Review One year in review 2020: comorbidities, diagnosis and treatment of primary Sjögren’s syndrome V. Manfrè1, G. Cafaro2, I. Riccucci2, A. Zabotti1, C. Perricone2, H. Bootsma3, S. De Vita1, E. Bartoloni2

1Clinic of Rheumatology, DAME, ABSTRACT Clinical phenotypes and University Hospital Santa Maria della Primary Sjögren’s syndrome (pSS) is comorbidities Misericordia, Udine; a complex and heterogeneous disor- Glandular manifestations 2Rheumatology Unit, Department of der characterised by a wide spectrum Involvement of the exocrine glands Medicine, University of Perugia, Italy; 3Department of Rheumatology and of glandular and extra-glandular fea- represents the main feature of pSS. In a Clinical Immunology, University tures. The discovery of novel biomark- recent analysis of a prospective multi- Medical Centre Groningen, University ers allowed to characterise the disease centre Spanish cohort of more than 400 of Groningen, the Netherlands. not only phenotypically on the basis of pSS patients, about 94% complained Valeria Manfrè*, MD clinical presentation, but also on the ba- dry eye or dry mouth symptoms at Giacomo Cafaro*, MD sis of the endotype. Moreover, a better diagnosis and around 30% of patients Ilenia Riccucci, MD stratification of patients has important presented with unilateral or bilateral Alen Zabotti, MD value in the evaluation of mechanisms parotid gland enlargement (6). Moreo- Carlo Perricone, MD, PhD underlying the risk of lymphoprolifera- ver, the severity of sicca symptoms Hendrika Bootsma, MD, PhD Salvatore De Vita, MD tive disorders in these patients. Finally, may hamper the quality of life. Dry eye Elena Bartoloni, MD novel targeted therapies may open new in pSS has more severe clinical course *These two authors equally. possibilities for the application of per- and functional damage in comparison Please address correspondence to: sonalised medicine in pSS. to non-SS dry eye. In order to better Salvatore De Vita, characterise features of dry eye in pSS, Clinica di Reumatologia, Introduction Yoon et al. performed a cross-sectional Dipartimento di Medicina (DAME), Primary Sjögren’s syndrome (pSS) is a study evaluating 91 pSS diagnosed ac- ASUFC Università di Udine, chronic systemic autoimmune disease cording to the 2012 American College Piazzale Santa Maria della characterised by a wide spectrum of of Rheumatology (ACR) criteria and Misericordia, 15 clinical features, extending from exo- 55 non-SS subjects with dry eye (7). 33100 Udine, Italy. E-mail: [email protected] crine involvement to extra-glandular Markers of ocular damage, including manifestations. Growing efforts have tear break-up time (BUT), Schirmer Received on June 29, 2020; accepted in revised form on July 29, 2020. been made during the last months to test I and corneal/conjunctival staining deeper characterise the disease, its scores, were significantly worse in pSS Clin Exp Rheumatol 2020; 38 (Suppl. 126): S10-S22. pathogenetic pathways and ultimate patients. Moreover, Authors compared searching for novel biomarkers that the characteristics of dry eye in pSS pa- © Copyright Clinical and Experimental Rheumatology 2020. may allow an earlier diagnosis and a tients who did and did not satisfy the more precise therapeutic intervention. 2016 ACR-European League Against Key words: Sjögren’s syndrome, In this review, following previous oth- Rheumatism (EULAR) classification lymphoproliferative, salivary gland ers (1-5), we will summarise the most criteria. Interestingly, there were no ultrasonography, comorbidities, recent literature on SS clinical presen- significant differences between the two therapy tation, diagnosis and treatment. More- groups in immunologic parameters as over, interest will be directed to the well as ocular surface scores while fo- analysis of recent literature on lym- cus score was higher in the group of phoproliferative risk and application patients fulfilling the 2016 ACR/EU- of salivary gland ultrasonography as LAR classification criteria (7). These diagnostic tool. Finally, we will high- data were further confirmed in a case- light the state of the art of pSS therapy. control study comparing features and In this perspective, we have performed medical and occupational history in a Medline search of English language patients with pSS, dry eye syndrome articles published in the PubMed da- and B-cell non-Hodgkin’s lymphoma tabase from 1st January 2019 to 31st (8). Primary SS patients were charac- Competing interests: none declared. December 2019. terised by an increased dryness sever-

S-10 Clinical and Experimental Rheumatology 2020 One year in review 2020: Sjögren’s syndrome / V. Manfrè et al. ity in comparison to subjects with dry of plaque and gingival bleeding. A re- specific. Even though lung involve- eye syndrome and healthy controls (8). cent population-based study found that ment may be present in nearly one fifth Interestingly, some novel autoantibod- patients with PD have a 50% increased of patients, it is often under-evaluated ies, including anti-salivary gland pro- risk of subsequent pSS, thus suggest- despite its important clinical implica- tein 1 (SP1), anti-carbonic anhydrase 6 ing that immune-mediated inflamma- tions. Moreover, patients with pulmo- (CA6) and anti-parotid secretory pro- tory mechanisms may contribute to this nary involvement have a decreased tein (PSP), suggested as useful markers association (12). However, conclusive quality of life and an increased mor- to identify pSS patients at early stage, evidence regarding increased risk of tality as compared to patients with- may be associated with dry eye occur- PD in pSS patients is lacking. A recent out lung disease (15, 16). Respiratory rence in these patients. In particular, meta-analysis and systematic review tract involvement in pSS may cause anti-CA6 were associated with severe evaluated PD prevalence in a cohort of tracheal, bronchiolar, and pulmonary aqueous deficient dry eye (9). Howev- 228 pSS patients (13). Outcome meas- complications including xerotrachea, er, future longitudinal larger studies are ures included plaque index, gingival bronchiolitis and bronchiectasis, pul- needed to evaluate their specificity in index, pocket-probing depth, clinical monary cysts and bronchus or lung- screening dry eye subjects for SS. attachment loss, decayed missing filled associated lymphomas (16, 17). In- Dry mouth represents an adjunctive teeth and decayed missing filling sur- terstitial lung disease (ILD) has been discomfort in these patients and sig- faces. No significant increased risk of reported in 3-11% of pSS patients and nificantly affects oral health. There are PD was observed in pSS patients in represents a significant cause of - mor data supporting a link between low sal- comparison to controls except for high- bidity due to its variable course. Non- ivary flow rates and increased risk for er susceptibility to caries in the former specific interstitial pneumonitis (NSIP) dental caries both in pSS patients and group. is the most common subtype, followed in subjects with other causes of sali- by usual interstitial pneumonia (UIP), vary hypofunction. A recent retrospec- Take home messages lymphoid interstitial pneumonia (LIP) tive study compared the risk factors for • Dry eye is more severe in patients and organising pneumonia (OP) (16). caries between patients with pSS sali- with SS, compared to subjects with Considering that patients with pSS- vary hypofunction and subjects with non-SS dry eye (7, 8). ILD may have a different prognosis, non-SS salivary hypofunction (10). • PSS patients have higher prevalence researchers focused on factors predic- The pSS group had a significant higher of dental caries, probably not only due tive of ILD development at disease number of total caries in comparison to to hyposalivation but also to altered diagnosis. Among these, older age, other groups. Interestingly, in the pSS mouth microbiota (10, 11). Raynaud’s phenomenon and oesopha- group, a focus score greater than 1 was geal involvement have been identified the only factor associated with a great- Extraglandular manifestations as predictive factors associated with er number of total caries (10). Thus, the There is growing awareness that extra- poorer outcome (15). In a retrospec- increased risk of caries in pSS patients glandular manifestations represent a tive multicentre study including 99 is not sufficiently explained by salivary clinical challenge in pSS patients due pSS patients with ILD, Kamiya et al. hyposalivation, and other pSS-related to the heterogeneous clinical presenta- demonstrated that elevated serum lev- factors should be investigated. In this tions. The analysis of a huge interna- els of Krebs von den Lungen-6 (KL-6), setting, a recent study explored the as- tional cohort of pSS patients enrolled a mucin-like glycoprotein expressed sociation between low salivary flow in the Big Data Sjögren Project Con- on type II alveolar epithelial cells, are and altered oral microbial homeostasis sortium registry showed that more than associated with higher mortality rate in pSS patients, non-SS sicca symp- a quarter of patients may have systemic (18). In addition, lower forced vital ca- toms and healthy controls (11). The manifestations not currently included pacity and older age at diagnosis were analysis of oral microbiota revealed in the EULAR SS Disease Activity significantly associated with worse dysbiosis in the salivary microbiota Index (ESSDAI), cardiovascular (CV) survival (18). Chest high-resolution from pSS and non-SS patients com- manifestations being the most frequent computed tomography (CT) patterns pared to healthy controls. In particular, (14). Moreover, although many of may also suggest worse outcome. In a the salivary microbiome in the pSS these manifestations are usually mild retrospective study, Guisado-Vasco et group, characterised by lower abun- and do not affect patient prognosis, al. evaluated the value of a quantitative dance of Neisseria and Porphyromonas some may have a relevant impact on CT (QCT) index in identifying the ex- and a higher abundance of Veillonella, disease outcome and patient quality of tension of lung disease in pSS patients differed significantly from non-SS life (14). In recent years, considerable with ILD (19). There was a statistically group, thus suggesting that hyposaliva- effort was directed to the investigation significant difference in QCT index tion alone is not necessarily the cause of biomarkers which may identify spe- distribution between pSS patients with of dysbiosis in pSS (11). Finally, xeros- cific disease phenotypes (15). and without ILD. Moreover, higher tomia in pSS patients may be associ- Clinical manifestations related to lung scores identified patients with more ex- ated with higher risk of periodontal dis- involvement in pSS patients are varied tensive parenchymal involvement (19). ease (PD), including higher prevalence and initial symptoms are usually non- Among serologic markers, a retrospec-

Clinical and Experimental Rheumatology 2020 S-11 One year in review 2020: Sjögren’s syndrome / V. Manfrè et al. tive analysis of the medical records of ative prognostic outcome (24). In fact, sion was observed during follow-up, in- a wide cohort of Korean pSS patients these patients usually experience high- cluding all pSS patients with anti-CCP without features of antineutrophil cy- er level of disease activity and onset or antibodies, and immunosuppressive toplasmic antibody (ANCA) vasculitis worsening of disease activity in the pe- agents, including hydroxychloroquine, demonstrated that positivity of ANCA- ripheral nervous system (PNS) domain methotrexate and rituximab, showed a myeloperoxidase at baseline is predic- is significantly associated with higher similar good efficacy in reducing pain tive of ILD development in pSS (20). level of disease activity after long- and joint inflammation (30). A recent Among the wide spectrum of systemic term follow-up (25). Finally, it exerts systematic review and meta-analysis extra-glandular manifestations, renal a negative impact on patient quality of ten studies involving 1322 pSS pa- involvement may significantly influ- of life due to its disabling symptoms, tients demonstrated that anti-CCP anti- ence disease course due to its insidious often requiring immunosuppressive bodies are associated with a significant clinical appearance which may delay therapies (26). Neurological mani- four-fold higher risk of arthritis in pSS the diagnosis. In a recent analysis of festations account for 10% to 60% of patients and with development of RA 20 pSS patients, tubulointerstitial ne- cases, being the PNS involvement the (31). phritis (TIN) occurred near or prior to most frequently reported (24). Sensory It is well known that pSS is frequently the onset of sicca symptoms manifest- or pure sensory neuropathies, in par- associated with organ-specific auto- ing as distal renal tubular acidosis with ticular painful small-fibre neuropathy immune disorders, in particular with hypokalaemia (21). On the opposite, (SFN) and dorsal root ganglionopathy, autoimmune thyroid disease. In or- glomerular involvement, mainly mem- have been frequently described as pe- der to evaluate if autoimmune thyroid branoproliferative glomerulonephritis culiar features (24). These patients are disease represents a distinct nosologic (GN) with cryoglobulinaemia, mani- characterised by a distinct clinical and condition differing from pSS, Anaya fested years after disease onset with serologic profile as highlighted in a et al. performed a retrospective analy- chronic kidney disease, haematuria or recent cross-sectional study involving sis of about 300 pSS patients compar- nephrotic proteinuria (21). Moreover, pSS patients with biopsy-proven SFN. ing clinical and serologic features of TIN was characterised by indolent Patients with SFN were mainly male patients with pSS alone and patients course not responding to immunosup- and had decreased frequency of anti- with pSS and Hashimoto’s thyroiditis pressive therapy while GN showed a SSA/Ro 52/60 antibodies and of rheu- (HT) (32). Primary SS with HT were favourable response to immunosup- matoid factor (27). Similarly, in a wide characterised by higher prevalence of pressive agents, including rituximab, prospective Korean cohort analysis, lymphadenopathy and urticaria while mycophenolate mofetil and cyclophos- anti-SSA/Ro-negative patients were anti-Ro/SSA antibodies were more phamide (21). Researchers investigated characterised by higher prevalence of frequent in the pSS group, suggest- biomarkers useful in identifying renal PNS at ESSDAI domain in comparison ing that, although SS and autoimmune disease in pSS. In a wide pSS cohort, to anti-SSA/Ro-positive (28). thyroid disease share common physi- renal involvement was associated with Besides the glandular disease, joint in- opathologic mechanisms as part of the higher levels of creatinine, cystatin C, volvement represents one of the most autoimmune background, they should and alpha-1-microglobulin (α1-MG) frequent disease manifestations. It has be considered two different entities. (22). Similarly, in a large cross-sec- been reported in 20% up to 60% of In the recent years, convincing evi- tional study of more than four hun- pSS patients, and about one third pre- dence suggested that patients with sys- dred Chinese pSS patients, histologi- sents synovitis resembling rheumatoid temic rheumatic diseases, in particular cal positivity of salivary gland biopsy, arthritis (RA) (29). In order to charac- pSS, may have an increased risk of coe- reduced C3 levels, hypoalbuminaemia terise the features and the therapeutic liac disease (CD). A recent multicentre, and anaemia were significantly associ- outcome of pSS-associated arthritis, case-control, Italian study involving ated with higher risk of renal involve- Mirouse et al. performed a retrospec- more than 1,400 patients with systemic ment. Interestingly, xerophthalmia and tive analysis of a French cohort of 57 autoimmune diseases, including pSS, anti-SSA/Ro52 positivity displayed a pSS patients with at least one episode systemic lupus erythematosus (SLE) negative association (23). This study of clinical and/or echography detected and systemic sclerosis, reinforced this suggests that pSS patients with renal synovitis (30). Patients with synovitis hypothesis (33). Primary SS patients involvement are characterised by a were characterised by higher frequency were characterised by significant high- distinctive clinical profile with higher of parotid gland swelling, lymph node er prevalence of CD in comparison to disease activity, higher prevalence of enlargement and a significantly higher a wide general population (6.78% vs. salivary gland biopsy positivity and el- ESSDAI score in comparison to pa- 0.64%). Moreover, pSS patients with evated inflammation, but a lower prev- tients without synovitis. No difference CD were younger at autoimmune dis- alence of xerophthalmia. between groups was detected regarding ease diagnosis in comparison to non- Neurological involvement represents a acute phase reactants, rheumatoid fac- coeliac group, thus suggesting that relevant clinical challenge in these pa- tor positivity or detectable anti-cyclic screening for CD may be considered in tients due to its heterogeneous presen- citrullinated peptide (CCP) antibodies. young pSS patients, especially at dis- tation, diagnostic complexity and neg- Of note, no structural erosive progres- ease diagnosis.

S-12 Clinical and Experimental Rheumatology 2020 One year in review 2020: Sjögren’s syndrome / V. Manfrè et al.

It is important to consider that concom- major CV events. The first was charac- immune checkpoint inhibitors (ICI)s, itant comorbidities, including infection terised by close interconnection of tra- and sicca syndrome is described as a risk, CV disease and non-lymphoma ne- ditional CV risk factors to each other complication of ICI therapy. Recently, oplastic diseases (in particular, thyroid and to pSS glandular involvement. The Warner et al. evaluated 20 patients who gland cancer), may also influence pSS- second pattern, including ischaemic developed sicca syndrome after ICI related morbidity and mortality (34). CV events, was closely associated with treatment (50). The median interval Indeed, pSS patients are characterised extra-glandular disease activity, longer between ICI introduction and symptom by increased prevalence of subclinical disease duration and some clinical or onset was 70 days. Dry mouth, assessed atherosclerosis and higher risk of both serological manifestations typical of by reduction of whole unstimulated sa- cerebrovascular and CV events in com- the autoimmune phenotype, including liva flow, was reported in all patients. parison to general population (35-37). purpura, leukopenia, low complement Acute dry eye developed in 6 patients Multiple interacting mechanisms have and cryoglobulinaemia. of which 5 had a positive Schirmer test been associated to the acceleration of Finally, pSS patients complain a re- in at least one eye. Only 3 patients had subclinical atherosclerosis and CV duced quality of life as result of sys- positive test for anti-nuclear antibody damage in these patients. Traditional temic chronic symptoms, like fatigue, (ANA) and 2 for rheumatoid factor and CV risk factors play a relevant role depression and anxiety, which signifi- anti-SSA antibodies. Almost all patients in the contribution to atherosclerotic cantly affect health-related quality of underwent labial salivary gland biopsy damage, as recently highlighted (38). life (HRQoL). Indeed, HRQoL reduc- with demonstration of a mild chronic In particular, hypertension emerged as tion in pSS is similar to that reported sialadenitis with focal lymphocytic a prominent CV risk factor being more in other systemic rheumatic disorders, infiltration in the majority of patients. prevalent in these patients and associ- as RA and SLE (45). In pSS patients, Interestingly, inflammatory infiltrate ated with increased risk of overt CV impaired HRQoL is associated with was mainly characterised by predomi- events (39, 40). In a recent study re- fatigue, pain, articular involvement, nance of CD3+ and CD4+ T cells with cruiting a cohort of 367 pSS patients, sicca symptoms, pulmonary mani- paucity of CD20 B cells. In addition to hypertension, older age and extra- festations, psychological dysfunction supportive measures and ICI therapy glandular involvement were indepen- and impaired physical function (45). withdrawn, corticosteroids therapy was dently correlated with CV events (41). Patients complain sleep problems, re- employed in almost all patients. Secondly, inflammatory mediators and duced sleep efficiency and daytime Ramos-Casals et al., in the Immuno disease-related immune markers coop- hyper-somnolence (46). In addition, Cancer International Registry, identi- erate with traditional CV risk factors mood and several neuropsychological fied a total of 26 patients who -devel in the pathogenesis of atherosclerotic domains such as cognition difficulties oped sicca syndrome after treatment damage (42). In particular, the high- with attention, focusing, memory and with ICI (51). These patients were est CV risk appears to be associated new learning, are commonly reported mainly men with a median age at di- with circulating anti-Ro/SSA and La/ problems in pSS (47). In order to bet- agnosis of 64 years. Of these, 25 pa- SSB, as demonstrated in a recent case- ter characterise factors contributing to tients developed dry mouth and 17 dry control study with a median follow-up fatigue in these patients, Pertovaara et eyes. Minor salivary gland biopsy was of 10 years (43). Finally, adjunctive al. have analysed a cohort of 100 pSS performed in 15 patients and depicted features, like disease duration, may patients and depicted that fatigue was mild chronic sialadenitis in 8 subjects further increase CV morbidity in pSS associated with disease duration and and focal lymphocytic sialadenitis in (43). In order to evaluate the interplay some inflammatory markers (48). Om- the remaining 7. Immunological mark- between disease-specific inflammatory dal et al. hypothesised that, besides in- ers included positive ANA and anti-Ro/ and autoimmune features, and tradi- flammation and cellular stress respons- SSA in the majority of cases. In sum- tional CV risk factors in influencing es, pain represents another activator of mary, ICIs should be included in the CV risk, an artificial neural network the sickness response, therefore induc- list of drugs causing sicca symptoms analysis has been recently applied to ing fatigue. In particular, interleukin but patients developing sicca syndrome a cohort of 408 pSS patients (44). In- (IL)-1β signalling in the brain possibly after therapy introduction display a terestingly, in the entire cohort, hy- represents a final common pathway for specific phenotype different from pSS, pertension resulted the most prevalent fatigue. Interleukin-1β has also been mainly characterised by increased traditional CV risk factor and patients implicated in depression, thus explain- prevalence of males, higher age at di- presenting with at least one CV event ing why fatigue and depression are so agnosis, negative immunologic profile displayed significant higher prevalence tightly associated (49). and extra-glandular involvement (51). of hypertension (77%) with respect to subjects free from CV comorbidity Sicca syndrome and immune Take home messages (35%). This new data mining computa- checkpoint inhibitors • Over one quarter of patients with pSS tional analysis allowed to identify two Rheumatic immune-related adverse display extra-glandular manifestations different patterns of distribution in CV events are often reported in patients not included among ESSDAI domains risk factors, pSS-related features and with cancer receiving therapy with (14).

Clinical and Experimental Rheumatology 2020 S-13 One year in review 2020: Sjögren’s syndrome / V. Manfrè et al.

• Alpha-1-microglobulin (α1-MG) may was similar in all the pSS biopsies, al- in associated autoimmune conditions prove a useful biomarker for renal in- though significantly higher than in con- (17.3%) in patients with DLBCL volvement in pSS (21, 22). trols. Finally, TSLP expression by sali- treated with R-CHOP/CHOP-like regi- • Patients with peripheral nervous sys- vary epithelium declined along with mens, compared to the general popula- tem involvement usually display more the progression of B-cell lymphopro- tion (3-10%) (59). Furthermore, NHL active systemic disease and lower liferation, the B-cells themselves in- associated with those with autoimmune prevalence of sicca features (24, 28). creasingly becoming TSLP-positive. A conditions driven by B-cell responses, • PSS-associated arthritis is usually pathogenetic role of TSLP in pSS-as- mainly women with pSS, SLE and RA, non-erosive and subjects with positive sociated lymphoproliferation was then had a worse survival (59). anti-CCP autoantibodies are at higher supported (55). Paediatric pSS is a relevant subset of risk of developing RA (30, 31). The role of TREX1 on the risk of pSS pSS. Tesher et al. presented two cases • Other autoimmune diseases, such as and pSS-related lymphoma was ex- of paediatric pSS and reviewed the autoimmune thyroiditis and coeliac plored by Nezos et al. The expression literature. Importantly, one of the two disease are more prevalent in pSS sub- of three single nucleotide polymor- patients was successfully treated with jects compared to the general popula- phisms of the TREX1 gene (rs11797, rituximab and hydroxychloroquine, tion (32, 33). rs3135941 and rs3135945) and of IFN- and did not need chemotherapy. The • Immune-checkpoint inhibitors can in- I genes was evaluated in patients with clinical differential diagnosis between duce sicca syndrome with features of pSS, pSS-associated lymphoma and non-malignant parotitis and parotid sialadenitis, though clinically, serolog- healthy controls. Patients carrying the NHL in pSS was also stressed by the ically and pathologically distinct from rs11797 AA genotype had increased Authors (60). SS (50, 51). type I IFN-related gene expression in A useful review by Talotta et al. inte- minor salivary glands. Significantly grates the role of dysbiosis and chronic Lymphoma in pSS: what is new? decreased prevalence of the rs11797 infections with the epigenetic control Novel biomarkers A minor allele was detected in pSS pa- of gene expression in pSS patients, Low miR200b-5p levels in minor tients with non-MALT lymphoma. A and their possible involvement in B- salivary glands (MSGs) represent a genetically related defective type I IFN cell lymphomagenesis (61). These fac- proposed novel predictor for the de- production could represent a potential tors act by inducing hyperexpression velopment of lymphoma in pSS. Ka- mechanism in pSS-related lymphom- of genes that are mainly involved in psogeorgou et al. provided additional agenesis (56). the innate and adaptive immune re- data supporting low miR200b-5p as an sponses and oncogenesis. Major ones independent predictor, since the pre- Pathogenetic issues are the interferon-I (IFN-I) and IFN- dicting power resulted independent Gorodetskiy et al. examined the clonal II signature (62) and IFN regulatory from the degree of MSGs infiltration relationship between low- and high- factor 5, mediating both viral latency and focus score (52-54). Another novel grade NHLs in pSS. Data from 6 pSS and B-cell transformation (63, 64). biomarker of lymphoproliferation in patients who had developed MZL and Microbial agents may also promote pSS indicated by Gandolfo et al. is synchronous or metachronous DLBC the activation of proinflammatory and thymic stromal lymphopoietin (TSLP). were analysed, identifying immuno- survival pathways in the salivary gland Significantly higher TSLP serum levels globulin heavy chain gene rearrange- epithelium and lymphocytes, through were found in pSS patients and, impor- ments by means of multiplex PCR the alteration of the epigenetic back- tantly, they increased from fully benign and GeneScan fragment analysis. In ground, giving to B and T lymphocytes infiltrates to parotid myoephitelial- si 5/6 cases, low and high-grade tumour an activated or transformed phenotype. aladenitis (MESA) and finally to NHL. pairs showed identical clonal pat- The role of transposable integrated ret- Of note, TSLP was also studied in pSS terns, despite being located in different roviral elements in B-cell deregulation pathologic tissues, again stratified from sites. Then, the concept that DLBCL was also commented (65). The review fully benign, MESA and NHL, and in frequently results from low-grade by Nakamura et al. is of value to con- controls. Both RT-PCR immunohis- lymphoma progression in pSS is sup- sider pSS-related lymphomagenesis in tochemistry and immunofluorescence ported (57). Xian et al. investigated the light of marginal zone/MALT lym- were used. A significant increase in the the association between B-cell growth phomagenesis in general, the Authors percentage of TSLP-positive B-cells factors and pSS-related autoantibod- focusing on the latter (66). along with the worsening of B-cell ies in patients with NHL, analysing lymphoproliferation was evidenced, BAFF, anti-SSA/Ro, IL-14, and tissue Lymphoma risk and lymphoma maximal in NHL. Furthermore, induc- specific autoantibodies (TSA) includ- diagnosis ible TSLP (the long isoform of TSLP ing SP1, CA6 and PSP (58). However, A novel methodology to develop lym- mRNA) was detected only in higher also a high number of pSS-unrelated phoma prediction in pSS patients, giv- grades of B-cell lymphoproliferation control NHLs patients were positive ing emphasis also on a quality control (MESA and NHL), whereas the short for pSS-associated antibodies in this pipeline for clinical data, was presented constitutive isoform of TSLP mRNA study. Mörth et al. detected an increase by Pezoulas et al. (67, 68). Such meth-

S-14 Clinical and Experimental Rheumatology 2020 One year in review 2020: Sjögren’s syndrome / V. Manfrè et al. odology is represented by a first rule- Take home messages SGUS-guided CNB was targeted to the based, binary supervised learning mod- • Thymic stromal lymphopoietin most suspicious sonographic detected el. A boosted decision tree model was (TSLP) expression in salivary glands glandular area, allowing the sampling used to identify prominent features with correlates with the degree of lym- of parotid and submandibular glandu- increased importance for lymphoma de- phoproliferation and is highest in non- lar tissues with different sonographic velopment in pSS. The results showed Hodgkin’s lymphoma (55). patterns. A targeted sonographic ap- an average accuracy 87.1% with an av- • Diffuse large B-cell lymphoma may proach improves the ability of SGUS- erage area under the curve (AUC) score represent a progression from low-grade guided CNB for differential diagnosis, 88%. This model supported the impor- B-cell lymphoma (57, 58). and also sarcoidosis and IgG4-related tance of C4, rheumatoid factor and lym- • Dysbiosis and chronic infections may disease were diagnosed. Importantly, phadenopathy as prominent lymphoma be able to promote B-cell proliferation the observation of fewer long-term and predictors, along with major salivary and transformation by epigenetic mod- transient complications in SGUS-guid- gland enlargement (67, 68). ulation of cell survival pathways (61). ed CNB in comparison to open surgical Prediction of lymphoma in pSS was • A composite prediction score for lym- biopsy, as reported, could have a high reviewed by several Authors. When phoma development is currently under impact on the patient’s acceptance of analysing classic and novel predictive investigation (72, 73). the proposed biopsy (76). Last-gener- markers of NHL, Kapsogeorgou et al. ation ultra-high-resolution ultrasound highlighted the relevance of recent Salivary gland ultrasonograpy (UHFUS) transducers, which can pro- multifactorial predicting models, and (SGUS)-assisted developments: duce frequencies up to 70 MHz and of novel analytical approaches in gen- salivary gland biopsy, image achieve tissue resolution up to 30μm, eral. These are based on machine learn- segmentation, glandular damage offer new possibilities to visualise labi- ing and on big data analyses, to permit and evaluation of disease activity al salivary glands and to guide diagnos- harmonisation of patients and the crea- Ultrasound-guided salivary gland tic biopsy procedure. Recently, Baldini tion of universal algorithms (69). biopsy et al. demonstrated that the mean labial Nocturne et al. highlighted the need of Salivary gland ultrasound-guided core glandular surface area obtained by the an international consensus on salivary needle biopsy (SGUS-guided CNB) is high-resolution ultrasound guided pro- gland histopathology in pSS and on an established, effective and safe pro- cedure was significantly higher than the the immunohistological definition of cedure currently applied in the diag- area obtained by traditional biopsy pro- germinal centres (70). The relevance nosis of salivary gland masses, mainly cedure. This procedure could facilitate of histopathology was also stressed by epithelial tumours. SGUS-guided CNB the assessment of the focus score (77). Delli et al. (71). The pathogenetic role might have a role also in the manage- of CD21 low B cells and SCOLYSS ment of the frequent pSS patients with The application of image-segmentation were also reported. SCOLYSS is a salivary gland enlargement, that could and of artificial intelligence to SGUS recently proposed composite score to underlie an already established lym- The significant intra- and inter-rater predict the risk of lymphoma in pSS, phoma or be a pre-lymphomatous pro- disagreement in SGUS scoring is cur- and is currently under investigation. It cess. Recently, two pilot studies have rently considered as a major obsta- was reported that seven simple varia- highlighted the role of SGUS-guided cle for the acceptance of SGUS as a bles, easy to be evaluated will be used: CNB as a safe and useful technique classification and management tool the variables to build SCOLYSS have for evaluation of suspected salivary for pSS. As an alternative to human- then been established a priori (70). gland lymphoma in pSS patients. In dependent assessment of sonographic Goules et al. reviewed the more recent- a retrospective study in patients with lesions from SGUS, it is possible to ly proposed molecular and genetic bio- suspected parotid lymphoma, Baer et employ computer algorithms for tex- markers for pSS-associated lymphoma al. described that SGUS-guided CNB ture analysis and use the extracted fea- prediction (72), and Retamozo et al. provided sufficient pathologic mate- tures to develop artificial intelligence emphasised the importance of studying rial to differentiate a range of salivary (AI) algorithms to assist human ex- synergistic models of lymphoma risk gland pathologic findings, from -nor perts in SGUS scorings (78). Recently, (73). mal salivary gland tissue to a diffuse Vukicevic et al. in a multi-centre col- Regarding the diagnosis of NHL in pSS, lymphocytic infiltration, representing laboration in the HarmonicSS project, Keraen et al. retrospectively examined either benign lymphoepithelial sialad- tested various radiomics-based AI the usefulness of 18F-FDG-PET-CT. enitis or MALT lymphoma (75). The algorithms for SGUS scoring in pSS The Authors reported three PET pat- accuracy of SGUS-guided CNB for the patients, identifying AI algorithms that terns associated with the presence of diagnosis of salivary gland lymphoma performed as human experts and could lymphoma in pSS with moderate to has been recently confirmed by Zabotti be therefore useful to assist clinicians high systemic disease activity. PET-TC et al. in a prospective cohort of pSS in SGUS (79). The diagnostic perfor- was found useful also in guiding the patients with parotid or submandibular mance of a deep learning system for histologic diagnostic procedure and in gland enlargement (76). Furthermore, the detection of pSS by SGUS in 100 monitoring response to treatment (74). differently from the previous study, patients with a confirmed diagnosis of

Clinical and Experimental Rheumatology 2020 S-15 One year in review 2020: Sjögren’s syndrome / V. Manfrè et al. pSS according to classification criteria rogates” of pathologic MALT involve- cytokine secretion via inhibition of au- was studied (80). The authors conclud- ment, clinical (e.g. parotid swelling tophagy (87). ed that the deep learning system had a and cryoglobulinaemic vasculitis) and Local cyclosporin A (CyA) is rou- high diagnostic ability for pSS by the laboratory (e.g. low C4, cryoglobuli- tinely used to treat xerophthalmia and use of SGUS images (80). The increase naemia, rheumatoid factor/idiotypes, corneal damage in SS. Despite hav- in case collection and sonographic im- free immunoglobulin light chains, se- ing demonstrated beneficial effects, its ages is needed. rum beta 2 microglobulin). The pres- use is limited by the poor tolerability ence of surrogates was introduced to and bioavailability due to the scarce Salivary gland damage allow some evaluation also when tis- hydrosolubility of the molecule. Sci- The role of the SGUS in monitoring sue biopsy is not available or cannot be entific efforts are therefore concen- the history of pSS in a non-invasive repeated, for any reason. trated towards an improvement of the manner, the response to treatment, in pharmacokinetics properties of topical predicting the outcomes and in detect- Take home messages CyA. A pooled analysis of the results ing lymphoma, although promising, is • Salivary gland ultrasound-guided of two phase III randomised clinical still not well delineated (81). The SG core needle biopsy is a safe and useful trials that tested the effect of a cationic abnormalities due to pSS are believed technique for evaluation of suspected emulsion of CyA on dry eye has been to progress slowly over time, resulting salivary gland lymphoma in pSS pa- recently performed with involvement in changes in SGUS findings. Based on tients (75, 76). of 734 patients of which about 1/3 had the present knowledge, SGUS could • Application of salivary gland ultra- SS-related sicca syndrome. The results help to identify active inflammatory le- sonography may have importance in showed a significant effect on signs sions, namely the hypo-anechoic areas, the evaluation of disease activity for and symptoms in the group of pSS pa- and the damage-related lesions, the hy- the future (84, 85). tients with severe dry eye, but not in perechoic bands (82). In a recent study, the overall pSS population, with a tol- the hyperechoic bands were identified What is novel in the erability profile equivalent to standard as the sonographic lesions mainly asso- treatment of pSS CyA formulations (88). Recently, as ciated with SG impairment, objectively It is well known that the majority of pSS an emulsion formulation tends to floc- evaluated by reduced salivary flow patients only manifest dry eye and dry culate and sediment over time, a more rate, in pSS patients with a disease du- mouth-related symptoms, which, how- stable and bioavailable nanoemulsion ration ≥5 years (83). ever, may have a severe impact on qual- has been tested in a clinical trial in ity of life. Current treatment is based South Korea with promising results. In Evaluation of pSS activity on local tear and saliva substitutes, fact, it improved both symptoms and It was recently highlighted that the immunosuppressants and systemic signs of dry eye with an equivalent ef- quantification of inflammation and secretagogues, though these strategies ficacy compared to the approved- for lymphoproliferation within the sali- are frequently ineffective and scarcely mulation of CyA. However, the effect vary MALT can be a novel tool to tolerated. For these reasons, a strong of the nanoemulsion was evident at an evaluate pSS disease activity (84, 85), scientific effort in this field is directed earlier time-point, presumably due to also related to the lymphoma risk. towards new potential approaches to its higher bioavailability (89). Despite being the pathobiologic and treat sicca syndrome. Recently, new in- Other immunosuppressants are un- phenotypic essence of pSS, glandular teresting data have been published from dergoing investigation for the local inflammation and lymphoproliferation in vitro, animal studies, clinical trials treatment of dry eye in pSS, such as contributes limitedly to ESSDAI. Fur- and observational studies. sirolimus, which exerts its activity by thermore, ESSDAI is low in about 30% Although there is no strong evidence inhibiting the signal transduction of in- of pSS who develop NHL and does not from clinical trials in support of the ef- terleukin (IL)-2 and, therefore, the ac- appear as a good predictor (86). In fect of conventional disease-modifying tivation of B and T cells, essential play- a cohort of 30 pSS cases with NHL, antirheumatic drugs (DMARD) on tear ers in the pathogenesis of the disease. persistent SG swelling and cryoglob- and saliva production, nor on the at- Its potency is higher compared to CyA ulinaemia were the major predictors of tenuation of sicca symptoms, evidence but similar in terms of water solubility, NHL in pSS. They mirror B-cell clones showing efficacy in animal models is limiting its capability of penetrating the employing peculiar rheumatoid-factor- growing. Lee et al. demonstrated that tear film barrier. Nonetheless, subcon- related immunoglobulin genes, prone NOD mice, a mouse model of diabetes junctival injection of sirolimus follow- to malignant transformation. A recent that spontaneously develop sialoadeni- ing microencapsulation in NOD mice subproject within the HarmonicSS pro- tis resembling SS, treated with chloro- showed a dose-dependent improve- ject (https://www.harmonicss.eu) is the quine in the early stages of the disease ment of tear secretion and corneal dam- creation of a new composite activity are characterised by improvement of age compared to controls, suggesting a index for pSS, based on histopathol- tear secretion, corneal damage, lacri- potential benefit in pSS patients (90). ogy as the golden standard whenever mal and salivary gland inflammatory The mTOR signalling pathway regu- possible, but also with additional “sur- cell infiltration and pro-inflammatory lated by sirolimus is also inhibited by

S-16 Clinical and Experimental Rheumatology 2020 One year in review 2020: Sjögren’s syndrome / V. Manfrè et al. metformin, via the activation of AMP- have the great advantage of being ac- complicate with the development of activated protein kinase (AMPK). It cessible and easy to extract. Their abil- abrasions, ulcerations and occasionally is known that the inhibition of mTOR ity to modulate the immune response corneal perforations, which require a in T cells promotes their preferential is now well established, however more more aggressive treatment. Shafer et differentiation towards a regulatory data are necessary to characterise their al. have attempted the use of cryopre- (Treg) phenotype. Similarly, AMPK behaviour in vivo. In a rabbit model of served amniotic membrane, locally ap- activation causes inhibition of signal dacryoadenitis, hUCMS were shown plied on the ocular surface, and showed transducer and activator of transcrip- to promote macrophage polarisation that after few days the symptoms and tion (STAT)3 which is involved in the towards an M2 phenotype, therefore ocular surface damage dramatically differentiation of Th17 and T follicular favouring an anti-inflammatory behav- improved, although the benefit was helper (Tfh) cells. Based on these data, iour and ultimately improving damage short-lasting. Being only a case series, a study performed on NOD mice treat- and function of lacrimal glands (96). it would be interesting to further ex- ed with metformin showed significant One of the limitations of the use of cell plore this therapeutic strategy, which improvement of saliva secretion and a therapy is the immunogenicity induced may exert its effect acting both as a reduction of salivary glands T cell infil- by the injection of allogenic cells into mechanical barrier and as a modulator tration and pro-inflammatory cytokines the host. Despite hUCMS should not of inflammation (100). levels, along with a promotion of T cell induce immunogenicity, their survival As previously mentioned, pSS may differentiation towards a regulatory in vivo is relatively short. Multiple be a systemic disease and almost all (Treg) phenotype (91). A similar effect methods have been attempted in order patients complain of systemic symp- on Th17, Treg and Breg cells and on to overcome these limitations, includ- toms such as fatigue. Several thera- pro-inflammatory cytokines in NOD ing administration of an extract, rather peutic strategies have been attempted mice salivary glands was observed fol- than viable cells, with preliminary data in order to improve fatigue, with very lowing the administration of rebami- showing equivalent effects (97). An scarce outcomes. However, some non- pide, a gastroprotective agent able to alternative potential method to modu- pharmacological strategies may have enhance prostaglandin synthesis. How- late immune system activity is through a potential benefit, such as supervised ever, the mechanisms underlying this therapeutic administration of antigens, exercise and non-invasive vagus nerve effect require further research (92). resembling a vaccination response. A stimulation, which have been demon- Some data on approaches other than recent study showed that the adminis- strated to improve fatigue, cardiores- systemic secretagogues for the treat- tration to a murine model of sialoadeni- piratory fitness and exercise tolerance. ment of xerostomia have been pub- tis of transgenic rice seeds expressing Vagus nerve stimulation was also able lished and showed an improvement peptide ligands of the M3 muscarinic to significantly reduce the secretion of of patient-reported outcomes (PRO) receptor engineered in order to re- pro-inflammatory cytokines by periph- and salivary secretion using salivary place amino acid residues at the sites eral blood mononuclear cells (PBMC) stimulants such as malic acid lozenges of interaction with the T cell receptor (101, 102), suggesting a potential wid- and citric acid solution, with a stronger (TCR), is able to modulate the immune er application of the technique. effect by the former. Additionally, in a response by increasing salivary flow, In patients with systemic involve- group of patients – 1/3 diagnosed with reducing glandular inflammation, pro- ment, treatment strategies are mostly SS and the other with xerostomia due to inflammatory cytokine secretion in the based on expert opinion and the use other causes – who underwent salivary gland and balance between Th17 and of pharmacological approach is mutu- gland irrigation procedures through the Treg cells. These aspects deserve how- ated from the evidence in other auto- retrograde injection of saline into the ever further investigation (98). immune and inflammatory diseases. four major salivary gland, a significant In patients with severe, long-lasting For this reason, there is great interest proportion experienced an increase of sicca syndrome, complications of the in building scientific evidence in sup- unstimulated salivary flow (93). Addi- lack of saliva and tears are frequent. port of the use of immunomodulatory tionally, two meta-analyses performed One of the most concerning aspects is and immunosuppressive therapies. Hy- on pharmacological treatment of xeros- the increased frequency of caries. One droxychloroquine (HCQ), methotrex- tomia in pSS confirmed a positive out- of the objectives of sialogogues pre- ate (MTX) and leflunomide (LEF) are come for interferon-α, cevimeline and scription, beyond mitigating the symp- commonly used in patients with mild pilocarpine (94, 95). toms, is the preservation of oral and oc- systemic disease, especially with ar- In recent years, potential applications ular health. However, unlike the results ticular involvement, but there is very of cell and antigen therapy for the on animal models and some recom- little evidence on their efficacy in SS. treatment of SS have been extensively mendations, a recent study showed no Interestingly, there is a rationale sup- investigated and data are progressively effect on the rate of caries development porting the combination of HCQ and accumulating. Human umbilical cord in patients treated with pilocarpine LEF. In fact, the pharmacological ef- mesenchymal stem cells (hUCMS) are compared to controls (99). Similarly, fect of LEF is mainly directed towards multipotent cells extracted from the dry eye can sometimes be refractive to the inhibition of T cell response, while Wharton jelly of umbilical cord and all the treatments and may sometimes HCQ mainly affects antigen presenta-

Clinical and Experimental Rheumatology 2020 S-17 One year in review 2020: Sjögren’s syndrome / V. Manfrè et al. tion and B cell response. An additive phosphatidylinositol 3-kinase (PI3Kδ) of antigen-driven and BAFF-mediated effect of the two medications has been as demonstrated by the increased con- B cell hyperactivation in the evolution demonstrated in vitro in terms of pro- centration of downstream peptides in of lymphoma in pSS (70, 117, 118). inflammatory cytokine secretion, T and biopsy samples. Thus, Nayar et al. have Rituximab monotherapy may be in- B cell proliferation. A clinical trial has demonstrated that treatment of a murine sufficient to deplete the B-cells in the also been carried out, though data are model of SS with the PI3Kδ-inhibitor salivary gland tissue, the resistance of not yet available (103). Albeit HCQ is eletalisib, actually used for B-cell ma- B-cells to rituximab being due to the a very well tolerated medication, its lignancies, significantly mitigates pro- concomitant hyperexpression of BAFF widespread use warrants careful atten- inflammatory cytokine and chemokine in this microenvironment (119). tion on the potential adverse events. A secretion, prevents the formation of Treatment with belimumab, an anti- recent case-control study suggested a GCs and improves salivary function BAFF monoclonal antibody registered potential association between the use (110). for the treatment of SLE (120), was em- of HCQ in pSS and SLE patients and ployed in the BELISS trial in pSS with higher prevalence of non-melanoma New advances in the treatment encouraging clinical results, including skin cancer. However, these data need of lymphoma pSS with parotid swelling. Novel treat- to be confirmed (104). Lymphoma development is the main ment strategies for pSS-related lym- Numerous clinical trials have been car- complication decreasing patient sur- phoproliferation then imply the com- ried out and others are currently on- vival in pSS. Low grade B-cell NHL bination of direct B-cell-depleting and going on the potential effect of target of MALT is the largely overrepresented anti-BAFF agents (116). therapy for more severe disease mani- histotype, followed by DLBCL, which Very long-term remission of a patient festations. Although some molecules, may also derive from MALT (15, 111). with pSS, parotid NHL of MALT, such as rituximab (RTX), are com- Treatment decisions for pSS-associated and cryoglobulinaemic vasculitis was monly used, little evidence is available NHL must be case tailored. Treatment achieved with a sequential treatment and the results from the trials to date are of indolent MALT NHL, much more with belimumab shortly followed by mostly inconclusive (105). Nonethe- frequent in pSS, may range widely, rituximab, while rituximab alone and less, some interesting studies recently from a “watch and wait” approach to belimumab alone, given previously, explored the effect of the blockade of cytotoxic therapies, low dose radio- were both ineffective (113). At present, various pathways. A small open label therapy or surgical excision. Chemo- a double-blind, randomised, placebo- study has demonstrated a significant therapy or chemoimmunotherapy may controlled trial (NCT02631538) is reduction of median ESSDAI score, also be used, with a combination of testing belimumab/rituximab coadmin- most evident in the articular and glan- rituximab with either alkylating agents istration (where belimumab is started dular domains, following treatment (cyclophosphamide/chlorambucil), pu- earlier) in comparison to belimumab with abatacept (106). Another study rine analogs (fludarabine, cladribine), monotherapy in pSS. demonstrated minimal beneficial -ef or bendamustine. Conversely, the R- Another encouraging approach under fect of ianalumab, a B-cell activating CHOP regimen (rituximab, cyclophos- investigation is the use of ianalumab factor (BAFF) receptor blocker, on phamide, doxorubicin, vincristine and (VAY736), an anti-BAFF receptor fatigue and circulating B-cell levels prednisone) is often employed in ag- monoclonal antibody (NCT02149420, (107). Very interestingly, Combier et gressive NHL (112). NCT 02962895), with double anti- al. have shown that the development of However, the major recent novelties BAFF and direct B-cell depleting prop- anti-RTX antibodies in connective tis- implicate biological agents for the erties. Ianalumab eliminates BAFF-R- sue diseases is more frequent compared treatment B-cell lymphoproliferative positive mature and immature B cells to RA and patients developing infusion disorders in pSS that do not require via antibody-dependent cytotoxicity reaction due to this phenomenon can be aggressive approaches. Although bio- (ADCC) and induces B-cell apoptosis effectively treated with ofatumumab, logics are now being investigated for by blocking BAFF/BAFF-R interac- another CD20 blocker (108). the treatment of pSS as a whole, their tion (107). Epratuzumab, an anti CD22 In addition, some new pathways are at- specific role in targeting the pSS sub- monoclonal antibody, showed some tracting interest as potential targets in set with heavier B-cell proliferation positive results in an older, small phase pSS. In NOD mice, blockade of CD40 deserves attention. Biologics might be I/II open-label study in pSS, and recent ligand was effective in abolishing the employed in borderline cases where the post hoc analyses of the EMBODY tri- formation of germinal centres (GC) in diagnosis of a definite B-cell malignan- als showed improvement in disease ac- salivary glands. CD40-CD40L pathway, cy is difficult, or in prelymphomatous tivity in patients with SLE and associ- in fact, has a crucial role in the co-stim- conditions in pSS, mainly cryoglobuli- ated SS, with a decrease in B-cells and ulation of T and B cells and is strongly naemic vasculitis with type II mixed IgM levels (121). involved in isotype switching and GC cryoglobulinaemia, and persistent pa- Other Authors recently focused on formation (109). Germinal centres in rotid swelling with heavy underlying T-cell proliferation, T-cell related cy- SS salivary gland also show a markedly MALT lesions (105, 113-116). Recent tokines and B-cell/T-cell co-stimulation increased activity of the δ isoform of studies focused on the fundamental role pathways in systemic and local MALT

S-18 Clinical and Experimental Rheumatology 2020 One year in review 2020: Sjögren’s syndrome / V. Manfrè et al. inflammation, especially in the ectopic Take home messages 8. BEN-ELI H, AFRAMIAN DJ, BEN-CHETRIT germinal centres (122-124). A recent • New formulations of topical cyclo- E et al.: Shared medical and environmental risk factors in Dry Eye syndrome, Sjögren’s randomised, double-blind, placebo- sporine A and sirolimus for dry eye Syndrome, and B-Cell Non-Hodgkin Lym- controlled Phase 3 Study, assessed the treatment may prove superior in terms phoma: A case-control study. J Immunol Res efficacy and safety of abatacept, which of bioavailability and efficacy (88, 89). 2019; 2019: 9060842. blocks the CD28:CD80/CD86 T cell • Metformin, interferon-a, cevimeline 9. KARAKUS S, BAER AN, AKPEK EK: Clini- cal correlations of novel autoantibodies in co-stimulation in pSS. Although IgG and pilocarpine may be effective in im- patients with dry eye. J Immunol Res 2019; and RF levels decreased, a significant proving salivary and tear secretion (91, 2019: 7935451. improvement in ESSDAI and salivary 94, 95). 10. BERMAN N, VIVINO F, BAKER J, DUNHAM J, PINTO A: Risk factors for caries develop- or lacrimal gland function was absent • Human umbilical cord mesenchymal ment in primary Sjögren’s syndrome. Oral (125). stem cells extracts are able to modulate Surg Oral Med Oral Pathol Oral Radiol Targeting the CD40/CD40L pathway the inflammatory response in murine 2019; 128: 117-122. represents another option under study models of SS, without being immuno- 11. RUSTHEN S, KRISTOFFERSEN AK, YOUNG A et al.: Dysbiotic salivary microbiota in (109, 126). The safety and efficacy of genic (96, 97). dry mouth and primary Sjögren’s syndrome a monoclonal antibody against CD40 • Recent reports suggest abatacept, patients. PLoS One 2019; 14: e021831. (iscalimab/CFZ533) in pSS patients ianalumab and ofatumumab may be ef- 12. LIN CY, TSENG CF, LIU JM et al.: Associa- was assessed in a phase II clinical fective for the treatment of more severe tion between periodontal disease and sub- sequent Sjögren’s syndrome: A nationwide trial (NCT02291029) with encour- clinical manifestations (105, 106, 107, population-based cohort study. Int J Envi- aging results. Another double-blind, 111). ron Res Public Health 2019; 16: 771. randomised, placebo-controlled trial • Treatment of pSS-associated lym- 13. MAARSE F, JAGER DHJ, KORFAGE A et al.: (NCT03905525) is ongoing. Fur- phoma needs to be tailored on the in- Sjögren’s syndrome is not a risk factor for periodontal disease: a systematic review. thermore, a randomised double-blind dividual cases. Multiple clinical trials Clin Exp Rheumatol 2019; 37 (Suppl. 118): placebo-controlled study exploring are currently being carried out testing S225-33. the efficacy and safety of VIB4920 the efficacy of different agents directed 14. 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