Letter to the editor

Failure of warfarin in treatment of calcinosis universalis

The management of systemic sclerosis (SSc) is complex, evolving, and requires a multidisciplinary approach. At diagnosis and throughout the disease course, clinical assessment and monitoring of skin involvement is vital using the modified Rodnan Skin Score, patient-reported outcomes, and new global composite scores (such as the Combined Response Index for Systemic Sclerosis, which also considers lung function). Immunomodulation is the mainstay of skin fibrosis treatment, with mycophenolate mofetil considered first line.

Meanwhile vasculopathy-related manifestations (Raynaud’s phenomenon, digital ulcers) and calcinosis, require general measures combined with specific pharmacologic (calcium-channel blockers, phosphodiesterase type 5 inhibitors, and prostanoids), nonpharmacologic (digital sympathectomy and botulinum toxin injections), and often multifaceted, management approaches. Patients should be screened at the time of diagnosis specifically for systemic manifestations and then regularly thereafter, with appropriate treatment. Numerous targeted therapeutic options for SSc, including skin fibrosis, are emerging and include B-cell depletion, anti-interleukin 6, Janus kinase, and transforming growth factor β inhibition.

This second article in the continuing medical education series discusses these key aspects of SSc assessment and treatment, with particular focus on skin involvement. It is vital that dermatologists play a key role in the multidisciplinary approach to SSc management.

Calcinosis, insoluble calcium compounds deposited in skin and other tissues, is a crippling sequela of dermatomyositis. Prolonged disease associated with ongoing inflammation, ischemia, repetitive trauma, and certain autoantibodies are associated with calcinosis. Herein, we describe potential pathogenic mechanisms including the role of mitochondrial calcification. There are no widely effective treatments for calcinosis. We review available pharmacologic therapies for calcinosis including those targeting calcium and phosphorus metabolism; immunosuppressive/anti-inflammatory therapies; and vasodilators. Mounting evidence supports the use of various formulations of sodium thiosulfate in the treatment of calcinosis. Although the early institution of aggressive immunosuppression may prevent calcinosis in juvenile dermatomyositis, only limited data support improvement once it has developed. Minocycline can be useful particularly for lesions associated with surrounding inflammation. Powerful vasodilators, such as prostacyclin analogs, may have promise in the treatment of calcinosis, but further studies are necessary. Surgical removal of lesions when amenable is our treatment of choice.

We have limited data on the treatment of calcinosis cutis associated with systemic sclerosis and dermatomyositis.

To assess the efficacy and tolerance of available treatments for calcinosis cutis based on previously published studies.

We performed a systematic review of studies published in Medline, Embase, and the Cochrane library during 1980-July 2018. The strength of clinical data was graded according to the modified Oxford Centre for Evidence-Based Medicine levels of evidence.

In all, 30 studies (288 patients) were included. Eleven therapeutic classes, surgery, and physical treatments were identified as potential treatment options for calcinosis cutis. On the basis of results of a small randomized controlled trial and 4 retrospective studies, low-dose warfarin should not be used for calcinosis cutis (level IB evidence). The results of several studies suggest diltiazem and bisphosphonates might be useful treatment options (level IV). Considering biologic therapies, rituximab has shown promising results in treating both dermatomyositis and systemic sclerosis, whereas tumor necrosis factor inhibitors might be useful for treating juvenile dermatomyositis (level IV). Intralesional sodium thiosulfate might be a promising alternative (level IV).

Few included studies had a high level of evidence.

This study highlights the efficacy and tolerance profiles of available treatments for calcinosis cutis, with a focus on level of evidence.

Les calcifications sous-cutanées constituent un groupe hétérogène d’affections du tissu conjonctif. Elles peuvent s’associer à des anomalies du métabolisme phosphocalcique (calcinoses métastatiques, tumorales, calciphylaxie) mais aussi survenir sans désordre métabolique, en particulier au cours de certaines connectivites. Parmi celles-ci, les plus représentées sont la dermatomyosite et les formes limitées de sclérodermie systémique. La physiopathologie de ces processus est très mal connue. Les calcifications sous-cutanées peuvent se compliquer de douleurs, d’ulcérations chroniques, de surinfection, parfois à l’origine d’un retentissement fonctionnel majeur. Le traitement des calcinoses est un véritable défi car aucun médicament n’a pu démontrer de façon reproductible son efficacité dans l’arrêt de la progression ou la diminution des calcifications dystrophiques. On prescrit généralement en première ligne un inhibiteur calcique et de la colchicine. Dans les formes localisées, l’excision chirurgicale est souvent efficace parfois précédée d’un traitement local (laser, lithotripsie extracorporelle, application de thiosulfate de sodium en topique, etc.) ou général (minocycline, warfarine). Pour ce qui concerne les formes disséminées et de plus grande taille, elles peuvent bénéficier de traitements additionnels systémiques (hydroxyde d’aluminium, biphosphonates) parfois en association avec un traitement chirurgical. La réponse thérapeutique est difficile à évaluer allant de plusieurs semaines à plusieurs mois. L’accumulation de calcifications peut se compliquer de surinfection, de douleur et d’impotence fonctionnelle contre lesquelles il faut lutter.

Calcinosis cutis constitutes a heterogeneous group of chronic disorder. It can be associated with disturbance of calcium and/or phosphate metabolism (metastatic, tumor calcinosis, calciphylaxis) but may also develop without any metabolic disorder, in particular during the course of connective tissue diseases. Among these, the most common are dermatomyositis and the limited form of systemic sclerosis. The physiopathology of calcinosis cutis is poorly known. It can cause pain, chronic ulcerations, infections, which are sources of sometimes major disability. Treatment of calcinosis is challenging because no drug has been shown to be reliably effective in stopping the progression or decreasing dystrophic calcifications in controlled trials. Calcium blocker and colchicine are generally prescribed as the first line systemic therapy. In the localized forms of small lesions, surgical excision is often effective and sometimes preceded by local treatments (laser therapy, extracorporeal shock wave lithotripsy, topical sodium thiosulfate, etc.) or systemic treatment (minocycline, warfarine). When calcinosis is disseminated, it may require additional treatments (aluminium hydroxyde, bisphosphonates) possibly associated with surgery in case of large lesions. Time to response may be prolonged from weeks to months. The calcinosis cutis can lead to secondary infection, pain and functional disability that have to be prevented.

Presentamos el caso de una mujer de 32 años, con dos años de evolución de lesiones en piel tipo placas, induradas, nodulares, dolorosas, inicialmente en miembros inferiores con posterior compromiso generalizado, con evidencia de lesiones cutáneas sugestivas de dermatomiositis y biopsia de piel que reporta calcinosis; inicialmente sin evidencia clínica ni paraclínica que sugiriera compromiso muscular inflamatorio asociado. La resonancia magnética nuclear de músculos y la biopsia muscular confirmaron la presencia de este compromiso, definiendo los diagnósticos de dermatomiositis hipomiopática y calcinosis universal, dos espectros de una patología con baja frecuencia de presentación en la población adulta.

The case is presented of a 32 year-old woman with indurated, raised and painful plaques in the skin of 2 years onset. It began in the legs, but later with a generalized extension to other regions, with evidence of cutaneous lesions very suggestive of dermatomyositis. The skin biopsy reported as calcinosis; initially without clinical evidence of inflammatory muscle compromise. A Nuclear Magnetic Resonance study and muscle biopsy showed this compromise, leading to the diagnosis of hypomyopathic dermatomyositis and universal calcinosis, two pathologies with rare presentation in an adult patient.

Os integrantes da Comissão de Esclerose Sistêmica da Sociedade Brasileira de Reumatologia (biênio 2010-2012) participaram do Curso de Elaboração de Evidências da Associação Médica Brasileira, em São Paulo, durante o primeiro semestre de 2011. As questões foram propostas e discutidas pela internet, no segundo semestre de 2011. As 15 questões clínicas consideradas relevantes foram estruturadas por meio da estratégia do P.I.C.O. (Paciente; Intervenção ou Indicador; Comparação; Outcome). As estratégias de busca avaliaram as bases de dados MEDLINE, EMBASE, Scielo/Lilacs, Cochrane Library até setembro de 2012 (Apêndice). Os artigos selecionados na primeira estratégia de busca foram submetidos à avaliação crítica das evidências, utilizando-se o escore de Jadad. Foram considerados também estudos observacionais e séries de casos na ausência de ensaios clínicos randomizados. Foi realizada inserção de estudos relevantes obtidos por busca manual. Posteriormente, foram elaboradas as respostas às perguntas das Recomendações, em que cada referência bibliográfica selecionada apresentava o correspondente grau de recomendação e força de evidência científica. Para as Recomendações finais, as referências bibliográficas foram atualizadas até dezembro de 2012, redigidas em texto único pelo coordenador, e submetidas aos coautores em quatro turnos, para elaboração do texto final.

• A:

  Estudos experimentais e observacionais de melhor consistência.

• B:

  Estudos experimentais e observacionais de menor consistência.

• C:

  Relatos de casos (estudos não controlados).

• D:

  Opinião desprovida de avaliação crítica, baseada em consensos, estudos fisiológicos ou modelos animais.

Estabelecer as recomendações para o manejo e para o tratamento da esclerose sistêmica.