Update on the treatment of calcinosis in dermatomyositis

Abstracts

Calcinose é uma afecção do tecido conjuntivo classificada em quatro tipos: metastática, idiopática, iatrogênica e distrófica. Esta última é o que acontece, por exemplo, em dermatomiosite, principalmente na forma juvenil, e é caracterizada por uma deposição anormal de sais de cálcio em pele afetada, tecidos subcutâneos, músculos ou tendões, sendo os níveis séricos de cálcio e fósforo normais. O tratamento da calcinose em dermatomiosite continua sendo um desafio, havendo poucas descrições na literatura, de pouca evidência científica. Não se apresenta, até o momento, nenhuma terapia altamente eficaz no combate e resolução dessa comorbidade. No presente trabalho, abordamos o conceito de calcinose, particularmente em dermatomiosite, assim como o seu tratamento descrito na literatura.

Revisão; Calcinose; Dermatomiosite; Terapêutica


Calcinosis is a connective tissue disorder classified into the following four types: metastatic; idiopathic; iatrogenic and dystrophic. Dystrophic calcinosis can occur, for example, in dermatomyositis, mainly in juvenile dermatomyositis, and is characterized by an abnormal deposition of calcium salts in affected skin, subcutaneous tissues, and muscles or tendons, with normal serum levels of calcium and phosphate. The treatment of calcinosis in dermatomyositis remains a challenge, with few descriptions in the literature of low scientific evidence. So far, no therapy has proved to be highly effective in the combat and resolution of that comorbidity. The present study discusses the concept of calcinosis, particularly in dermatomyositis, as well as its treatment described in the literature.

Review; Calcinosis; Dermatomyositis; Therapy


REVIEW ARTICLE

  • Update on the treatment of calcinosis in dermatomyositis
    Samuel Katsuyuki Shinjo*; Fernando Henrique Carlos de Souza
  • Service of Rheumatology, Hospital das Clínicas, Medical School, Universidade de São Paulo (HC-FMUSP), São Paulo, SP, Brazil

    ABSTRACT

    Calcinosis is a connective tissue disorder classified into the following four types: metastatic; idiopathic; iatrogenic and dystrophic. Dystrophic calcinosis can occur, for example, in dermatomyositis, mainly in juvenile dermatomyositis, and is characterized by an abnormal deposition of calcium salts in affected skin, subcutaneous tissues, and muscles or tendons, with normal serum levels of calcium and phosphate. The treatment of calcinosis in dermatomyositis remains a challenge, with few descriptions in the literature of low scientific evidence. So far, no therapy has proved to be highly effective in the combat and resolution of that comorbidity. The present study discusses the concept of calcinosis, particularly in dermatomyositis, as well as its treatment described in the literature.

    Keywords: Review, Calcinosis, Dermatomyositis, Therapy

    Concept of calcinosis

    Calcinosis is a connective tissue disorder classified into the four following types: metastatic; idiopathic; iatrogenic and dystrophic.1,2 Metastatic calcinosis refers to the deposition of calcium salts in normal tissues, with increased serum levels of calcium and/or phosphate, whose product is > 70.1,2 Idiopathic calcification occurs in normal tissues, with normal serum levels of calcium and phosphate.1,2 Iatrogenic calcinosis includes the hypersensitivity reaction, which usually begins with livedo reticularis rapidly progressing to the formation of skin ulcers and necrosis; it is more commonly reported in patients with chronic renal failure on hemodialysis.1 Dystrophic calcinosis is the abnormal deposition of calcium salts in affected skin, subcutaneous tissue, and muscles or tendons, with normal serum levels of calcium and phosphate.2,3 Dystrophic calcinosis can occur, for example, in dermatomyositis (DM).

    Calcinosis in dermatomyositis

    In patients with DM, calcinosis is much more frequent in the pediatric age group, being present in 10%-70% of the cases.4-9 In adults, it is reported in about 20% of the patients,10,11 and can precede the diagnosis of DM or even appear years after that. Usually, calcinosis appears between the first and third years of the disease.6

    In DM, calcinosis can present as follows: (a) hard nodules or plaques in subcutaneous or periarticular regions; (b) tumors; (c) deposits in the intermuscular fascia, leading to mobility limitation of the affected muscles; (d) severe dystrophic calcification similar to an exoskeleton; and (e) mixed form.4 Calcinosis can have a negative impact on the patients' quality of life, causing weakness, functional disability, joint contractures, muscle atrophy, skin ulcers, and, consequently, local pains and secondary infections.

    Pathogenesis and risk factors

    The etiopathogenesis of calcinosis in DM is unknown. Based on case reports, calcinosis is believed to result from the intracellular accumulation of calcium secondary to a change in cell membrane. It can be triggered by trauma and/or chronic inflammation,12,14-31 such as in cases nonresponsive to corticotherapy, in the presence of generalized cutaneous vasculitis, important muscle weakness, and persistent elevation in muscle enzymes.4-6,13-15

    The hypothesis of inflammation at the calcinosis site is plausible, because several authors have shown the presence of cells and pro-inflammatory cytokines, such as IL-116 and TNF-alpha,17 and a variety of proteins related to mineralization, such as osteopontin, osteonectin, bone sialoprotein and hydroxyapatite,18 at the calcinosis site.17 It has also been associated with the presence of antibodies against the 140 kDa protein19 and with TNF-alpha-308A polymorphism.16

    Fisler et al.20 have studied 35 cases and reported an association between calcinosis and a delay in the diagnosis and/or beginning of treatment, increased muscle enzymes, and prolonged disease duration. Similarly, Pachman et al.13 have observed calcinosis and a delay in disease diagnosis. However, Sallum et al.6 have reported the association of the development of calcified nodules, systemic involvement of the myopathy and aggressive use of medicaments. Bowyer et al.4 have shown that inadequate initial therapy plays an important role in the development of calcinosis. In addition, as previously mentioned, calcinosis is less frequent in adults with DM, raising the possibility that age-dependent factors could influence the risk of developing ectopic calcifications.21

    Treatment of calcinosis in dermatomyositis

    The present study systematically review the treatments reported for calcinosis in DM. A literature search was conducted in the MEDLINE database by using the following terms: calcinosis and dermatomyositis.

    Except for 14 cases reported as having spontaneous resolution,1-4,9,22-24 calcinosis in DM tends to increase with disease progression. An early and aggressive therapeutic intervention against DM activity has been suggested to possibly reduce the musculocutaneous sequelae of the disease, including calcinosis itself.20

    However, so far, no consensus has been achieved about the effective treatment for calcinosis in DM, and the data available in the literature are based only on reports and/or case series, particularly in juvenile DM. The use of the following medications has been mentioned: bisphosphonates; probenecid; warfarin; aluminum hydroxide; colchicine; diltiazem; and infliximab.

    Ambler et al.25 have reported the case of an 8-year-old child with chronic juvenile DM, whose calcinosis was completely resolved after using alendronate (10 mg/day) for 12 months. The patient had previously received diltiazem (15 mg, 2x/day) and probenecid (500 mg, 2x/day), with no resolution of the calcinosis. Similarly, Mukamel et al.26 have reported an improvement in calcinosis in a 6-year-old patient with juvenile DM by introducing alendronate (10 mg/day) for 12 months.

    Mori et al.27 have reported the use of etidronate (800 mg/day) in a 26-year-old patient with DM, who, in addition to calcinosis, had osteoporosis. Those authors have reported the regression of calcinosis three months after beginning drug therapy. In addition, a significant improvement was observed in densitometric values after a three-year follow-up. Nevertheless, Metzger et al.28 have assessed the effect of etidronate in three patients with DM and calcinosis for 12 months, no satisfactory effect being observed.

    The use of pamidronate has also been described.29,30 Three patients with juvenile DM received pamidronate at the dosage of 1 mg/kg/day for three consecutive days, repeated every month. A satisfactory response was observed in all cases, including one complete resolution of the calcinosis.

    Based on the principle that probenecid might reduce the local inflammatory process, it has been used, but the results are controversial.8,9,31-33

    Fuchs et al.34 have described a case of juvenile DM with calcinosis in the prepatellar region, accompanied by inflammation and localized cutaneous ulcer. An improvement in the cutaneous lesions was observed two months after using colchicine at the dosage of 1 mg/day.

    Based on the theory of having an inhibitory effect on the calcium channels of the cell membrane, diltiazem has proved to be, mainly in cases of juvenile DM, a therapeutic alternative.35-39 Its dosages have varied from 30-180 mg/day, and that drug was introduced to patients whose treatments with bisphosphonate and aluminum hydroxide did not succeed. All cases described35-39 showed an excellent response in follow-ups ranging from 6-10 months.

    Miyamae et al.40 have assessed the beneficial effect of thalidomide in one 14-year-old female patient with juvenile DM for ten years, who had previously undergone pulse therapy with methylprednisolone, cyclophosphamide, cyclosporine, azathioprine, probenecid, magnesium hydroxide, aluminum hydroxide, in addition to infliximab (suspended due to adverse effects) and etanercept for disease activity and calcinosis progression. Later, at the age of 12 years, thalidomide was introduced (1.3 mg/kg/day, orally, in the first month, and, then, 2 mg/kg/day), the response being satisfactory.

    Older descriptions have evidenced good results with aluminum hydroxide for patients with juvenile DM, no adverse effects being reported.41-44 Nakagawa et al.42 have reported a case with an almost complete resolution of calcinosis after eight months of treatment.

    Vitamin K plays an important role in calcium binding with bones and tissues.23 Based on this concept, Berger et al.45 and Matsuoka et al.46 have used low doses of warfarin to patients with juvenile DM and nodular calcinosis. Those authors have reported a reduction in the size of the lesions after using warfarin for three years.

    Regression of cutaneous calcinosis following intralesional infiltration of corticosteroid has been described by Al-Mayouf et al.47 in a 10.5-year-old patient, preceded by use of methotrexate and corticosteroid for disease activity. For the calcinosis located in one of the elbows, colchicine and pamidronate infusion every three months (total of five doses) were unsuccessfully used. Corticosteroid infiltration using the barbotage technique was performed, with consequent regression of the calcinosis.

    Surgical procedures have been reserved to extensive areas of calcification,48,49 with incision and local drainage, and have shown satisfactory results.

    In the era of biological therapy, infliximabe has been used at the dosage of 3 mg/kg (same schedule for rheumatoid arthritis) to treat five patients with juvenile DM refractory to previously proposed treatments; all cases had a positive response, with calcinosis regression in periods ranging from 8-30 months after beginning treatment.50 Arabshahi et al.51 have reported the use of abatacept (10 mg/kg, monthly, after fortnightly application in the first month) and sodium thiosulfate (topic, initially at 3%, and, then, at 10%, fortnightly) to a 14-year-old patient with juvenile DM for three years, refractory to corticosteroid, tacrolimus and intravenous human immunoglobulin, who had progressive calcinosis and ulcerated cutaneous lesions. The therapy instituted determined a reduction in musculocutaneous inflammation and calcinosis regression.

    In conclusion, the treatment of calcinosis in both adult and juvenile DM remains a challenge, with few descriptions in the literature of low scientific evidence. So far, no therapy has proved to be highly effective in the combat and resolution of that comorbidity.

    Conflicts of interest

    The authors declare no conflicts of interest.

    REFERENCES

    • 1
      Walsh JS, Fairley JA. Calcifying disorders of skin. J Am Acad Dermatol. 1995;33(5Pt1):693-706.
    • 2
      Touart DM, Sau P. Cutaneous deposition diseases. Part II. J Am Acad Dermatol. 1998;39(4 Pt1):527-44.
    • 3
      Paul H, Reginato AJ, Schumacher HR. Alizarin red S staining as a screening test to detect calcium compounds in synovial fluid. Arthritis Rheum. 1983;26(2):191-200.
    • 4
      Bowyer SL, Blane CE, Sullivan DB, Cassidy JT. Childhood dermatomyositis: factors predicting functional outcome and development of dystrophic calcification. J Pediatr. 1983;103(6):882-8.
    • 5
      Sogabe T, Silva CA, Kiss MHB. Clinical and laboratory characteristics of 50 children with dermato/polymyositis. Rev Bras Reumatol. 1996;36:351-9.
    • 6
      Sallum AM, Kiss MH, Sachetti S, Resende MB, Moutinho KC, Carvalho M de S, et al. Juvenile dermatomyositis: clinical, laboratorial, histological, therapeutical and evoluative parameters of 35 patients. Arq Neuropsiquiatr. 2002;60(4):889-99.
    • 7
      Ravelli A, Trail L, Ferrari C, Ruperto N, Pistorio A, Pilkington C, et al. Long-term outcome and prognostic factors of juvenile dermatomyositis: a multinational, multicenter study of 490 patients. Arthritis Care Res. 2010;62(1):63-72.
    • 8
      Eddy MC, Leelawattana R, McAlister WH, Whyte MP. Calcinosis universalis complicating juvenile dermatomyositis: resolution during probenecid therapy. J Clin Endocrinol Metab. 1997;82(11):3536-42.
    • 9
      Sewell JR, Liyanage B, Ansell BM. 1978 Calcinosis in juvenile dermatomyositis. Skeletal Radiol. 1978;3:137-43.
    • 10
      Muller DA, Winkelmann RK, Brunstig LA. Calcinosis in dermatomyositis. Arch Dermatol. 1959;79(6):669-73.
    • 11
      Weinel S, Callen JP. Calcinosis cutis complicating adult-onset dermatomyositis. Arch Dermatol. 2004;140(3):365-6.
    • 12
      Crowe WE. Dermatomyositis and polymyositis In: Gershwin ME, Robbins DL. Musculoskeletal diseases of children. New York: Grune & Stratton; 1983. p.113-37.
    • 13
      Pachman LM, Boskey AL. Clinical manifestations and pathogenesis of hydroxyapatite crystal deposition in juvenile dermatomyositis. Curr Rheumatol Rep. 2006;8(3):236-43.
    • 14
      Burgos-Vargas R, Vázquez-Mellado J, Gómez-Gordillo Y, Katona G. Clinical study of dermato/polymyositis with onset in childhood . Bol Med Hosp Infant Mex. 1987;44(8):463-70.
    • 15
      Miller LC, Michael AF, Kim Y. Childhood dermatomyositis. Clinical course and long-term follow-up. Clin Pediatr. 1987;26(11):561-6.
    • 16
      Pachman LM, Liotta-Davis MR, Hong DK, Kinsella TR, Mendez EP, Kinder JM, et al. TNFalpha-308A allele in juvenile dermatomyositis: association with increased production of tumor necrosis factor alpha, disease duration, and pathologic calcifications. Arthritis Rheum. 2000;43(10):2368-77.
    • 17
      Mukamel M, Horev G, Mimouni M. New insight into calcinosis of juvenile dermatomyositis: a study of composition and treatment. J Pediatr. 2001;138(5):763-6.
    • 18
      Pachman LM, Veis A, Stock S, Abbott K, Vicari F, Patel P, et al. Composition of calcifications in children with juvenile dermatomyositis: association with chronic cutaneous inflammation. Arthritis Rheum. 2006;54(10):3345-50.
    • 19
      Gunawardena H, Wedderbun LR, Chinoy H, Betteridge ZE, North J, Ollier WER, et al. Juvenile dermatomyositis research group, UK and Ireland Autoantibodies to a 140-kd protein in juvenile dermatomyositis are associated with calcinosis. Arthritis Rheumatism. 2009;60(6):1807-14.
    • 20
      Fisler RE, Liang MG, Fuhlbrigge RC, Yalcindag A, Sundel RP. Aggressive management of juvenile dermatomyositis results in improved outcome and decreased incidence of calcinosis. J Am Acad Dermatol. 2002;47(4):505-11.
    • 21
      Callen JP. Dermatomyositis. Lancet 2000; 355 (9197):53-7.
    • 22
      Cassidy JT, Petty RE. Dermatomyositis. In: Pediatric rheumatology, 3rd ed. Philadelphia: W.B. Saunders Co. 1995; 323-64.
    • 23
      Wilsher ML, Holdaway IM, North JD. Hypercalcemia during resolution of calcinosis in juvenile dermatomyositis. Brit Med J (Clin Res Ed). 1984;288(6427):1345.
    • 24
      Ostrov BE, Goldsmith DP, Eichenfield AH, Athreya BH. Hypercalcemia during the resolution of calcinosis universalis in juvenile dermatomyositis. J Rheumatol. 1991;18(11):1730-4.
    • 25
      Ambler GR, Chaitow J, Rogers M, McDonald DW, Ouvrier RA. Rapid improvement of calcinosis in juvenile dermatomyositis with alendronate therapy. J Rheumatol. 2005;32(9):1837-9.
    • 26
      Mukamel M, Horev G, Mimouni M. New insight into calcinosis of juvenile dermatomyositis: a study of composition and treatment. J Pediatr. 2001;138(5):763-6.
    • 27
      Mori H, Okada Y, Yamaoka K, Saito K, Tanaka Y. Marked improvement of calcinosis in adult dermatomyositis with etidronate therapy. J Bone Miner Metab. 2012;30(1):114-8.
    • 28
      Metzger AL, Singer FR, Bluestone R, Pearson CM. Failure of disodium etidronate in calcinosis due to dermatomyositis and scleroderma. N Engl J Med. 1974;291(24):1294-6.
    • 29
      Marco Puche A, Calvo Penades I, Lopez Montesinos B. Effectiveness of the treatment with intravenous pamidronate in calcinosis in juvenile dermatomyositis. Clin Exp Rheumatol. 2010;28(1):135-40.
    • 30
      Slimani S, Abdessemed A, Haddouche A, Ladjouze-Rezig A. Complete resolution of universal calcinosis in a patient with juvenile dermatomyositis using pamidronate. Jt, Bone Spine. 2010;77(1):70-2.
    • 31
      Skuterud E, Sydnes OA, Haavik TK. 1981 Calcinosis in dermatomyositis treated with probenecid. Scand J Rheumatol. 1981;10(2):92-4.
    • 32
      Ansell BM. Treatment of dermatomyositis. Arthritis Rheum. 1977;20:341.
    • 33
      Ansell BM. Management of polymyositis and dermatomyositis. Clin Rheum Dis. 1984;10(1):205-13.
    • 34
      Fuchs D, Fruchter L, Fishel B, Holtzman M, Yaron M. Colchicine suppression of local inflammation due to calcinosis in dermatomyositis and progressive systemic sclerosis. Clin Rheumatol. 1986;5(4):527-30.
    • 35
      Downey EC, Woolley MM, Hanson V. Required surgical therapy in the pediatric patient with dermatomyositis. Arch Surg. 1988;123(9):1117-20.
    • 36
      Ichiki Y, Akiyama T, Shimozawa N, Suzuki Y, Kondo N, Kitajima Y. An extremely severe case of cutaneous calcinosis with juvenile dermatomyositis, and successful treatment with diltiazem. Br J Dermatol. 2001;144(4):894-7.
    • 37
      Jiang X, Yi Q, Liu D, Wang S, Li L. A case of juvenile dermatomyositis with severe calcinosis and successful treatment with prednisone and diltiazem Int J Dermatol. 2011;50(1):74-7.
    • 38
      Oliveri MB, Palermo R, Mautalen C, Hübscher O. Regression of calcinosis during diltiazem treatment in juvenile dermatomyositis. J Rheumatol. 1996;23(12):2152-5.
    • 39
      Vinen CS, Patel S, Bruckner FE. Regression of calcinosis associated with adult dermatomyositis following diltiazem therapy. Rheumatology (Oxford). 2000;39(3):333-4.
    • 40
      Miyamae T, Sano F, Ozawa R, Imagawa T, Inayama Y, Yokota S. Efficacy of thalidomide in a girl with inflammatory calcinosis, a severe complication of juvenile dermatomyositis. Pediatr Rheumatol Online J. 2010;8(1):6.
    • 41
      Aihara Y, Mori M, Ibe M, Kuriyama T, Takahashi Y, Shimizu C, et al. A case of juvenile dermatomyositis with calcinosis universalis-remarkable improvement with aluminum hydroxide therapy. Ryumachi. 1994;34(5):879-84.
    • 42
      Nakagawa T, Takaiwa T. Calcinosis cutis in juvenile dermatomyositis responsive to aluminum hydroxide treatment. J Dermatol. 1993;20(9):558-60.
    • 43
      Wang WJ, Lo WL, Wong CK. Calcinosis cutis in juvenile dermatomyositis: remarkable response to aluminum hydroxide therapy. Arch Dermatol. 1988;124(11):1721-2.
    • 44
      Nassim JR, Connolly CK. Treatment of calcinosis universalis with aluminium hydroxide. Arch Dis Child. 1970;45(239):118-21.
    • 45
      Berger RG, Featherstone GL, Raasch RH, McCartney WH, Hadler NM. Treatment of calcinosis universalis with low-dose warfarin. Am J Med. 1998;83(1):72-6.
    • 46
      Matsuoka Y, Miyajima S, Okada N. A case of calcinosis universalis successfully treated with low-dose warfarin. J Dermatol. 1998;25(11):716-20.
    • 47
      Al-Mayouf SM, Alsonbul A, Alismail K. Localized calcinosis in juvenile dermatomyositis: successful treatment with intralesional corticosteroids injection. Int J Rheumatic Dis. 2010;13(3):e26-e28.
    • 48
      Jashin J, Bradie J, Metz MD. Calcinosis Cutis of Juvenile Dermatomyositis Treated with Incision and Drainage Dermatol Surg. 2008;34(4):575-7.
    • 49
      Vitale A, Delia G, La Torre F, Calcagno G, D Alcontres FS. Massive gluteal calcinosis in a 10-year-old girl with juvenile dermatomyositis: successful surgical management. Plast Reconstr Surg. 2009;124(6):456e-8e.
    • 50
      Riley P, McCann LJ, Maillard SM, Woo P, Murray KJ, Pilkington CA. Effectiveness of infliximab in the treatment of refractory juvenile dermatomyositis with calcinosis. Rheumatology (Oxford). 2008;47(6):877-80.
    • 51
      Arabshahi B, Silverman RA, Jones OY, Rider LG. Abatacept and sodium thiosulfate for treatment of recalcitrant juvenile dermatomyositis complicated by ulceration and calcinosis. J Pediatr. 2012;160(3):520-2.

    Update on the treatment of calcinosis in dermatomyositis Samuel Katsuyuki Shinjo*; Fernando Henrique Carlos de Souza

    Publication Dates

    • Publication in this collection
      30 Oct 2015
    • Date of issue
      Apr 2013

    History

    • Received
      02 Feb 2012
    • Accepted
      13 Dec 2012
    Sociedade Brasileira de Reumatologia Av Brigadeiro Luiz Antonio, 2466 - Cj 93., 01402-000 São Paulo - SP, Tel./Fax: 55 11 3289 7165 - São Paulo - SP - Brazil
    E-mail: sbre@terra.com.br