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Treatment goals for children with localized scleroderma.


MAUI, HAWAII -- One of the most important steps to take when a child has received a biopsy-confirmed diagnosis of localized scleroderma is to sit down with the family and explain the rationale for the aggressive therapies to come, Anne M. Stevens, MD, PhD, said at the 2019 Rheumatology Winter Clinical Symposium.

It can be a tough sell at first, especially when a child has only a small red streak on the nose and perhaps a subtle linear lesion on the forehead or scalp. But the family has to come to understand that this is a serious, chronic, progressive fibrotic disease.

"Talk about what a big impact this disease can have on growth of a limb and the normal life of a child because of the cosmetic appearance. Explain that the length of treatment course is based on the long-term outcomes and quality of life. This discussion is usually sufficient" to convince people to give their children "these pretty serious medications," said to Dr. Stevens, professor of pediatrics and head of the division of pediatric rheumatology at the University of Washington, Seattle.

"The treatment goal is to control inflammation and prevent damage in these patients, who we like to catch very early, when it's a subtle lesion," she added.

The biggest problem

The biggest contributors to poor quality of life in patients with juvenile localized scleroderma are the extracutaneous manifestations, which occur in up to 50% of cases. Joint pain occurs in roughly 20% of patients, joint contractures due to fibrosis of skin and/ or tendons in 30%, and myalgia with or without myositis in 15%. Muscle atrophy due to the deep component of the scleroderma can occur. Moreover, growth problems--especially leg or arm length discrepancies--happen in about 20% of patients in prospective studies. These growth problems may not be obvious until a child enters a growth spurt, at which point there is a limited ability to achieve improvement. That's why Dr. Stevens recommends that every child with localized scleroderma should get a full joint exam at every visit, with measurement and photos of lesions and recording of all erythematous, violaceous, and waxy-hued areas. And if there are lesions on the head, annual eye exams are warranted.

The prevalence of juvenile localized scleroderma in the United States is about 3 per 100,000, with a mean age of onset of 8.2 years. That makes it 100-fold more common than pediatric systemic sclerosis.

The treatment ladder

There are no Food and Drug Administration-approved medications for localized scleroderma in children. It's all off label. That being said, there is strong consensus among members of the Childhood Arthritis and Rheumatology Research Alliance that the first-line therapy is methotrexate at 15 mg/[m.sup.2] or a maximum of 20 mg/week plus intravenous corticosteroids weaned over the course of 3-6 months. This is the treatment regimen with the best supporting evidence of safety and efficacy, including a single Italian randomized, double-blind, placebo-controlled clinical trial (Arthritis Rheum. 2011 Jul;63[7]: 1998-2006) and an accompanying long-term, open-label follow-up study (J Am Acad Dermatol. 2012 Dec;67[6]: 1151-6).

All of the other treatments she uses for juvenile localized scleroderma - mycophenolate mofetil (CellCept), abatacept (Orencia), tocilizumab (Actemra), and occasionally others--are backed only by a smattering of small case series. However, given the serious potential trajectory of this disease, that modest evidence base has been sufficient for her to receive insurance coverage approval of these agents.

In the randomized trial of first-line methotrexate, 48 of 65 patients treated with methotrexate plus steroid (74%) were responders. And among those 48 responders, 35 (73%) maintained a clinical remission for a mean of 25 months off-drug, while another 13 (27%) were in clinical remission on methotrexate. Twenty-eight patients developed side effects that were generally mild; no one required treatment discontinuation. At the 5-year mark after an average of an initial 2 years on methotrexate, half of the patients were in a sustained clinical remission, which Dr. Stevens deemed "pretty good" considering the well established and manageable safety profile of the drug.

If a patient fails to respond to methotrexate plus corticosteroids within a few months or later experiences disease progression, Dr. Stevens's second-line therapy is mycophenolate mofetil in conjunction with corticosteroids. Its use in arresting juvenile localized scleroderma is supported by two favorable published case series, the largest of which includes 10 patients (Rheumatology [Oxford]. 2009 Nov;48[ll]: 1410-3).

Dr. Stevens's third-line therapy is intravenous abatacept at 10 mg / kg monthly along with intravenous methylprednisolone at 500 mg/ week. There are five published case series, the most recent and largest of which included 13 adult patients, 2 of whom had en coup de sabre lesions (Acta Derm Venereol. 2018 Apr 16;98[4]:465-6). The biologic also shows promise in patients with advanced severe disease with deep tissue involvement (Semin Arthritis Rheum. 2017jun;46[6]:775-81). And abatacept has a plausible mechanism of action in localized scleroderma: French investigators have shown it induces regression of skin fibrosis in a mouse model of the disease (Ann Rheum Dis. 2016 Dec;75[12]:2142-9).

Her fourth-line strategy is the anti-interleukin-6 agent tocilizumab, again in conjunction with corticosteroids. In a translational study, tocilizumab has been shown to normalize dermal fibroblasts and collagen in patients with systemic sclerosis (Ann Rheum Dis. 2018 Sep;77[9]:1362-71). And there have been two promising small retrospective case series as well. A more definitive clinical trial is planned.

Dr. Stevens said that, when starting a biologic agent in a child with localized scleroderma, she routinely adds methotrexate until the disease is under control.

Drugs supported by case reports and worth considering on an individual basis as a last resort are hydroxychloroquine, azathioprine, cyclosporine, and imatinib mesylate (Gleevec).

For mild, superficial lesions that don't cross joints, ultraviolet light A phototherapy is a therapeutic option. It displayed significant benefit in a systematic review and meta-analysis of 19 studies comparing it to methotrexate, although the results with methotrexate were deemed superior (Semin Arthritis Rheum. 2018 Dec;48[3]:495-503).

The pros and cons of getting a baseline brain MRI

Children with localized scleroderma have increased rates of severe headache, peripheral neuropathy, complex partial seizures, and stroke. So it had been Dr. Stevens's routine practice to obtain an initial brain MRI at the time of diagnosis. Of late, though, she has reconsidered that practice.

"The problem is that some patients with abnormal MRI lesions have no CNS disease at all, and there are also a fair number of patients with a normal MRI who have CNS symptoms. So in our practice we're pulling back on doing screening MRIs because we don't know what to do with the findings, and it just makes everybody worried," she said.

However, if a child with localized scleroderma develops headaches, seizures, neuropathies, or other CNS symptoms, then by all means get an MRI, and if it shows findings such as brain atrophy, white-matter lesions, calcifications, or leptomeningeal enhancement, consider treatment, she added.

Dr. Stevens reported receiving research funding from Kineta and Seattle Genetics.


Caption: Dr. Anne M. Stevens: "The treatment goal is to control inflammation and prevent damage in these patients, who we like to catch very early, when it's a subtle lesion."

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Title Annotation:PEDIATRICS
Author:Jancin, Bruce
Publication:Dermatology News
Date:May 1, 2019
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