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Therapy-resistant dermatomyositis with extensive ‘lumbar belt’ calcinosis
  1. Juan Manuel Linan-Barroso1,
  2. Alexei Gonzalez-Estrada2 and
  3. Jose Salvador García-Morillo3
  1. 1Dermatology, Hospital Universitario Virgen del Rocio, Seville, Spain
  2. 2Division of Pulmonary, Allergy and Sleep Medicine, Department of Medicine, Mayo Clinic, Jacksonville, Florida, USA
  3. 3Systemic Autoimmune and Rares Diseases Unit. Internal Medicine Department, Hospital Virgen del Rocio, Seville, Spain
  1. Correspondence to Dr Alexei Gonzalez-Estrada; gonzalez.alexei{at}mayo.edu

Abstract

Calcinosis cutis (CC) is the umbrella term for calcium salt deposition on skin and subcutaneous tissue. We present a unique case of CC associated with anti-Mi2-positive dermatomyositis, having a distinctive distribution of subcutaneous calcifications appearing as a ‘lumbar belt’. Treatment of CC remains challenging for clinicians due to a lack of high-quality evidence. Corticosteroids, methotrexate, bisphosphonates, intravenous immunoglobulin replacement, rituximab and sodium thiosulfate failed to halt calcinosis progression in this case. Newer therapies, such as Janus kinase inhibitors, should be considered.

  • Musculoskeletal syndromes
  • Radiology
  • Biological agents
  • Rheumatology

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Background

Calcinosis cutis (CC) is the umbrella term for calcium salt deposition on skin and subcutaneous tissue. The most common subtype is dystrophic calcification, often associated with connective tissue disease (CTD) such as dermatomyositis (DM) and systemic sclerosis (SSc). Standard treatments include diltiazem, bisphosphonates, intravenous immunoglobulin, rituximab, sodium thiosulfate, surgery, and more recently, Janus kinase (JAK-1) inhibitors. However, to date, none of these treatment options has been proven effective for calcinosis.1 2 We report a patient with extensive ‘lumbar belt’ CC related to anti-Mi2-positive DM who failed multiple therapies.

Case presentation

A woman in her 50s was referred to our clinic with a 3-month history of bilateral proximal muscle weakness, dyspnoea, dysphagia to solids and liquids, and severe fatigue. The patient was obese. Her physical examination showed multiple hyperpigmented, sclerotic, atrophic plaques with erythematous borders on the lumbar back region and extending to her flanks, which were firm on palpation (figure 1). Additional lesions were located on the lateral aspects of the thighs, resembling the ‘Holster sign’. Also present was diffuse facial and upper trunk erythema; however, it was not thought to be consistent with a heliotrope rash. Further examination revealed Gottron’s papules on metacarpophalangeal joints.

Figure 1

Clinical aspect of suprajacent cutaneous lesions to calcinosis. We describe a stone-consistency brownish plaque surrounding lumbar region, showing characteristic ‘lumbar belt’ distribution.

Investigations

Laboratory test results showed the presence of serum creatine kinase elevation 1447 U/L (reference 23–187), anaemia 9.8 g/dL (reference 11.8–15.7) and leucopenia 3370 cells/µL (reference 4000–11 000). HIV, syphilis and hepatitis viral serologies were negative. Antinuclear antibodies immunofluorescence was positive. Myositis-associated autoantibodies were positive for anti-Mi2; all others were negative.

To rule out malignancy, a whole-body CT scan was performed, as well as cranial and axial MRI, mammography and gynaecological examination. The CT scan showed moderate ground-glass opacities in the lungs and unilateral pleural effusion. CT of the abdomen and pelvis revealed augmented enhancement on lumbar subcutaneous tissue (figure 2), which illustrated the ‘lumbar belt’ distribution. In addition, the CT also showed augmented enhancement on the lateral aspects of her thighs (figure 3).

Figure 2

CT of the abdomen and pelvis showing extensive subcutaneous calcification in subcutaneous fat interval of lumbar region.

Figure 3

CT of the abdomen and pelvis showing subcutaneous calcification in subcutaneous fat interval of lateral aspects of the thighs.

Skin biopsies were performed and histology revealed mild lymphocytic perivascular infiltration and interstitial mucin deposits in the dermis, without sclerodermiform changes. These histological features were compatible with a diagnosis of DM. Muscle biopsy showed necrosis and muscular regeneration phenomena, without associated inflammation or perifascicular atrophy. Intense, major histocompatibility complex class 1 (MHC-1) expression was found, indicating an immune-mediated cause of myopathy. Electromyography testing showed a myopathic pattern.

Differential diagnosis

Sclerotic skin lesions on the thighs made us consider morphea in the differential diagnosis, but proximal muscle weakness, classic DM lesions, histopathology and electromyography confirmed DM, meeting DM criteria.3 Muscle biopsy showed necrosis and muscular regeneration, but did not show inflammation or perifascicular atrophy, possibly due to concomitant systemic corticosteroid treatment. MHC-1 expression indicated an immune-mediated myopathy. Differential diagnosis included immune-mediated necrotising myopathies observed in overlapping syndromes. Also in the diagnostic differential is ‘overlap myositis’ anti-Mi2-positive severe calcinosis. However, CC is more often associated with SSc and DM; it is an uncommon finding in overlap syndromes. Additionally, it occurs less frequently in classic DM than in juvenile DM, where onset is typically rapid following diagnosis.4 Non-uraemic calcified arteriolopathy (non-uraemic calciphylaxis) is also in the differential for this case; differentiation can only made by deep muscle biopsy, as laboratory investigations are usually not helpful. Deep muscle biopsy was not performed since the mentioned diagnosis was considered unlikely due to the fact that the patient did not present with painful necrotic ulcers or livedo reticularis. Moreover, the patient was not previously treated with vitamin K antagonists, which are shown to be risk factors for this condition. Finally, paraneoplastic DM was ruled out by radiological studies and clinical examination.

Presence of mild cognitive impairment made us consider mitochondrial myopathies and metabolic disorders in the differential. Since the patient’s mother was being followed by a neurologist because of a gait disorder, our patient was referred to neurology and psychiatry. Neurology ruled out mitochondrial disorders with muscle biopsy, which did not reveal ragged red fibres. Cognitive impairment was determined to be unrelated to skin disease. Tandem mass spectrometry was also performed and ruled out any metabolic disorders.

Treatment

We started the patient on prednisone 30 mg/day, methotrexate 15 mg/week and six cycles of intravenous immunoglobulins 2 g/kg/day for 2 days, every 30 days. Alendronic acid at 70 mg/week was started to prevent osteoporosis and to treat calcinosis. On follow-up, prednisone doses were reduced to 10 mg/day and methotrexate doses were increased to 20 mg/week.

Outcome and follow-up

The patient responded well to therapy, recovering proximal muscle strength and resolution of cutaneous lesions. Creatine kinase levels were reduced from initial 1447 U/L to 119 U/L. Interstitial involvement of lung and pleural effusion resolved. Unfortunately, lumbar subcutaneous calcification extension continued to increase, despite therapy. Rituximab was initiated at 1 g/15 days every 6 months, intravenous sodium thiosulfate 25 g for 3 days every week and diltiazem at 60 mg/day; however, this regimen failed to reduce calcifications.

Discussion

This is an unusual case of anti-Mi2-positive DM with extensive calcinosis in lumbar subcutaneous tissue.

In our patient, only anti-Mi2 antibody was positive. Mi2 is a nucleosome helicase involved in histone deacetylase and demethylase functions, regulating gene transcription. Anti-Mi2 antibody-positive DM is generally associated with a favourable prognosis due to corticosteroid responsivity and usually having a low incidence of interstitial lung disease with CC. Although the patient achieved considerable response to therapy, calcinosis extension could not be halted despite our aggressive treatment approach. Several case series have shown increased muscular involvement, prominent necrosis and higher creatine kinase levels in anti-Mi2-positive DM than in anti-Mi2-negative DM. Anti-Mi2 autoantibody levels correlate with creatine kinase levels and disease severity. Additionally, anti-Mi2 DM has a higher rate of characteristic skin findings, such as the ‘Holster sign’, Gottron’s papules and/or heliotrope eruption. Anti-Mi2-positive DM is more frequently associated with CC than anti-Mi2-negative DM.5–7

Calcinosis management is a controversial topic. A recent systematic review pointed out the lack of evidence-based studies on treatment of calcinosis in SSc and DM. Traineau et al do not recommend using low-dose warfarin, whereas diltiazem and bisphosphonates were useful treatments. Among other promising treatments, they highlight intralesional sodium thiosulfate.1 From our experience with this patient, corticosteroids, methotrexate, bisphosphonates, immunoglobulins, rituximab, and topical and intravenous sodium thiosulfate were unsuccessful treatments for CC. Thus, new approaches for CC should be explored.

JAK-1 inhibitors such as tofacitinib and baricitinib are among the latest therapies for CTD; they interfere with JAK-STAT signalling pathways and downregulate cytokine expression in DM. Tofacitinib 5 mg two times per day has shown clinical response in DM, but to date, there are few case reports in calcinosis. Some reports have suggested that tofacitinib resolved calcification after 28 weeks of treatment. More evidence on safety and efficacy of JAK-1 in calcinosis is needed.8 Tofacitinib will be considered as our next treatment approach.

Patient’s perspective

(Translated from Spanish)

First symptoms I felt were intense tiredness and muscle weakness. It was impossible to get up from the chair and comb my hair. I even had to go to my family doctor and because I have fallen down several times while walking. I also noticed some dark spots on my back and redness on my face. My family doctor finally referred me to Internal Medicine.

Once I was done lots of blood tests and radiographies, doctors told me I had been diagnosed with dermatomyositis, a rare disease. When I started the first treatment I could walk and do housework without any help. I felt lucky about having a supporting husband. Despite of treatment, my back continued being hard and rigid, but did not hurt. I do not care about aesthetics; I just want to feel no pain and be able to make a normal life. I am happy that doctors are learning from my case. If they report it, I am going to become famous.

Learning points

  • The most common subtype of calcinosis cutis is dystrophic calcification, often linked to connective tissue disease.

  • An early diagnosis of calcinosis cutis and prompt treatment are important to halt its progression.

  • Response to currently available therapies is often unsatisfactory and there is lack of evidence regarding management of calcinosis.

  • Diltiazem, intravenous sodium thiosulfate and biphosphonates should be considered as first-line treatments.

Ethics statements

Patient consent for publication

References

Footnotes

  • Twitter @LinanBarroso, @UCAMIraras

  • Contributors JML-B obtained information from the patient and drafted the initial manuscript. All authors (JML-B, AG-E and JSG-M) reviewed, edited and approved the final version of the manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.