Paraproteinemia-Associated Scleredema Treated Successfully

Letters

Corresponding Author: Natalie Z. Sun, MD, Department of Dermatology, Figure 2. Biopsy Specimen Taken From the Patient’s Groin University Hospitals Case Medical Center, 11100 Euclid Ave Lakeside 3500, Cleveland, OH 44106 ([email protected]). Published Online: April 30, 2014. doi:10.1001/jamadermatol.2013.8679. Conflict of Interest Disclosures: None reported. 1. Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy. A newly recognized benign clinicopathological entity. Arch Pathol. 1969;87(1): 63-70. 2. Foucar E, Rosai J, Dorfman R. Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease): review of the entity. Semin Diagn Pathol. 1990;7(1):19-73. 3. Frater JL, Maddox JS, Obadiah JM, Hurley MY. Cutaneous Rosai-Dorfman disease: comprehensive review of cases reported in the medical literature since 1990 and presentation of an illustrative case. J Cutan Med Surg. 2006;10(6): 281-290. 4. Nasseri E, Belisle A, Funaro D. Rosai-Dorfman disease treated with methotrexate and low-dose prednisone: case report and review of the literature. J Cutan Med Surg. 2012;16(4):281-285.

A dense infiltrate of lymphocytes, neutrophils, and large histocytes with 5. Scheel MM, Rady PL, Tyring SK, Pandya AG. Sinus histiocytosis with massive abundant cytoplasm; histiocytes show emperipolesis of lymphocytes lymphadenopathy: presentation as giant granuloma annulare and detection of (hematoxylin-eosin, original magnification ×40). human herpesvirus 6. J Am Acad Dermatol. 1997;37(4):643-646. 6. Gebhardt C, Averbeck M, Paasch U, et al. A case of cutaneous Rosai-Dorfman disease refractory to imatinib therapy. Arch Dermatol. 2009;145(5):571-574. weekly for the next 4 months, and patient showed a com- 7. Bassis AV, Fairley JA, Ameln RT, Swick BL. Cutaneous Rosai-Dorfman disease plete clinical response. During this time, she also received sev- following pneumococcal vaccination. J Am Acad Dermatol. 2011;65(4):890-892. eral intralesional Kenalog injections to the larger nodules of the face and groin. Paraproteinemia-Associated Scleredema Treated Successfully With Intravenous Immunoglobulin Discussion | There have been a variety of treatment techniques Scleredema is a fibromucinous connective tissue disease used for CRDD, including cryotherapy, surgical excision, irra- characterized by symmetric, nonpitting edema and indura- diation, oral corticosteroids, dapsone, thalidomide, and tion of the face, neck, and trunk. Although the pathogenesis isotretinoin. To our knowledge, the use of methotrexate alone remains elusive, associations with infection, diabetes or in combination with other agents has been reported in 9 mellitus, and paraproteinemia have been established.1 cases of systemic Rosai-Dorfman, and a complete to partial re- Paraproteinemia-associated scleredema is typically charac- sponse was reported in most cases.4 By contrast, methotrex- terized by a progressive course, for which no standard ate therapy has been reported in only 3 cases of CRDD, and par- therapeutic protocol exists.2 To our knowledge, the patient tial or no improvement was reported.3,5,6 However, in all of described herein represents the first reported case of scler- these cases, the eruption had already been present for well over edema with paraproteinemia successfully treated with a year. In our patient, a lack of response to prednisone, preex- intravenous immunoglobulin (IVIG). isting diabetes, and significant disease burden prompted the choice of low-dose methotrexate, to which a complete clini- Report of a Case | A woman in her 40s presented with a 2-year cal response was seen over 11 months. history of progressive erythema and induration of the face, Though the exact cause of CRDD remains unknown, the neck, and upper trunk. She denied a history of preceding in- presence of Epstein-Barr virus, human herpesvirus 6 by poly- fection or diabetes mellitus. Physical examination revealed ery- 7 merase chain reaction, and reported eruption after vaccination thema, brawny edema, and induration of the face, neck, up- with spontaneous remission over months to years suggests that per trunk, and upper arms. There was significant limitation of CRDD is a benign reactive process involving a particular pat- neck flexion, extension, and lateral rotation as well as shoul- tern of immune dysregulation. Early diagnosis remains a chal- der abduction and internal rotation (Figure, A). The patient de- lenge in CRDD owing to its nonspecific clinical manifesta- nied difficulty swallowing or restricted breathing. tions, including variable numbers of papules, nodules, plaques, A skin biopsy from the upper back revealed dermal thick- or tumors. Timely diagnosis and initiation of methotrexate ening with separation of enlarged collagen bundles by Alcian therapy may be key to effecting a rapid clinical remission while blue–positive mucin deposition, consistent with a diagnosis this disease remains in its active phase. of scleredema. Findings from a complete metabolic panel, complete blood cell count, and assays for fasting glucose and gly- Natalie Z. Sun, MD cosylated hemoglobin levels were within normal limits. Se- Jessica Galvin, DO rum protein electrophoresis revealed an abnormal globulin Kevin D. Cooper, MD peak. Immunofixation confirmed an IgA κ-band, and serum IgA level was elevated (933 mg/dL; normal range, 140-260 mg/ Author Affiliations: Department of Dermatology, University Hospitals Case Medical Center, Case Western Reserve University School of Medicine, dL). Investigation for multiple myeloma was negative, with nor- Cleveland, Ohio. mal findings on skeletal survey, bone marrow biopsy, and urine

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Discussion | Although the efficacy of IVIG has been established Figure. Limited Range of Motion in a Woman With Scleredema in a variety of inflammatory diseases, its mechanism of ac-

A tion remains elusive. It may exert immunomodulatory and anti- inflammatory effects by suppression of proinflammatory cy- tokines, downregulation of adhesion molecules and chemokine receptors, and neutralization of superantigens.5 Treatment of scleredema, regardless of subtype, remains a challenge. Variable improvement has been reported with pho- totherapy, systemic corticosteroids, methotrexate, cyclospor- ine, ECP, and radiation.1 IVIG has had reported success in diabetes-associated and streptococcal-associated scleredema, in 1 case each. The rapid response to IVIG in this patient with IgA-κ paraproteinemia further supports the potential efficacy of IVIG treatment for scleredema. Despite marked clinical improve-

B ment, the patient’s IgA levels did not significantly decrease in concordant fashion with IVIG treatment. This finding suggests that the mechanism of action of IVIG resulting in therapeutic benefit in paraproteinemia-associated scleredema may be similar to that seen in scleredema associated with other causes rather than from directly lowering the paraprotein level. Additional investigation is necessary to further define the role of IVIG in the treatment of scleredema.

A. Brooke Eastham, MD Alisa N. Femia, MD Nicole F. Velez, MD Hedy P. Smith, MD A, This image demonstrates marked restriction in shoulder abduction before Ruth Ann Vleugels, MD, MPH intravenous immunoglobulin (IVIG) therapy. B, This image demonstrates significant improvement in shoulder abduction following IVIG therapy. Author Affiliations: Harvard Combined Dermatology Residency Program, Boston, Massachusetts (Eastham, Velez); Department of Dermatology, Brigham protein electrophoresis. A diagnosis of scleredema associ- and Women’s Hospital, Boston, Massachusetts (Eastham, Femia, Velez, Vleugels); Harvard Medical School, Boston, Massachusetts (Eastham, Femia, ated with IgA-κ paraproteinemia was established. Velez, Vleugels); Division of Hematology, Department of Medicine, Tufts Initial treatment with thalidomide was unsuccessful. The Medical School, Boston, Massachusetts (Smith). patient then completed a 1-year regimen of weekly to bi- Corresponding Author: Ruth Ann Vleugels, MD, MPH, Autoimmune Skin monthly extracorporeal photophoresis (ECP) with initial suc- Disease Center, Department of Dermatology, Brigham and Women’s Hospital, 221 Longwood Ave, Boston, MA 02115 ([email protected]). cess. However, therapeutic response to ECP plateaued, and eventually skin induration worsened and neck and shoulder Published Online: May 21, 2014. doi:10.1001/jamadermatol.2013.8835. range of motion (ROM) became more restricted. Interest- Conflict of Interest Disclosures: None reported. ingly, the patient subsequently reported improvement in symp- Funding/Support: Dr Vleugels’ career has been supported by a Medical toms after a flulike illness. For this reason, a 6-week course of Dermatology Career Development Award from the Dermatology Foundation. pegylated-interferon was administered by her hematologist, Role of the Sponsor: The Dermatology Foundation had no role in the design but this resulted in no benefit. and conduct of the study; collection, management, analysis, and interpretation Based on 2 recent publications demonstrating the effi- of the data; preparation, review, or approval of the manuscript; and decision to cacy of IVIG for scleredema associated with diabetes3 and strep- submit the manuscript for publication. tococcal infection,4 monthly IVIG treatment was initiated at Additional Information: Dr Femia is now with the Department of Dermatology, New York University Medical Center, New York. a dose of 2 g/kg over 2 consecutive days. After just 2 cycles, the 1. Bowen AR, Smith L, Zone JJ. Scleredema adultorum of Buschke treated with patient noted significant improvement. After 5 cycles, her ROM radiation. Arch Dermatol. 2003;139(6):780-784. continued to improve, as evident on clinical examination and 2. Stables GI, Taylor PC, Highet AS. Scleredema associated with careful evaluation of high-quality photographs of shoulder and paraproteinaemia treated by extracorporeal photopheresis. Br J Dermatol. neck ROM before and after IVIG therapy (Figure). Shoulder ab- 2000;142(4):781-783. duction improved from approximately 140 to 170 degrees over 3. Barde C, Masouyé I, Saurat JH, Le Gal FA. Scleroedema adultorum Buschke in this time period. Serum IgA level after 6 monthly cycles of IVIG a diabetic subject: intravenous immunoglobulin therapy [in French]. Ann Dermatol Venereol. 2009;136(4):360-363. therapy remained elevated, though less than the initial mea- 4. Aichelburg MC, Loewe R, Schicher N, et al. Successful treatment of surement (841 mg/dL). At the patient’s most recent follow-up poststreptococcal scleredema adultorum Buschke with intravenous evaluation, the patient continued to receive monthly IVIG treat- immunoglobulins. Arch Dermatol. 2012;148(10):1126-1128. ments with ongoing improvement in skin induration and sta- 5. Gelfand EW. Intravenous immune globulin in autoimmune and inflammatory bilized ROM. diseases. N Engl J Med. 2012;367(21):2015-2025.

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