Conference Scene: Updating the Highlights of SjöGren‘s Syndrome

The International Symposium on Sjögren‘s syndrome (SS), launched by Rolf Manthorpe (Sjögren‘s syndrome Research Center, Sweden) in 1986, is held every 3 years. The main thrust of Pierre Youinou, chairman of the 10th International Symposium on SS, was to avoid superficial discussion whilst trying to cover the entire disease spectrum, and rather to encourage lively debate. Five sessions were organized. These were dedicated to etiology, clinics and biology, pathophysiology, and treatment and epidemiology, through introductions by experts who argued for and against theories based on their own clinical and basic data. The symposium took place in Brest, France, with over 350 participants from 42 countries.

In parallel with guided visits around posters (232 abstracts were submitted), four informal working discussions were organized during lunchtime and in the late afternoon. These sessions focussed on: ‘Ultrasonography of the salivary glands‘ (moderated by A Tzioufas from the University of Athens, Greece, and S Jousse-Joulin from the University of Brest, France); ‘Refining the criteria for Sjögren‘s syndrome‘ (moderated by T Daniels from the University of California, CA, USA; M Ramos-Casals from Barcelona, Spain, and AL Fauchais from the University of Limoges, France); ‘Epigenetics‘ (moderated by S Gay from the University of Zurich, Switzerland, Y Renaudineau from the University of Brest, France, and Q Lu from the University of Changsha, China) and ‘Monitoring the disease under treatment‘ (moderated by C Vitali from Piombino, Italy; S Bowman from the University of Birmingham, UK, and X Mariette from the Bicêtre hospital, Paris, France). The ultimate aim of these meetings was to reach a consensus and encourage the development of joint projects.

One of the most important innovations was to welcome delegates of 20 National Associations of Patients (such as Finland, India, Japan, New Zealand, Russia, Spain, UK and the USA) to participate in this meeting, under the auspices of the French Association of patients with SS. They met to figure out what actions can be undertaken to improve the quality of life of the patients all over the world. The Sjögren‘s associations of patients worldwide have also decided to join and set out an International SS Network.

In this article we present the highlights of the symposium.

Etiology of Sjögren‘s syndrome

In the first session dedicated to etiology of SS, HM Moutsopoulos (University of Athens, Greece) discussed ‘Viruses in terms of pathophysiology‘. His lecture referred to epithelial cells as pivotal regulators of autoimmune responses, suggesting that SS is basically an autoimmune epithelitis. Epithelial cells inappropriately express oncogenes (c-Myc and p53) and nuclear autoantigens (La/SSB) that are translocated to the plasma membrane. Most importantly, SS salivary gland epithelial cells (SGECs) appear suitably equipped to recruit and activate immunocytes. They express molecules involved in antigen presentation (MHC, CD40 and B7 costimulatory molecules), lymphoid-cell homing and expansion of immune responses (adhesion molecules, lymphoattractant chemokines and proinflammatory cytokines). Moreover, the expression of functional innate immune receptors such as Toll-like receptors (TLRs)-3, -4, -7 and -9, and CD91 heat shock protein receptor, suggest that SGECs are likely able to directly recognize pathogens and to cross-present antigenic molecules, respectively.

JM Anaya (University of Rosario, Bogota, Colombia) discussed the genetic basis of SS. He recalled that to date, there is no specific gene for primary SS, and all of the polymorphisms associated with primary SS have also been associated with other autoimmune diseases. Ancestral haplotype 8.1, IL-10, SSA1, IRF5 and STAT4 loci have been consistently associated with the disease, although they are not specific for SS. He also reported a meta-analysis to identify common HLA class II alleles contributing to progressive SS (pSS) susceptibility in a worldwide population. Analysis of susceptibility and protective alleles revealed physicochemical differences of critical amino acids located in the antigen-binding groove at DQ-α (DQA1*0502), DQ-β (DQB1*0201) and DR-b (DRB1*0301) chains. Finally, by using a combined approach of gene expression and genome-wide association study, it has been reported that both proapoptotic/antiapoptotic and type I interferon signaling inhibition/stimulation balances occur in SS labial SGECs, and that loci harboring the genes involved in these pathways are candidates for disease susceptibility.

On the sidelines of this etiology session, the creation of an international epigenetic autoimmune group has been proposed to establish gold standards and to launch collaborative studies. S Gay has presented the Swiss epigenetic group and has reviewed the main epigenetic modifications associated with autoimmune diseases (histone modifications, DNA methylations and miRNA). The discussion has mainly concerned the role of microparticles expressing miRNA and their importance as prognostic/diagnostic tools, as cellular activation markers or as effectors owing to their potential role on target cells.

W Brooks (Tampa, FL, USA) discussed his theory regarding the importance of S-adenosyl methionine (SAM) degradation by SAM decarboxylase, which may explain, in part, the observed DNA methylation defect in autoimmune diseases. Briefly, overexpression of the putrecine pathway (by virus and/or as a consequence of X-chromosome demethylation) is suspected to increase the activity of the SAM decarboxylase during autoimmune diseases. Following this, Brook‘s group developed a SAM-decarboxylase inhibitor in order to increase the level of the SAM methylation donor and in turn restore DNA methylation. The discussion has concerned the validation of this theory and the necessity to test the inhibitor(s), not only in cancer models but also in autoimmune models, both in vitro(T and B lymphocytes) and in vivo. For example, the nonspecific cellular action of the drug was also mentioned with a risk for developing cancer.

C Selmi (University of Milan, Italy) and E Gershwin (University of California, CA, USA) have presented their work regarding the importance of X-chromosome deletion (monosomy X) in primary biliary cirrhosis (PBC) and scleroderma. A call to study X-chromosome epigenetic modifications between twins that either develop or do not an autoimmune disease (PBC) was presented in order to identify autoimmune-susceptibility genes that could be present among the 15% of X-chromosome genes.

G Illei (National Institute of Health, MD, USA) discussed his results regarding the expression of two miRNAs overexpressed in salivary glands from SS. He reported that two suspected epithelial cell miRNAs (miR-574 and miR-768–3p) may be used to predict the evolution of the disease. Propositions to include more patients and to analyze the different cellular subpopulations in parallel with the blood analysis were suggested.

S Cha (University of Florida, FL, USA) presented her nondiabetic NOD-derived animal model (B6DC), which develops a disease similar to human SS. From her study, she highlighted two miRNAs (150 and 146) to be upregulated in the target tissues as well as in peripheral blood mononuclear cells (PBMCs) from B6DC mice. Consistently, she reported that miR-146 expression was also increased in PBMC and salivary glands from SS patients. Elevated expression of the two miRNAs was detected. A proposition to validate and define gold standards in order to analyze miRNAs (in particular miR-146 and miR-155) in large cohorts with different sample origins was made. Q Lu presented his group and its contribution to the elucidation of aberrant epigenetic regulation including DNA methylation, histone modifications and miRNA in lupus. Propositions to develop an epigenetic bank and to establish gold standards in an epigenetic consortium were put forward. Y Renaudineau presented the contribution of DNA demethylation to the autoreactivity of B cells leading to the overexpression of repressed genes such as human endogenous retrovirus. A proposition to establish gold standards to analyze epigenetic modifications was made.

To conclude this informal working discussion, A Tzioufas and S Bombardieri (University of Pisa, Italy) also reported epigenetic modifications (e.g., methylation, acetylation and sumoylation) of nucleic acid binding proteins (Ro60 and histones). Recognition of these modifications by autoantibodies may reflect an epigenetic disruption during autoimmune diseases. The Brest Epigenetic Task Force was born and has scheduled a meeting in Ljubljana, Slovenia, during the 7th Autoimmunity Congress in May 2010.

Clinics & biology in Sjögren‘s syndrome

The debate in Clinics and Biology was dedicated to a new clinical entity, systemic immunoglobulin G4 (IgG4)-related disease. H Takahashi (University of Sapporo, Japan) representing the Japanese Medical society for SS reported that Mikulicz‘s disease (MD) has long been considered as a manifestation of SS. However, in cases representing a symmetrical and persistent enlargement of the lacrimal and salivary glands compatible with MD, Japanese physicians noticed several clinical differences compared with SS as follows: there was no deflection of female sex differences; extent of xerostomia and xerophthalmia was mild; corticosteroid therapy led to a rapid reduction in glandular swelling and remarkable improvement of secretory function; and no positivity of anti-SSA/B antibodies was observed. In addition, elevated serum levels of IgG4 and abundant infiltration of plasmocytes expressing IgG4 into the lacrimal and salivary glands were reported in MD patients. These are common features of IgG4-related disease, which is a recently proposed clinical entity including autoimmune pancreatitis (AIP), sclerosing cholangitis, Küttner‘s tumor, retroperitoneal fibrosis and interstitial nephritis. MD often coexisted with IgG4-related diseases such as AIP. Based on those findings, it was proposed that MD be recognized as a new clinical entity of IgG4-related disease. The Japanese Medical Society for SS designed the diagnostic criteria for IgG4-related MD in 2008; persistent symmetrical swelling of two or more pairs of lacrimal and salivary glands, serum level of IgG4 above 1.35 g/l, and infiltration of IgG4⁺ plasmocytes in the tissue (IgG4⁺:IgG ratio >50%). In the daily clinical setting, it is important to distinguish MD from SS in the patient with swelling of lacrimal and salivary glands, because examinations of the involved organs are different, and early intervention with corticosteroids should be recommended in MD. The etiology of MD and IgG4-related diseases remains to be elucidated. Consequently, it is necessary to accumulate and analyze larger data from patients worldwide. Despite this, a new entity was suggested in Brest as IgG4-related disease.

R Seror (University of Paris VII, France) and C Vitali retrieved the conclusions of the European League Against Rheumatism (EULAR) SS group on the monitoring of SS. A total of 39 SS experts participated in an international collaboration, to develop the EULAR SS Disease Activity Index (ESSDAI), a disease activity index for patients with pSS. Experts identified 12 organ-specific ‘domains‘ contributing to disease activity. For each domain, features were classified into three or four levels according to their severity. A total of 96 real profiles of SS patients with systemic complications, including three successive visits, were abstracted from medical charts and used to generate 702 realistic vignettes. Real patient profiles were scored with the ESSDAI, the SS disease activity index (SSDAI) and the Sjögren‘s Systemic Clinical Activity Index (SCAI). Each expert, blind to theses scores, assessed activity of five real profiles and 20 realistic vignettes using the 0–10 physician global assessment (PhGA), and determined for real profiles whether disease activity improved, worsened or remained stable at visits two and three. It was found that all 12 domains were significantly associated with disease activity in the multivariate model, domain weights ranged from one to six. The ESSDAI scores varied from two to 47 and were significantly correlated with PhGA for both real patient profiles and realistic vignettes. Compared with 57 (59.4%) of the real patient profiles, 468 (66.7%) of the realistic vignettes were considered likely or very likely to be true. In conclusion, the ESSDAI has been designed as a clinical index to measure disease activity in patients with primary SS. Once validated, such a standardized evaluation of primary SS should facilitate clinical research and should be helpful as an outcome measure in clinical trials. A website has been created to facilitate exchanges with an open-access space to all information on the scores, the recent news on the project and a restricted area for members of the panel with questionnaires for all studies and material for ethical procedures [101].

Pathophysiology of Sjögren‘s syndrome

ME Gershwin has developed a model for the use of antimitochondrial antibodies in defining disease pathogenesis in PBC for other epithelial diseases such as SS. PE Lipsky (National Institute of Health, MD, USA) described the characteristics of circulating B cells with a special emphasis on transitional 1 (T1) B cells (IgD⁺, CD38^high) that phenotypically and functionally resemble murine T1 B cells. These cells rapidly die in vitro and fail to respond to BCR-mediated stimulation. Furthermore, IL-4 or stromal cells (but not BAFF/BLyS) may be important for T1 B-cell survival and maturation. Systemic lupus erythematosus (SLE) patients have increased proportions of T1 B cells, but not absolute numbers, and this is associated with lymphopenia. T1 B cells have unmutated Ig VH genes and there are no major differences in the VH repertoire of these cells and naive B cells. Gershwin then focused on CD27^-CD38^IntIgD⁺ intermediate B cells, which constitute a phenotypically distinct population with characteristics between transitional and naive B cells. CD27^-CD38^IntIgD⁺ (intermediate) B cells expressed CD5 as did CD27^-CD38^highIgD⁺ transitional B cells. Since transitional B cells account for only 1–2% of the total circulating B cells, this CD38 intermediate population accounted for the majority of circulating CD5⁺ B cells. Intermediate B cells were significantly increased in cord blood, but were infrequent in normal bone marrow, suggesting peripheral maturation of the intermediate B-cell population. Bone marrow intermediate B cells also expressed CD5, but not pro- or pre-B cells, suggesting the functional role of inhibiting antigen response in immature B cells before full maturation. Pre-naive B cells have acquired some of the functions associated with mature naive B cells, such as plasma cell differentiation upon stimulation with anti-CD40 and IL-21, or expression of CD86 and the ability to function as antigen-presenting cells for CD4⁺ T cells. These findings also suggest the possibility that under certain circumstances, activation of pre-naive B cells, perhaps during noncognate bystander interactions with activated T cells, could contribute to the functional activation and differentiation of these cells and the emergence of autoimmunity. In addition, SLE and SS patients have increased proportions of pre-naive B cells.

F Mackay (Monash University, Melbourne, Australia) discussed the role of B-cell activating factor (BAFF) in autoimmunity. Indeed, overproduction of BAFF in transgenic (Tg) mice triggers autoimmune disorders similar to SLE and SS, possibly as the result of abnormal self-reactive B-cell survival. Intriguingly, she demonstrated that excess BAFF only mildly affected B-cell immune tolerance and could not prevent deletion of high-affinity self-reactive B cells, but could rescue some low-affinity self-reactive B cells, in particular, marginal-zone B cells. As germinal-center formation and antibody affinity maturation were not essential for disease in these mice, she questioned the real implication of low-affinity autoreactive B cells in driving the disease. Indirect and direct effects of BAFF on T-cell activation, and expansion of the effector T-cell compartment in BAFF Tg mice were then suspected to contribute to nephritis in these animals. Surprisingly, BAFF Tg mice lacking T cells developed the same autoimmune disease as the original BAFF Tg mice. Interestingly, MyD88^-/- B cells had impaired autoantibody production in BAFF Tg mice. Overall, this work revealed that autoimmunity in BAFF Tg mice is the result of an abnormal innate B-cell response involving the combined effects of excess BAFF and TLR signaling.

T Defrance (University of Lyon, France) reviewed the functional aspects of the TLR, with a special emphasis on their involvement in autoimmune disorders. He hypothesized an interesting possibility whereby TLR signaling activates the immune response after antigenic stimulation leading to an upregulation of TLR expression, which in turn would facilitate an aberrant autoimmune response following autoantigen encounters.

Classification criteria in Sjögren‘s syndrome

T Daniels discussed the Sjögren‘s International Collaborative Clinical Alliance (SICCA) that began enrolling participants for baseline examinations at collaborating sites in Argentina, China, Denmark, Japan, UK and USA in 2004. The SICCA cohort includes participants with a broad range of signs or symptoms, ranging from possible early SS to well-established disease. However, to avoid circular reasoning in developing a new definition of SS, no diagnostic labels are used at study entry, even for participants previously diagnosed with SS. Goals of the SICCA project include: establishing an international registry; collecting and storing clinical data and biospecimens; developing standardized classification criteria that are universally applicable; and providing these resources for future studies of SS. All SICCA participants are prospectively enrolled and evaluated using the same protocols to provide uniform data and biospecimen collection from ocular, oral and rheumatologic examinations. Biospecimens include serum, DNA, whole and parotid saliva, tears, conjunctival cells, frozen and paraffin-embedded labial salivary gland (LSG) biopsy specimens and DNA from blood-related controls. By July 2009, SICCA had completed 1447 baseline evaluations. Most participants were reexamined using the same protocols 2 years after their baseline evaluation. The current SICCA natural history data are based on over 300 2-year recall examinations, and will report on changes in physiologic measures such as: salivary and tear production; presence or quantity of serum antibodies; serum complement; LSG histopathology; and development of other organ system diseases or lymphoma.

JP Whitcher (University of California, CA, USA) described the Ocular Sicca Score (OSS), a new simplified quantitative grading system for keratoconjunctivitis sicca (KCS) that was developed by the eight participating ophthalmologists in the SICCA study to analyze the distribution of KCS among the SICCA cohort and its association with other phenotypic characteristics of SS. The ocular exam included an unanesthetized Schirmer test, tear break-up time, ocular surface staining and an external eye examination at the slit lamp. Using statistical analyses and proportional Venn diagrams, the relationships were examined between an abnormal OSS (>3) and other phenotypic characteristics of SS (LSG biopsies with focal lymphatic sialadenitis focus scores >1, and positive anti-SSA and/or anti-SSB antibodies). Among 1208 SICCA participants, there were strong associations between abnormal OSS, positive serology and positive LSG focus scores (p < 0.0001). Analysis of the overlapping relationships of the three measures identified a large group of participants who had definite KCS but none of the other components of SS. These patients, designated as KCS-only, appear to represent a clinical entity distinct from the KCS associated with SS (SS-KCS). Therefore, Whitcher proposed OSS as a new method for assessing KCS that could be used for diagnosing the ocular component of SS in establishing future classification criteria. Two clinical entities of KCS have been identified, SS-KCS and KCS-only, which may have different etiologies.

Using latent class analysis applied to a wide range of diagnostic tests and phenotypic features to derive a model-based disease classification, S Shiboski confirmed that focal lymphocytic sialadenitis with a focus score greater than or equal to one, anti-SSA/B seropositivity, and an OSS greater than or equal to three, all had high sensitivity against model-based classification criteria. A 2-year follow-up analysis in the SICCA study revealed great stability over time of a working standard with ‘two out of three‘ positive diagnostic tests. During an informal working discussion on ‘redefining classification criteria of SS‘, T Daniels listed the future objectives of the SICCA project: put forward the notion of keeping patient symptoms in the classification criteria versus replacing them with a simplified menu of objective tests; identify groups of patients to participate in clinical trials of new therapeutic agents, or focus laboratory research into the causes or mechanisms of SS; respect and value the opinions of others, and see the SICCA data set as, ultimately, property of the greater scientific community, and generate proposed classification criteria using internal validation (e.g., subsequent data sets and 2-year follow-up data sets); and look forward to the views and suggestions of this and other scientific communities.

AL Fauchais described and discussed a cohort of 419 pSS patients and applied multivariate analysis (detrended correspondence analysis) to identify subgroup characteristics. She observed that a positive LSG focus score (and lymphoma) were independent from other SS components, particularly anti-SSA/B antibodies, hyperglobulinemia and parotid enlargement. Since American–European Consensus criteria exclude pSS patients with negative biopsy and anti-SS-A/B antibodies, she used hyper-γ-globulinemia, rheumatoid factor or positive antinuclear antibodies at the bedside to diagnose pSS, and proposed adding minor autoantibodies as a solution.

JO Pers (University of Brest, France) evaluated the relevance of the blood B-cell subset profile to the diagnosis of SS. Using flow-cytometry analyses with anti-CD38 and anti-IgD, distribution of mature blood B cells from Bm1 through Bm5 was determined in 161 patients, consisting of 25 who fulfilled the American–European Consensus Group criteria for pSS and 136 who served as disease controls. The percentages of Bm2 and Bm2´ cells were increased and those of early Bm5 (eBm5) and Bm5 decreased in pSS patients. The receiver-operating characteristic curves allowed for optimizing a cut-off value of Bm2⁺Bm2´/eBm5⁺Bm5 at greater than or equal to five for 88.0% sensitivity and 84.6% specificity. There was admiration for the unique assay, although some concern regarding relatively low sensitivity and small numbers, but it offers good future promise.

An informal working discussion was organized around ultrasonography (US) scoring of salivary glands in SS. S Jousse described the usefulness of US in this indication. Some authors have evaluated abnormal sonoanatomy in pSS while others have studied the vascularization of the gland to demonstrate that pSS glands were in a hyperhemic state. The parotids and submandibular glands were most commonly evaluated using imaging pictures and dynamic studies. They observed length, volume, margins of salivary glands, hypoechoic areas and parenchymal heterogeneity. Sensitivity of US to help clinicians in the diagnosis of pSS ranged from 50 to 70%, and specificity from 70 to 90%. All the experts described US as noninvasive, inexpensive and easy to perform (i.e., facilities in virtually all hospitals and short time of examination). However, this technique lacks a universally accepted grading scale for the interpretation of the results. Consequently, A Tzioufas proposed the elaboration of an objective grading system, including all possible pictures of SS, and subsequently, their validation in multicenter studies and their correlation with other subjective and objective items of the syndrome in order to define the diagnostic utility of the method. In the future, it would be interesting to have a new noninvasive tool such as US to help clinicians establish the diagnosis of pSS, to use it in the classification criteria and to evaluate the treatment effect.

Immunotherapy of Sjögren‘s syndrome

A Saraux (cochairman of the symposium from the Brest group) discussed B-depleting trials currently in progress around the world in SS. He highlighted that although many anti-B cell treatments are actually available, no data regarding anti-B treatments other than anti-CD22 (epratuzumab) and anti-CD20 (rituximab) in SS are currently available. In an open-label study, 16 pSS patients (14 women and two men) were scheduled to receive four epratuzumab infusions (360 mg/m² each) at 2-week intervals (Steinfeld group). The most commonly improved parameters were the Schirmer test, nonstimulated whole-salivary flow and visual analog scales (VAS) fatigue score. A clinical response was noted in 53% of patients at 6 weeks and 67% at 32 weeks. This study indicated that epratuzumab holds promise for the treatment of pSS. Human–anti-human antibodies were found in three patients, but were not associated with adverse events. Randomized placebo-controlled trials of epratuzumab are now needed. Subsequently, on the basis of recent evidence concerning the efficacy and safety of the use of anti-CD20 antibodies in various autoimmune diseases, some groups described retrospective cohorts or set up open pilot studies of rituximab in patients with active primary SS. All these publications described improvement of dryness and extraglandular features in approximately 50% of patients, but they pointed out some adverse events, particularly serum sickness-like reactions, that may occur. Five open-label studies prospectively evaluated rituximab in SS. The first one, by Pijpe et al., conducted in 15 pSS patients with either early pSS or mucosa-associated lymphoid tissue (MALT)-type lymphoma of the salivary glands, suggested an improvement of subjective symptoms and an increase in salivary gland function in patients with residual salivary gland function. However, three patients developed a sickness-like disorder [1].

Saraux then discussed the open-label study he has conducted that consisted of two rituximab infusions (375 mg/m²) 1 week apart in 16 patients with pSS (14 women and two men), who were followed up for 36 weeks. No steroid premedication was used. Patients were eligible if they had active disease with VAS scores greater than 50/100 mm for at least two of the following four variables: global disease activity (including extraglandular manifestations), pain, sicca symptoms and fatigue. The primary end points were safety and biological effects of rituximab. Secondary end points were variations in the four VAS scores from baseline to week 36. Rituximab treatment induced rapid depletion of all peripheral blood B-cell subsets for at least 1.5 months and depleted salivary gland B cells for at least 12 months. At weeks 12 and 36, significant improvements were noted in the VAS fatigue score, VAS sicca-symptom score, tender-point count, and SF36 quality-of-life score. In one patient who had pulmonary manifestations, these improved markedly. Mean disease duration was shorter in patients with improvements on at least three of the four VAS scores at any visit than in the other patients. Interestingly, the timing of B-cell repopulation was modulated by BAFF. Pretreatment serum BAFF levels demonstrated a strong negative correlation with time-to-reconstitution. Saraux related an interesting unpublished study kindly sent by M Manoussakis (University of Athens, Greece), in which the authors evaluated 11 patients with type 1 pSS and five patients with pSS-related MALT lymphoma and at least one of the following manifestations: persistent salivary gland enlargement; recurrent cryoglobulinemic or hyperglobulinemic palpable purpura; vasculitic ulcer(s) resistant to local therapy; peripheral neuropathy (mononeuritis multiplex and/or sensory/mixed polyneuropathy) confirmed by electrophysiologic evaluation; biopsy-proven active proliferative glomerulonephritis with proteinuria (>1 gr/24 h); microscopic hematuria (>10 red blood cells/hpf) and creatinine serum levels less than 4.0 mg/dl; asymptomatic type II cryoglobulinemia; and/or C4 hypocomplementemia (C4 < 15 mg/dl). They evaluated complete, partial or no response to treatment according to these objective criteria of selection. At 6 months, only seven manifestations had a complete response, but response was partial for all patients having mononeuritis multiplex, cryoglobulinemic purpura or proliferative glomerulonephritis. Their conclusion was that rituximab treatment of pSS patients ameliorates certain type I disease-associated clinical features (mononeuritis multiplex, ulcers, cryoglobulinemic purpura and hyperglobulinemic purpura and proliferative glomerulonephritis), and further limits lymphoid neoplastic disease in some patients. However, no evidence of improvement could be observed in fatigue or laboratory aberrations of the disease, although a high rate of infusion-related reactions was observed.

During this 10^th International Symposium on SS, several works on rituximab immunotherapy in patients with SS were presented. A Migliore (Rome, Italy) showed the efficacy of rituximab in ten patients with SS associated with rheumatoid arthritis and who were unresponsive to TNF-α inhibitors. In this cohort, rituximab demonstrated significant amelioration for general condition VAS, asthenia VAS and salivary gland secretion. By contrast, Schirmer‘s test did not change. None of the patients had any adverse events. JJ Scali (Buenos Aires, Argentina) retrospectively evaluated the efficacy and tolerance of rituximab in 31 patients with pSS. A total of 22 patients presented with an improvement in constitutional symptoms, arthritis and myalgias. In addition, subjective improvement in sicca symptoms was evidenced in 16 patients. No adverse events were related. OA Logvinenko (Moscow, Russian Federation) evaluated the efficacy of rituximab in pSS with severe extraglandular manifestations (eight patients with cryoglobulinemic vasculitis and glomerulonephritis in one patient) and MALT lymphoma (14 patients). All patients with cryoglobulinemic vasculitis demonstrated improvement in clinical and biologic markers, but relapsed at 6 months. Complete clinical remission of MALT lymphoma was achieved in nine patients with combined therapy and in six patients with monotherapy based on rituximab. Two patients relapsed. H Bootsma (University of Groningen, The Netherlands) presented a randomized, double-blind trial with rituximab compared with placebo in 29 patients with pSS. In the rituximab group, significant improvements were found for the primary end point of secretion of whole saliva, some laboratory parameters (B cells and rheumatoid factor), subjective symptoms and extraglandular manifestations. One patient treated with rituximab developed mild serum sickness-like disease.

In conclusion, in open-label studies and randomized trials, rituximab appeared effective for at least 6–9 months in pSS patients with active disease, improving both the subjective and the objective complaints. The sicca symptoms abated in some patients, and the objective measures of salivary function improved in patients with early disease. Extraglandular clinical manifestations of pSS responded to rituximab. Retreatment with rituximab resulted in a similarly effective clinical response. Laboratory abnormalities associated with B-cell overactivity also improved. To confirm these promising results, additional randomized, placebo-controlled trials are ongoing (University of Copenhagen, Rigshospitalet, Denmark; University Medical Centre Groningen, Groningen, The Netherlands; Duke University Medical Center and University of Pennsylvania, USA; and University Hospital, Brest, Ministry of Health, France). Interestingly, a new anti-B-cell therapy study in patients with pSS (the TRACTISS study; S Bowman, Birmingham, UK) has been harmonized with the Tolerance and Efficacy of Rituximab in pSS (TEARS; A Saraux, Brest, France) study for most of the assessment process and entry criteria. Thus, we can consider that a meta-analysis should be achieved once data from both projects are available.

The 11^th International symposium on SS will take place in 2011 in Athens, Greece.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.