Treatment of calcinosis cutis in systemic sclerosis and dermatomyositis: A review of the literature

doi:10.1016/j.jaad.2019.07.006

Journal of the American Academy of Dermatology

Volume 82, Issue 2, February 2020, Pages 317-325

https://doi.org/10.1016/j.jaad.2019.07.006 Get rights and content

Background

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

Objective

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

Methods

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.

Results

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).

Limitations

Few included studies had a high level of evidence.

Conclusion

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

Section snippets

Material and methods

This systematic review was performed according to the 2009 Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist.²²

Literature search and characteristics of included studies

Our literature search identified 3032 citations; reports for 30 studies10, 20, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53 were included in this systematic review (Fig 1), including 2 RCTs,20, 30 11 prospective cohort studies,31, 32, 36, 43, 44, 45, 46, 47, 48, 51, 53 and 17 retrospective studies.^∗ The sample size ranged 3-78 patients, for a total of 288 patients

Discussion

In this systematic review, we identified 30 studies (288 patients) focusing on the treatment of calcinosis cutis associated with SSc and dermatomyositis. Table IV summarizes the available treatments for calcinosis cutis with a focus on underlying diseases and levels of evidence.10, 20, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 47, 50, 51, 52, 53

Currently, we lack specific guidelines for managing calcinosis cutis in the setting of autoimmune connective tissue disorders.

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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.
Subcutaneous tissue involvement in idiopathic inflammatory myopathies: Systematic literature review including three new cases and hypothetical mechanisms
2023, Autoimmunity Reviews
Involvement of subcutaneous tissue in idiopathic inflammatory myopathies (IIM) is poorly known.
We conducted a systematic review of the literature regarding panniculitis and lipodystrophy/lipoatrophy in juvenile and adult IIM via PubMed/Medline, Embase and Scopus databases. Three local observations are included in this review. Epidemiological, clinical, paraclinical and therapeutic data were collected.
Panniculitis appears to be more common in adults than in juveniles. It was mainly localised in the upper and lower limbs. Panniculitis improved in most cases with steroids and panniculitis and myositis had a similar course in 83.3% and 72.2% of cases in juveniles and adults, respectively. Lipodystrophy appeared to be more frequent in juveniles and was only observed in dermatomyositis in both juveniles and adults. Lipodystrophy was mainly partial in juveniles and adults. The median time from myositis to the diagnosis of lipodystrophy was 6 years [0–35] and 2.5 years [0−10] in juveniles and adults, respectively. Lipodystrophy was associated with anti-TIF1 gamma auto-antibody positivity, a polycyclic/chronic course of myositis and the occurrence of calcinosis and might be an indicator of poor disease control.
Adipose tissue involvement, particularly lipodystrophy, occurs almost exclusively in dermatomyositis. The insidious onset and lack of awareness of the diagnosis may underestimate its prevalence. Larger studies are needed to identify possible risk factors in these patients, to better potential underlying pathophysiological process, in order to discuss potential therapeutic targets.
Systemic sclerosis in adults. Part II: management and therapeutics
2022, Journal of the American Academy of Dermatology
Citation Excerpt :
Immunomodulation forms the cornerstone of SSc skin fibrosis management. Systemic corticosteroids have been used in SSc,31,32 particularly during the initial edematous phase; however, they can precipitate scleroderma renal crisis (SRC) and are not recommended at high doses (Table II).33-35 MMF is considered first-line therapy for skin fibrosis in SSc, including in those with concomitant SSc-ILD.36-38
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.
Cancellous bone-like tissue replacement from calcinosis in patients with systemic sclerosis with multiple external root resorption
2022, Bone Reports
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In Patient 3, although calcification was observed in the anterior nasal spine, bone-like tissue replacement was not observed. Bisphosphonates, which lead to osteoclast apoptosis (Drake et al., 2008), have been reported to be effective against calcinosis (Mori et al., 2012; Traineau et al., 2020), FOP, and HO (Aubut et al., 2011; Yolcu et al., 2020), although there is no consensus on their effectiveness. Patient 3 was clinically injected with denosumab (an inhibitor of receptor activator of nuclear factor-kappa B [RANK] ligand), which prevents the activation of RANK on the surface of osteoclasts and osteoclast precursors, ultimately inhibiting osteoclast formation preparation for osteoporosis (Castellano et al., 2011).
Calcinosis is frequently observed in patients with systemic sclerosis (SSc). The fundamental treatment of calcinosis has not yet been established. During follow-up, calcinosis in the subcutaneous surface is often spontaneously extracted or remains confined by fibrous tissues. We previously identified a new symptom in SSc patients, multiple external root resorption (MERR), and these patients had calcifications in the nasal spine. Here, we report for the first time that calcinosis at the nasal spine in patients with MERR can be replaced by cancellous bone-like tissue. Patients 1 and 2 were a 62-year-old Japanese female and a 45-year-old Japanese female (respectively) with MERR who had been previously treated for SSc (Patient 1: limited type, positive for anti-centromere antibody; Patient 2: diffuse type, positive for anti-Scl70 and anti-SS-A antibodies). Patient 3 was a 57-year-old female with MERR who had been previously treated for SSc (diffuse type, positive anti-Scl-70 antibody) and underwent denosumab injection for osteoporosis. Cone-beam computed tomography (CBCT) and CT images in the calcifications at the nasal spine in Patient 1 and 2 were replaced with cancellous bone-like tissue, but not in Patient 3. Serum laboratory examination was performed to assess the systemic bone disease. All three patients had normal clinical data within the references, apart from slightly higher 1,25-dihydroxyvitamin D levels in Patient 1. SSc patients with calcinosis in the maxillofacial area need to be examined carefully for bone replacement using CBCT or CT.
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: Funding sources: None.

: Conflicts of interest: Dr Arnaud has received honoraria from Roche-Chugaï, Grifols, LFB, Pfizer, and UCB. Dr Chizzolini has received travel support from Roche-Chugaï. Dr Traineau, Dr Aggarwal, Dr Monfort, Dr Senet, Dr Oddis, Dr Barbaud, Dr Francès, and Dr Chasset have no conflicts of interest to disclose.

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Original articleTreatment of calcinosis cutis in systemic sclerosis and dermatomyositis: A review of the literature

Background

Objective

Methods

Results

Limitations

Conclusion

Section snippets

Material and methods

Literature search and characteristics of included studies

Discussion

J Am Acad Dermatol

Rheum Dis Clin North Am

Joint Bone Spine

Autoimmun Rev

Am J Med

Am J Med

Autoimmun Rev

J Am Acad Dermatol

J Am Acad Dermatol

Joint Bone Spine

Autoimmun Rev

Soft tissue and subcutaneous calcification in connective tissue diseases

Curr Opin Rheumatol

Risk factors associated with calcinosis of juvenile dermatomyositis

J Pediatr (Rio J)

The Juvenile Dermatomyositis National Registry and Repository (UK and Ireland)–clinical characteristics of children recruited within the first 5 yr

Rheumatology

High frequency of calcinosis in juvenile dermatomyositis: a risk factor study

Rev Bras Reumatol

Clinical characteristics of children with juvenile dermatomyositis: the Childhood Arthritis and Rheumatology Research Alliance Registry: investigating juvenile DM through a national multicenter registry

Arthritis Care Res

Clinical and serological features of systemic sclerosis in a multicenter African American cohort: analysis of the genome research in African American scleroderma patients clinical database

Medicine (Baltimore)

Clinical, biochemical, and radiological characterization of the calcinosis in a cohort of Mexican patients with systemic sclerosis

Clin Rheumatol

Clinical significance of subcutaneous calcinosis in patients with systemic sclerosis. Does diltiazem induce its regression?

Ann Rheum Dis

Role of fetuin-A in systemic sclerosis-associated calcinosis

J Rheumatol

Calcinosis is associated with digital ischaemia in systemic sclerosis—a longitudinal study

Rheumatology

Morbidity and mortality in adult polymyositis and dermatomyositis

Curr Rheumatol Rep

Calcinosis Cutis of juvenile dermatomyositis treated with incision and drainage

Dermatol Surg

Long-term outcome and prognostic factors of juvenile dermatomyositis: a multinational, multicenter study of 490 patients

Arthritis Care Res

Complete and sustained remission of juvenile dermatomyositis resulting from aggressive treatment

Arthritis Rheum

Consensus-based recommendations for the management of juvenile dermatomyositis

Ann Rheum Dis

Calcinosis in scleroderma

Curr Opin Rheumatol

The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration

PLoS Med

Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses

Eur J Epidemiol

Cochrane handbook for systemic reviews of interventions

Original article
Treatment of calcinosis cutis in systemic sclerosis and dermatomyositis: A review of the literature