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Journal of Hematology

Case Report

Volume 5, Number 3, September 2016, pages 113-115

IgG4-Related Disorder Masquerading as an Indurated Skin Lesion

IgG4-related disorder (IgG4-RD) mimics several malignant, infectious, and inflammatory conditions [1]. IgG4-RD may present as Mikulicz’s disease, autoimmune pancreatitis, hypophysitis, Riedel thyroiditis, interstitial pneumonitis, interstitial nephritis, prostatitis, lymphadenopathy, retroperitoneal fibrosis, inflammatory aortic aneurysm, and other inflammatory states [2]. Until now, IgG4-RD has been considered rare in the West and exclusive to the Japanese and Korean population [3]. The exact pathological role of IgG4 antibodies underlying this disorder is not yet defined. The existence of the IgG4 subclass, with enhanced production of anti-inflammatory factors including production of IL-10 and other anti-inflammatory cytokines may help the immune system to dampen inappropriate inflammatory response, and IgG4 in IgG4-RD may not be responsible for the inflammatory reaction [4]. The identification of an antigenic trigger, the implications of IgG4 antibodies for pathophysiology and the precise immunological mechanisms leading to fibrosis is still elusive [5].

Here we present the case of a 55-year-old African-American female with past medical history significant for diabetes mellitus, hypertension, coronary artery disease and obesity. She presented with a chronic indurated, painful, hyper-pigmented skin lesion on her right thigh which measured 6 inches in diameter (Fig. 1a). Sarcoidosis was initially suspected, as a bilateral hilar prominence was noted in X-ray of the chest. After a period of follow-up, the patient presented with pain and tenderness over the lesion, which prompted a referral to the dermatologist. A biopsy of the thigh lesion revealed lymphoplasmacytic infiltrate with positive immunohistochemistry staining for IgG4 (Fig. 2a, b). Her serum IgG4 level was 65 mg/dL (normal range 4 - 86 mg/dL). A 24-h urine collection contained 1 g of protein of glomerular type, secondary to long-standing diabetic nephropathy. There was no evidence of peripheral lymphadenopathy. CT of chest, abdomen and pelvis did not show evidence of mediastinal lymphadenopathy, hepatosplenomegaly, retroperitoneal lymphadenopathy or fibrosis. Initially, she was treated with prednisone. After 3 months of treatment with prednisone, significant resolution was achieved (Fig. 1b). However, the lesions recurred after discontinuing steroid therapy. At this time, she began treatment with four weekly courses of rituximab. Six weeks after the last dose of rituximab, near complete clearance of the lesion was noted. Four months after completing rituximab treatment, the lesions reappeared at the same site. She then received imuran with no appreciable benefit. Presently, she is on mycophenolate mofetil and is in remission.

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Figure 1. (a, b) Lesion in thigh 6 inches in diameter before and after treatment with prednisone.

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Figure 2. (a, b) H&E and immunohistochemistry staining of the skin lesion.

Unlike IgG1, IgG4 antibody is unable to participate in a tissue-destruction, but is associated with an inflammatory immune response [6]. IgG4-RD produces inflammatory response involving salivary glands, periorbital tissues, kidneys, lungs, lymph nodes, meninges, aorta, breast, prostate, thyroid, pericardium and the biliary system [7]. In addition to lymphoplasmacytic infiltrate with predominance of IgG4-positive plasma cells, IgG4-RD is associated with fibrosis. In IgG4-RD, regulatory T helper 2 cell-derived cytokines appear to contribute to the pathogenesis of the disease [8]. The structural basis for this abnormal behavior of IgG4 seems to be secondary to substitution of a single amino acid substitution of proline in core hinge of IgG1 to serine, altering configuration of IgG molecule [9]. This has a bearing on the management, as immunomodulatory therapy is the mainstay in the treatment IgG4-RD. A study from Japan showed that IgG4 levels fail to normalize in 63% of patients treated with glucocorticoids [10]. Our patient showed a relapsing course, following treatment with prednisone and other immunosuppressive agents consistent with literature presented by Kamisawa et al [11]. After recurrent relapses and exposure to immunosuppressive agents, non-Hodgkin lymphoma developed in about 3% during the follow-up of 3 - 5 years, suggesting that patients with IgG4-RD may be at an increased risk of secondary malignancy [12]. A review of the current literature suggests that our case is a previously unrecognized manifestation of IgG4-RD presenting as an indurated skin lesion with normal IgG4 levels. This case and variable nature of the disease illustrate the need for high index of suspicion to diagnose IgG4-RD.

Acknowledgments

We would like to thank Paul Rodriguez, MD, PhD, Dermatopathologist, University of South Florida for the photomicrographs.

Conflicts of Interest

Authors report no conflicts of interest.

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Journal of Hematology is published by Elmer Press Inc.