Introduction

Calcinosis is an uncommon condition occurring due to abnormal accumulation of calcium crystals in the body. It is classified into four types based on etiology: dystrophic, metastatic, iatrogenic, and idiopathic [1]. Dystrophic calcinosis refers to the abnormal deposition of calcium in the affected skin, subcutaneous tissues, muscles, and/or tendons in the presence of normal serum calcium and phosphate levels [2]. Calcinosis associated with rheumatic diseases is usually of dystrophic type. We present a case of adult dermatomyositis (DM) with calcinosisuniversalis in unusual locations like the face, and submandibular region and review of literature on calcinosis in rheumatological disorders.

Case Report:

A 40-year-old female presented with a history of progressive proximal muscle weakness and multiple swellings in the skin for a 1-year duration. She had mild discomfort over the swellings. The swelling initially started as a single firm to hard swelling over her thigh. The swelling gradually increased in number progressively and involved other areas like the face, neck, arms, and legs. She also gave a history of white chalky discharge from a few of the swellings. She also gave a history of rashes over her face, neck, chest, and upper back. She was a known case of diabetes mellitus on oral hypoglycemic drugs for 3 years. On examination, she had multiple subcutaneous hard swellings involving the infraorbital region (Figure 1), submandibular region, extensor aspects of both arms, forearms, and extensor aspect of both thigh and calf regions. The size of the swelling ranged from 0.5x0.5cm to 3x3 cm in size. Tenderness was noted in a few of the swellings, and some had extrusion of chalky white discharge (Figure 1). She had hyperpigmentation of the skin over her face, and a V-shaped area of her chest and upper back (Shawl sign). She also had Raynaud’s of both hands and proximal muscle weakness with power 3/5 in both lower limbs and 2/5 in both upper limbs (MMT8 32/80).

Fig 1: A: Clinical picture showing calcinosis in infraorbital and right submandibular region. B: Calcinosis in thigh with extrusion of white chalky material from one of the nodules

Fig 2: X-ray showing calcinosis in infraorbital, submandibular region (A) and pelvis (B)

Fig 3: MRI thigh showing gluteal muscle atrophy (A) and perifascial muscle edema (B)

On evaluation, her blood counts, blood sugar (fasting and postprandial), and renal function tests were normal. Her CPK was 3450 IU/l, LDH was 940 IU/l, SGOT was 125 IU/l and SGPT was 85 IU/l. serum calcium, phosphorus, and ALP were normal. ANA by IIF showed a cytoplasmic pattern (3+). The ANA profile was positive for Mi-2. X-ray showed diffuse calcification involving the infraorbital region, submandibular region, bilateral arms, forearms, thighs, and legs (Figure 2). Her CT chest showed no evidence of ILD. Her 2D ECHO was normal. MRI thighs showed atrophy of gluteal muscles with perifascial muscle edema of the posterior compartment (Figure 3). EMG showed a myopathic pattern and NCS was normal. She was managed with pulse methylprednisolone 1gm for 3 days followed by oral prednisolone, HCQs, and Diltiazem, I.V. Zoledronic acid, and supportive measures. She started on methotrexate as a steroid steroid-sparing agent and advised regular follow-up. At 1 year of follow-up, her muscle power increased to 4/5 in both her upper and lower limbs. She had no new lesions of calcinosis, a decrease in pain of 90% on the visual analog scale, and no discharge from lesions.

Discussion:

We did a literature review of calcinosis in rheumatology in PubMed and Google Scholar using the keywords, “calcinosis” and “Rheumatology”. There are no RCTs available. Only one controlled clinical trial was done in 4 patients of systemic sclerosis with calcinosis which assessed the efficacy and safety of extracorporeal shock wave therapy (ESWL) [3].

Calcinosis associated with rheumatic diseases is usually dystrophic calcinosis, which can be localized or generalized. Among the rheumatic diseases, calcinosis is commonly seen in dermatomyositis, often in juvenile-onset type. Calcinosis can also occur in other rheumatic diseases like systemic sclerosis, SLE, MCTD, Rheumatoid arthritis, and overlap syndromes [4]. The incidence of calcinosis in juvenile dermatomyositis (JDM) ranges from 10-70% compared to adult dermatomyositis with 20% of cases [5]. The sites commonly affected include elbows, knees, hands, feet, trunk, buttocks, and head. They tend to deposit at the sites of repeated trauma or periarticularly [6]. In our patient, unusual sites like the infraorbital region of the face, and submandibular region were involved, in addition to the extremities. Most common presentation of calcinosis is in the form of superficial plaques or nodules, especially in the extremities. Other forms are calcinosis circumscripta where large tumoural deposits occur in the proximal muscles; calcinosis universalis where deposits occur in intermuscular fascial planes and very rarely mixed forms [6]. Our patient presented with both subcutaneous nodules and calcinosis in intermuscular fascial planes.

Risk factors associated with calcinosis are male sex, older age of disease onset, delay in diagnosis, long duration of active disease, inadequate therapy, underlying cardiac or pulmonary disease, and need for immunosuppressive therapy [6]. Our case is a middle-aged female with a disease duration of 1 year and active myositis at presentation. Etiopathogenesis for the development of calcinosis is not known although various hypotheses have been proposed. The presence of chronic inflammation and/or tissue injury plays a role in the formation of calcium crystals. Chronic inflammation may alter the cell membrane and lead to the accumulation of calcium intracellularly [7]. Other pathogenic mechanisms proposed for calcinosis include local vascular ischemia, mitochondrial damage of muscle cells, and dysregulation of mechanisms controlling the deposition and solubility of calcium, and phosphate [8].

Increased production of TNF alpha and association with TNF alpha 308A allele are noted in patients with juvenile dermatomyositis and calcinosis. Elevated TNF alpha leads to persistent chronic inflammation and prolonged disease course, which are the major risk factors for the development of calcinosis [9]. Other proinflammatory mediators like Interleukin 1, 6 are also found to be elevated locally at the site of calcinosis [10]. Our patient with a history of rashes over the face, and neck suggests active inflammation at these sites which would have predisposed to calcinosis at these unusual sites. The composition of calcinosis in a study done in JDM showed the presence of hydroxyapatite minerals along with bone proteins namely osteopontin, osteocalcin, and bone sialoprotein. The mineral content of calcinosis is extremely high than the matrix as well and the distribution was irregular when compared to normal bone tissue [11].

Complications of calcinosis include pain due to stretching or compression over nerves, secondary infection, ulceration, muscular atrophy, weakness, and joint contractures. Conventional radiography is commonly used as a screening tool to detect the lesions of calcinosis. In a few cases, a CT scan may be required to visualize early lesions. Although MRI scans are not routinely done, they help detect subcutaneous edema and calcified lesions which are the precursors of radiographic calcinosis [12]. MRI can also identify muscle edema in patients with inflammatory myositis and calcinosis.

Treatment of calcinosis in rheumatological conditions is challenging and responses are not uniform. Only limited evidence exists from case studies while high-grade evidence from randomized trials is lacking. Diltiazem is a calcium channel-blocking agent, most widely studied in the treatment of calcinosis. It is used in the dose of 5mg/kg/day. It acts by reducing the calcium influx into the cells and decreasing the tendency to form calcific lesions [13]. The second group of drugs used for calcinosis are bisphosphonates. Bisphosphonates inhibit the osteoclast activity thereby inhibiting bone remodeling. They also have additional effects on macrophages and cytokines in calcific lesions [14]. Reports from case studies showed that Etidronate, alendronate, and pamidronate were found to be effective in the treatment of calcinosis [15]. Other less commonly used drugs for calcinosis include topical sodium thiosulfate, aluminum hydroxide, and probenecid. Our patient showed no progression or appearance of new lesions at the end of 1 year of follow-up after treatment with zoledronic acid.

Among the anti-inflammatory agents, Colchicine is the most frequently used drug. Colchicine has been found to improve both local and systemic inflammatory responses as well as promote the healing of skin ulcers secondary to calcinosis [16]. Thalidomide was tried in a case of JDM with calcinosis and was found to show clinical improvement. Thalidomide acts by inhibiting the expression of TNF and IL-6 mRNA in monocytes. Thalidomide has limited clinical utility due to its teratogenicity and neuropathy. Intralesional steroids have been tried in JDM patients with olecranon bursa calcinosis. TNF α blockers like infliximab, adalimumab, etanercept have been tried in the treatment of calcinosis. Infliximab was given in the dose of 3mg/kg at 0,2,6 weeks followed by every 8 weeks. Refractory JDM patients treated with infliximab showed improvement in joint contractures and muscle weakness associated with calcinosis [17].

Rituximab showed some improvement in a patient with scleroderma with calcinosis. In a study done by Narvaez et al, on refractory calcinosis in systemic sclerosis, rituximab was found to be effective in 50% of patients [18]. Tofacitinib demonstrated improvement of calcinosis in refractory dermatomyositis [19]. Surgical options including excision, and extracorporeal shock wave therapy have been tried with recurrent or refractory calcinosis to medical therapy. Carbon dioxide laser therapy has also been tried in a few cases with promising results.

Conclusion:

We described a case of adult dermatomyositis with calcinosis in unusual locations like the face and submandibular region. More studies are required for a better understanding of the causes, pathogenesis, and management of this rare condition.

References:

1. Walsh JS, Fairley JA. Calcifying disorders of the skin. Journal of the American Academy of Dermatology. 1995;33(5 Pt 1):693–710. https://doi.org/10.1016/0190-9622(95)91803-5
2. Touart DM, Sau P. Cutaneous deposition diseases. Part II. Journal of the American Academy of Dermatology. 1998;39(4 Pt 1):527–546. https://doi.org/10.1016/s0190-9622(98)70001-5
3. Blumhardt S, Frey DP, Toniolo M, Alkadhi H, Held U, Distler O. Safety and efficacy of extracorporeal shock wave therapy (ESWT) in calcinosis cutis associated with systemic sclerosis. Clinical and Experimental Rheumatology. 2016;34 Suppl 100(5):177–180
4. Balin SJ, Wetter DA, Andersen LK, Davis MD. Calcinosis cutis occurring in association with autoimmune connective tissue disease: the Mayo Clinic experience with 78 patients, 1996-2009. Archives of Dermatology. 2012;148(4):455–462. https://doi.org/10.1001/archdermatol.2011.2052
5. Hoeltzel MF, Oberle EJ, Robinson AB, Agarwal A, Rider LG. The presentation, assessment, pathogenesis, and treatment of calcinosis in juvenile dermatomyositis. Current Rheumatology Reports. 2014;16(12):467. https://doi.org/10.1007/s11926-014-0467-y
6. Rider LG, Lindsley CB, Miller FW. Juvenile Dermatomyositis. In: Petty RE (ed) Textbook of Pediatric Rheumatology, 7^thedn. Elsevier, Philadelphia PA. 2016. pp 361
7. Pachman LM, Boskey AL. Clinical manifestations and pathogenesis of hydroxyapatite crystal deposition in juvenile dermatomyositis. Current Rheumatology Reports. 2006;8(3):236–243. https://doi.org/10.1007/s11926-996-0031-5
8. Chung MP, Richardson C, Kirakossian D et al and International Myositis Assessment, & Clinical Studies Group (IMACS) Calcinosis Scientific Interest Group. Calcinosis Biomarkers in Adult and Juvenile Dermatomyositis. Autoimmunity Reviews. 2020;19(6):102533. https://doi.org/10.1016/j.autrev.2020.102533
9. Pachman LM, Liotta-Davis MR, Hong DK, Kinsella TR, Mendez EP, Kinder JM, Chen EH. TNFalpha-308A allele in juvenile dermatomyositis: association with increased production of tumor necrosis factor-alpha, disease duration, and pathologic calcifications. Arthritis and Rheumatism. 2000;43(10):2368–2377. https://doi.org/10.1002/1529-0131(200010)43:10<2368::AID-ANR26>3.0.CO;2-8
10. Mukamel M, Horev G, Mimouni M. New insight into calcinosis of juvenile dermatomyositis: a study of composition and treatment. The Journal of Pediatrics. 2001;138(5):763–766. https://doi.org/10.1067/mpd.2001.112473
11. Pachman LM, Veis A, Stock S, Abbott K, Vicari F, Patel P, Giczewski D, Webb C, Spevak L, Boskey AL. Composition of calcifications in children with juvenile dermatomyositis: association with chronic cutaneous inflammation. Arthritis and Rheumatism. 2006;54(10):3345–3350. https://doi.org/10.1002/art.22158
12. Kimball AB, Summers RM, Turner M, Dugan EM, Hicks J, Miller FW, Rider LG () Magnetic resonance imaging detection of occult skin and subcutaneous abnormalities in juvenile dermatomyositis. Implications for diagnosis and therapy. Arthritis and Rheumatism. 2000;43(8):1866–1873.
13. Oliveri MB, Palermo R, Mautalen C, Hübscher O. Regression of calcinosis during diltiazem treatment in juvenile dermatomyositis. The Journal of Rheumatology. 1996;23(12):2152–2155
14. Gelder JV, Breuer E, Ornoy A, Schlossman A, Patlas N, Golomb G. Anticalcification and antiresorption effects of bisacylphosphonates. Bone. 1995;16(5): 511-520. doi:10.1016/8756-3282(95)00081-n
15. Ambler GR, Chaitow J, Rogers M, McDonald DW, Ouvrier RA. Rapid improvement of calcinosis in juvenile dermatomyositis with alendronate therapy. The Journal of Rheumatology. 2005;32(9):1837–1839
16. Taborn J, Bole GG, Thompson GR. Colchicine suppression of local and systemic inflammation due to calcinosisuniversalis in chronic dermatomyositis. Annals of Internal Medicine. 1978;89(5 Pt 1):648–649. https://doi.org/10.7326/0003-4819-89-5-648
17. Boulter EL, Beard L, Ryder C, Pilkington CA. Effectiveness of anti-TNF-α agents in the treatment of refractory juvenile dermatomyositis. Pediatric Rheumatology Online Journal. 2011;9(Suppl 1):O29. https://doi.org/10.1186/1546-0096-9-S1-O29
18. Narváez J, Pirola JP, LLuch J, Juarez P, Nolla JM, Valenzuela A. Effectiveness and safety of rituximab for the treatment of refractory systemic sclerosis associated calcinosis: A case series and systematic review of the literature. Autoimmunity Reviews. 2019;18(3): 262–269. https://doi.org/10.1016/j.autrev.2018.10.006
19. Shneyderman M, Ahlawat S, Christopher-Stine L, Paik JJ. Calcinosis in refractory dermatomyositis improves with tofacitinib monotherapy: a case series. Rheumatology. 2021 Nov 3;60(11): e387–8. https://doi:10.1093/rheumatology/keab421