQ and quinacrine, 4.9% chloroquine, and 2.4% chloroquine and quinacrine. Although 24.4% of patients were managed with HCQ alone, the researchers highlight that this is an overestimation of the efficacy of HCQ monotherapy, because four of the ten patients had quinacrine prescribed on their very last study visit.

Just 14.6% of patients with skin-only disease were managed with HCQ alone, which suggests that HCQ is less effective in the treatment of patients with cutaneous DM than patients with cutaneous lupus erythematosus, the researchers say.

Initial disease severity and outcomes were assessed using the Cutaneous Dermatomyositis Disease Area and Severity Index. After a median duration of treatment of 24 months, the median final CDASI score for all patients with skin-only disease was 13.5.  Most patients did not experience complete resolution of skin symptoms and had at least mild disease activity at the time of their final visit.

Eleven of the patients (26.8%) received prednisone which may have contributed to clinical improvements and changes in CDASI activity scores.

Prospective trials have reported a significant improvement in cutaneous DM symptoms with IVIg treatment, and good results were seen in the small number of most refractory patients treated with IVIg in the University of Pennsylvania study. However, the researchers point out that since patients with a more severe disease status received escalating therapy, it was difficult to compare final CDASI scores across treatment groups and that clinical trials are needed to assess the efficacy of agents alone or in combination with others.

The same researchers looked in detail at the course of the skin only DM treated according to the algorithm in 40 patients who had their CDASI activity recorded for at least 2 years.ⁱⁱ Sixteen patients began the study with mild disease and 24 with moderate to severe disease.

More patients with moderate-severe disease (n=19, 79.2%) experienced an improvement in disease activity compared to those with mild disease (n=2, 12.5%) in whom the disease was more likely to remain stable (n=10, 62.5%) than in those with moderate-severe disease (n=2, 8.3%). The variability of disease activity (flares/year) was nearly identical with 87.5% of patients with mild disease and 79% of patients with moderate-severe disease experienced waxing and waning of disease activity.

The researchers suggest that there may be a “floor effect,” meaning it is harder to see a significant change in CDASI score when starting with mild disease and that clinicians may offer less aggressive treatment options to milder patients resulting in less therapeutic benefit.

Researcher Dr Victoria Werth says: “Better treatments are needed for both moderate/severe and mild disease, since current treatments are relatively toxic and don’t always work. With relatively new disease severity tools that measure the skin (CDASI) it is now possible to assess new therapeutics using the skin as a window.  This is a very exciting time for developing rationale new therapeutics for dermatomyositis.”

The Cutaneous Dermatomyositis Disease Area and Severity Index was initially developed and validated to enable dermatologist to assess the impact of therapy on cutaneous manifestations in DM. Quantifying skin disease activity can offer early insight into the relative efficacy of treatment in clinical practice and research trials, Dr Werth’s research group has shown that other specialties, including rheumatology and neurology, “who do not regularly evaluate cutaneous DM are capable of using the CDASI effectively”ⁱⁱⁱ .

POTENTIAL NEW TREATMENTS

In terms of potential new treatments, Dr Werth’s group has just completed a single centre NIH-funded phase 2 randomized, placebo-controlled trial of skin predominant dermatomyositis with a nonpsychoactive cannabinoid called lenabasum - the first placebo controlled randomized trial for skin-predominant disease.  The results, presented at the American College of Rheumatology meeting in November, showed that patients on active drug demonstrated greater improvement in disease activity and several measurements of quality of life, and that the drug was well tolerated. A larger study is now in the planning stages

Other treatments being evaluated include IVIg, Tofacitinib (a JAK inhibitor), CTLA4Ig (inhibits T cell activation), and novel approaches related to intervening pathways known to be activated in dermatomyositis, Dr Werth says.

REFERENCES

i. Anyanwu CO, Chansky PB, Feng R, Carr K, Okawa J, Werth VP. The systemic management of cutaneous dermatomyositis: Results of a stepwise strategy. International Journal of Women's Dermatology 2017; 3: 189–194.

ii. Chansky PB, Olazagasti J M, Feng R, Werth VP. Cutaneous dermatomyositis disease course followed over time using the Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI). Journal of the American Academy of Dermatology DOI 10.1016/j.jaad.2017.10.022

iii. Tiao J, Feng R, Bird S, Choi J K, Dunham J, George M, Gonzalez-Rivera TC et al. The reliability of the Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) among dermatologists, rheumatologists and neurologistsBr J Dermatol 2017;176(2):423-430. DOI 10.1111/bjd.15140