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Figure.  Manifestations of Calcinosis Cutis in Chronic Graft-Versus-Host Disease
Manifestations of Calcinosis Cutis in Chronic Graft-Versus-Host Disease

CT indicates computed tomographic imaging. A, Thin sheets of superficial calcification with punctate calcium deposits in an area of sclerosis resembling pseudoxanthoma elasticum. B, Calcified nodules forming plaques on the lateral thigh with accompanying sclerotic-type chronic skin graft-versus-host disease. C, Extrusion of chalky white calcium from areas of ulceration. D, Circumferential sheetlike calcification with ulceration on the bilateral lower extremities. E, Three-dimensional reconstruction of a CT study details extensive periulcer soft tissue calcification.

Table.  Patient Characteristics
Patient Characteristics
Three-dimensional video reconstruction of computed tomographic study detailing extensive lower extremity calcinosis
1.
Bolognia  JL, Schaffer  JV, Cerroni  L.  Dermatology. Elsevier Health Sciences; 2017.
2.
Hymes  SR, Alousi  AM, Cowen  EW.  Graft-versus-host disease: part I: pathogenesis and clinical manifestations of graft-versus-host disease.   J Am Acad Dermatol. 2012;66(4):515.e1-515.e18. doi:10.1016/j.jaad.2011.11.961PubMedGoogle ScholarCrossref
3.
Man  J, Kalisiak  M, Birchall  IWJ, Salopek  TG.  Chronic cutaneous graft-versus-host disease manifesting as calcinosis cutis universalis on a background of widespread sclerodermatoid changes.   J Cutan Med Surg. 2010;14(5):249-253. doi:10.2310/7750.2010.09034PubMedGoogle ScholarCrossref
4.
Lipshutz  GH, Chew  FS.  Calcinosis cutis related to sclerodermatous chronic graft versus host disease.   Radiol Case Rep. 2015;3(4):242. doi:10.2484/rcr.v3i4.242PubMedGoogle ScholarCrossref
5.
Quaranta  S, Shulman  H, Ahmed  A,  et al.  Autoantibodies in human chronic graft-versus-host disease after hematopoietic cell transplantation.   Clin Immunol. 1999;91(1):106-116. doi:10.1006/clim.1998.4666PubMedGoogle ScholarCrossref
6.
Patriarca  F, Skert  C, Sperotto  A,  et al.  The development of autoantibodies after allogeneic stem cell transplantation is related with chronic graft-vs-host disease and immune recovery.   Exp Hematol. 2006;34(3):389-396. doi:10.1016/j.exphem.2005.12.011PubMedGoogle ScholarCrossref
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    Research Letter
    May 20, 2020

    Calcinosis Cutis in the Setting of Chronic Skin Graft-Versus-Host Disease

    Author Affiliations
    • 1Department of Dermatology, MedStar Washington Hospital Center/Georgetown University Hospital, Washington, DC
    • 2Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland
    • 3Washington University School of Medicine in St Louis, Division of Dermatology, St Louis, Missouri
    • 4Perelman School of Medicine, Department of Dermatology, University of Pennsylvania, Philadelphia
    • 5Perelman School of Medicine, Department Medicine, University of Pennsylvania, Philadelphia
    • 6Editor, JAMA Dermatology
    • 7Division of Environmental Autoimmunity Group, National Institute of Environmental Health Sciences, National Institutes of Health, Bethesda, Maryland
    • 8Immune Deficiency Cell Therapy Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
    JAMA Dermatol. 2020;156(7):814-817. doi:10.1001/jamadermatol.2020.1157

    Calcinosis cutis is a recognized sequela of systemic sclerosis (SS).1 Systemic sclerosis and sclerotic-type chronic skin graft-versus-host disease (ScGVHD) share several clinical and histologic features; however, high-titer antibodies specifically associated with SS are not typically found in ScGVHD, and the fibrotic features in ScGVHD more closely resemble morphea and eosinophilic fasciitis.2 Whereas calcinosis is well described in SS, there are only 2 reports of calcinosis in the setting of chronic graft-versus-host disease (cGVHD), to our knowledge.3,4 We sought to identify patients with cGVHD with calcinosis to explore predisposing factors and clinical features.

    Methods

    We identified 7 patients with GVHD-associated calcinosis cutis (GVHD-CC) from 3 academic dermatology programs. Data were collected retrospectively from medical chart review. Patients evaluated at the National Institutes of Health were evaluated under a research protocol (04-C-0281) approved by the National Institutes of Health institutional review board. The institutional review board of the University of Pennsylvania and Washington University School of Medicine at St Louis did not require institutional review board approval for the contribution of single cases. The deidentified data are presented as a retrospective case series collected from 2014 to 2018.

    Results

    On average, calcinosis was diagnosed 7.5 years after transplantation (range, 1-13 years) and 5.5 years after the onset of cGVHD (range, 3 months-12 years). Osteoporosis or osteopenia were the most common comorbidities and were present in 5 patients. In all included patients, ScGVHD preceded calcinosis and 6 patients had fascial cGVHD involvement.

    All patients manifested papular or nodular calcification, which was followed by the development of sheets of calcification in 4 patients. Five patients had antecedent ulceration and 6 had active ScGVHD at the time calcinosis was identified. Two patients had chalky white fluid extrusion. The most common site of calcinosis was the lower extremities (5 patients) (Figure) (Video). Calcinosis progressed in 3 patients and remained stable in 4. Contracture, immobility, and considerable pain were reported in 5 patients.

    Other than a slightly decreased mean 25-hydroxy vitamin D level (28 ng/mL; reference range, >29 ng/mL), there were no significant abnormalities in calcium, phosphorus, parathyroid hormone, or creatinine levels, consistent with dystrophic calcification. Four patients had strongly positive antinuclear antibody titers (2 patients not tested) (Table). One patient had a strongly positive anticentromere antibody (>10 units; normal range, <1.0 units).

    Systemic complications included heart failure owing to cardiac calcinosis in 1 patient and restrictive lung disease due to sclerosis/calcinosis of the chest wall in another. Topical sodium thiosulfate (STS) was the most commonly used treatment (4 patients) but was followed by minimal improvement in 2 cases, stabilization in 1 patient, and progression in 1 patient.

    Discussion

    The pathogenesis of cutaneous calcinosis in autoimmune disease is unclear. Sclerotic-type chronic skin graft-versus-host disease shares many clinical features with SS, suggesting a common pathway leading to calcinosis. The 7 cases described herein are similar to 2 previously reported cases in the literature, including a long latency period (12 and 14 years) and antecedent ScGVHD.3,4 The lower extremities are a common site of skin sclerosis in ScGVHD and were the most common location for calcinosis in these patients. Joint range-of-motion restriction was frequently observed and calcinosis likely worsened existing functional limitations caused by ScGVHD.

    Elevated antinuclear antibody (ANA) was detected in 4 of the 5 patients who underwent testing, which appears to be higher than in other reports in cGVHD populations. Although ANA titers do not correlate with specific cutaneous features,5,6 elevated ANA in the setting of ScGVHD may be a risk factor for GVHD-CC. One patient had strongly positive anticentromere antibodies, which are seen in limited SS, a condition associated with calcinosis cutis. Further exploration of autoantibodies associated with calcinosis in cGVHD, particularly anticentromere antibodies, is warranted.

    In addition to systemic therapy for cGVHD, treatment with STS for calcinosis yielded mixed results. Success with diltiazem has been reported,3 but failed to benefit 2 patients in this series. The rarity of GVHD-CC makes drawing conclusions difficult. We hope to increase awareness of GVHD-CC because subtle calcinosis may be overlooked, particularly in patients with long-standing skin sclerosis.

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    Article Information

    Accepted for Publication: March 17, 2020.

    Corresponding Author: Edward W. Cowen, MD, MHSc, National Institutes of Health, Dermatology Branch, 10 Center Dr, MSC 1908, Bldg 10, Room 12N240A, Bethesda, MD 20892(cowene@mail.nih.gov).

    Published Online: May 20, 2020. doi:10.1001/jamadermatol.2020.1157

    Author Contributions: Dr Cowen had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Saardi and Rosenstein contributed equally to the work.

    Concept and design: Saardi, Rosenstein, Anadkat, Schiffenbauer, Pavletic, Cowen.

    Acquisition, analysis, or interpretation of data: All authors.

    Drafting of the manuscript: Saardi.

    Critical revision of the manuscript for important intellectual content: All authors.

    Statistical analysis: Saardi.

    Administrative, technical, or material support: Anadkat, Pavletic.

    Supervision: Anadkat, Pavletic, Cowen.

    Conflict of Interest Disclosures: None reported.

    Funding/Support: This research was supported in part by the Intramural Research Program of the National Cancer Institute, National Institute of Arthritis and Musculoskeletal and Skin Diseases, and National Institute of Environmental Health Sciences.

    Role of the Funder/Sponsor: The Intramural Research Program of the National Cancer Institute, National Institute of Arthritis and Musculoskeletal and Skin Diseases, and National Institute of Environmental Health Sciences played no part in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Additional Contributions: We thank the patients for granting permission to publish this information. We also thank Marcus Chen, MD, National Heart, Lung, and Blood Institute, National Institutes for Health, for assistance with computed tomographic imaging and Dominique C. Pichard, MD, Dermatology Branch, National Institutes for Health, for her help in reviewing the final manuscript.

    Disclaimer: Dr Micheletti is an Images in Dermatology Editor and Dr Cowen is a member of the Editorial Board of JAMA Dermatology, but they had no role in the decision to accept this article for publication.

    References
    1.
    Bolognia  JL, Schaffer  JV, Cerroni  L.  Dermatology. Elsevier Health Sciences; 2017.
    2.
    Hymes  SR, Alousi  AM, Cowen  EW.  Graft-versus-host disease: part I: pathogenesis and clinical manifestations of graft-versus-host disease.   J Am Acad Dermatol. 2012;66(4):515.e1-515.e18. doi:10.1016/j.jaad.2011.11.961PubMedGoogle ScholarCrossref
    3.
    Man  J, Kalisiak  M, Birchall  IWJ, Salopek  TG.  Chronic cutaneous graft-versus-host disease manifesting as calcinosis cutis universalis on a background of widespread sclerodermatoid changes.   J Cutan Med Surg. 2010;14(5):249-253. doi:10.2310/7750.2010.09034PubMedGoogle ScholarCrossref
    4.
    Lipshutz  GH, Chew  FS.  Calcinosis cutis related to sclerodermatous chronic graft versus host disease.   Radiol Case Rep. 2015;3(4):242. doi:10.2484/rcr.v3i4.242PubMedGoogle ScholarCrossref
    5.
    Quaranta  S, Shulman  H, Ahmed  A,  et al.  Autoantibodies in human chronic graft-versus-host disease after hematopoietic cell transplantation.   Clin Immunol. 1999;91(1):106-116. doi:10.1006/clim.1998.4666PubMedGoogle ScholarCrossref
    6.
    Patriarca  F, Skert  C, Sperotto  A,  et al.  The development of autoantibodies after allogeneic stem cell transplantation is related with chronic graft-vs-host disease and immune recovery.   Exp Hematol. 2006;34(3):389-396. doi:10.1016/j.exphem.2005.12.011PubMedGoogle ScholarCrossref
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