Deep immunophenotyping reveals that autoimmune and autoinflammatory disorders are spread along two immunological axes capturing disease inflammation levels and types.

OBJECTIVES: Based on genetic associations, McGonagle and McDermott suggested a classification of autoimmune and autoinflammatory diseases as a continuum ranging from purely autoimmune to purely autoinflammatory diseases and comprising diseases with both components. We used deep immunophenotyping to identify immune cell populations and molecular targets characterising this continuum. METHODS: We collected blood from 443 patients with one of 15 autoimmune or autoinflammatory diseases and 71 healthy volunteers. Deep phenotyping was performed using 13 flow cytometry panels characterising over 600 innate and adaptive cell populations. Unsupervised and supervised analyses were conducted to identify disease clusters with their common and specific cell parameters. RESULTS: Unsupervised clustering categorised these diseases into five clusters. Principal component analysis deconvoluted this clustering into two immunological axes. The first axis was driven by the ratio of LAG3+ to ICOS+ in regulatory T lymphocytes (Tregs), and segregated diseases based on their inflammation levels. The second axis was driven by activated Tregs and type 3 innate lymphoid cells (ILC3s), and segregated diseases based on their types of affected tissues. We identified a signature of 23 cell populations that accurately characterised the five disease clusters. CONCLUSIONS: We have refined the monodimensional continuum of autoimmune and autoinflammatory diseases as a continuum characterised by both disease inflammation levels and targeted tissues. Such classification should be helpful for defining therapies. Our results call for further investigations into the role of the LAG3+/ICOS+ balance in Tregs and the contribution of ILC3s in autoimmune and autoinflammatory diseases. TRIAL REGISTRATION NUMBER: NCT02466217.

Counteracting tryptophan metabolism alterations as a new therapeutic strategy for rheumatoid arthritis.

OBJECTIVES: Alterations in tryptophan (Trp) metabolism have been reported in inflammatory diseases, including rheumatoid arthritis (RA). However, understanding whether these alterations participate in RA development and can be considered putative therapeutic targets remains undetermined.In this study, we combined quantitative Trp metabolomics in the serum from patients with RA and corrective administration of a recombinant enzyme in experimental arthritis to address this question. METHODS: Targeted quantitative Trp metabolomics was performed on the serum from 574 previously untreated patients with RA from the ESPOIR (Etude et Suivi des POlyarthrites Indifférenciées Récentes) cohort and 98 healthy subjects. A validation cohort involved 69 established patients with RA. Dosages were also done on the serum of collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA) mice and controls. A proof-of-concept study evaluating the therapeutic potency of targeting the kynurenine pathway was performed in the CAIA model. RESULTS: Differential analysis revealed dramatic changes in Trp metabolite levels in patients with RA compared with healthy controls. Decreased levels of kynurenic (KYNA) and xanthurenic (XANA) acids and indole derivatives, as well as an increased level of quinolinic acid (QUIN), were found in the serum of patients with RA. They correlated positively with disease severity (assessed by both circulating biomarkers and disease activity scores) and negatively with quality-of-life scores. Similar profiles of kynurenine pathway metabolites were observed in the CAIA and CIA models. From a mechanistic perspective, we demonstrated that QUIN favours human fibroblast-like synoviocyte proliferation and affected their cellular metabolism, through inducing both mitochondrial respiration and glycolysis. Finally, systemic administration of the recombinant enzyme aminoadipate aminotransferase, responsible for the generation of XANA and KYNA, was protective in the CAIA model. CONCLUSIONS: Altogether, our preclinical and clinical data indicate that alterations in the Trp metabolism play an active role in the pathogenesis of RA and could be considered as a new therapeutic avenue.

The universal effects of low-dose interleukin-2 across 13 autoimmune diseases in a basket clinical trial.

BACKGROUND: A Tregs insufficiency is central to autoimmune and inflammatory diseases pathophysiology and low dose interleukin-2 (IL-2LD) can specifically activate Tregs. OBJECTIVE: To assess IL-2LD therapeutic potential and select diseases for further clinical development, we performed an open-label, phase 2a, disease-finding, "basket trial" involving patients with one of 13 different autoimmune diseases. METHODS: 81 patients treated with IL-2LD (1 million IU/day) for 5 days, followed by fortnightly injections. The first 48 patients received diluted Proleukin®, while the subsequent 33 received ready-to-use ILT-101®. The primary endpoint was the change in Tregs at day-8 compared to baseline. Key secondary endpoints included clinical efficacy assessments using the Clinical Global Impression (CGI) scale, disease-specific scores, and EuroQL-5D-5L. RESULTS: Our study unveiled a universal and significant expansion and activation of Tregs, without concomitant Teffs activation, across all 13 autoimmune diseases. Both Proleukin® and ready-to-use ILT-101® demonstrated identical effects on Tregs. CGI scores reflecting activity, severity, and efficacy were significantly reduced in the overall patient population. Disease-specific clinical scores improved in five of the six disease cohorts with at least six patients, namely ankylosing spondylitis, systemic lupus erythematosus, Behçet's disease, Sjögren's syndrome, and systemic sclerosis. Urticaria was the only severe adverse event related to treatment. CONCLUSION: IL-2LD was well-tolerated, exhibiting specific Treg activation and clinical improvements across the 13 autoimmune diseases. CLINICAL IMPLICATION: Tregs stimulation by IL-2LD is a promising therapeutic strategy and IL-2LD holds considerable promise for integration into combinatorial therapeutic approaches.

A new serum biochemical marker of synovium turnover predicts radiographic progression in patients with early arthritis.

OBJECTIVE: To investigate whether serum Col 3-4, a new biochemical marker of synovial tissue turnover, was associated with progression of joint damage in patients with early arthritis. METHODS: A total of 788 early arthritis patients (<6 months of symptoms, 82% diagnosis of RA, 18% undifferentiated arthritis) from the prospective ESPOIR study were investigated. Progression was defined as an increase of 1 or 5 unit(s) in radiographic van der Heijde modified Sharp score between baseline and 1 or 5 years, respectively. Associations between baseline Col 3-4 and progression were assessed by logistic regression. RESULTS: Each standard deviation increase of baseline Col 3-4 levels was associated with an increased 5-yr total damage progression with an odds ratio (OR, 95% CI) of 1.51 (1.21, 1.88), which remained significant when DAS28, C-reactive protein and anti-citrullinated protein antibodies positivity were included in the model [OR (95% CI): 1.34 (1.01, 1.76)]. Further adjustment for bone erosion did not modify the association. Patients with both Col 3-4 in the highest quintile and bone erosion had a >2-fold higher risk of progression [OR (95% CI): 7.16 (2.31, 22)] than patients with either high Col 3-4 [2.91 (1.79, 4.73)] or bone erosion [2.36 (2.38, 3.70)] alone. Similar associations were observed for prediction of 12 months progression. CONCLUSIONS: Increased serum Col 3-4 is associated with a higher risk of structural progression, independently of major risk factors. Col 3-4 may be useful in association with bone erosion to identify patients with early arthritis at higher risk.

Do subjective components of disease activity contribute to heterogeneity in opioid prescriptions in inflammatory rheumatic diseases? Results from ESPOIR and DESIR cohorts.

OBJECTIVES: To determine whether subjective components of disease activity are associated with heterogeneity in opioid prescription in inflammatory rheumatic diseases (IRDs) after accounting for objective inflammatory markers. METHODS: Data from two prospective observational cohorts of early IRDs (ESPOIR for rheumatoid arthritis (RA) and DESIR for spondyloarthritis (SpA)) were included. Opioid prescription duration (converted to monthly binary opioid prescription), disease activity (Disease activity score 28 (DAS28) for RA; Axial spondyloarthritis disease activity score-C-reactive protein (ASDAS-CRP) for SpA) and its components were measured respectively at 13 and 9 occasions spanning 10- and 6-years of follow-up. Group-based trajectory modelling defined opioid-prescription trajectories and mixed-models characterised the evolution of disease activity and its subjective components by opioid-prescription trajectories. RESULTS: Four distinct opioid-prescription trajectories: no/low (60.5% and 54.3%), declining (14.7% and 15.8%), augmenting (11.9% and 10.7%), and persistent (12.9% and 19.1%) were identified in RA and SpA respectively (60% were prescribed opioids at least once). Those with regular opioid prescriptions (up to 30%) are often older, less educated, have higher BMI and worse disease. No/low trajectory was the reference for examining evolution of disease activity and subjective components (n=810 RA, n=679 SpA). In IRDs, consistently higher disease activity throughout follow-up were seen with persistent (DAS28(ß=0.4-0.8); ASDAS-CRP(ß=0.4-0.6)), and augmenting (DAS28(ß=0.2-0.5); ASDAS-CRP(ß=0.3-0.6)) trajectories and until 3- or 4-years of follow-up (DAS28(ß=0.3-0.4); ASDAS-CRP(ß=0.2-0.3)) with declining trajectory. Likewise, despite accounting for objective inflammation, subjective components had worse scores over follow-up in augmenting and persistent trajectory. CONCLUSIONS: Non-inflammatory pain mechanisms amplify subjective outcomes, thus, worsening composite measures like disease activity.

Human-specific duplicate CHRFAM7A gene is associated with more severe osteoarthritis and amplifies pain behaviours.

OBJECTIVES: CHRFAM7A is a uniquely human fusion gene that functions as a dominant negative regulator of alpha 7 acetylcholine nicotinic receptor (α7nAChR) in vitro. This study determined the impact of CHRFAM7A on α7nAChR agonist responses, osteoarthritis (OA) severity and pain behaviours and investigated mechanisms. METHODS: Transgenic CHRFAM7A (TgCHRFAM7A) mice were used to determine the impact of CHRFAM7A on knee OA histology, pain severity in OA and other pain models, response to nAchR agonist and IL-1ß. Mouse and human cells were used for mechanistic studies. RESULTS: Transgenic (Tg) TgCHRFAM7A mice developed more severe structural damage and increased mechanical allodynia than wild type (WT) mice in the destabilisation of medial meniscus model of OA. This was associated with a decreased suppression of inflammation by α7nAchR agonist. TgCHRFAM7A mice displayed a higher basal sensitivity to pain stimuli and increased pain behaviour in the monoiodoacetate and formalin models. Dorsal root ganglia of TgCHRFAM7A mice showed increased macrophage infiltration and expression of the chemokine fractalkine and also had a compromised antinociceptive response to the α7nAchR agonist nicotine. Both native CHRNA7 and CHRFAM7A subunits were expressed in human joint tissues and the CHRFAM7A/CHRNA7 ratio was increased in OA cartilage. Human chondrocytes with two copies of CHRFAM7A had reduced anti-inflammatory responses to nicotine. CONCLUSION: CHRFAM7A is an aggravating factor for OA-associated inflammation and tissue damage and a novel genetic risk factor and therapeutic target for pain.

Efficacy and management of tocilizumab in polymyalgia rheumatica: results of a multicenter retrospective observational study.

OBJECTIVES: The efficacy of anti-IL6 receptors such as Tocilizumab (TCZ) was demonstrated in patients with Polymyalgia Rheumatica (PMR) in two recent randomized controlled trials. The objective of this multicentre retrospective study was to assess the efficacy of TCZ in PMR patients requiring GC-sparing treatment, as well as different strategies for TCZ withdrawal. METHODS: We conducted a multicentre study in French tertiary health care departments for patients with PMR. PMR patients receiving off-label TCZ between 2015 and 2022 were included. The primary end point was the proportion of patients tapering to glucocorticoids (GCs) ≤5mg/day 6 months after the first TCZ infusion. The secondary endpoints were the proportion in whom GC was discontinued during follow-up, and the proportion of patients in whom TCZ was discontinued. RESULTS: Fifty-three PMR patients were included. Thirty-one (31) patients suffered from active PMR despite csDMARDs. GCs were ≤5mg/day in 77% of the patients (95% confidence interval [CI95%]: 36-89) at 6 months, and in 97% of the patients at 12 months. Six and 12 months after the first TCZ infusion, the proportions of GC-free patients were 22.5% (CI95%: 12.7-37.8) and 58.3% (CI95%: 43.2-74.1), respectively. Among TCZ withdrawal strategies, TCZ infusion spacing and TCZ dose reduction were more successful (success in 87% and 79% of attempts, respectively) than TCZ discontinuation (success in 52% of attempts; p= 0.012 and p= 0.039, respectively). CONCLUSION: In GC-dependent PMR patients, treatment with TCZ led to a drastic decrease in GC dose and remission of PMR. TCZ dose reduction or TCZ infusion spacing are good options to consider in TCZ withdrawal.

Pregnancy and neonatal outcomes in women with axial spondyloarthritis: pooled data analysis from the European Network of Pregnancy Registries in Rheumatology (EuNeP).

OBJECTIVE: To investigate outcome and course of pregnancies in women with axial spondyloarthritis (axSpA) in a pooled data analysis of pregnancy registries in rheumatology. METHODS: Prospectively followed women with axSpA, fulfilling ASAS classification criteria and for whom a pregnancy outcome was reported, were eligible for the analysis. Anonymised data of four registries was pooled. Rates of adverse pregnancy outcomes were calculated. Systemic inflammation, disease activity and treatment patterns with tumour necrosis factor inhibitor (TNFi) before, during and after pregnancy were analysed. RESULTS: In a total of 332 pregnancies from 304 axSpA women, 98.8% of the pregnancies resulted in live birth. Mean maternal age was 31 years and disease duration 5 years. Most of these patients received pre-conception counselling (78.4%). Before pregnancy, 53% received TNFi treatment, 27.5% in first and 21.4% in third trimester. Pregnancy and neonatal outcomes were favourable with rates of 2.2% for pre-eclampsia, 4.9% for preterm birth, 3.1% for low birth weight and 9.5% for small for gestational age. Neonates were delivered by caesarean section in 27.7% of pregnancies, of which 47.4% were emergencies. Pooled mean CRP was 4 mg/L before conception peaking in the second trimester at 9.4 mg/L. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was below 4 at all time-points. CONCLUSIONS: Pooled rates of most outcomes were better than what had been reported in the literature and within expected rates of those reported for the general population. Pre-conception counselling, planned pregnancies and a tight management in expert centres applying a tailored treatment approach may have contributed to the favourable pregnancy outcomes.

Socio-demographic determinants in the evolution of pain in inflammatory rheumatic diseases: results from ESPOIR and DESIR cohorts.

OBJECTIVE: To determine whether socio-demographic factors are associated with heterogeneity in pain evolution in inflammatory rheumatic diseases (IRDs) after accounting for disease-specific characteristics in a system with universal health care. METHODS: This analysis included the data from two prospective observational cohorts of early IRDs (ESPOIR for early RA and DESIR for early SpA). Data on pain was measured, respectively, on 13 and 9 occasions spanning 10 and 6 years of follow-up using the Short-Form 36 bodily pain score for 810 participants of ESPOIR, and 679 participants of DESIR. Linear mixed models were used to characterize differences in pain evolution as a function of age (tertiles), sex, ethnicity, education, marital, and professional status, after accounting for disease-related, treatment, lifestyle, and health factors. RESULTS: While transitioning from early (disease duration ≤6 months for RA and ≤3 years for SpA) to long-standing disease, differences in pain evolution emerged as a function of age (P < 0.001), sex (P = 0.050), and ethnicity (P = 0.001) in RA, and as a function of age (P = 0.048) in SpA; younger age, males, and Caucasians exhibited lower pain in the latter phases of both diseases. Highly educated participants (RA, ß = -3.8, P = 0.007; SpA, ß = -6.0, P < 0.001) for both diseases, and Caucasians (ß = -5.6, P = 0.021) for SpA presented with low pain early in the disease, with no changes throughout disease course. CONCLUSION: Being older, female, non-Caucasian and having lower education was found to be associated with worse pain in early and/or long-standing IRDs, despite universally accessible health-care. Early identification of at-risk populations and implementation of multidisciplinary strategies may reduce patient-reported health outcome disparities. TRIAL REGISTRATION REGISTRATIONS: ESPOIR: ClinicalTrials.gov, www.clinicaltrials.gov, NCT03666091. DESIR: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01648907.

Immune response profiling of patients with spondyloarthritis reveals signalling networks mediating TNF-blocker function in vivo.

OBJECTIVES: Antitumour necrosis factor (TNF) therapy has revolutionised treatment of several chronic inflammatory diseases, including spondyloarthritis (SpA). However, TNF inhibitors (TNFi) are not effective in all patients and the biological basis for treatment failure remains unknown. We have analysed induced immune responses to define the mechanism of action of TNF blockers in SpA and to identify immunological correlates of responsiveness to TNFi. METHODS: Immune responses to microbial and pathway-specific stimuli were analysed in peripheral blood samples from 80 patients with axial SpA before and after TNFi treatment, using highly standardised whole-blood stimulation assays. Cytokines and chemokines were measured in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory, and gene expression was monitored using nCounter assays. RESULTS: Anti-TNF therapy induced profound changes in patients' innate immune responses. TNFi action was selective, and had only minor effects on Th1/Th17 immunity. Modular transcriptional repertoire analysis identified prostaglandin E2 synthesis and signalling, leucocyte recirculation, macrophage polarisation, dectin and interleukin (IL)-1 signalling, as well as the nuclear factor kappa B (NF-kB) transcription factor family as key pathways targeted by TNF blockers in vivo. Analysis of induced immune responses before treatment initiation revealed that expression of molecules associated with leucocyte adhesion and invasion, chemotaxis and IL-1 signalling are correlated with therapeutic responses to anti-TNF. CONCLUSIONS: We show that TNFi target multiple immune cell pathways that cooperate to resolve inflammation. We propose that immune response profiling provides new insight into the biology of TNF-blocker action in patients and can identify signalling pathways associated with therapeutic responses to biological therapies.

Efficacy of tocilizumab in patients with hand osteoarthritis: double blind, randomised, placebo-controlled, multicentre trial.

OBJECTIVE: To evaluate the efficacy of tocilizumab, an antibody against IL-6 receptor, in patients with hand osteoarthritis. METHODS: This was a multicentre, 12-week, randomised, double-blind, placebo-controlled study from November 2015 to October 2018. Patients with symptomatic hand osteoarthritis (pain ≥40 on a 0-100 mm visual analogue scale (VAS) despite analgesics and non-steroidal anti-inflammatory drugs; at least three painful joints, Kellgren-Lawrence grade ≥2) were randomised to receive two infusions 4 weeks apart (weeks 0 and 4) of tocilizumab (8 mg/kg intravenous) or placebo. The primary endpoint was changed in VAS pain at week 6. Secondary outcomes included the number of painful and swollen joints, duration of morning stiffness, patients' and physicians' global assessment and function scores. RESULTS: Of 104 patients screened, 91 (45 to tocilizumab and 46 to placebo; 82% women; mean age 64.4 (SD 8.7) years) were randomly assigned and 79 completed the 12-week study visit. The mean change between baseline and week 6 on the VAS for pain (primary outcome) was -7.9 (SD 19.4) and -9.9 (SD 20.1) in the tocilizumab and placebo groups (p=0.7). The groups did not differ for any secondary outcomes at weeks 4, 6, 8 or 12. Overall, adverse events were slightly more frequent in the tocilizumab than placebo group. CONCLUSION: Tocilizumab was no more effective than placebo for pain relief in patients with hand osteoarthritis.

Influence of inflammatory and non-inflammatory rheumatic disorders on the clinical and biological profile of type-2 diabetes.

OBJECTIVE: To study the profile of type-2 diabetes (T2D) in patients with RA or OA. METHODS: This observational, multicentre, cross-sectional study included, over a 24-month period, consecutive patients with adult-onset diabetes and RA or OA. We collected demographics, disease activity and severity indices, current treatments for RA and diabetes, history and complications of diabetes. A systematic blood test was performed, assessing inflammatory, immunological and metabolic parameters. The homoeostasis model assessment (HOMA)2-S was used to assess insulin resistance. RESULTS: We included 167 patients with T2D, 118 with RA and 49 with OA. RA and OA patients had severe T2D with suboptimal metabolic control and a biological profile of insulin resistance. Insulin resistance was significantly higher in RA than in OA patients after stratification on age, BMI and CS use [HOMA2-S: 63.5 (35.6) vs 98.4 (69.2), P < 0.001]. HOMA2-S was independently associated with DAS28 [odds ratio (OR): 4.46, 95% CI: 1.17, 17.08]. T2D metabolic control was not related to disease activity and functional impairment, but HbA1c levels were independently associated with bone erosions (OR: 4.43, 95% CI: 1.18, 16.61). Treatment with low-dose CSs was not associated with decreased insulin sensitivity or increased HbA1c levels. Treatment with TNF-α inhibitors was associated with increased insulin sensitivity compared with patients not receiving biologics [101.3 (58.71) vs 60.0 (32.5), P = 0.001]. CONCLUSION: RA patients display severe T2D with inflammation-associated insulin resistance. These findings may have therapeutic implications, with the potential targeting of insulin resistance through the treatment of joint and systemic inflammation.

Secukinumab and ustekinumab treatment in psoriatic arthritis: results of a direct comparison.

OBJECTIVES: To evaluate the characteristics of patients (pts) with PsA treated by ustekinumab (UST) or secukinumab (SEK) and to compare real-world persistence of UST and SEK in PsA. METHODS: In this retrospective, national, multicentre cohort study, pts with PsA (CASPAR criteria or diagnosis confirmed by the rheumatologist) initiating UST or SEK with a follow-up ≥6 months were included from January 2011 to April 2019. The persistence between SEK and UST was assessed after considering the potential confounding factors by using pre-specified propensity-score methods. Causes of discontinuation and tolerance were also collected. RESULTS: A total of 406 pts were included: 245 with UST and 161 with SEK. The persistence rate was lower in the UST group compared with the SEK group [median persistence 9.4 vs 14.7 months; 26.4% vs 38.0% at 2 years; weighted hazard ratio (HR) = 1.42; 95% CI: 1.07, 1.92; P =0.015]. In subgroup analysis, the persistence rate of SEK associated with MTX was significantly higher than that of UST associated with MTX: HR = 2.20; 95% CI: 1.30, 3.51; P =0.001, in contrast to SEK vs UST monotherapy: HR = 1.06; 95% CI: 0.74, 1.53; P =0.75. Discontinuation due to inefficacy was reported in 91.7% (SEK) and 82.4% (UST) of pts. Discontinuation due to an adverse event was reported in 12.2% (SEK) and 7.7% (UST) of pts. CONCLUSION: In this first study comparing UST and SEK, the persistence of SEK was higher than that of UST in PsA. In subgroup analysis, this difference was only found in association with MTX.

Influence of perceived barriers and facilitators for physical activity on physical activity levels in patients with rheumatoid arthritis or spondyloarthritis: a cross-sectional study of 150 patients.

BACKGROUND: Barriers and facilitators to physical activity in inflammatory arthritis can be assessed through the Inflammatory arthritis FAcilitators and Barriers (IFAB) questionnaire. The objective was to measure the correlation between IFAB and self-reported physical activity levels. METHODS: This was an international, multicentric, cross-sectional study in 2019-20. Consecutive spondyloarthritis (axSpA), rheumatoid arthritis (RA) or psoriatic arthritis (PsA) patients completed the 10-item IFAB, which ranges from - 70 to 70 with lower scores indicating more barriers. Physical activity was measured by the IPAQ-S questionnaire, steps per day collected by smartphone, and psychological readiness to change by stages of behaviour change. Spearman correlations and multivariable linear regression were calculated. RESULTS: Of 245 patients included, 150 were analysed: 69 (46%) axSpA, 63 (42%) RA, 18 (12%) PsA. Mean age was 48.6 years (standard deviation, SD 17.1), mean disease duration 11.7 (10.1) years and 60% were women. Barriers to physical activity were moderate: mean IFAB, 6 (SD 19.2); 39 (26%) patients scored less than - 5, corresponding to significant barriers. The mean physical activity was 2837 (SD 2668, median 1784) MET-minutes per week. The IPAQ-S questionnaire was correlated with the IFAB (rho 0.28, p < 0.001), as well as the stage of behaviour change (rho 0.35, p < 0.001) though not with steps per day. Multivariable analyses were confirmatory. CONCLUSION: Perceived barriers and facilitators to physical activity were correlated with physical activity, indicating that targeting patients with high barriers and low facilitators to physical activity could be an effective option to improve physical activity levels. TRIAL REGISTRATION: ClinicalTrial NCT04426747 . Registered 11 June 2020 - Retrospectively registered.

Immunological and clinical effects of low-dose interleukin-2 across 11 autoimmune diseases in a single, open clinical trial.

OBJECTIVE: Regulatory T cells (Tregs) prevent autoimmunity and control inflammation. Consequently, any autoimmune or inflammatory disease reveals a Treg insufficiency. As low-dose interleukin-2 (ld-IL2) expands and activates Tregs, it has a broad therapeutic potential. AIM: We aimed to assess this potential and select diseases for further clinical development by cross-investigating the effects of ld-IL2 in a single clinical trial treating patients with 1 of 11 autoimmune diseases. METHODS: We performed a prospective, open-label, phase I-IIa study in 46 patients with a mild to moderate form of either rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, psoriasis, Behcet's disease, granulomatosis with polyangiitis, Takayasu's disease, Crohn's disease, ulcerative colitis, autoimmune hepatitis and sclerosing cholangitis. They all received ld-IL2 (1 million IU/day) for 5 days, followed by fortnightly injections for 6 months. Patients were evaluated by deep immunomonitoring and clinical evaluation. RESULTS: ld-IL2 was well tolerated whatever the disease and the concomitant treatments. Thorough supervised and unsupervised immunomonitoring demonstrated specific Treg expansion and activation in all patients, without effector T cell activation. Indication of potential clinical efficacy was observed. CONCLUSION: The dose of IL-2 and treatment scheme used selectively activate and expand Tregs and are safe across different diseases and concomitant treatments. This and preliminary indications of clinical efficacy should licence the launch of phase II efficacy trial of ld-IL2 in various autoimmune and inflammatory diseases. TRIAL REGISTRATION NUMBER: NCT01988506.

The nuclear factor-erythroid 2-related factor/heme oxygenase-1 axis is critical for the inflammatory features of type 2 diabetes-associated osteoarthritis.

Epidemiological findings support the hypothesis that type 2 diabetes mellitus (T2DM) is a risk factor for osteoarthritis (OA). Moreover, OA cartilage from patients with T2DM exhibits a greater response to inflammatory stress, but the molecular mechanism is unclear. To investigate whether the antioxidant defense system participates in this response, we examined here the expression of nuclear factor-erythroid 2-related factor (Nrf-2), a master antioxidant transcription factor, and of heme oxygenase-1 (HO-1), one of its main target genes, in OA cartilage from T2DM and non-T2DM patients as well as in murine chondrocytes exposed to high glucose (HG). Ex vivo experiments indicated that Nrf-2 and HO-1 expression is reduced in T2DM versus non-T2DM OA cartilage (0.57-fold Nrf-2 and 0.34-fold HO-1), and prostaglandin E2 (PGE2) release was increased in samples with low HO-1 expression. HG-exposed, IL-1ß-stimulated chondrocytes had lower Nrf-2 levels in vitro, particularly in the nuclear fraction, than chondrocytes exposed to normal glucose (NG). Accordingly, HO-1 levels were also decreased (0.49-fold) in these cells. The HO-1 inducer cobalt protoporphyrin IX more efficiently attenuated PGE2 and IL-6 release in HG+IL-1ß-treated cells than in NG+IL-1ß-treated cells. Greater reductions in HO-1 expression and increase in PGE2/IL-6 production were observed in HG+IL-1ß-stimulated chondrocytes from Nrf-2-/- mice than in chondrocytes from wild-type mice. We conclude that the Nrf-2/HO-1 axis is a critical pathway in the hyperglucidic-mediated dysregulation of chondrocytes. Impairments in this antioxidant system may explain the greater inflammatory responsiveness of OA cartilage from T2DM patients and may inform treatments of such patients.

Doses of rituximab for retreatment in rheumatoid arthritis: influence on maintenance and risk of serious infection.

Objective: To investigate maintenance of rituximab (RTX) in RA patients re-treated with reduced doses compared with standard dose in a real life setting. Methods: The Autoimmunity and Rituximab (AIR) registry is a nationwide prospective observational cohort investigating the long-term safety and efficacy of RTX in RA. The present study included patients from the AIR registry that have been re-treated with RTX after a first course of RTX standard dose (1000 mg × 2). Two groups were defined according to dose of RTX of the first retreatment course (i.e. second course): standard dose group and reduced dose group. Five years' maintenance and rate of serious infections of the retreatment period were compared between standard dose and reduced dose groups. Analyses used the inverse probability of treatment weighting propensity score adjusted method. Results: Among the 1986 patients from the AIR registry, 1278 were included, 1093 (85.5%) treated with standard dose and 185 (14.5%) with reduced doses. Maintenance of RTX at 5 years in the standard and reduced groups was 55.5 and 53.8%, respectively, and did not significantly differ between groups in adjusted analyses (hazard ratio = 1.03; 95% CI: 0.81, 1.30), but the cumulative RTX dose received for retreatment [1.4 (0.6) vs 2.3 (1.0) g/year, P < 0.001] and the rate of serious infections were significantly lower in the reduced dose group (adjusted hazard ratio = 0.50; 95% CI: 0.27, 0.92; P = 0.02). Conclusion: Use of reduced doses of RTX for retreatment did not alter the maintenance of RTX at 5 years in RA patients, but allowed a 39% total dose reduction and a lower rate of serious infections.

Extra-haematological manifestations related to human parvovirus B19 infection: retrospective study in 25 adults.

BACKGROUND: To describe extra-haematological manifestations associated with human parvovirus B19 (HPV-B19) infection. METHODS: We conducted a nationwide multicentre study to retrospectively describe the characteristics and outcome of extra-haematological manifestations in French adults. RESULTS: Data from 25 patients followed from 2001 to 2016 were analysed. Median age was 37.9 years (range: 22.7-83.4), with a female predominance (sex ratio: 4/1). Only 3 patients had an underlying predisposing condition (hemoglobinopathy or pregnancy). The most common manifestations were joint (80%) and skin (60%) involvement. Four patients (16%) had renal involvement (endocapillary proliferative or membranoproliferative glomerulonephritis, focal segmental glomerulosclerosis). Three patients (12%) had peripheral nervous system involvement (mononeuritis, mononeuritis multiplex, Guillain-Barré syndrome) and 2 (8%) presented muscle involvement. Other manifestations included hemophagocytic lymphohistiocytosis (n = 1), myopericarditis and pleural effusion (n = 1), and lymphadenopathy and splenomegaly mimicking lymphoma with spleen infarcts (n = 1). Immunological abnormalities were frequent (56.5%). At 6 months, all patients were alive, and 54.2% were in complete remission. In 2 patients, joint involvement evolved into rheumatoid arthritis. Six patients (24%) received intravenous immunoglobulin (IVIg), with a good response in the 3 patients with peripheral nervous system involvement. CONCLUSIONS: HPV-B19 infection should be considered in a wide range of clinical manifestations. Although the prognosis is good, IVIg therapy should be discussed in patients with peripheral nerve involvement. However, its efficacy should be further investigated in prospective studies.

Subclasses of Monoclonal (Type I) Immunoglobulin G Cryoglobulins: Report on Two Distinct Cases with Myeloma.

BACKGROUND: While different clinical manifestations of IgM and IgG monoclonal cryoglobulins have been demonstrated, little is known about the roles of IgG subclasses in the pathophysiology of these conditions. METHODS: In two cases of myeloma-associated monoclonal (type I) cryoglobulinemia with quite distinct clinical and biological features, serum samples were analyzed using an original IgG subclass-specific immunoblotting technique. RESULTS: The first case had painful arthritis of hands and feet, with skin purpura and a sharp decrease of complement C4 level, and the cryoglobulin was of IgG1 subclass. The second case displayed mostly thrombotic lesions of the limb extremities, C3 and C4 serum levels were normal, and the cryoglobulin belonged to the IgG2 subclass. CONCLUSIONS: Type I cryoglobulins of distinct IgG subclasses may result in different syndromes. In both cases, the treatment relies on eradication of the underlying plasma cell dyscrasia.

Metabolic syndrome-associated osteoarthritis.

PURPOSE OF REVIEW: Interest in the metabolic syndrome-associated osteoarthritis phenotype is increasing. Here, we summarize recently published significant findings. RECENT FINDINGS: Meta-analyses confirmed an association between type 2 diabetes and osteoarthritis and between cardiovascular diseases and osteoarthritis. Recent advances in the study of metabolic syndrome-associated osteoarthritis have focused on a better understanding of the role of metabolic diseases in inducing or aggravating joint damage. In-vivo models of obesity, diabetes, or dyslipidemia have helped to better decipher this association. They give emerging evidence that, beyond the role of common pathogenic mechanisms for metabolic diseases and osteoarthritis (i.e., low-grade inflammation and oxidative stress), metabolic diseases have a direct systemic effect on joints. In addition to the impact of weight, obesity-associated inflammation is associated with osteoarthritis severity and may modulate osteoarthritis progression in mouse models. As well, osteoarthritis synovium from type 2 diabetic patients shows insulin-resistant features, which may participate in joint catabolism. Finally, exciting data are emerging on the association of gut microbiota and circadian rhythm and metabolic syndrome-associated osteoarthritis. SUMMARY: The systemic role of metabolic syndrome in osteoarthritis pathophysiology is now better understood, but new avenues of research are being pursued to better decipher the metabolic syndrome-associated osteoarthritis phenotype.