Calcinosis Cutis in a Patient With Eosinophilia-Myalgia Syndrome: Case Report

Elizabeth Smith, MD; Marsha Gordon, MD; Mark Lebwohl, MD

Eosinophilia-myalgia syndrome (EMS) often is a and neuropsychiatric disease. Eighty-seven percent disabling disorder caused by the consumption of patients with EMS have cutaneous manifestations of contaminated L-tryptophan. Affected patients ranging from alopecia to eosinophilic fasciitis or dif- present with an array of symptoms, includ- fuse or localized .3,4 To date, the literature ing cutaneous manifestations, peripheral eosino- documents no patients with EMS developing calci- philia, myalgias, and long-term neurocognitive nosis cutis. We report one case of cutis in disability. This article is the first reported case a patient with EMS. The patient had calcinosis of a patient with EMS who developed calcinosis in areas of sclerosis and induration on the elbows, cutis. While many long-term sequelae of EMS are forearms, hips, and buttocks. This finding pre- reported in the literature, there are no reports of sents a therapeutic challenge to physicians managing the development of dystrophic in patients with EMS. these patients. The calcinosis cutis in this patient with EMS may represent a new manifestation of Case Report EMS that has not been documented to date. If A 78-year-old white woman with a history of EMS more patients with EMS develop calcinosis cutis, diagnosed in 1990 presented with a chief complaint it will present a therapeutic challenge to the phy- of “pebbles under my skin.” The lesions first appeared sicians managing these patients. on the extensor surfaces of the elbows and forearms Cutis. 2006;77:361-364. and progressed to her hips and buttocks. She was told that she had subcutaneous calcium after a wrist radiograph in 1999, but the hard papules emerged 3 years after the radiograph. Her digits were not osinophilia-myalgia syndrome (EMS), first affected. These hard nodules were located in areas described in 1990,1 is a systemic illness charac- of residual sclerosed skin secondary to her EMS. terized by peripheral eosinophilia of greater than She complained that the nodules caused a moder- E 3 1000 cells/mm , severe myalgias, and the exclusion of ate amount of pain, and they often ulcerated and infectious or neoplastic processes that may account failed to heal. The ulcerated areas occasionally oozed for these findings.2 Belongia et al2 conducted epide- serosanguinous exudate, and her clothing often was miologic analysis of patients presenting with EMS stained by the discharge. She tried silver sulfadiazine and found L-tryptophan, specifically L-tryptophan cream with no relief. She denied Raynaud phenom- manufactured in one plant, to be the etiologic factor. enon, past or present. She had no family history of The clinical manifestations vary but often include rheumatic disease or calcinosis cutis. cutaneous abnormalities, severe myalgias, neuropa- Her medications included alendronate sodium thies, neuromuscular abnormalities, cardiopulmonary 70 mg/wk, raloxifene hydrochloride 60 mg/d, and disease, gastrointestinal disease, articular pathology, calcium citrate 400 mg twice daily for osteoporosis. She had been taking calcium citrate for at least Accepted for publication November 2, 2004. 5 years, and she started taking alendronate sodium From the Department of Dermatology, Mount Sinai Medical Center, in January 1998. Raloxifene hydrochloride was New York, New York. added to her treatment regimen in January 2000. The authors report no conflict of interest. Reprints: Mark Lebwohl, MD, Department of Dermatology, She had no known drug allergies. Mount Sinai Medical Center, One Gustave L. Levy Place, Box 1048, Her past medical history indicated EMS and New York, NY 10029. osteoporosis. She was diagnosed with EMS after

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Figure 1. A pitting with residual chalky residue in an area of sclerosed skin on the forearm. Hard discrete 2- to 5-mm papules surround the scar.

Figure 2. Patchy extending from subcutaneous tissue to the dermis.

developing severe myalgias, skin puckering, non- 5-mm nodules were scattered. The sclerosed plaques pitting edema, and a peripheral eosinophilia of on the hips contained ulceration with a dark sero- 46%. She had a cutaneous biopsy of an area of skin sanguinous exudate. She also had areas of induration puckering that showed eosinophilic fasciitis. After in the pretibial area bilaterally, but these sclerosed further questioning, we learned that she had taken areas did not contain hard nodules. vitamins that contained L-tryptophan. At the time Laboratory investigation revealed her complete of diagnosis, she also suffered from alopecia and blood count, blood chemistry, serum thyrotropin, peripheral neuropathy. Her eosinophilia, alopecia, and liver function tests to be within reference and neuropathy resolved with oral corticosteroids, range. Antinuclear antibodies and scleroderma but she continued to suffer from myalgias and antibody–70 were within reference range. Radio- cutaneous sclerosis and induration of the forearms, graphic examination of her pelvis revealed patchy lower legs, and lateral hips. calcifications in the subcutaneous tissue (Figure 2). Physical examination revealed indurated plaques on the extensor surfaces of the elbows, forearms Comment (Figure 1), hips, and buttocks. Within the scle- EMS was first recognized in 1990 when approxi- rosed and indurated skin, hard and chalky 2- to mately 1500 patients who had taken L-tryptophan

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were found to have a constellation of clinical mani- sclerodermatous skin disease, to date, this case festations.1 After a mean latent period of 84 days, represents the first documentation of such changes patients developed an acute syndrome manifested by occurring in a patient with EMS. sudden severe myalgias, fever, cough, and dyspnea; There are 4 types of calcinosis cutis: metastatic, a faint maculopapular rash; and cutaneous edema.3 idiopathic, iatrogenic, and dystrophic.12 Metastatic Eosinophil counts rose to a mean of 6.3109/L.3 calcification occurs when there is a defect in cal- After a period of weeks to months, most of the early cium and phosphate regulation or metabolism, symptomatology resolved and eosinophil counts which results in calcium deposition in normal tis- returned to baseline. However, most patients con- sue. In this case, calcification often affects the blood tinued to suffer from severe myalgias and peripheral vessels, kidneys, gastric mucosa, and lungs.12 When neuropathies, and skin thickening or scleroderma- no disorder of calcium or phosphate metabolism tous changes were seen in 33% of patients.5 Months is identified and calcium deposits are present in to years later, up to 62% of patients with EMS normal tissue, the cause is classified as idiopathic.12 developed neurocognitive dysfunction.6 Iatrogenic calcification is a recognized complication Kaufman et al5 documented cutaneous mani- of intravenous calcium chloride administration as festations in 26 patients (87%) with EMS. At well as calcium gluconate administration. Iatrogenic presentation, these patients generally complained calcification also occurs in areas of trauma and in of faint erythematous macular eruptions, nonpit- some patients with a history of extensive contact ting edema, alopecia, and pruritus. In one series, with calcium salts.12 Generally, the anatomic loca- 13 patients (43%) initially complained of a diffuse ery- tion of iatrogenic calcification is on an extremity, thematous macular rash on the trunk and 3 patients proximal or distal to the intravenous catheter.13 (10%) complained of multiple ecchymoses. These , the most common cause manifestations resolved over a period of months, but of calcinosis cutis, occurs in patients with normal 16 patients (53%) developed nonpitting edema.5 calcium and phosphorus levels who have areas of Three to 6 months after patients discontinued tissue damage like with dermatomyositis or connec- taking L-tryptophan, chronic skin changes devel- tive tissue disease.12 oped, resembling scleroderma. Nine patients (33%) In our patient, the sclerotic areas of skin second- developed induration and puckering of the skin, ary to EMS provided the tissue damage for dystro- accompanied by skin thickening. Although the find- phic calcification.14 The mechanism of calcium ings resembled those of eosinophilic fasciitis, only deposition is poorly understood, but it presents a 4 patients (13%) were diagnosed with eosinophilic therapeutic challenge for the physician. The cutane- fasciitis as a component of their EMS. The remain- ous mineralization is painful and the tissue affected ing patients presented with cutaneous manifesta- often ulcerates and fails to heal. Multiple medical tions resembling diffuse or localized scleroderma. therapies have been used including calcium channel Thus, up to 15 patients (50%) with EMS devel- blockers and colchicine, but success has been lim- oped eosinophilic fasciitis and/or sclerodermatous ited. A low calcium diet may be helpful.14 skin changes.5 Osteoporosis is the most common clinical skeletal Pseudosclerodermas are skin diseases of unre- disorder.15 Women primarily are affected as bone lated etiology with induration of the skin resem- mass decreases with age. Patients generally do not bling scleroderma, either localized or systemic. have any clinical manifestations until there is a Histologically, the pseudosclerodermas have marked fracture, most commonly an asymptomatic vertebral dermal or subcutaneous fat fibrosis.7 The histology compression fracture. The diagnosis of osteoporosis of EMS patients with skin induration and thicken- is made if the patient has low bone mass, microar- ing typically reveals cutaneous and subcutaneous chitectural disruption of bone, and increased skel- fibrosis with marked collagen deposition. The der- etal fragility. In the case of osteoporosis, the bone mal thickening and collagen infiltration of chronic density of the patient is more than 2.5 SDs below EMS has been described as identical to scleroderma the mean value of young adults of the same sex and or .8 Dermal fibroblasts in patients with race. In clinical practice, microarchitecture of bone EMS synthesize collagen at a rate of up to 3 times is not routinely assessed, because it requires a bone normal controls.9 biopsy. Often, low bone mass alone or a history of Up to 10% of patients with systemic sclero- a nontraumatic fracture with no other explanation sis develop calcinosis cutis, and there have been confirms the clinical impression of osteoporosis. reports of patients with localized scleroderma devel- Laboratory investigations should aim to exclude sec- oping calcinosis and subsequent ulceration.7,10,11 ondary causes of osteoporosis, which include osteo- Despite the histologic clinical resemblance to malacia, hyperthyroidism, hyperparathyroidism, renal

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failure, and malignancy. Expert opinion currently 4. Gordon ML, Lebwohl MG, Phelps RG, et al. Eosinophilic recommends that all patients with osteoporosis have fasciitis associated with tryptophan ingestion. Arch Dermatol. blood chemistry, complete blood count, and serum 1991;127:217-220. thyrotropin measured15; all were within reference 5. Kaufman LD, Seidman RJ, Phillips ME, et al. Cutaneous range in our patient. manifestations of L-tryptophan-associated eosinophilia- Our patient’s osteoporosis complicated her treat- myalgia syndrome: a spectrum of sclerodermatous skin ment plan; the cessation of calcium citrate, alen- disease. J Am Acad Dermatol. 1990;23(6 pt 1):1063-1069. dronate sodium, and raloxifene hydrochloride could 6. Greenfield BM, Mayer JW, Sibbitt RR. The eosinophilia- result in further bone density loss and subsequent myalgia syndrome and the brain. Ann Intern Med. fractures. The literature does not report the devel- 1991;115:159-160. opment of calcinosis cutis in patients taking alen- 7. Lebwohl M. Difficult Diagnosis in Dermatology. New York, dronate sodium or raloxifene hydrochloride, and a NY: Churchill Livingston; 1998. small pilot study conducted by Hill et al16 found that 8. Lin JD, Phelps RG, Gordon ML, et al. Pathologic mani- the rate of coronary arterial calcification was not festations of the eosinophilia myalgia syndrome: analysis affected by alendronate sodium. of 11 cases. Hum Pathol. 1992;23:429-437. Robertson et al17 investigated the use of mino- 9. Hitraya EG, Jiminez SA, Ludwicka A, et al. Increased cycline as therapy for calcinosis cutis patients activity of the alpha 1(I) procollagen promoter in skin with limited cutaneous systemic sclerosis. Eight fibroblasts from patients with chronic eosinophilia-myalgia of 9 patients had a reduction in the frequency of syndrome. Int J Biochem Cell Biol. 1997;29:134-141. ulceration and inflammation associated with the 10. Yamamoto A, Morita A, Shintani Y, et al. Localized calcium deposits, and the deposits decreased in linear scleroderma with cutaneous calcinosis. J Dermatol. size. However, the drug had the unanticipated side 2002;29:112-114. effect of making the calcium deposits bluish-black, 11. Vereecken P, Stallenberg B, Tas S, et al. Ulcerated dystro- which may be intolerable for patients.17 Thus, the phic calcinosis cutis secondary to localized linear sclero- only treatment option in many cases is surgical derma. Int J Clin Pract. 1998;52:593-594. removal of affected areas. 12. Walsh JS, Fairley JA. Cutaneous mineralization and ossi- In summary, this case of calcinosis cutis may fication. In: Freedberg TB, Eisen AZ, Wolff K, et al, represent a late sequelae of EMS, which has not eds. Fitzpatrick’s Dermatology in General Medicine. 5th ed. been previously documented. This finding presents New York, NY: McGraw-Hill; 1999:1829-1833. a therapeutic challenge to the physicians managing 13. Kagen MH, Bansal MG, Grossman M. Calcinosis cutis fol- patients. Physicians still are trying to determine how lowing the administration of intravenous calcium therapy. these patients are best managed and what workup Cutis. 2000;65:193-194. is required. 14. Ogretmen Z, Akay A, Bicakci C, et al. Calcinosis cutis universalis. J Eur Acad Dermatol Venereol. 2002;16: REFERENCES 621-624. 1. Hertzman PA, Blevins WL, Mayer J, et al. Association of 15. Rosen HN, Drenzer MK. Clinical manifestations and the eosinophilia myalgia syndrome with the ingestion of diagnosis of osteoporosis. Available at: www.uptodate.com. tryptophan. N Engl J Med. 1990;322:869-873. Accessed September 2003. 2. Belongia EA, Hedberg CW, Gleich GJ, et al. An investiga- 16. Hill JA, Goldin JG, Gjertson D, et al. Progression of coro- tion of the cause of eosinophilia-myalgia syndrome associ- nary artery calcification in patients taking alendronate for ated with tryptophan use. N Engl J Med. 1990;323:992-993. osteoporosis. Acad Radiol. 2002;9:1148-1152. 3. Freundlich B. Pathogenesis and clinical manifestations of 17. Robertson LP, Marshall RW, Hickling P. Treatment of cuta- the eosinophilia-myalgia syndrome. Available at: www. neous calcinosis in limited systemic sclerosis with minocy- uptodate.com. Accessed September 2003. cline. Ann Rheum Dis. 2003;62:267-269.

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