Disrupting B and T cell Collaboration in Autoimmune Disease: T cell engagers versus CAR T cell therapy?

B and T cells collaborate to drive autoimmune disease (AID). Historically, B and T cell (B-T cell) co-interaction was targeted through different pathways such as alemtuzumab, abatacept, and dapirolizumab with variable impact on B cell depletion (BCD), whereas the majority of patients with AID including rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis and organ transplantation benefit from targeted BCD with anti-CD20 monoclonal antibodies such as rituximab, ocrelizumab or ofatumumab. Refractory AID is a significant problem for patients with incomplete BCD with a greater frequency of IgD-CD27+ switched memory B cells, CD19+CD20- B cells and plasma cells that are not directly targeted by anti-CD20 antibodies, whereas most lymphoid tissue plasma cells express CD19. Furthermore, B-T cell collaboration is predominant in lymphoid tissues and at sites of inflammation such as the joint and kidney, where BCD may be inefficient, due to limited access to key effector cells. In the treatment of cancer, chimeric antigen receptor (CAR) T cell therapy and T cell engagers (TCE) that recruit T cells to induce B cell cytotoxicity have delivered promising results for anti-CD19 CAR T cell therapies, the CD19 TCE blinatumomab and CD20 TCE such as mosunetuzumab, glofitamab or epcoritamab. Limited evidence suggests that anti-CD19 CAR T cell therapy may be effective in managing refractory AID whereas we await evaluation of TCE for use in non-oncological indications. Therefore, here, we discuss the potential mechanistic advantages of novel therapies that rely on T cells as effector cells to disrupt B-T cell collaboration toward overcoming rituximab-resistant AID.

Concomitant Sjögren's disease as a biomarker for treatment effectiveness in rheumatoid arthritis - results from the Swiss clinical quality management cohort.

OBJECTIVE: To investigate the clinical phenotype and treatment response in patients with rheumatoid arthritis (RA) with and without concomitant Sjögren's disease (SjD). METHODS: In this observational cohort study, patients with RA from the Swiss Clinical Quality Management in Rheumatic Diseases registry were categorised according to the presence or absence of SjD. To assess treatment effectiveness, drug retention of tumor necrosis factor-α-inhibitors (TNFi) was compared to other mode of action (OMA) biologics and Janus kinase-inhibitors (JAKi) in RA patients with and without SjD. Adjusted hazard ratios (HR) for time to drug discontinuation were compared in crude and adjusted Cox proportional regression models for potential confounders. RESULTS: We identified 5974 patients without and 337 patients with concomitant SjD. Patients with SjD were more likely to be female, to have a positive rheumatoid factor, higher disease activity scores, and erosive bone damage. For treatment response, a total of 6781 treatment courses were analysed. After one year, patients with concomitant SjD were less likely to reach DAS28 remission with all three treatment modalities. Patients with concomitant SjD had a higher hazard for stopping TNFi treatment (adjusted HR 1.3 [95% CI 1.07-1.6]; OMA HR 1.12 [0.91-1.37]; JAKi HR 0.97 [0.62-1.53]). When compared to TNFi, patients with concomitant SjD had a significantly lower hazard for stopping treatment with OMA (adjusted HR 0.62 [95% CI 0.46-0.84]) and JAKi (HR 0.52 [0.28-0.96]). CONCLUSION: RA patients with concomitant SjD reveal a severe RA phenotype, are less responsive to treatment, and more likely to fail TNFi.

The impact of concomitant Sjögren's disease on rheumatoid arthritis disease activity: a systematic review and meta-analysis.

OBJECTIVES: Rheumatoid arthritis (RA) and Sjögren's syndrome (SS) frequently co-exist but the consequence for RA disease activity of having concomitant SS (RA/SS) is not well established. We conducted a systematic review and meta-analysis to investigate the impact of SS on disease outcomes in individuals with RA. METHODS: We searched Web of Science (Core Collection, FSTA, Medline), PubMed and Cochrane databases, without language restriction. Studies reporting RA disease activity scores, joint counts, visual analogue scales (VAS), disability and joint damage, and comparing RA and RA/SS were selected. Outcomes reported in at least 3 studies in which the diagnosis of SS fulfilled classification criteria underwent meta-analysis, using a random effects model where heterogeneity was detected. RESULTS: The literature search identified 2991 articles and abstracts; 23 underwent full-text review and 16 were included. The studies included a total of 29722 patients (8614 with RA/SS and 21108 with RA). Using studies eligible for meta-analysis (744 patients with RA/SS and 4450 with RA), we found higher DAS-28 ESR scores (mean difference 0.50, 95% CI -0.008-1.006; p=0.05), higher swollen joint count scores (mean difference 1.05, 95% CI 0.42-1.67; p=0.001), and greater functional disability as measured by HAQ (mean difference 0.19, 95% CI 0.05-0.34; p=0.009) in RA/SS compared to RA alone. Other outcome measures (tender joint count, fatigue VAS) showed a numerical trend towards higher scores in RA/SS but were not statistically significant. CONCLUSIONS: RA/SS patients appear to have higher disease activity and more functional disability than patients with RA alone. The aetiology and clinical implications of this are unclear and warrant further investigation.

Phenotyping by persistent inflammation in systemic sclerosis associated interstitial lung disease: a EUSTAR database analysis.

BACKGROUND: Systemic sclerosis (SSc) is a heterogeneous disease with frequently associated interstitial lung disease (SSc-ILD). We aimed to determine the prognostic potential of phenotyping patients with SSc and SSc-ILD by inflammation and to describe disease trajectories stratified by inflammation and immunosuppressive treatment. METHODS: Patients from the European Scleroderma Trials and Research (EUSTAR) group cohort were allocated to persistent inflammatory, intermediate and non-inflammatory phenotypes if C-reactive protein (CRP) levels were ≥5 mg/L at ≥80%, at 20-80% and at <20% of visits, respectively. Cox regression models were used to analyse mortality risk and mixed effect models to describe trajectories of FVC and diffusing capacity for carbon monoxide (DLCO) %-predicted stratified by inflammation and immunosuppressive treatment. RESULTS: 2971 patients with SSc and 1171 patients with SSc-ILD had at least three CRP measurements available. Patients with SSc-ILD with a persistent inflammatory phenotype had a 6.7 times higher risk of mortality within 5 years compared with those with a persistent non-inflammatory phenotype (95% CI 3 to 15). In the inflammatory phenotype, FVC %-predicted was declining without (-1.11 (95% CI -2.14 to -0.08)/year), but stable with immunosuppressive treatment (-0.00 (95% CI -0.92 to 0.92)/year). In the non-inflammatory phenotype, patients with and without immunosuppressive treatment had a significant decline in FVC %-predicted, which was more pronounced in those with immunosuppressive treatment (-1.26 (95% CI -1.87 to -0.64) and -0.84 (95% CI -1.35 to -0.33)/year, respectively). CONCLUSIONS: Phenotyping by persistent inflammation provides valuable prognostic information, independent of demographics, disease duration, cutaneous subtype, treatment and SSc-ILD severity. The findings from this study support early immunosuppressive treatment in patients with SSc-ILD with persistent inflammation.

Serum proteomics in giant cell arteritis in response to a three-day pulse of glucocorticoid followed by tocilizumab monotherapy (the GUSTO trial).

Objective: Proteome analyses in patients with newly diagnosed, untreated giant cell arteritis (GCA) have not been reported previously, nor are changes of protein expression upon treatment with glucocorticoids (GC) and/or tocilizumab (TCZ) known. The GUSTO trial allows to address these questions, provides the opportunity to learn about the differential effects of GC and TCZ on proteomics and may help to identify serum proteins to monitor disease activity. Methods: Serum samples obtained from 16 patients with new-onset GCA at different time points (day 0, 3, 10, and week 4, 24, 52) during the GUSTO trial (NCT03745586) were examined for 1436 differentially expressed proteins (DEPs) based on proximity extension assay technology. The patients received 500 mg methylprednisolone intravenously for 3 consecutive days followed by TCZ monotherapy. Results: When comparing day 0 (before the first GC infusion) with week 52 (lasting remission), 434 DEPs (213↑, 221↓) were identified. In response to treatment, the majority of changes occurred within 10 days. GC inversely regulated 25 proteins compared to remission. No difference was observed between weeks 24 and 52 during established remission and ongoing TCZ treatment. Expression of CCL7, MMP12, and CXCL9 was not regulated by IL6. Conclusion: Disease-regulated serum proteins improved within 10 days and were normalized within 24 weeks, showing a kinetic corresponding to the gradual achievement of clinical remission. The proteins inversely regulated by GC and TCZ shed light on the differential effects of the two drugs. CCL7, CXCL9, and MMP12 are biomarkers that reflect disease activity despite normalized C-reactive protein levels.

Belimumab treatment in autoimmune hepatitis and primary biliary cholangitis - a case series.

Background: The majority of patients with autoimmune hepatitis (AIH) achieve complete remission with established treatment regiments. In patients with intolerance or insufficient response to these drugs, the remaining options are limited and novel treatment approaches necessary. In primary biliary cholangitis (PBC), ursodeoxycholic acid (UDCA) and fibrates have improved prognosis dramatically, but there remains a proportion of patients with refractory disease.In patients with refractory AIH and/or PBC, we used a novel treatment strategy with the anti-B cell activating factor, belimumab. The first three patients had concomitant Sjögren's disease. The connecting element between all three diseases is B cell activation, including elevated levels of the B cell activating factor (BAFF). Furthermore, belimumab has been shown to be beneficial in Sjögren's disease. Aims and methods: To retrospectively investigate treatment response in six patients with AIH or PBC with or without concomitant Sjögren's disease treated with the anti-BAFF therapy belimumab at the University Hospital in Bern, Switzerland. Results: In all three patients with AIH, belimumab improved disease control and helped by-pass or reduce problematic side effects from corticosteroids and calcineurin inhibitors. In PBC patients (n = 3), there was no clear improvement of liver function tests, despite reduction or normalization of IgM. All patients with concomitant Sjögren's disease (n = 3) had an improvement of sicca symptoms and two out of three patients experienced an initially marked reduction in fatigue, which lessened over time. Conclusions: Belimumab may be a promising treatment option for patients with AIH and further investigations are needed. In PBC however, response was not convincing. The effects on sicca symptoms and fatigue were encouraging.

Sjögren's and non-Sjögren's sicca share a similar symptom burden but with a distinct symptom-associated proteomic signature.

OBJECTIVES: Given the similarity in symptoms between primary Sjogren's syndrome (SjS) and non-SjS sicca syndrome (sicca), we sought to characterise clinical and proteomic predictors of symptoms in both groups in order to better understand disease mechanisms and help guide development of immunomodulatory treatments. These have not, to date, unequivocally improved symptoms in SjS clinical trials. METHODS: Serum proteomics was performed using O-link inflammation and cardiovascular II panels. SjS (n=53) fulfilled 2016 ACR/European Alliance of Associations for Rheumatology (EULAR) criteria whereas sicca (n=60) were anti-Ro negative, displayed objective or subjective dryness, and either had a negative salivary gland biopsy or, in the absence of a biopsy, it was considered that a biopsy result would not change classification status. Linear regression analysis was performed to identify the key predictors of symptoms. Cluster analysis was completed using protein expression values. RESULTS: EULAR-Sjögren's-Syndrome-Patient-Reported-Index (ESSPRI), EuroQoL-5 Dimension utility values, and anxiety and depression did not differ between SjS and sicca. Correlations between body mass index (BMI) and ESSPRI were found in sicca and to a lesser extent in SjS. Twenty proteins positively associated with symptoms in sicca but none in SjS. We identified two proteomically defined subgroups in sicca and two in SjS that differed in symptom burden. Within hierarchical clustering of the SjS and sicca pool, the highest symptom burden groups were the least distinct. Levels of adrenomedullin (ADM), soluble CD40 (CD40) and spondin 2 (SPON2) together explained 51% of symptom variability in sicca. ADM was strongly correlated with ESSPRI (spearman's r=0.62; p<0.0001), even in a multivariate model corrected for BMI, age, objective dryness, depression and anxiety scores. CONCLUSIONS: Obesity-related metabolic factors may regulate symptoms in sicca. Further work should explore non-inflammatory drivers of high symptom burden in SjS to improve clinical trial outcomes.

Inflammatory arthritis in systemic sclerosis is associated with elevated C-reactive protein and requires musculoskeletal ultrasound for reliable detection.

Objectives: About 25% of patients with systemic sclerosis (SSc) have elevated C-reactive protein (CRP) levels. Specific causes of CRP elevation are unknown so far. We aimed to investigate whether inflammatory arthritis is associated with CRP elevation. Furthermore, we evaluated the sensitivity and specificity of clinical examination compared to musculoskeletal ultrasound (MSUS) for detection of arthritis. Methods: Sixty-five patients with SSc (51 females) were enrolled and allocated into a CRP-positive (CRP+, n = 20; CRP elevated for at least two years prior to enrollment) and a CRP-negative (CRP-; n = 45) cohort. All patients were examined clinically (modified Rodnan Skin Score, mRSS; swollen/tender joint count 66/68), received a comprehensive MSUS of their hands and feet, as well as laboratory testing (antibody status; CRP). Statistical analyses were performed using non-parametrical tests without adjustments. Results: Patient with a disease duration <3 years had higher CRP levels (p = 0.042). Anti-centromere antibodies dominated in CRP- patients (p = 0.013), and anti-Scl70 antibodies in CRP + patients (p = 0.041). Joint effusion and B-mode synovitis prevailed in male (p < 0.00001; p < 0.0001) and CRP + (p = 0.001; p < 0.00001) patients. Power Doppler (PD)-synovitis predominated in patients with diffuse SSc (p = 0.0052). Joint effusion and B-/PD-synovitis were mostly confined to wrists, MTPs and talo-navicular joints. Compared to MSUS, sensitivity of clinical examination was as low as 14.6%; specificity was 87.7%. Sensitivity was reduced by the presence of soft tissue edema or a mRSS > 10. Conclusion: Arthritis is more frequent in CRP + compared to CRP- SSc patients. Compared to MSUS sensitivity of clinical examination is low for the detection of arthritis; this is likely due to skin fibrosis and soft tissue edema. Therefore, regular monitoring via MSUS should be considered as routine assessment in SSc patients.

Quantitative ultrasound to monitor the vascular response to tocilizumab in giant cell arteritis.

OBJECTIVES: To characterize the effect of ultra-short glucocorticoids followed by Tocilizumab monotherapy on the intima-media thickness (IMT) in GCA. METHODS: Eighteen GCA patients received 500 mg for 3 consecutive days (total of 1500mg) i.v. methylprednisolone on days 0-2, followed by i.v. Tocilizumab (8 mg/kg) on day 3 and thereafter weekly s.c. Tocilizumab injections (162 mg) over 52 weeks. US of temporal (TAs), axillary (AAs) and subclavian (SAs) arteries was performed at baseline, on days 2-3, and at weeks 4, 8, 12, 24 and 52. The largest IMT of all segments and IMT at landmarks of AA/SA were recorded. IMT was scaled by mean normal values and averaged. Each segment was classified according to diagnostic cut-offs. RESULTS: Of the 18 GCA patients, 16 patients had TA and 6 had extracranial large artery involvement. The IMT showed a sharp decline on day 2/3 in the TAs and AAs/SAs. In TAs, this was followed by an increase to baseline levels at week 4 and a subsequent slow decrease, which was paralleled by decreasing symptoms and achievement of clinical remission. The AAs/SAs showed a new signal of vasculitis at week 4 in three patients, with an IMT increase up to week 8. CONCLUSION: Glucocorticoid pulse therapy induced a transient decrease of the IMT in TAs and AAs/SAs. Tocilizumab monotherapy resulted in a slow and steady decrease in IMT of the TAs and a smaller and delayed effect on the AAs/SAs. The data strongly support a remission-inducing effect of Tocilizumab and argue the case for US having an important role in monitoring disease activity in GCA. TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT03745586.

Vision loss in patients with giant cell arteritis treated with tocilizumab.

OBJECTIVES: Giant cell arteritis (GCA) may lead to vision loss. To what extent tocilizumab (TCZ) is able to prevent vision loss is unknown. The aim was to analyze the occurrence of vision loss in a large GCA cohort treated with TCZ. METHODS: In this observational monocentric study, GCA patients treated with TCZ between the years 2010 and 2018 were studied. Demographic, clinical, and laboratory data were analyzed. RESULTS: A total of 186 patients were included (62% female); 109 (59%) fulfilled the American College of Rheumatology (ACR) criteria, in 123 (66%) patients, large vessel vasculitis was diagnosed by magnetic resonance-angiography (MRA). Cumulative duration of TCZ treatment was 224 years, median treatment duration was 11.1 (IQR 5.6-17.9) months. Glucocorticoids (GC) were tapered over a median of 5.8 (IQR 3.0-8.5) months. At baseline, visual symptoms were present in 70 (38%) and vision loss in 21 (11%) patients. Patients with vision loss at baseline were older (p = 0.032), had a lower C-reactive protein (p = 0.002), and showed a negative association with MRA of the aorta (p = 0.006). Two patients (1.1%) developed vision loss, both at the initiation of TCZ treatment. CONCLUSION: Our data show a very low incidence of vision loss in TCZ-treated patient. The two cases of AION occurred at the initiation of therapy, they support the hypothesis that advanced, and established structural changes of arteries are key factors for this accident. Whether a shorter duration of concomitant GC treatment is risky regarding vision loss needs to be studied.

Tocilizumab monotherapy after ultra-short glucocorticoid administration in giant cell arteritis: a single-arm, open-label, proof-of-concept study.

BACKGROUND: Two randomised controlled trials showed a glucocorticoid-sparing effect of tocilizumab in patients with giant cell arteritis. In the GUSTO trial we aimed to evaluate the efficacy and safety of tocilizumab monotherapy after ultra-short-term glucocorticoid treatment in patients with new-onset giant cell arteritis. METHODS: This investigator-initiated, single-arm, single-centre, open-label, proof-of-concept trial with a Simon's two stage design was done at University Hospital Bern, Bern, Switzerland. We enrolled patients aged older than 50 years newly diagnosed with giant cell arteritis (within 4 weeks before the screening visit) satisfying the American College of Rheumatology criteria or with large vessel vasculitis-associated polymyalgia rheumatica. The participants received 500 mg methylprednisolone intravenously for 3 consecutive days. Thereafter, glucocorticoid treatment was discontinued and a single infusion of tocilizumab (8 mg/kg bodyweight) was administered intravenously, followed by weekly subcutaneous tocilizumab injections (162 mg) until week 52. The primary endpoint was the proportion of patients who had remission within 31 days and showed no relapse at week 24. The secondary endpoints were the proportion of patients with complete relapse-free remission of disease at weeks 24 and 52, and time to first remission, first relapse (after induction of remission), and first partial remission. This study is registered with ClinicalTrials.gov, NCT03745586. FINDINGS: From Nov 23, 2018, to Sept 22, 2019, 18 patients were enrolled (12 of 18 were female, 18 of 18 were White) with a median age of 72 (IQR 67-75) years. Overall, 15 of 18 patients had cranial symptoms, ten of 18 had polymyalgia rheumatica symptoms, and 13 of 18 showed a positive histopathology. At the interim analysis, three (25%) of 12 patients were in remission. The null hypothesis could not be rejected, and the study was futile with respect to the primary endpoint. However, 14 (78%) of 18 patients had remission within 24 weeks (mean time to first remission 11·1 weeks, 95% CI 8·3-13·9) and 13 of 18 showed no relapses up to 52 weeks (72%, 47-90). Mean time to first partial remission was 6·2 [3·7-8·7] weeks. Time to first relapse (after induction of remission) could not be estimated as there was no relapse after induction of remission. Overall, three of 18 patients did not respond to treatment and two of 18 discontinued the study due to an adverse event (hepatopathy [one] and diverticulitis [one]). Anterior ischaemic optic neuropathy occurred in one patient. INTERPRETATION: The data show a slow remission-inducing and a lasting remission-maintaining effect of tocilizumab after an ultra-short pulse of glucocorticoids in patients with newly diagnosed giant cell arteritis. As a proof-of-concept study, our data do not allow us to propose clinical recommendations. FUNDING: Bern University Hospital, University of Bern, and F Hoffmann-La Roche.

Infectious Triggers in Periodontitis and the Gut in Rheumatoid Arthritis (RA): A Complex Story About Association and Causality.

Rheumatoid arthritis (RA) is a systemic immune mediated inflammatory disease of unknown origin, which is predominantly affecting the joints. Antibodies against citrullinated peptides are a rather specific immunological hallmark of this heterogeneous entity. Furthermore, certain sequences of the third hypervariable region of human leukocyte antigen (HLA)-DR class II major histocompatibility (MHC) molecules, the so called "shared epitope" sequences, appear to promote autoantibody positive types of RA. However, MHC-II molecule and other genetic associations with RA could not be linked to immune responses against specific citrullinated peptides, nor do genetic factors fully explain the origin of RA. Consequently, non-genetic factors must play an important role in the complex interaction of endogenous and exogenous disease factors. Tobacco smoking was the first environmental factor that was associated with onset and severity of RA. Notably, smoking is also an established risk factor for oral diseases. Furthermore, smoking is associated with extra-articular RA manifestations such as interstitial lung disease in anatomical proximity to the airway mucosa, but also with subcutaneous rheumatoid nodules. In the mouth, Porphyromonas gingivalis is a periodontal pathogen with unique citrullinating capacity of foreign microbial antigens as well as candidate RA autoantigens. Although the original hypothesis that this single pathogen is causative for RA remained unproven, epidemiological as well as experimental evidence linking periodontitis (PD) with RA is rapidly accumulating. Other periopathogens such as Aggregatibacter actinomycetemcomitans and Prevotella intermedia were also proposed to play a specific immunodominant role in context of RA. However, demonstration of T cell reactivity against citrullinated, MHC-II presented autoantigens from RA synovium coinciding with immunity against Prevotella copri (Pc.), a gut microbe attracted attention to another mucosal site, the intestine. Pc. was accumulated in the feces of clinically healthy subjects with citrulline directed immune responses and was correlated with RA onset. In conclusion, we retrieved more than one line of evidence for mucosal sites and different microbial taxa to be potentially involved in the development of RA. This review gives an overview of infectious agents and mucosal pathologies, and discusses the current evidence for causality between different exogenous or mucosal factors and systemic inflammation in RA.

Equal rights in autoimmunity: is Sjögren's syndrome ever 'secondary'?

Sjögren's syndrome (SjS) accompanied by other systemic autoimmune rheumatic connective tissue diseases has historically been termed 'secondary' in contrast to 'primary' SjS as a standalone entity. However, it is a matter of a long-standing debate whether the prefixes 'primary' and 'secondary', including a temporal component, are obsolete in the terminology of SjS. We review the history and the pathophysiological, chronological, genetic, histological and clinical data underlying the concept of 'secondary' SjS. There are important unintended consequences of the nomenclature; notably 'secondary' SjS has been much less researched and is often excluded from clinical trials. We argue for further research, a change in terminology and more stringent classification. Further we highlight possible opportunities for trials in SjS and other systemic autoimmune diseases that might contribute to an advance in care for all patients with SjS.

Inflammatory stays inflammatory: a subgroup of systemic sclerosis characterized by high morbidity and inflammatory resistance to cyclophosphamide.

BACKGROUND/PURPOSE: Elevated levels of C-reactive protein (CRP) in systemic sclerosis (SSc) have been linked to early inflammatory stages of the disease. This study has been designed to investigate CRP levels longitudinally in a cohort of SSc patients and to correlate these findings with comorbidities and disease characteristics. METHODS: In this retrospective study, patients with SSc treated at the outpatient clinic of the Department of Rheumatology and Clinical Immunology, University Medical Center Freiburg, were analyzed. Only patients with at least three consecutive visits and at least 1 year follow-up were included in this study. CRP serum levels were measured at every visit and categorized as positive if CRP concentrations were ≥ 5 mg/l. Subjects with elevated CRP levels at more than 80% of visits were defined as inflammatory SSc. The longitudinal CRP profiles were correlated with disease characteristics and comorbidities. RESULTS: A total of 1815 consecutive visits of 131 SSc patients were analyzed. Over the observed time span (7.6 (1.0-19.5) years), 18.3% (n = 24) of patients had continuously elevated CRP levels (inflammatory SSc), whereas in 29% (n = 38), CRP levels were always in the normal range. There was no association between disease duration and CRP levels at first visit. Inflammatory SSc was associated with male gender (p = 0.022), anti-Scl-70 antibodies (p = 0.009), diffuse cutaneous SSc (p = 0.036), pulmonary fibrosis (p < 0.001), rheumatoid arthritis (p = 0.007), and cardiac arrhythmia (p = 0.048). Moreover, patients with inflammatory SSc revealed higher modified Rodnan skin scores (p < 0.001); lower forced vital capacity (FVC) (p < 0.001), total lung capacity (p = 0.001), and diffusing capacity (p = 0.008); and faster decline of FVC per year (p = 0.007). Even treatment with cyclophosphamide (CYC) did not decrease CRP levels (p = 0.754). CONCLUSION: Inflammatory SSc is characterized by a more severe phenotype, high morbidity, and a large proportion of male patients. Even treatment with CYC does not alter CRP levels in this subpopulation with a high unmet medical need.

Phosphatidylinositol 3-kinase delta pathway: a novel therapeutic target for Sjögren's syndrome.

BACKGROUND: The phosphatidylinositol 3-kinase delta isoform (PI3Kδ) belongs to an intracellular lipid kinase family that regulate lymphocyte metabolism, survival, proliferation, apoptosis and migration and has been successfully targeted in B-cell malignancies. Primary Sjögren's syndrome (pSS) is a chronic immune-mediated inflammatory disease characterised by exocrine gland lymphocytic infiltration and B-cell hyperactivation which results in systemic manifestations, autoantibody production and loss of glandular function. Given the central role of B cells in pSS pathogenesis, we investigated PI3Kδ pathway activation in pSS and the functional consequences of blocking PI3Kδ in a murine model of focal sialoadenitis that mimics some features of pSS. METHODS AND RESULTS: Target validation assays showed significant expression of phosphorylated ribosomal protein S6 (pS6), a downstream mediator of the phosphatidylinositol 3-kinase delta (PI3Kδ) pathway, within pSS salivary glands. pS6 distribution was found to co-localise with T/B cell markers within pSS aggregates and the CD138+ plasma cells infiltrating the glands. In vivo blockade of PI3Kδ activity with seletalisib, a PI3Kδ-selective inhibitor, in a murine model of focal sialoadenitis decreased accumulation of lymphocytes and plasma cells within the glands of treated mice in the prophylactic and therapeutic regimes. Additionally, production of lymphoid chemokines and cytokines associated with ectopic lymphoneogenesis and, remarkably, saliva flow and autoantibody production, were significantly affected by treatment with seletalisib. CONCLUSION: These data demonstrate activation of PI3Kδ pathway within the glands of patients with pSS and its contribution to disease pathogenesis in a model of disease, supporting the exploration of the therapeutic potential of PI3Kδ pathway inhibition in this condition.