Characterisation of airway disease associated with Sjögren disease.

OBJECTIVE: Although airway disease associated with Sjögren's disease (Sjo-AD) is common, it is poorly studied compared with interstitial lung disease (ILD). In this study, we aimed to assess factors associated with Sjo-AD, the characteristics and prognosis of this manifestation. METHODS: We performed a retrospective multicentric study involving nine centres. We included Sjo-AD patients confirmed by at least one clinician and one CT scan report. Clinical and biological data, pulmonary function test (PFT), and CT scans were collected. A single radiologist specialist in thoracic diseases reviewed CT scans. Sjo-AD patients were compared with Sjo controls without pulmonary involvement, randomly selected after matching for age and disease duration. RESULTS: We included 31 Sjo-AD and 62 Sjo controls without pulmonary history. Sjo-AD had a higher disease activity (ESSDAI) compared with controls, even when excluding the pulmonary domain of the score (7 vs 3.8, p<0.05), mainly due to the biological activity. Sjo-AD was multilobar (72%) and associated with signs of both bronchiectasis and bronchiolitis (60%). Obstructive lung disease occurred in 32% at the time of Sjo-AD diagnosis. Overall, PFT was stable after 8.7±7 years follow-up but repeated CT scans showed extended lesions in 41% of cases within 6±3.2 years. No patient developed Sjo-ILD. Sjo-AD progression was independent of the global disease activity. CONCLUSIONS: Sjo-AD preferentially affects Sjo patients with higher biological activity. It is often characterised as a diffuse disease, affecting both proximal and distal airways, with a slow evolution over time and no progression to Sjo-ILD.

Identification of distinct subgroups of Sjögren's disease by cluster analysis based on clinical and biological manifestations: data from the cross-sectional Paris-Saclay and the prospective ASSESS cohorts.

BACKGROUND: Sjögren's disease is a heterogenous autoimmune disease with a wide range of symptoms-including dryness, fatigue, and pain-in addition to systemic manifestations and an increased risk of lymphoma. We aimed to identify distinct subgroups of the disease, using cluster analysis based on subjective symptoms and clinical and biological manifestations, and to compare the prognoses of patients in these subgroups. METHODS: This study included patients with Sjögren's disease from two independent cohorts in France: the cross-sectional Paris-Saclay cohort and the prospective Assessment of Systemic Signs and Evolution of Sjögren's Syndrome (ASSESS) cohort. We first used an unsupervised multiple correspondence analysis to identify clusters within the Paris-Saclay cohort using 26 variables comprising patient-reported symptoms and clinical and biological manifestations. Next, we validated these clusters using patients from the ASSESS cohort. Changes in disease activity (measured by the European Alliance of Associations for Rheumatology [EULAR] Sjögren's Syndrome Disease Activity Index [ESSDAI]), patient-acceptable symptom state (measured by the EULAR Sjögren's Syndrome Patient Reported Index [ESSPRI]), and lymphoma incidence during follow-up were compared between clusters. Finally, we compared our clusters with the symptom-based subgroups previously described by Tarn and colleagues. FINDINGS: 534 patients from the Paris-Saclay cohort (502 [94%] women, 32 [6%] men, median age 54 years [IQR 43-64]), recruited between 1999 and 2022, and 395 patients from the ASSESS cohort (370 [94%] women, 25 [6%] men, median age 53 years [43-63]), recruited between 2006 and 2009, were included in this study. In both cohorts, hierarchical cluster analysis revealed three distinct subgroups of patients: those with B-cell active disease and low symptom burden (BALS), those with high systemic disease activity (HSA), and those with low systemic disease activity and high symptom burden (LSAHS). During follow-up in the ASSESS cohort, disease activity and symptom states worsened for patients in the BALS cluster (67 [36%] of 186 patients with ESSPRI score <5 at month 60 vs 92 [49%] of 186 at inclusion; p<0·0001). Lymphomas occurred in patients in the BALS cluster (five [3%] of 186 patients; diagnosed a median of 70 months [IQR 42-104] after inclusion) and the HSA cluster (six [4%] of 158 patients; diagnosed 23 months [13-83] after inclusion). All patients from the Paris-Saclay cohort with a history of lymphoma were in the BALS and HSA clusters. This unsupervised clustering classification based on symptoms and clinical and biological manifestations did not correlate with a previous classification based on symptoms only. INTERPRETATION: On the basis of symptoms and clinical and biological manifestations, we identified three distinct subgroups of patients with Sjögren's disease with different prognoses. Our results suggest that these subgroups represent different heterogeneous pathophysiological disease mechanisms, stages of disease, or both. These findings could be of interest when stratifying patients in future therapeutic trials. FUNDING: Fondation pour la Recherche Médicale, French Ministry of Health, French Society of Rheumatology, Innovative Medicines Initiative 2 Joint Undertaking, Medical Research Council UK, and Foundation for Research in Rheumatology.

Inclusion-body myositis associated with Sjögren's disease: clinical characteristics and comparison with other Sjögren-associated myositis.

OBJECTIVES: To describe the characteristics of patients with Sjögren's disease (SjD) and inclusion-body myositis (IBM), and how they compare to SjD patients with other inflammatory myopathies (IM). METHODS: Patients were retrospectively recruited from 13 French centers and included if they met the ACR/EULAR criteria for SjD and for IM. They were categorized as SjD-IBM if sub-criteria for IBM were met, or as SjD-other IM if not. RESULTS: SjD-IBM patients (n = 22) were mostly females (86%), with a median [Q1; Q3] age of 54 [38.5; 64] years at SjD diagnosis, and 62 [46.5; 70] years at first IBM symptoms. Although most patients displayed glandular and immunological abnormalities, additional extra-glandular manifestations were uncommon, resulting in moderate disease activity at SjD diagnosis (ESSDAI 5.5 [1; 7.8]). Classic IBM features were frequent, such as progressive symptom onset (59%), asymmetrical (27%) and distal (32%) involvements, dysphagia (41%), low CPK (386.5 [221.8; 670.5] UI/l) and CRP (3.0 [3; 8.5] mg/l) levels. Immunosuppressants were reported as efficient in 55% of cases.Compared with SjD-IBM patients, SjD patients with other IM (n = 50) were significantly younger, displayed more frequent additional extra-glandular disease, higher ESSDAI score (11 [3; 30]), shorter delay between SjD diagnosis and myositis onset (0 [-0.5; 26]), more frequent CPK values over 1000 UI/l (36%), and less frequent classic IBM features. CONCLUSION: IBM can occur in SjD patients, with muscle features reminiscent of classic sporadic IBM characteristics, but mostly affecting women. In SjD patients with muscle involvement, extra-glandular manifestations, high ESSDAI score, elevated CPK values, and shorter delay after SjD diagnosis plead against IBM.

Liposomal AntagomiR-155-5p Restores Anti-Inflammatory Macrophages and Improves Arthritis in Preclinical Models of Rheumatoid Arthritis.

OBJECTIVE: We previously reported an increased expression of microRNA-155 (miR-155) in the blood monocytes of patients with rheumatoid arthritis (RA) that could be responsible for impaired monocyte polarization to anti-inflammatory M2-like macrophages. In this study, we employed two preclinical models of RA, collagen-induced arthritis and K/BxN serum transfer arthritis, to examine the therapeutic potential of antagomiR-155-5p entrapped within PEGylated (polyethylene glycol [PEG]) liposomes in resolution of arthritis and repolarization of monocytes towards the anti-inflammatory M2 phenotype. METHODS: AntagomiR-155-5p or antagomiR-control were encapsulated in PEG liposomes of 100 nm in size and -10 mV in zeta potential with high antagomiR loading efficiency (above 80%). Mice were injected intravenously with 1.5 nmol/100 µL PEG liposomes containing antagomiR-155-5p or control after the induction of arthritis. RESULTS: We demonstrated the biodistribution of fluorescently tagged PEG liposomes to inflamed joints one hour after the injection of fluorescently tagged PEG liposomes, as well as the liver's subsequent accumulation after 48 hours, indicative of hepatic clearance, in mice with arthritis. The injection of PEG liposomes containing antagomiR-155-5p decreased arthritis score and paw swelling compared with PEG liposomes containing antagomiR-control or the systemic delivery of free antagomiR-155-5p. Moreover, treatment with PEG liposomes containing antagomiR-155-5p led to the restoration of bone marrow monocyte defects in anti-inflammatory macrophage differentiation without any significant functional change in other immune cells, including splenic B and T cells. CONCLUSION: The injection of antagomiR-155-5p encapsulated in PEG liposomes allows the delivery of small RNA to monocytes and macrophages and reduces joint inflammation in murine models of RA, providing a promising strategy in human disease.

PET/CT in Inflammatory and Auto-immune Disorders: Focus on Several Key Molecular Concepts, FDG, and Radiolabeled Probe Perspectives.

Chronic immune diseases mainly include autoimmune and inflammatory diseases. Managing chronic inflammatory and autoimmune diseases has become a significant public health concern, and therapeutic advancements over the past 50 years have been substantial. As therapeutic tools continue to multiply, the challenge now lies in providing each patient with personalized care tailored to the specifics of their condition, ushering in the era of personalized medicine. Precise and holistic imaging is essential in this context to comprehensively map the inflammatory processes in each patient, identify prognostic factors, and monitor treatment responses and complications. Imaging of patients with inflammatory and autoimmune diseases must provide a comprehensive view of the body, enabling the whole-body mapping of systemic involvement. It should identify key cellular players in the pathology, involving both innate immunity (dendritic cells, macrophages), adaptive immunity (lymphocytes), and microenvironmental cells (stromal cells, tissue cells). As a highly sensitive imaging tool with vectorized molecular probe capabilities, PET/CT can be of high relevance in the management of numerous inflammatory and autoimmune diseases. Relying on key molecular concepts of immunity, the clinical usefulness of FDG-PET/CT in several relevant inflammatory and immune-inflammatory conditions, validated or emerging, will be discussed in this review, together with radiolabeled probe perspectives.

[18F]FDG-PET/CT in Polymyalgia Rheumatica: An Update and Future Aspects.

Polymyalgia rheumatica (PMR) is an inflammatory disorder usually diagnosed in patients older than 50 years of age. It is characterized by sudden onset pain and prolonged morning stiffness in the scapular and/or pelvic girdle, sometimes debilitating and accompanied by constitutional symptoms such as weight loss. In approximately 20% of the cases, it is linked to giant cell arteritis (GCAV) representing a disease continuum. The diagnosis is mainly clinical and noninvasive imaging such as ultrasound of joints may be helpful. In atypical PMR cases, whole body imaging using [18F]FDG-PET/CT may be useful. First, to confirm or rule out the diagnosis of PMR, secondly, to assess the coexistence of a GCA, and thirdly to establish the differential diagnosis with other types of arthritides encountered in this age group, such as elderly-onset rheumatoid arthritis, spondyloarthropathies, crystal-induced arthropathies or the rare remittent seronegative symmetrical synovitis with pitting edema. Relatively typical patterns of [18F]FDG-PET/CT are well known, based on the clinical distribution of the disease (eg, scapular and pelvic girdle, interspinous bursae, sterno-costoclavicular joints, entheses), especially the hypermetabolism at the interspinous lumbar bursae that has shown the best post-test likelihood ratio in a meta-analysis. This article focuses on the differential diagnosis and on the visual and semi-quantitative tools that can be used to guide to the correct diagnosis of PMR as an add-on to the clinical picture. Further, we briefly discuss the options that can improve molecular imaging in the future for inflammatory rheumatisms in elderly.

Comparison between primary Sjögren's disease patients with high or low level of dryness.

OBJECTIVES: To describe primary Sjögren's disease (SjD) patients presenting no or low level of dryness and to compare them with SjD patients with oral or ocular dryness features. METHODS: All patients diagnosed with SjD according to AECG or ACR/EULAR criteria in our tertiary reference centre were included. Patients with high or low subjective symptoms or objective signs of dryness were compared. RESULTS: Overall, 509 patients were included for the comparison of patients with high (n=456) or low (n=53) level of subjective dryness and 472 for the comparison of patients with (n=359) or without (n=113) high objective dryness. Compared with patients with subjective dryness, patients without high subjective dryness were significantly younger (median 49 (39-62) years vs 58 (47-67) years, p<0.01), diagnosed earlier (median time from first symptoms to diagnosis 2 (0.5-4.5) years vs 4 (1-9.25), p=0.0056), more frequently anti-SSA positive ((83% vs 64%, p=0.008) and had less focal sialadenitis in minor salivary gland biopsy (69% vs 83%, p=0.02).The patients without high level of objective dryness (n=113) were also younger (51 (41-60) vs 58 (47-67) years, p<0.001) and were more frequently anti-SSA positive (79% vs 63%, p=0.002).In both groups, no difference was observed regarding disease activity. CONCLUSIONS: Among the patients with SjD, those without high subjective or objective dryness features had a younger profile, a faster diagnosis which may result from a more acute onset, were more frequently anti-SSA positive than patients with high dryness features.

[Inflammatory diseases of the salivary]. / Pathologies inflammatoires des glandes salivaires.

INFLAMMATORY DISEASES OF THE SALIVARY GLANDS. Salivary glands can be affected by inflammatory pathologies. They are most often manifested by the occurrence of swelling of the main salivary glands that can be associated with a dryness. Main inflammatory diseases with salivary gland involvement are Sjögren's disease, IgG4-associated disease and sarcoidosis. These diseases are rare and characterized by systemic involvement. The existence of multiple organ involvement must lead to the diagnosis. The first step in the diagnostic process is to eliminate the much more frequent differential diagnoses, primarily lithiasis and infectious diseases, as well as nutritional causes. In case of suspicion, a biopsy of the minor salivary glands may help to advance the etiological investigation.

glandes salivaires peuvent être le siège de pathologies inflammatoires. Celles-ci se manifestent le plus souvent par la survenue du gonflement des glandes salivaires principales, parfois associé à un syndrome sec. Les principales pathologies inflammatoires avec atteinte des glandes salivaires sont le la maladie de Sjögren, la maladie associée aux IgG4 et la sarcoïdose. Ces maladies sont des pathologies rares avec atteintes systémiques ; l'existence d'atteintes d'organes multiples doit en faire évoquer le diagnostic. La démarche diagnostique élimine dans un premier temps les pathologies lithiasiques et infectieuses, plus fréquentes, ainsi que les causes nutritionnelles. En cas de suspicion, la réalisation d'une biopsie des glandes salivaires accessoires permet d'avancer dans l'enquête étiologique.

French national diagnostic and care protocol for Sjögren's disease.

Sjögren's disease (SD), also known as Sjögren's syndrome (SS) or Gougerot-Sjögren's syndrome in France, is a rare systemic autoimmune disease in its primary form and is characterised by tropism for the exocrine glandular epithelia, particularly the salivary and lacrimal glands. The lymphocytic infiltration of these epithelia will clinically translate into a dry syndrome which, associated with fatigue and pain, constitutes the symptom triad of the disease. In about one third of patients, SD is associated with systemic complications that can affect the joints, skin, lungs, kidneys, central or peripheral nervous system, and lymphoid organs with an increased risk of B-cell lymphoma. SD affects women more frequently than men (9/1). The peak frequency is around the age of 50. However, the disease can occur at any age, with paediatric forms occurring even though they remain rare. SD can occur alone or in association with other systemic autoimmune diseases. In its isolated or primary form, the prevalence of SD is estimated to be between 1 per 1000 and 1 per 10,000 inhabitants. The most recent classification criteria were developed in 2016 by EULAR and ACR. The course and prognosis of the disease are highly variable and depend on the presence of systemic involvement and the severity of the dryness of the eyes and mouth. The current approach is therefore to identify at an early stage those patients most at risk of systemic complications or lymphoma, who require close follow-up. On the other hand, regular monitoring of the ophthalmological damage and of the dental status should be ensured to reduce the consequences.

Expert Perspective: Challenges in Sjögren's Disease.

The management of Sjögren's disease is challenging because of several factors. Indeed, the clinical presentations are heterogeneous, and one must be able to identify prognostic markers to adapt the follow-up. In addition, there is no validated treatment. Nevertheless, international experts have been working for several years to establish recommendations to guide management. Since research in this field is extremely active, we anticipate the development of effective treatments for our patients in the near future.

Association Between Bruton's Tyrosine Kinase Gene Overexpression and Risk of Lymphoma in Primary Sjögren's Syndrome.

OBJECTIVE: We undertook this study to analyze whole blood gene expression and to investigate the role of B cell genes in primary Sjögren's syndrome-related non-Hodgkin lymphoma (primary SS-NHL). METHODS: Peripheral whole blood samples were collected from 345 well-phenotyped patients with primary SS enrolled in the prospective Assessment of Systemic Signs and Evolution in Sjögren's Syndrome (ASSESS) cohort. Transcriptomic analysis was performed using human Clariom S Arrays (Affymetrix). In our primary analysis, we considered patients with incident lymphoma (i-primary SS-NHL) as the case group and all patients without lymphoma as the comparison group. In our sensitivity analyses, we considered all patients with primary SS-NHL, including those with a history of lymphoma (h-primary SS-NHL), as the case group and primary SS patients without lymphoma, stratified on their risk factors of lymphoma, as the comparison group. RESULTS: Twenty-one patients with primary SS-NHL (including 8 with i-primary SS-NHL and 13 h-primary SS-NHL) were eligible for transcriptomic analysis; we compared these patients to 324 primary SS controls without lymphoma, including 110 with moderate to severe disease activity and 61 with no risk factor of lymphoma. Functional clustering analyses revealed an enrichment of genes related to innate and adaptive immunity, including B cell-related genes. Bruton's tyrosine kinase (BTK) and a proliferation-inducing ligand (APRIL) genes were overexpressed before the occurrence of lymphoma in patients with incident lymphoma compared with patients without lymphoma. In sensitivity analyses, BTK was consistently up-regulated across all comparisons performed. BTK expression was associated with risk of lymphoma on multivariate analyses, which considered 9 validated predictors of lymphoma in primary SS. CONCLUSION: BTK and APRIL were overexpressed in the peripheral blood of primary SS patients prior to lymphoma. The association between BTK, APRIL, and primary SS-NHL requires confirmation in other prospective cohorts.

Mutations in the B30.2 and the central helical scaffold domains of pyrin differentially affect inflammasome activation.

Familial Mediterranean Fever (FMF) is the most common monogenic autoinflammatory disorder. FMF is caused by mutations in the MEFV gene, encoding pyrin, an inflammasome sensor. The best characterized pathogenic mutations associated with FMF cluster in exon 10. Yet, mutations have been described along the whole MEFV coding sequence. Exon 10 encodes the B30.2 domain of the pyrin protein, but the function of this human-specific domain remains unclear. Pyrin is an inflammasome sensor detecting RhoA GTPase inhibition following exposure to bacterial toxins such as TcdA. Here, we demonstrate that the B30.2 domain is dispensable for pyrin inflammasome activation in response to this toxin. Deletion of the B30.2 domain mimics the most typical FMF-associated mutation and confers spontaneous inflammasome activation in response to pyrin dephosphorylation. Our results indicate that the B30.2 domain is a negative regulator of the pyrin inflammasome that acts independently from and downstream of pyrin dephosphorylation. In addition, we identify the central helical scaffold (CHS) domain of pyrin, which lies immediately upstream of the B30.2 domain as a second regulatory domain. Mutations affecting the CHS domain mimic pathogenic mutations in the B30.2 domain and render the pyrin inflammasome activation under the sole control of the dephosphorylation. In addition, specific mutations in the CHS domain strongly increase the cell susceptibility to steroid catabolites, recently described to activate pyrin, in both a cell line model and in monocytes from genotype-selected FMF patients. Taken together, our work reveals the existence of two distinct regulatory regions at the C-terminus of the pyrin protein, that act in a distinct manner to regulate positively or negatively inflammasome activation. Furthermore, our results indicate that different mutations in pyrin regulatory domains have different functional impacts on the pyrin inflammasome which could contribute to the diversity of pyrin-associated autoinflammatory diseases.

Impact of patient ancestry on heterogeneity of Sjögren's disease.

OBJECTIVES: We aimed to compare disease characteristics between primary Sjögren's syndrome (pSS) patients of African ancestry (AA) and Caucasian ancestry. METHODS: We conducted a retrospective, case-control study in a French national and European referral centre for pSS. All patients with pSS of AA were matched with two Caucasians patients having similar follow-up duration. We explored clinical and biological parameters associated with a cumulative EULAR Sjögren's Syndrome Disease Activity Index (cumESSDAI ≥5) (consisting of individual clinESSDAI domain maximum throughout follow-up). RESULTS: We identified 74 patients of AA matched with 148 Caucasian. Median age at pSS diagnosis was younger in AA patients (43 years (IQR 33-51) vs 56 years (44.8-59.2), p<0.001). AA patients presented higher median titre of gammaglobulins (18.5 g/L (IQR 15-22.8) vs 13.4 g/L (9.9-16.9), p<0.001), more frequently positive for anti-SSA (88% vs 72%, p=0.007) and anti-RNP (11% vs 2.7%, p=0.023) antibodies. During the follow-up (median: 6 years (IQR 2-11)), AA patients presented more systemic complications: arthritis, myositis, interstitial lung disease, lymphadenopathy, central nervous system involvement. Median cumESSDAI score was higher in AA patients (7.5 (IQR 3.2-16.0) vs 4.0 (IQR 2.0-9.0), p=0.002). Interestingly, in multivariate analyses, factors associated with disease activity were sub-Saharan AA (OR 2.65 (95% CI 1.06 to 6.94)), rheumatoid factor (OR 2.50 (95% CI 1.28 to 4.96)) and anti-RNP positivity (OR 11.1 (95% CI 1.88 to 212)). CONCLUSION: Patients of AA display higher disease activity with a hallmark of higher B-cell activation. Studies to investigate biological drivers behind such differences are needed.

Hyperosmolar environment and salivary gland epithelial cells increase extra-cellular matrix remodeling and lymphocytic infiltration in Sjögren's syndrome.

Salivary gland epithelial cells (SGECs) play an active role in primary Sjogren's syndrome (pSS) pathogenesis. Quantitative and qualitative abnormalities of saliva might expose SGECs to chronic hyperosmolarity. We aimed to decipher the links between hyperosmolar stimulation of SGECs and lymphocytic infiltration of the salivary glands (SG) observed in pSS. RNAseq was performed on NS-SV-AC cells stimulated with hyperosmolar media containing NaCl (100 mM) or sucrose (200 mM), or with iso-osmolar (Iso) medium. RNAseq was performed on primary cultured SGECs from pSS and controls, in the presence or not of B cells. Hyperosmolar stimulation of NS-SV-AC-cells identified an upregulation of interferon-induced (MX1, IFIT2) and MMPs genes. Enrichment analysis revealed an over-representation of fibrosis pathway. In parallel, RNAseq of SGECs comparing pSS to controls identified an over-representation of a pathway involving MMPs. Given the unexpected upregulation of collagen (COL3A1, COL1A2) and ADAMTS genes in pSS SGECs, we hypothesized that SGECs might undergo epithelial-mesenchymal transition. ZEB2 was upregulated and SLUG was down regulated in SGECs from pSS versus controls. MMP24 and ZEB2 were higher in SGECs from pSS with a focus score ≥1 versus <1. Lastly, SGECs cocultured with B cells expressed higher levels of COL1A2. These results suggest the existence of a vicious circle. Alteration of SGECs in pSS participates in the establishment of a hyperosmolar microenvironment, which in turn promotes SGECs transcriptomic modifications. These modifications include extracellular matrix remodeling and promote SG lymphocytic infiltration.

Janus kinase inhibitors alter NK cell phenotypes and inhibit their antitumour capacity.

OBJECTIVE: Janus kinase inhibitors (JAKi) are efficacious in RA but concerns regarding the risk of cancer associated with their exposure have recently emerged. Given the role of NK cells in antitumour response, we investigated the impact of JAKi [tofacitinib (TOFA), baricitinib (BARI), upadacitinib (UPA) and filgotinib (FIL)] on NK cells. METHODS: We first performed an ex vivo phenotype of NK cells in RA patients treated with TOFA, BARI or MTX. We next phenotyped sorted NK cells from healthy donors cultured with four JAKi or dimethyl sulphoxide (DMSO) at three concentrations, including the licensed dose (therapeutic concentration). Third, we assessed NK cell function using anti-NKp30 cross-linking and co-cultures with two different tumour cell lines: A549 and SU-DHL-4. RESULTS: Twenty-eight RA patients were included. Patients treated with TOFA had reduced expression of CD69 on NK cells compared with MTX (P < 0.05). We confirmed in vitro the negative impact of JAKi on NK cell maturation (CD57), activation (CD69) and activating receptor (NKp30), these latter two being specifically altered with TOFA and UPA. When NK cells were stimulated by NKp30, we observed reduced CD107a (P < 0.01) and IFN-γ/TNF expression (P < 0.05) with TOFA. Lastly, NK cells exposed to TOFA showed reduced CD107a (P < 0.05) and altered cytotoxicity (P < 0.05) when co-cultured with the two cell lines. CONCLUSION: JAKi have a phenotypic and functional impact on NK cell activation and impair their antitumour activity, with a variable impact depending on the JAKi. It remains an open question whether this mechanism can explain the increased tumour risk observed with TOFA.

Pregnancy outcomes in women with primary Sjögren's syndrome: an analysis of data from the multicentre, prospective, GR2 study.

BACKGROUND: Adverse pregnancy outcomes in women with primary Sjögren's syndrome have only been evaluated retrospectively using heterogeneous methods and with contradictory results. We aimed to describe adverse pregnancy, delivery, and birth outcome risks in pregnant women with primary Sjögren's syndrome compared with those of a matched general population in France, and to identify factors predictive of disease flares or adverse pregnancy outcomes. METHODS: We conducted a multicentre, prospective, cohort study in France using the GR2 (Groupe de Recherche sur la Grossesse et les Maladies Rares) registry. Women from the GR2 study were eligible if they had conceived before March, 2021, had primary Sjögren's syndrome according to the American College of Rheumatology and European Alliance of Associations for Rheumatology (EULAR) 2016 classification criteria, and had an ongoing pregnancy at 12 weeks of gestation. In women who entered in the registry with pregnancies before 18 weeks of gestation, we sought to identify factors associated with primary Sjögren's syndrome flare (≥3-point increase in EULAR Sjögren's Syndrome Disease Activity Index [ESSDAI] score) or adverse pregnancy outcomes (fetal or neonatal death, placental insufficiency leading to a preterm delivery [<37 weeks of gestation], or small-for-gestational-age birthweight). A matched controlled study compared adverse pregnancy, delivery, and birth outcome rates between pregnant women with primary Sjögren's syndrome from the GR2 registry and matched controls from the general population included in the last French perinatal survey (Enquête Nationale Périnatale 2016). FINDINGS: 1944 pregnancies were identified in the GR2 cohort, of which 106 pregnancies in 96 women with primary Sjögren's syndrome were included in this analysis. The median age at pregnancy onset was 33 years (IQR 31-36). 87 (83%) of 105 pregnancies (with ethnicity data) were in White women, 18 (17%) were in Black women; 92 (90%) of 102 had previous systemic activity (ESSDAI score of ≥1; data missing in four pregnancies), and 48 (45%) of 106 had systemic activity at inclusion. Of 93 pregnancies included at week 18 of gestation or earlier, primary Sjögren's syndrome flares occurred in 12 (13%). No baseline parameters were associated with primary Sjögren's syndrome flare. Four twin pregnancies and one medical termination were excluded from the adverse pregnancy outcome analysis; of the remaining 88, adverse pregnancy outcomes occurred in six (7%). Among pregnancies in women with data for antiphospholipid antibodies (n=55), antiphospholipid antibody positivity was more frequent among pregnancies with adverse outcomes (two [50%] of four pregnancies) compared with those without adverse outcomes (two [4%] of 51 pregnancies; p=0·023). Anti-RNP antibody positivity was also more frequent among pregnancies with adverse outcomes than those without, although this was not statistically significant. In the matched controlled study, adverse pregnancy outcomes occurred in nine (9%) of 105 pregnancies in women with primary Sjögren's syndrome and 28 (7%) of the 420 matched control pregnancies; adverse pregnancy outcomes were not significantly associated with primary Sjögren's syndrome (odds ratio 1·31, 95% CI 0·53-2·98; p=0·52). INTERPRETATION: Pregnancies in women with primary Sjögren's syndrome had very good prognoses for mothers and fetuses, with no overall increase in adverse pregnancy outcome risk compared with the general population. Women with antiphospholipid antibodies or anti-RNP antibodies require close monitoring, because these factors might be associated with a higher risk of adverse pregnancy outcomes. FUNDING: Lupus France, Association des Sclérodermiques de France, Association Gougerot Sjögren, Association Francophone Contre la Polychondrite Chronique Atrophiante, AFM-Telethon, Société Nationale Française de Médecine Interne, Société Française de Rhumatologie, Cochin Hospital, French Health Ministry, Fondation for Research in Rheumatology, Association Prix Véronique Roualet, Union Chimique Belge.

18F-FDG PET molecular imaging: A relevant tool to investigate chronic inflammatory rheumatisms in clinical practice?

18F-Labeled Fluorodeoxyglucose-Positron Emission Tomography (18F-FDG PET) is a molecular imaging tool commonly used in practice for the assessment of many cancers. Thanks to its properties, its use has been progressively extended to numerous inflammatory conditions, including chronic inflammatory rheumatism (CIR) such as rheumatoid arthritis (RA), spondylarthritis (SpAs) and polymyalgia rheumatica (PMR). 18F-FDG PET is currently not recommended for the diagnostic of CIRs. However, this whole-body imaging tool has emerged in clinical practice, providing a general overview of systemic involvement occurring in CIRs. Numerous studies have highlighted the capacity of 18F-FDG PET to detect articular and extra articular involvements in RA and PMR. However, the lack of specificity of 18F-FDG limits its use for diagnosis purpose. Finally, the key question is the definition of the best way to integrate this whole-body imaging tool in the patient's management workflow.