Dogan, A

Du, MQ

Isaacson, PG

English

UCL Discovery

The new england journal of medicine1746 n engl j med 353;16 www.nejm.org october 20, 2005tient), despite the fact that the risk of permanent dis-ability in such patients is very low.2 These problemswith the diagnostic criteria for multiple sclerosisand the entry criteria for clinical trials need to beaddressed.Annette Langer-Gould, M.D.Scott W. Atlas, M.D.Stanford UniversityStanford, CA 94305-5405annette1@stanford.eduDaniel Pelletier, M.D.University of California, San FranciscoSan Francisco, CA 94143Since publication of the article, Dr. Langer-Gould reports havingreceived consulting fees from Genentech.1. Kruit MC, van Buchem MA, Hofman PA, et al. Migraine as a riskfactor for subclinical brain lesions. JAMA 2004;291:427-34.2. Achiron A, Barak Y, Rotstein Z. Longitudinal disability curvesfor predicting the course of relapsing-remitting multiple sclerosis.Mult Scler 2003;9:486-91.A Relapsing Inflammatory Syndrome and HHV-8to the editor: The case of human herpesvirus 8(HHV-8) reported by Dagna et al. (July 14 issue)1is considered to be distinct from HHV-8–associat-ed multicentric Castleman’s disease owing to theabsence of typical histologic findings and elevat-ed plasma levels of interleukin-6. The histopa-thology of HHV-8–associated multicentric Castle-man’s disease is variable, as compared with theclassic descriptions of HHV-8–negative Castle-man’s disease2-4 and would encompass the changesdescribed in the report, especially in the context ofcytotoxic treatment before biopsy. In HHV-8–associ-ated multicentric Castleman’s disease, the HHV-8–infected B-lineage cells can be seen either withinthe B-cell follicles or in the interstitium of manytissues, including bone marrow4,5 and lymph nodes,as seen in this case. Phenotypically, these cells re-semble the plasmablasts in the follicles and theplasma cells in the interstitium. The infected cellssecrete viral interleukin-6, which triggers an auto-crine feedback loop involving human interleukin-6,3 as reflected by the elevated plasma levels of in-terleukin-6, particularly at the time of the biopsy.The downstream effects of interleukin-6 areprobably the cause of the clinical syndrome, whichis indistinguishable from HHV-8–associated mul-ticentric Castleman’s disease. We feel that this casereport represents an HHV-8–associated multicen-tric Castleman’s disease, rather than a newly recog-nized HHV-8–associated inflammatory syndrome.Ahmet Dogan, M.D., Ph.D.Mayo ClinicRochester, MN 55905dogan.ahmet@mayo.eduMing-Qing Du, M.B., Ph.D.University of CambridgeCambridge CB2 2QQ, United KingdomPeter G. Isaacson, M.B., Ch.B.University College London HospitalsLondon WC1E 6JJ, United Kingdom1. Dagna L, Broccolo F, Paties CT, at al. A relapsing inflammatorysyndrome and active human herpesvirus 8 infection. N Engl J Med2005;353:156-63.2. Dupin N, Diss TL, Kellam P, et al. HHV-8 is associated with aplasmablastic variant of Castleman disease that is linked to HHV-8-positive plasmablastic lymphoma. Blood 2000;95:1406-12.3. Du MQ, Liu H, Diss TC, et al. Kaposi sarcoma-associated her-pesvirus infects monotypic (IgM lambda) but polyclonal naiveB cells in Castleman disease and associated lymphoproliferative dis-orders. Blood 2001;97:2130-6. [Erratum, Blood 2001;97:3678.]4. Bacon CM, Miller RF, Noursadeghi M, McNamara C, Du MQ,Dogan A. Pathology of bone marrow in human herpes virus-8(HHV8)-associated multicentric Castleman disease. Br J Haematol2004;127:585-91.5. Meggetto F, Cesarman E, Mourey L, Massip P, Delsol G, BroussetP. Detection and characterization of human herpesvirus-8-infectedcells in bone marrow biopsies of human immunodeficiency virus-positive patients. Hum Pathol 2001;32:288-91.the authors reply: It seems to us that the issueraised by Dogan and colleagues is one of defini-tion. From the clinical standpoint, severe symmetricarthrosynovitis (hardly ever observed in patientswith HHV-8–associated multicentric Castleman’sdisease) was the referring symptom. Our patienthad anemia of chronic inflammatory disease butnone of the hematologic abnormalities and bonemarrow features characteristically associated withHHV-8–associated multicentric Castleman’s dis-ease.1,2 On only two occasions was the level of hu-man interleukin-6 increased; rather, it remainednormal throughout the follow-up, regardless of dis-ease activity.3 Although there is some variability inthe features of Castleman’s disease, some of whichis apparently related to the HHV-8 infection,1,4 Cas-tleman’s disease remains primarily a morpholog-ic diagnosis: a minimum set of criteria must beCopyright © 2005 Massachusetts Medical Society. All rights reserved. Downloaded from www.nejm.org at UNIVERSITY COLLEGE LONDON on August 22, 2008 . n engl j med 353;16 www.nejm.org october 20, 2005correspondence1747met or else the diagnosis ceases to have meaning.The microscopical appearance of the lymph nodes(including one excised before treatment) did notbear even a remote resemblance to any recognizedtype or variant of Castleman’s disease. For thesereasons, we do not believe that our patient shouldbe given the diagnosis of Castleman’s disease,but we do acknowledge the likelihood of a sharedetiologic factor and pathogenesis.Lorenzo Dagna, M.D.Università Vita-Salute San Raffaele School of MedicineI-20132 Milan, Italylorenzo.dagna@hsr.itJuan Rosai, M.D.Centro Diagnostico ItalianoI-20147 Milan, ItalyPaolo Lusso, M.D., Ph.D.San Raffaele Scientific InstituteI-20132 Milan, Italy1. Casper C. The aetiology and management of Castleman diseaseat 50 years: translating pathophysiology to patient care. Br J Haema-tol 2005;129:3-17.2. Bacon CM, Miller RF, Noursadeghi M, McNamara C, Du MQ,Dogan A. Pathology of bone marrow in human herpes virus-8(HHV8)-associated multicentric Castleman disease. Br J Haematol2004;127:585-91.3. Oksenhendler E, Carcelain G, Aoki Y, et al. High levels ofhuman herpesvirus 8 viral load, human interleukin-6, interleukin-10, and C reactive protein correlate with exacerbation of multicen-tric Castleman disease in HIV-infected patients. Blood 2000;96:2069-73.4. Amin HM, Medeiros LJ, Manning JT, Jones D. Dissolution of thelymphoid follicle is a feature of the HHV8+ variant of plasma cellCastleman’s disease. Am J Surg Pathol 2003;27:91-100.A Fractured Diagnosisto the editor: Cukierman et al., in their ClinicalProblem-Solving article (Aug. 4 issue),1 affirm that“the clinical picture suggests primary Sjögren’ssyndrome because of the lack of clinical featuresassociated with rheumatoid arthritis or other au-toimmune disorders,” according to the revised Eu-ropean criteria.2 The more recent American–Euro-pean Consensus Group classification3 establishesas exclusion criteria for primary Sjögren’s syndromethe presence of infection with hepatitis C virus(HCV) or the human immunodeficiency virus (HIV).Were HCV and HIV infection considered in thispatient? Is there another fragment in the fractureddiagnosis?Francisco López-Medrano, M.D.Manuel Lizasoain, M.D.José María Aguado, M.D., Ph.D.University Hospital 12 de Octubre28041 Madrid, Spainflmedrano@yahoo.es1. Cukierman T, Gatt ME, Hiller N, Chajek-Shaul T. A fractureddiagnosis. N Engl J Med 2005;353:509-14.2. Vitali C, Bombardieri S, Moutsopoulos HM, et al. Preliminarycriteria for the classification of Sjogren’s syndrome: results of a pro-spective concerted action supported by the European Community.Arthritis Rheum 1993;36:340-7.3. Vitali C, Bombardieri S, Jonsson R, et al. Classification criteriafor Sjogren’s syndrome: a revised version of the European criteriaproposed by the American–European Consensus Group. Ann RheumDis 2002;61:554-8.the authors reply: The revised American–Euro-pean Consensus Group classification scheme re-quires that before the diagnosis of primary Sjögren’ssyndrome be made, the following conditions mustbe ruled out: infection with HCV or HIV, lympho-ma, sarcoidosis, graft-versus-host disease, and theuse of anticholinergic drugs.Our patient was tested for HCV and HIV and wasnegative for both. Therefore, the diagnosis of pri-mary Sjögren’s syndrome is still plausible. Despitethis fact, it is possible that longer follow-up mightreveal another underlying diagnosis.An increasing body of evidence supports astrong association between HCV infection and aSjögren’s syndrome–like condition. In one study,12 percent of patients with Sjögren’s syndrome wereHCV-positive.1 In another study,  25.9 percent ofpeople with chronic HCV infection met the Euro-pean criteria for Sjögren’s syndrome.2 Clinically,primary  Sjögren’s syndrome may be differentiatedfrom Sjögren’s syndrome associated with HCV in-fection by the absence of neuropathy, vasculitis, orliver involvement, as well as by the much higherfrequency of antibodies to Ro and La.1Tali Cukierman, M.D.Nurith Hiller, M.D.Tova Chajek-Shaul, M.D.Hadassah–Hebrew University Medical Center, Mount ScopusJerusalem 91240, Israelchajek@hadassah.org.il1. Ramos-Casals M, De Vita S, Tzioufas AG. Hepatitis C virus,Sjogren’s syndrome and B-cell lymphoma: linking infection, auto-immunity and cancer. Autoimmun Rev 2005;4:8-15.2. Nagao Y, Hanada S, Shishido S, et al. Incidence of Sjogren’s syn-drome in Japanese patients with hepatitis C virus infection. J Gastro-enterol Hepatol 2003;18:258-66.Copyright © 2005 Massachusetts Medical Society. All rights reserved. Downloaded from www.nejm.org at UNIVERSITY COLLEGE LONDON on August 22, 2008 . 

A relapsing inflammatory syndrome and HHV-8

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