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Sjögren’s syndrome: what is new in 2017

<p class="article-intro">Sjögren’s syndrome is an autoimmune disease characterised by inflammation of exocrine glands, leading to symptoms of dryness which are frequently associated with disabling fatigue and sometimes with systemic manifestations. New classification criteria for Sjögren’s syndrome have been published and several scores are available to assess symptoms severity. Although there is still no curative drug for Sjögren’s syndrome, a significant research effort is ongoing to find an effective treatment for this disease. </p> <p class="article-content"><div id="keypoints"> <h2>Keypoints</h2> <ul> <li>New classification criteria for pSS have been published in 2016 and are likely to be the new standard.</li> <li>Salivary gland ultrasonography is a promising diagnostic tool.</li> <li>Several scores are available to assess systemic manifestations (ESSDAI) in pSS and patient&rsquo;s symptoms (ESSPRI), which can be used in research or clinical practice.</li> <li>There is still no curative treatment for pSS. Sicca symptoms should be treated symptomatically.</li> <li>There are currently several ongoing controlled trials assessing targeted therapies in pSS.</li> </ul> </div> <p>Sj&ouml;gren&rsquo;s syndrome (SS) is a systemic autoimmune disease characterised by inflammation of exocrine glands, especially salivary and lachrymal glands, associated with ocular and oral dryness. Se&shy;vere fatigue and widespread pain are also frequently reported by patients.<sup>1</sup> Some patients present with systemic features like interstitial lung disease, neurologic or renal involvement which can be severe. SS can be diagnosed as a stand-alone disease (primary SS, pSS) or can occur in association with other autoimmune disorders like rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) (secondary SS).<br /> Health-related quality of life of patients with pSS has been shown to be reduced to a similar extent as with RA or SLE. In a UK population the indirect costs of pSS have been estimated at 80 % of those of RA.<sup>2</sup> A recent study showed that two years after diagnosis of pSS the relative risk of being unable to work was more than two times that of the general population.<sup>3</sup><br /> A significant worldwide research effort is ongoing in the fields of pathogenesis, disease diagnosis, outcome measures and treatment. This article will now focus on some of the new evidence available regarding selected topics in pSS.</p> <h2>Pathogenesis</h2> <p>The aetiology of this systemic autoimmune exocrinopathy is still unknown. Several viruses with glandular tropism such as cytomegalovirus, Epstein-Barr virus, herpes virus 6 and 8 and others have been reported to be potentially involved in the first steps of the disease by damaging gland epithelial cells leading to the release of autoantigens.<sup>4</sup><br /> In pSS a number of cytokines are upregulated (TNF-&alpha;, IFN-&alpha;, IFN-&gamma;, IL-1, IL-6, IL-10, IL-18) in the salivary glands. Chemokines (CXCL13, CCL21) are expressed and promote B-cell aggregation. Type 1 interferon (IFN) genes&rsquo; upregulation induces B-cell-activating factor (BAFF) expression which in turn can induce polyclonal B-cell stimulation and autoantibody production. T-helper cell (Th) 1, Th2, Th17-derived cytokines and cells are thought to play an important role in the development of pSS.<sup>5</sup><br /> Some human leukocyte antigen (HLA) alleles are associated with pSS with ethnic and geographical variations. For example, DRB1*0301, DRB1*03, DQA1*0501 and DQB1*0201 alleles have been associated with the presence of anti-SSA/SSB antibodies in pSS. Other HLA alleles may also play a role in pSS.<sup>6</sup> A recently published multicentre collaborative study including around 8000 patients with pSS also provides evidence for a strong influence of geolocation and ethnicity on the pheno&shy;type of pSS at diagnosis.<sup>7</sup><br /> Recent genome-wide association studies have associated pSS with STAT4, IRF5, IL-12A, BLK, TNIP1 and CXCR5 polymorphisms. These genes are involved in B-cell and T-cell signaling, NF-kB pathway and type 1 IFN response.<sup>8</sup><br /> MicroRNAs (miRNAs), which are small non-coding RNAs recently discovered, play a critical role in regulating gene expression. More than 10 miRNAs have been reported to be overexpressed and 3 lower expressed in pSS. MiRNAs are subject to ongoing research work which could lead to the identification of new disease-specific biomarkers and new targets for treatments.<sup>9</sup><br /> Epigenetics refers to the process of DNA modifications without alteration in the DNA sequence itself. This process typically in&shy;volves DNA methylation, allowing for modulation of gene expression. A potential role of DNA methylation in the pathogenesis of pSS is supported by preliminary data.<sup>10</sup></p> <h2>New classification criteria</h2> <p>New classification criteria for pSS have been issued by the American College of Rheumatology and the European League Against Rheumatism and were published in 2016 (Table 1). They have been designed primarily for research purpose but are likely to be used in routine practice too. Unlike the American/European Consensus Group criteria which have been the gold standard for the classification of pSS since 2002, anti-SSB antibodies are no longer part of these criteria. Patients can be classified as pSS even without sicca symptoms if they present with systemic features suggestive of pSS with concurrent anti-SSA or focal lymphocytic sialadenitis in labial salivary gland biopsy samples.<sup>11</sup></p> <p><img src="/custom/img/files/files_datafiles_data_Zeitungen_2017_Leading Opinions_Ortho_1703_Weblinks_s68_1.jpg" alt="" width="1417" height="1256" /></p> <h2>Disease activity scores</h2> <p>Several scores have been published in order to help to assess outcomes reliably as there are an increasing number of clinical trials in pSS. Some of them could be used in routine care as they are easy to use or may serve as a checklist for a structured clinical assessment.<br /> The EULAR Sj&ouml;gren&rsquo;s Syndrome Disease Activity Index (ESSDAI) evaluates systemic complications of the disease and consists of twelve domains.<sup>12</sup> Recently, the ClinESSDAI has been proposed, which is a modification of the ESSDAI without the biological domain (evaluating B-cell activity).<sup>13</sup> The EULAR Sj&ouml;gren&rsquo;s Syndrome Patient Reported Index (ESSPRI) is a patient reported index assessing the severity of pain, dryness and fatigue.<sup>14</sup> The Sj&ouml;gren&rsquo;s Syndrome Disease Damage Index (SSDDI) reports damage accumulation in major organs such as the kidneys, lungs, and peripheral nerves.<sup>15</sup></p> <h2>Salivary glands biopsies</h2> <p>Major (parotid) and minor (labial) salivary gland biopsies play a critical role in pSS diagnostic workup, especially for patients who are anti-SSA/SBB negative. Salivary gland tissue-based studies have helped significantly to understand the pathogenesis of pSS. Parotid gland biopsy is performed less often than labial salivary gland biopsy as it requires more surgical expertise. Salivary gland histology assessment could also help to stratify patients according to their risk of developing lymphoma, a severe complication of pSS. For example, the presence of germinal centres in salivary gland tissue as a risk factor for lymphoma development is being discussed.<sup>16</sup> As salivary glands biopsies are now frequently performed as outcome measures in clinical trials in pSS, a consensus paper aimed at supporting standardisation of this procedure has recently been published.<sup>17</sup></p> <h2>Salivary gland ultrasonography</h2> <p>Salivary gland ultrasonography (SGU) is simple and non-invasive and allows for the assessment of the major salivary glands (parotid and sub-mandibular). The characteristic ultrasound feature in pSS is the heterogeneity of the parenchyma. SGU is not included in the current classification criteria for pSS, but there is an intense research effort aimed at assessing the diagnostic performance of SGU. Recently published data showed a good agreement between SGU and labial gland biopsy outcomes and, when combined with the presence of anti-SSA, SGU highly predicts classification as pSS with commonly used classification criteria.<sup>18</sup></p> <h2>Management</h2> <p>There is currently no curative treatment for pSS. Symptomatic treatment of dry eyes and dry mouth are the mainstay of pSS management. Patients with pSS should pay attention to lid hygiene and oral hygiene and have regular dental check-ups. They often need tear substi&shy;tutes and/or saliva substitutes. Pilocarpine, which is a secretagogue, can also be helpful, when there is residual salivary production, for the management of mouth dryness. The Sj&ouml;gren&rsquo;s Syndrome Foundation has recently published treatment recommendations for pSS.<sup>19</sup><br /> Conventional disease-modifying drugs do not seem to be effective in pSS. How&shy;ever, arthralgia and fatigue are often treated empirically with hydroxychloroquine and low-dose prednisolone. <br /> In terms of biological therapies, two controlled trials studied etanercept and infliximab and failed to show an improvement in outcomes, thus TNF-&alpha; inhibitors are not recommended for pSS.<br /> Rituximab, a monoclonal antibody targeting CD20 and mature B-cells, has been assessed in four randomised controlled trials (RCT). Primary endpoints were not met and rituximab did not demonstrate any significant changes in terms of fatigue and dryness symptoms after one year in patients with low systemic activity.<sup>20, 21</sup> However, evidence from case series and registries support the use of rituximab in patients with high systemic activity and some severe systemic manifestations. Thus, rituximab might be beneficial in selected patients, but there is not enough evidence supporting its general use to treat fatigue and dryness symptoms.<br /> Belimumab, a monoclonal antibody targeting BAFF, is routinely used to treat SLE patients. It has been studied in an open label trial and showed promising results in terms of systemic activity and glandular swelling.<sup>22</sup> A trial is now ongoing in pSS, where belimumab is combined with rituximab.<br /> Abatacept has been studied in two open label trials and showed a significant improvement in systemic complications and patient&rsquo;s symptoms.<sup>23</sup> Two phase 3 RCTs are ongoing.<br /> More research on other targeted therapies is ongoing as there is a renewed interest from pharmaceutical companies to find curative treatments for pSS. For example, there are ongoing controlled trials studying drugs targeting IFN, IL-6 with tocilizumab, CD40, cathepsin S, Bruton tyrosine kinase (BTK), inducible T-cell costimulator (ICOS) ligand and phosphoinositide 3-kinase (PI3K).<br /> In conclusion, this is an exciting time for clinical research on pSS and an in&shy;crease in treatment progress is hoped for in the near future.</p></p> <p class="article-footer"> <a class="literatur" data-toggle="collapse" href="#collapseLiteratur" aria-expanded="false" aria-controls="collapseLiteratur" >Literatur</a> <div class="collapse" id="collapseLiteratur"> <p><strong>1</strong> Brito-Zer&oacute;n P et al.: Nat Rev Dis Prim 2016; 2: 16047 <strong>2</strong> Bowman SJ et al.: J Rheumatol 2010; 37(5): 1010-5 <strong>3</strong> Mandl T et al.: J Rheumatol 2017; 44(2): 209-15 <strong>4</strong> Kivity S et al.: J Autoimmun 2014; 51: 17-22 <strong>5</strong> Campos J et al.: Rheum Dis Clin North Am 2016; 42(3): 473-83 <strong>6</strong> Reksten TR et al.: Rheum Dis Clin North Am 2016; 42(3): 435-47 <strong>7</strong> Brito-Zer&oacute;n P et al.: Ann Rheum Dis 2017; 76(6): 1042-50 <strong>8</strong> Lessard CJ et al.: Nat Genet 2013; 45(11): 1284-92 <strong>9</strong> Chen JQ et al.: Autoimmun Rev 2016; 15(12): 1171-80 <strong>10</strong> Imgenberg-Kreuz J et al.: Ann Rheum Dis 2016; 75(11): 2029-36 <strong>11</strong> Shiboski CH et al.: Ann Rheum Dis 2017; 76(1): 9-16 <strong>12</strong> Seror R et al.: Ann Rheum Dis 2010; 69(6): 1103-9 <strong>13</strong> Seror R et al.: Ann Rheum Dis 2016; 75(11): 1945-50 <strong>14</strong> Seror R et al.: Ann Rheum Dis 2011; 70(6): 968-72 <strong>15</strong> Vitali C et al.: Arthritis Rheum 2007; 56(7): 2223-31 <strong>16</strong> Haacke EA et al.: Ann Rheum Dis 2017; [Epub ahead of print] <strong>17</strong> Fisher BA et al.: Ann Rheum Dis 2017; 76(7): 1161-8 <strong>18</strong> Mossel E et al.: Ann Rheum Dis 2017; [Epub ahead of print] <strong>19</strong> Vivino FB et al.: Rheum Dis Clin North Am 2016; 42(3): 531-51 <strong>20</strong> Devauchelle-Pensec V et al.: Ann Intern Med 2014; 160(4): 233-42 <strong>21</strong> Bowman SJ et al.: Arthritis Rheumatol 2017; 69(7): 1440-50 <strong>22</strong> Mariette X et al.: Ann Rheum Dis 2015; 74(3): 526-31 <strong>23</strong> Haacke EA et al.: Clin Exp Rheumatol 2017; 35(2): 317-20</p> </div> </p>
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