Available online: 31 July 2012

Presse Med. 2012; 41: e437–e439 on line on� 2012 Elsevier Masson SAS.All rights reserved.

www.em-consulte.com/revue/lpmSJOGREN’S SYNDROME: THE LATE NEWSwww.sciencedirect.com

In this issueLatest update on the primarySjögren’s syndromeP. Youinou and J.O. Pers, Brest,France

Do we need new diagnosticcriteria for Sjögren’s syndrome?T.E. Daniels, San Francisco, USA

Autoantibodies in Sjögren’ssyndrome: Clinical Presentationand Regulatory MechanismsA.G. Tzioufas et al. Athens, Greece

Pathogenic role of anti-M3muscarinic acetylcholine receptorimmune response in Sjögren’ssyndromeT. Sumida et al. Ibaraki, Japan

Pathophysiological cytokinenetwork in primary Sjögren’ssyndromeJ.O Pers et al. Brest, France

B-cell populations and sub-populations in Sjögren’ssyndromeN. Hamza et al. Groningen, TheNetherlands

Central and peripheralneurological complications ofprimary Sjögren’s syndromeA.L Fauchais et al. Limoges, France

Predictors for the development ofnon-Hodgkin lymphoma inprimary Sjögren’s syndromeM.V. Jonsson et al. Bergen,Norway

Biologic treatments in Sjögren’ssyndromeS. Bowman and F. Barone,Birmingham, United Kingdom

tome 41 > n89 > septembre 2012http://dx.doi.org/10.1016/j.lpm.2012.05.020

Quarterly Medical Review

Latest update on the primary Sjögren’ssyndrome

Pierre Youinou, Jacques-Olivier Pers

European University of Brittany, Research Unit EA 2216 on ‘‘B cell-mediated Immunology, Pathology and Immunotherapy’’,29609 Brest cedex, France

Correspondence:

Pierre Youinou, Brest University Medical School Hospital, Laboratory of Immunology, 5, Avenue Foch, BP 824, 29609 Brestcedex, France.youinou@univ-brest.fr

A utoimmune exocrinopathy, referred to as Sjögren’s syndrome (SS) and located in exocrineglands, e.g., the lacrimal and salivary glands (SGs), is estimated the second most commonautoimmune disease [1]. Regardless of whether their condition exists alone as a primary SS, orassociated with other connective diseases as secondary SS, the patients display intense site ofimmune activity in their exocrine tissues. A number of environmental, genetic and epigeneticfeatures conspire stochastically to favour its development. In spite of such a complexity,noteworthy contributions to our understanding of its pathogenesis are currently being suppliedby clinicians and basic immunologists.Keratoconjunctivitis and xerostomia are usually prominent, but primary SS presents a multi-system complaint, with a broad variety of clinical manifestations and biological abnormalities. Atleast in part, this polymorphism accounts for the delay in the diagnosis, which is over-ridden bythe progress of immunomodulating agents. Whilst not being the case beforehand, the introduc-tion of biologics as a treatment has generated a need for an early diagnosis. To this end, criteriafor classification of the diseases have been selected by the European community study group [2],and reappraised by the American-European consensus group [3]. The concept of IgG4-relatedpathology has then been forwarded [4], and dictated as an exclusion criterion for primary SS. Theblood B-cell subset profile has been suspected to be diagnostic for primary SS as well [5].Ironically, there have been 11 sets of criteria published since the Bloch et al.’s landmark study [6].It is, therefore, of no surprise to hear that an additional classification has just been introduced bythe SS international collaborative clinical alliance [7].Their epithelial structures are wrapped in a sheet of lymphocytes. Their majority are CD4 + T cells,with a few B cells and some interleukin (IL) 17-producing cells. Indeed, patients exhibit featuressuggestive of the greater significance of T-lymphocytes versus B-lymphocytes, including theirpredominance within the inflamed SGs, with B cells confined to antibody (Ab) production. UponT-cell activation, the cytokine milieu enjoins T helper (Th) cell polarization. Thus, interferon (IFN)-gand IL-12 polarize naïve CD4 + T cells towards Th1 lymphocytes, involved in the production of IFN-g and tumour-necrosis factor (TNF)-a. Patients with primary SS have long been thought to sufferfrom a Th1-mediated condition. This interpretation was supported by high levels of IFN-g in theserum and a predominance of Th1 over Th2 cells in the blood. Despite a number of caveats,

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primary SS is currently conceived as a model for B cell-inducedautoimmune diseases [8], through Ab-dependent and Ab-in-dependent mechanisms. Beyond the paradigm that T-lympho-cytes hold strict control over their B-lymphocyte counterparts,the activities of these latter cells are orchestrated by repre-sentatives of the TNF group, most notably the B cell-activatingfactor of the TNF family (BAFF) described in the late 1990s.Especially, BAFF mediates survival of immature B cells andthereby rescues those autoreactive from peripheral deletion[9]. An aberrant expression of BAFF has been found not only inepithelial cells and activated T-lymphocytes, but also in B-lymphocytes eluted from the SG infiltrates and purified assingle-cell suspensions.Several contradictory hypotheses have thus been promoted toresolve the complexity of the syndrome. One of its hallmarksremains the production of autoAbs. They are indeed routinelyrequested as a guide to clinical decision-making. They recog-nize a vast array of organ-specific and nonorgan-specific struc-tures, with the most common being directed to Ro/SSA and La/SSB complexes [10]. Other autoAbs are associated with parti-cular complications, viz. those to the centromeres in the contextof Raynaud’s phenomenon, those to carbonic anhydrase II inthat of distal renal tubular acidosis, or those to mitochondrias inthat of primary biliary cirrhosis. Given the absence of correlationbetween SG damage and the flux of saliva, abnormal Ab andT cell responses to muscarinic type 3 receptors has beenconceived to be pathogenic in primary SS patients [11].Of important note, these are at risk of developing non-Hodg-kin’s lymphoma (NHL), so that considerable efforts have beenafforded to identify risk factors for this life-threatening com-plication. As such, recurrent SG swelling, neutropenia, cryoglo-bulinemia, splenomegaly, cutaneous vasculitis, palpablepurpura and low serum level of C4 have been documented[12]. More recently, lymphoid organisation in SGs, especially

References[1] Ng WF, Bowman SJ, Griffiths B. United

Kingdom primary Sjögren’s syndrome reg-istry-a united effort to tackle an orphanrheumatic disease. Rheumatology (Oxford)2011;50:32-9.

[2] Vitali C, Bombardieri S, Moutsopoulos HM,Balestrieri G, Bencivelli W, Bernstein RMet al. Preliminary criteria for the classifica-tion of Sjogren’s syndrome. Results of aprospective concerted action supported bythe European Community. Arthritis Rheum1993;36:340-7.

[3] Vitali C, Bombardieri S, Jonsson R, Moutso-poulos HM, Alexander EL, Carsons SE et al.

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the presence of germinal center-like structures [13], and over-production of Fms-like tyrosine kinase 3 ligand [14], a cytokinemediating B-cell survival, have been shown to unveil theemergence of NHL in these patients.Now comes the issue of treatment. Attention has been focusedon biotherapies, to such an extent that a new dawn may havearrived [15]. Negative ground notwithstanding, TNF-a antago-nists have first been claimed to be successful in the treatment ofthese patients. They have subsequently proven not to be efficientat all [16]. In contrast, B cell-depleting therapy with the anti-CD20 monoclonal Ab (mAb) rituximab, already in use for thetreatment of lymphoma, rheumatoid arthritis and systemic lupuserythematosus, has shown promise in primary SS [17]. Despitethe rituximab-induced reduction in the number of circulating Bcells, autoAbs keep being generated. Nonetheless, the latestanti-B cells mAbs, for example those binding to CD22, seem to beless active than rituximab [18]. Inhibitors of BAFF are also beingdeveloped, be they mAbs or decoy receptors, or at early stages ofclinical testing [19]. Current insight into interconnecting cyto-kines, where IL-6, IL-17 and BAFF are major agents [20], mayhence lead to new treatments. Above all, given that B cellsgovern the pathogenesis of primary SS [8], there remains a needfor progress with refining B cell-targeted therapies. For example,there is an inverse correlation between the initial level of BAFFand the length of rituximab-induced B-cell depletion. This intri-guing observation encourages the association of anti-CD20 andanti-BAFF Abs in the treatment of the patients. All the above-renewed concepts warrant to be examined in this special issue.

or Sjothe

rican Dis

N, Uvel l

an ce3-20 L, D

P, Pdiagheu

Disclosure of interest: the authors declare that they have no conflicts ofinterest concerning this article.

Acknowledgements: Thanks are due to Simone Forest and Geneviève Michelfor their help with the typing of this manuscript.

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[7] Shiboski S, Shiboski C, Criswell L, Baer A,Challacombe S, Lanfranchi H et al. Americancollege of rheumatology classificationcriteria for Sjogren’s syndrome: a data-driven, expert consensus approach in theSjogren’s international collaborative clinicala l l iance cohort . Arthr i t is Care Res2012;64:475-87.

[8] Youinou P, Devauchelle-Pensec V, Pers JO.Significance of B cells and B cell clonality in

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[9] Youinou P, Pers JO. The late news on BAFFin autoimmune diseases. Autoimmun Rev2010;9:804-6.

[10] Routsias JG, Tzioufas AG. Autoimmuneresponse and target autoantigens inSjögren’s syndrome. Eur J Clin Invest2010;40:1026-36.

[11] Sumida T, Tsuboi H, Iizuka M, Nakamura Y,Matsumoto I. Functional role of M3 mus-carinic acetylcholine receptor (M3R) reac-tive T cells and anti-M3R autoantibodies inpatients with Sjögren’s syndrome. Autoim-mun Rev 2010;9:615-7.

[12] Ioannidis JP, Vassiliou VA, MoutsopoulosHM. Long-term risk of mortality and lym-phoproliferative disease and predictiveclassification of primary Sjögren’s syn-drome. Arthritis Rheum 2002;46:741-7.

[13] Theander E, Vasaitis L, Baecklund E, Nord-mark G, Warfvinge G, Liedholm R et al.Lymphoid organisation in labial salivarygland biopsies is a possible predictor forthe development of malignant lymphoma inprimary Sjogren’s syndrome. Ann Rheum Dis2011;70:1363-8.

[14] Tóbon GJ, Renaudineau Y, Hillion S, CornecD, Devauchelle-Pensec V, Youinou P et al.The Fms-like tyrosine kinase 3 ligand, amediator of B-cell survival, is also a markerof lymphoma in primary Sjogren’s syn-drome. Arthritis Rheum 2010;62:3447-56.

[15] Ng WF. Primary Sjögren’s syndrome researchand therapy: has a new dawn arrived? CurrPharm Biotechnol 2012: in press.

[16] Mariette X, Ravaud P, Steinfeld S, Baron G,Goetz J, Hachulla E et al. Inefficacy ofinfliximab in primary Sjogren’s syndrome:results of the randomized, controlled trial of

remicade in Primary Sjogren’s Syndrome.Arthritis Rheum 2004;50:1270-6.

[17] Pijpe J, van Imhoff GW, Spijkervet FK,Roodenburg JL, Wolbink GJ, Mansour Ket al. Rituximab treatment in patients withprimary Sjogren’s syndrome: an open-labelp h a s e I I s t u d y. A r t h r i t i s R h e u m2005;52:2740-50.

[18] Steinfeld SD, Tant L, Burmester GR, Teoh NK,Wegener WA, Goldenberg DM et al. Epra-tuzumab (humanised anti-CD22 antibody) inprimary Sjogren’s syndrome: an open-labelphase I/II study. Arthritis Res Ther2006;8:129.

[19] Liu Z, Davidson A. BAFF inhibition: a newclass of drugs for the treatment of auto-immunity. Exp Cell Res 2011;317:1270-7.

[20] Youinou P, Pers JO. Disturbance of cytokinenetworks in Sjögren’s syndrome. ArthritisRes Ther 2011;13:227.

Latest update on the primary Sjögren’s syndromeSJOGREN’S SYNDROME: THE LATE NEWS

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