Abatacept and Sodium Thiosulfate for Treatment of Recalcitrant Juvenile Dermatomyositis Complicated by Ulceration and Calcinosis

doi:10.1016/j.jpeds.2011.11.057

The Journal of Pediatrics

Volume 160, Issue 3, March 2012, Pages 520-522

https://doi.org/10.1016/j.jpeds.2011.11.057 Get rights and content

We report the successful use of abatacept and sodium thiosulfate in a patient with severe recalcitrant juvenile dermatomyositis complicated by ulcerative skin disease and progressive calcinosis. This combination therapy resulted in significant reductions in muscle and skin inflammation, decreased corticosteroid dependence, and halted the progression of calcinosis.

Section snippets

Case Report

A 14-year-old Caucasian girl with severe JDM presented at age 11 years with swelling of the hands and feet, arthralgia, and subsequent heliotrope rash; Gottron papules overlying extensor joints of the fingers, elbows, and knees; shawl sign rash; and periungual telangiectasia. Initially, the patient demonstrated mild to moderate weakness of the proximal muscles, elevated serum lactate dehydrogenase (LDH) level (970 U/L; normal range, 470-750 U/L), elevated serum aldolase level (10.1 U/L; normal,

Discussion

Abatacept is a fusion protein between immunoglobulin and the extracellular domain of cytotoxic T-lymphocyte antigen 4 that exerts an anti-inflammatory effect by down- regulating T-cell activation.³ The efficacy of this biological therapy has been established in adult and juvenile rheumatoid arthritis⁴; however, there have been no previous reports on the use of abatacept to treat inflammatory myopathies, and the present study is the first to suggest a beneficial effect. Abatacept has the added

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Effectiveness of topical sodium thiosulfate for ectopic calcifications and ossifications. Results of the CATSS-O study
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Ectopic calcifications (ECs) and heterotopic ossifications (HOs) form in non-mineralized tissues, most often in subcutaneous and muscular areas. Local and systemic complications can cause severe disability. Systemic administration of sodium thiosulfate (STS) gives promising results but is difficult to use in clinical practice.
Evaluation of the efficacy and safety of topical STS in ECs and HOs.
Retrospective analysis of the CATSS-O registry that included patients receiving topical STS 25 % prepared by the pharmacy of Limoges hospital during 2014–2020. The efficacy of STS was assessed by imaging (radiography or CT) after at least 6 months’ treatment.
Among 126 patients who received STS 25 %, 35 had complete clinical and radiographic data for analysis (28 with ECs and 7 with HOs; 18 children [mean age 8.9 years, range 1.5–16], 17 adults [mean age 52.4 years, range 24–90]). Calcifications or ossifications were due to dermatomyositis (8 children, 6 adults), systemic scleroderma (6 adults) or pseudo-hypoparathyroidism 1A (7 children). They were single (37.1 %) or multiple (62.9 %). Treated regions were in the lower limbs (31.4 %), upper limbs (37.1 %) or both (28.6 %) and the axial region (2.9 %). Topical STS was clinically effective in 9/28 (32.1 %) patients with ECs and 2/7 (28.6 %) children with HOs. Three patients experienced complete disappearance of their calcifications. Response for ECs was better in children than adults (54.5% vs 17.6 %, p = 0.035). Topical STS was well tolerated.
Local STS seems effective for ossifications, particularly pediatric calcifications or ossifications. Randomized and experimental studies are needed to confirm this observation and to identify the underlying mechanisms.
Distinguishing dystrophic calcification from calciphylaxis
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The role of bDMARDs in idiopathic inflammatory myopathies: A systematic literature review
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Idiopathic inflammatory myopathies (IIM) are a group of different conditions typically affecting striate muscle, lung, joints, skin and gastrointestinal tract. Treatment typically relies on glucocorticoids and synthetic immunosuppressants, but the occurrence of refractory, difficult to treat, manifestations, may require more aggressive treatment, borrowed from other autoimmune diseases, including biologic disease modifying drugs (bDMARDs). In this regard, we conducted a systemic literature review in order to depict the current evidence about the use of bDMARDs in IIM. A total of 78 papers, published during the last 21 years, were retrieved. The majority of patients was treated with TNF-α inhibitors, whose effectiveness was assessed particularly in recalcitrant striate muscle, skin and joints involvement. Rituximab, whose evidence is supported by a large number of real-life studies and trials, seems to be an excellent option in case of ILD and anti-synthetase syndrome, while Tocilizumab, despite not meeting primary and secondary endpoints in a recently published clinical trial, proved its effectiveness in rapidly progressing ILD. Similarly, Abatacept, studied in a phase IIb clinical trial with conflicting evidence, was reported to be effective in some case reports of refractory dermatomyositis. Less data exist for anti-IL1 and anti-IL23 agents, which were employed particularly for inclusion body myositis and severe skin disease, respectively. This study provides an organ-focused assessment of bDMARDs in IIM, which display encouraging results in the treatment of refractory subsets of disease.
Current and new targets for treating myositis
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Citation Excerpt :
Abatacept, which targets CD80 and CD86 on antigen presenting cells, was reported to be successful in a patient with refractory PM [42]. A child with severe recalcitrant JDM with ulcerative cutaneous disease and progressive calcinosis also demonstrated a favorable response to combination therapy with abatacept and sodium thiosulfate [43]. In another case report from Japan, abatacept therapy was associated with a favorable outcome in an anti-SRP positive patient with refractory myositis [44].
As treatment of refractory idiopathic inflammatory myopathies (IIM) has been challenging, there is growing interest in assessing new therapies that target various pathways implicated in the pathogenesis of IIM. In the largest clinical trial to date, rituximab was studied in adult and juvenile myositis, but the primary outcome was not met despite 83 percent of subjects with refractory myositis meeting the definition of improvement. The U.S. Food and Drug Administration (FDA) has recently granted approval to Octagam 10% immune globulin intravenous (IVIg), for the treatment of adult dermatomyositis based on impressive results from a double-blind placebo-controlled trial. Anti-tumor necrosis factor (anti-TNF) utility in IIM is not recommended and recent reports suggest this therapy may induce systemic autoimmune disease including myositis. Further, anti-IL6 therapy cannot be recommended as a recent trial of tocilizumab failed to reach its primary endpoint.
Further studies are needed to assess the role of newer therapies such as abatacept (inhibition of T cell co-stimulation), sifalimumab (anti-IFNα), Janus kinase [JAK] inhibitors, apremilast (phosphodiesterase 4 inhibitor), and KZR-616 (selective inhibitor of the immunoproteasome) given their biological plausibility and encouraging recent small-case series results. The future of IIM therapy will depend on exploring biomarkers implicated in the etiopathogenesis of IIM, improvements in myositis classification based on serological and histopathological features, and well-designed controlled clinical trials using validated consensus outcome measures.
Emerging therapeutics in the management of connective tissue disease. Part II: Dermatomyositis and scleroderma
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A phase 3 clinical trial for its use in inflammatory myopathy is ongoing.30,31 Abatacept, a fusion protein composed of IgG1 fused to the extracellular domain of cytotoxic T-lymphocyte associated protein-4 approved for rheumatoid arthritis, has shown mild efficacy for both juvenile and adult patients with DM.32-34 Despite positive results in case reports, the Abatacept Treatment in Polymyositis and Dermatomyositis trial, a phase IIb randomized delayed-start pilot study that included 9 adult patients with refractory DM (and 11 patients with polymyositis), reported only 2 patients with DM as responders (vs 6 with polymyositis).32
The management of connective tissue diseases is dramatically evolving with the advent of biologics and novel oral systemic therapeutics. Despite involvement in the care of these complex patients, there is a knowledge gap in the field of dermatology regarding these emerging agents. The second article in this continuing medical education series discusses new and emerging therapeutics for dermatomyositis and scleroderma that target cells, intracellular signaling pathways, and cytokines.
Possible future avenues for myositis therapeutics: DM, IMNM and IBM
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Citation Excerpt :
A phase III, randomized, double-blind trial comparing abatacept with standard treatment in patients with refractory disease failed to meet its primary endpoints, but subgroup analysis suggest efficacy for non-DM patients (Clinical Trial Identifier: NCT02971683). There have also been case reports of the benefit of abatacept in combination with sodium thiosulfate in a JDM patient with severe, recalcitrant calcinosis [48]. Belimumab is a monoclonal antibody that inhibits B-cell survival [49].
Idiopathic inflammatory myopathies (IIMs) represent a heterogeneous group of systemic autoimmune diseases characterized by immune-mediated muscle injury. As insights into pathogenesis of IIM evolve, novel therapeutic strategies have become available to optimize outcomes. Herein, we summarize novel and emerging strategies in the management of dermatomyositis (DM), immunemediated necrotizing myopathy (IMNM), and inclusion body myositis (IBM).

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: Supported by the intramural research program of the National Institute of Environmental Health Sciences, National Institutes of Health; the Cure JM Foundation; and the Mohsen Ziai, MD Pediatric Endowment at Inova Fairfax Hospital for Children, Inova Health System Foundation. The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of Defense or the US Government. The authors declare no conflicts of interest.

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Clinical and Laboratory ObservationAbatacept and Sodium Thiosulfate for Treatment of Recalcitrant Juvenile Dermatomyositis Complicated by Ulceration and Calcinosis

Section snippets

Case Report

Discussion

Autoimmun Rev

Clin Immunol

Juvenile dermatomyositis: new developments in pathogenesis, assessment and treatment

Best Pract Res Clin Rheumatol

Calcinosis in juvenile dermatomyositis: pathogenesis and current therapies

Pediatr Rheum Online J

Long-term safety and efficacy of abatacept in children with juvenile idiopathic arthritis

Arthritis Rheum

Clinical and Laboratory Observation
Abatacept and Sodium Thiosulfate for Treatment of Recalcitrant Juvenile Dermatomyositis Complicated by Ulceration and Calcinosis