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IgG4-related disease: clinical and laboratory features in one hundred ... B, Biopsy specimen from the skin, ... cutaneous tissue, with leukocytoclastic vasculitis.



2. Wallace ZS, Deshpande V, Mattoo H, Mahajan VS, Kulikova M, Pillai S, et al. IgG4-related disease: clinical and laboratory features in one hundred twenty-five patients. Arthritis Rheumatol 2015;67:2466–75. 3. Zen Y, Nakanuma Y. IgG4-related disease: a cross-sectional study of 114 cases. Am J Surg Pathol 2010;34:1812–9. 4. Huggett MT, Culver EL, Kumar M, Hurst JM, Rodriguez-Justo M, Chapman MH, et al. Type 1 autoimmune pancreatitis and IgG4-related sclerosing cholangitis is associated with extrapancreatic organ failure, malignancy, and mortality in a prospective UK cohort. Am J Gastroenterol 2014;109:1675–83. 5. Umehara H, Okazaki K, Masaki Y, Kawano M, Yamamoto M, Saeki T, et al. Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011. Mod Rheumatol 2012;22:21–30. 6. Zhao Z, Wang Y, Guan Z, Jin J, Huang F, Zhu J. Utility of FDG-PET/CT in the diagnosis of IgG4-related diseases. Clin Exp Rheumatol 2016;34:119–25. 7. Hart PA, Law RJ, Dierkhising RA, Smyrk TC, Takahashi N, Chari ST. Risk of cancer in autoimmune pancreatitis: a case-control study and review of the literature. Pancreas 2014;43:417–21. 8. Asano J, Watanabe T, Oguchi T, Kanai K, Maruyama M, Ito T, et al. Association between immunoglobulin G4-related disease and malignancy within 12 years after diagnosis: an analysis after longterm followup. J Rheumatol 2015;42:2135–42. 9. Hirano K, Isayama H, Tada M, Koike K. Association between autoimmune pancreatitis and malignancy. Clin J Gastroenterol 2014;7:200–4.

DOI 10.1002/art.39969

Relapsing polychondritis complicated by myelodysplastic syndrome is resistant to immunosuppression: comment on the article by Dion et al To the Editor: We read with interest the recent article by Dion and colleagues, in which they reported that patients with relapsing polychondritis (RP) could be classified into 3 clinical phenotypes: hematologic, respiratory, and mild (1). The hematologic phenotype was associated with death, the respiratory phenotype was associated with infections and admission to the intensive care unit, and the mild phenotype was associated with the absence of severe complications. This report was of great interest to us, because we also encountered a lethal case of RP complicated by myelodysplastic syndrome (MDS) and Sweet syndrome. The clinical course of this patient was quite unusual, suggesting that RP complicated by these diseases is a distinct syndrome, and development of specific therapeutic strategies is needed. We had been treating 14 RP patients at our institution (57.1% male, mean 6 SD age 53.36 6 16.51 years, mean 6 SD follow-up time 5.67 6 4.2 years). The affected cartilages were auricular (85.7%), nasal (14.3%), and tracheal (7.1%). In 57.1% of the patients, extracartilage symptoms developed, including encephalitis and meningitis, scleritis, uveitis, hypothyroidism, rheumatoid arthritis, Behc ¸et’s syndrome, IgA nephropathy, MDS, and Sweet syndrome. Patients were treated with corticosteroids (mean 6 SD prednisolone dosage 42.3 6 20.9 mg/day), but most of the patients who were treated solely with steroids experienced a relapse (relapse rate 71.4%), and additional immunosuppressants (methotrexate, cyclosporine, or cyclophosphamide) were needed. However, their survival was excellent except for a case that was complicated by MDS and Sweet syndrome. The patient, a 56-year-old man, developed arthritis, eruptions, and swelling of the right auricular cartilage. Based on the symptoms together with the histologic findings (Figure 1A), he was diagnosed as having RP. One month later, erythema and

Figure 1. Histologic findings in a patient with relapsing polychondritis and myelodysplastic syndrome. A, Biopsy specimen from the auricle, showing degeneration of the cartilage (arrowheads) and infiltration of inflammatory cells (arrow). Hematoxylin and eosin (H&E) stained. Bar 5 200 mm. B, Biopsy specimen from the skin, showing massive infiltration of neutrophils into the dermis and subcutaneous tissue, with leukocytoclastic vasculitis. H&E stained. Bar 5 50 mm. C, Bone marrow aspirate, showing a multinucleated erythroblast and hypogranular neutrophils with a pseudo2PelgerHu€ et nucleus. D, Computed tomography image, showing multiple small nodules in the lungs (top) and a mass in the left adrenal gland (bottom). E, Histologic assessment of a nodule in the left adrenal gland, showing viable cells with irregular and hyperchromatic nuclei. These cells were immunopositive for CD20 and CD79a, and positive for Epstein-Barr virus2encoded small RNA in situ hybridization (EBER-ISH). H&E stained. Bar 5 50 mm.

papules appeared on his face, and he was diagnosed as having Sweet syndrome (Figure 1B). The next year, he developed uveitis and MDS (refractory anemia) (Figure 1C). He sometimes experienced disease flare, and it was difficult to reduce the dose of prednisolone below 15 mg even though other immunosuppressive drugs (methotrexate, cyclosporine, mizorivine, or azathioprine) were added. Two years after diagnosis, he was admitted to our hospital to control his disease. He was treated with pulsed methylpred-



nisolone and administered 5.5 mg of betamethasone. His symptoms improved, but multiple small nodules and a mass appeared in his lungs and left adrenal gland, respectively (Figure 1D). Because nontuberculous mycobacteria were found in the sputum, gastric fluid, and bone marrow, he was diagnosed as having disseminated nontuberculous mycobacterial infection and received drugs to treat this infection, including rifampicin. Although the small nodules in the lung regressed, the adrenal mass progressed very rapidly. We performed a computed tomography–guided biopsy of this adrenal lesion, but histology showed only a necrotic lesion without nontuberculous mycobacteria. Meanwhile, his disease relapsed again, and he developed vasculitic lesions on his legs. He was treated again with pulsed methylprednisolone, but he next developed disseminated candidiasis that resulted in multiple organ failure and eventual death. An autopsy was performed, and a nodule (;5 cm) with massive necrosis was detected in the left adrenal gland. Histologically, viable cells with irregular and hyperchromatic nuclei invaded diffusely (Figure 1E). These cells were immunopositive for CD20, CD79a, and CD45 and immunonegative for CD3, CD5, CD10, Bcl-6, and Bcl-2. Epstein–Barr virus–encoded small RNA in situ hybridization was diffusely positive in these cells. The histologic diagnosis was diffuse large B cell lymphoma (DLBCL). This patient had experienced multiple complications at the same time, including Sweet syndrome, MDS, uveitis, and vasculitis, as well as RP. Considering the rarity of each condition, it is reasonable to consider that each represented one syndrome, and that this syndrome would be distinct from other RP phenotypes. The presentations of disseminated nontuberculous mycobacterial infection and DLBCL are also unusual even after the consideration of immunosuppressive therapy, and this strongly suggests immune dysfunction in this patient. Therefore, this syndrome appears to be paraneoplastic and very difficult to treat using conventional immunosuppressive therapy. It has been reported that the hypomethylating agent 5-azacytidine is effective for controlling paraneoplastic autoimmune disease in patients with MDS (2). On the other hand, hematopoietic cell transplantation is the only curative option for MDS (3). These treatments should be considered in cases of RP complicated by MDS and Sweet syndrome. Tsuyoshi Shirai, MD, PhD Hiroshi Fujii, MD, PhD Ryoko Saito, MD, PhD Kentaro Nasu, MD, PhD Yukiko Kamogawa, MD Noriko Fukuhara, MD, PhD Yoko Fujita, MD Yuko Shirota, MD, PhD Tomonori Ishii, MD, PhD Hideo Harigae, MD, PhD Tohoku University Graduate School of Medicine Sendai, Japan 1. Dion J, Costedoat-Chalumeau N, Sene D, Cohen-Bittan J, Leroux G, Dion C, et al. Relapsing polychondritis can be characterized by three different clinical phenotypes: analysis of a recent series of 142 patients. Arthritis Rheumatol 2016;68:2992–3001. 2. Frietsch JJ, Dornaus S, Neumann T, Scholl S, Schmidt V, Kunert C, et al. Paraneoplastic inflammation in myelodysplastic syndrome or bone marrow failure: case series with focus on 5-azacytidine and literature review. Eur J Haematol 2014;93:247–59.

3. Grunwald MR, Avalos BR, Copelan EA. Hematopoietic cell transplantation in MDS: undervalued and underutilized. Bone Marrow Transplant 2016;51:1069–70. DOI 10.1002/art.39972

Reply To the Editor: We thank Dr. Shirai and colleagues for their interest in our recent study. In their letter, they describe the particularity of patients with MDS-associated RP based on 1 case in a series of 14 patients. In our series, 12 of 142 patients (8%) with RP had MDS. Consistent with the reported case, our patients were exclusively men and were older at the time of diagnosis compared with patients without MDS. Cutaneous involvement was frequent (n 5 9), especially neutrophilic dermatosis (3 patients had Sweet syndrome and 1 patient had pyoderma gangrenosum). Of note, these cutaneous manifestations were previously described extensively by France`s et al (1). The prognosis was poor, with markedly reduced survival and a high rate of infection (including 1 case of cutaneous nontuberculous mycobacterial infection and 1 case of lethal disseminated toxoplasmosis). All of these particularities, as well as the results of a cluster analysis (separating patients with MDS, those with tracheobronchial involvement, and others), strongly suggest that MDS-associated RP is a distinct phenotype. Furthermore, a recent report that 4 patients with MDS-associated RP were successfully treated with the hypomethylating agent 5azacytidine suggests that RP might be paraneoplastic (2). However, this preliminary report needs to be confirmed in a larger series with a longer follow-up. The other particularity of this case was the concomitant occurrence of extranodal Epstein-Barr virus (EBV)–induced DLBCL. In our series, 4 patients had lymphoid malignancies during the course of the disease (2 had DLBCL, 1 had chronic lymphocytic leukemia, and 1 had marginal zone lymphoma), but none of the malignancies was induced by EBV, and no patient had associated MDS. The association between EBV-induced lymphoid malignancies and MDS has already been reported, with this complication being possibly promoted by MDSassociated immunosuppression (3). Moreover, age-related EBV-associated lymphoproliferative disorder is a recently described entity characterized by a high frequency of aggressive and extranodal forms in elderly patients without immunosuppression (4). Thus, several factors may have contributed to the occurrence of EBV-induced DLBCL in this patient: age, MDS, and immunosuppressive drugs. Jeremie Dion, MD Nathalie Costedoat-Chalumeau, MD, PhD Service de Medecine Interne Centre de Reference Maladies Auto-Immunes et Systemiques Rares Universite Rene Descartes Paris V, AP-HP and H^ opital Cochin, AP-HP Jean-Charles Piette, MD Departement de Medecine Interne 1 Centre de Reference Maladies Auto-Immunes et Systemiques Rares Universite Pierre et Marie Curie Paris VI, AP-HP Paris, France 1. France`s C, el Rassi R, Laporte JL, Rybojad M, Papo T, Piette JC. Dermatologic manifestations of relapsing polychondritis: a study of 200 cases at a single center. Medicine (Baltimore) 2001;80:173–9.

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