Risk of severe infection associated with immunoglobulin deficiency under rituximab therapy in immune-mediated inflammatory disease.

OBJECTIVES: We evaluated the risk of severe infection in patients with immune-mediated inflammatory disease (IMID) treated with RTX and with Ig deficiency. METHODS: This was an observational, retrospective single-centre study of patients undergoing treatment with at least one rituximab (RTX) infusion for an IMID until 31 May 2020. Patients were followed up for at least 12 months after the last infusion or until severe infection or death. Ig deficiency was classified as prevalent (before RTX) or acquired (normal Ig assay results before RTX but Ig deficiency during a follow-up). RESULTS: Of 311 patients, 10.6% had prevalent and 19.6% acquired Ig deficiency. Prevalent Ig deficiency was related to concomitant treatment with glucocorticoids (GCs), in particular with a high daily dose at baseline; and acquired Ig deficiency to cumulative dose of RTX, mean Disease Activity Score in 28 joints (DAS28), immunosuppressor or GCs therapy at baseline, diabetes mellitus and obesity. Overall, 14.5% of patients had a severe infection during follow-up, which was numerically but not statistically more frequent in patients with prevalent Ig deficiency than normal Ig level. On multivariate analysis, risk of severe infection was associated with chronic pulmonary disease, GCs dose and mean DAS28-C reactive protein. In a time-dependent analysis, risk of severe infection was not associated with Ig deficiency, either acquired or prevalent (adjusted HR 1.04 (95% CI 0.5 to 2.3), p=0.92). CONCLUSION: Risk of severe infection was not associated with RTX-induced Ig deficiency in patients with an IMID. RTX management should be discussed according to an individual assessment of the infectious risk, especially in patients with GC therapy or chronic lung disease.

Dysbiosis in imiquimod-induced psoriasis alters gut immunity and exacerbates colitis development.

Psoriasis has long been associated with inflammatory bowel disease (IBD); however, a causal link is yet to be established. Here, we demonstrate that imiquimod-induced psoriasis (IMQ-pso) in mice disrupts gut homeostasis, characterized by increased proportions of colonic CX3CR1hi macrophages, altered cytokine production, and bacterial dysbiosis. Gut microbiota from these mice produce higher levels of succinate, which induce de novo proliferation of CX3CR1hi macrophages ex vivo, while disrupted gut homeostasis primes IMQ-pso mice for more severe colitis with dextran sulfate sodium (DSS) challenge. These results demonstrate that changes in the gut environment in psoriasis lead to greater susceptibility to IBD in mice, suggesting a two-hit requirement, that is, psoriasis-induced altered gut homeostasis and a secondary environmental challenge. This may explain the increased prevalence of IBD in patients with psoriasis.

CXCR5/CXCL13 pathway, a key driver for migration of regulatory B10 cells, is defective in patients with rheumatoid arthritis.

OBJECTIVES: Chemokines (CKs) are key players of immune-cell homing and differentiation. CK receptors (CKRs) can be used to define T-cell functional subsets. We aimed to characterize the CKR profile of the regulatory B-cell subset B10+ cells and investigate the CKs involved in their migration and differentiation in healthy donors and patients with RA. METHODS: RNA sequencing and cytometry were used to compare CKR expression between B10+ and B10neg cells. Migration of B10+ and B10neg cells and IL-10 secretion of B cells in response to recombinant CKs or synovial fluid (SF) were assessed. RESULTS: CXCR5 was expressed at a higher level on the B10+ cell surface as compared with other B cells (referred to as B10neg cells). In line with this, its ligand CXCL13 preferentially attracted B10+ cells over B10neg cells. Interestingly, synovial fluid from RA patients contained high levels of CXCL13 and induced strong and preferential migration of B10+ cells. Besides its role in attracting B10+ cells, CXCL13 also promoted IL-10 secretion by B cells. In RA patients, the level of CXCR5 on B-cell surface was reduced. The preferential migration of RA B10+ cells toward CXCL13-rich SF was lost and CXCL13 stimulation triggered less IL-10 secretion than in healthy donors. CONCLUSION: Our results identify that the CXCR5/CXCL13 axis is essential for B10+ cell biology but is defective in RA. Restoring the preferential migration of B10+ within the affected joints to better control inflammation may be part of the therapeutic approach for RA.

EULAR points to consider for conducting clinical trials and observational studies in individuals at risk of rheumatoid arthritis.

BACKGROUND: Despite growing interest, there is no guidance or consensus on how to conduct clinical trials and observational studies in populations at risk of rheumatoid arthritis (RA). METHODS: An European League Against Rheumatism (EULAR) task force formulated four research questions to be addressed by systematic literature review (SLR). The SLR results informed consensus statements. One overarching principle, 10 points to consider (PTC) and a research agenda were proposed. Task force members rated their level of agreement (1-10) for each PTC. RESULTS: Epidemiological and demographic characteristics should be measured in all clinical trials and studies in at-risk individuals. Different at-risk populations, identified according to clinical presentation, were defined: asymptomatic, musculoskeletal symptoms without arthritis and early clinical arthritis. Study end-points should include the development of subclinical inflammation on imaging, clinical arthritis, RA and subsequent achievement of arthritis remission. Risk factors should be assessed at baseline and re-evaluated where appropriate; they include genetic markers and autoantibody profiling and additionally clinical symptoms and subclinical inflammation on imaging in those with symptoms and/or clinical arthritis. Trials should address the effect of the intervention on risk factors, as well as progression to clinical arthritis or RA. In patients with early clinical arthritis, pharmacological intervention has the potential to prevent RA development. Participants' knowledge of their RA risk may inform their decision to participate; information should be provided using an individually tailored approach. CONCLUSION: These consensus statements provide data-driven guidance for rheumatologists, health professionals and investigators conducting clinical trials and observational studies in individuals at risk of RA.

Dietary carbohydrate, particularly glucose, drives B cell lymphopoiesis and function.

While diet modulates immunity, its impact on B cell ontogeny remains unclear. Using mixture modeling, a large-scale isocaloric dietary cohort mouse study identified carbohydrate as a major driver of B cell development and function. Increasing dietary carbohydrate increased B cell proportions in spleen, mesenteric lymph node and Peyer's patches, and increased antigen-specific immunoglobulin G production after immunization. This was linked to increased B lymphopoiesis in the bone marrow. Glucose promoted early B lymphopoiesis and higher total B lymphocyte numbers than fructose. It drove B cell development through glycolysis and oxidative phosphorylation, independently of fatty acid oxidation in vitro and reduced B cell apoptosis in early development via mTOR activation, independently of interleukin-7. Ours is the first comprehensive study showing the impact of macronutrients on B cell development and function. It shows the quantitative and qualitative interplay between dietary carbohydrate and B cells and argues for dietary modulation in B cell-targeting strategies.

2021 EULAR recommendations for the implementation of self-management strategies in patients with inflammatory arthritis.

BACKGROUND: An important but often insufficient aspect of care in people with inflammatory arthritis (IA) is empowering patients to acquire a good understanding of their disease and building their ability to deal effectively with the practical, physical and psychological impacts of it. Self-management skills can be helpful in this regard. OBJECTIVES: To develop recommendations for the implementation of self-management strategies in IA. METHODS: A multidisciplinary taskforce of 18 members from 11 European countries was convened. A systematic review and other supportive information (survey of healthcare professionals (HCPs) and patient organisations) were used to formulate the recommendations. RESULTS: Three overarching principles and nine recommendations were formulated. These focused on empowering patients to become active partners of the team and to take a more proactive role. The importance of patient education and key self-management interventions such as problem solving, goal setting and cognitive behavioural therapy were highlighted. Role of patient organisations and HCPs in promoting and signposting patients to available resources has been highlighted through the promotion of physical activity, lifestyle advice, support with mental health aspects and ability to remain at work. Digital healthcare is essential in supporting and optimising self-management and the HCPs need to be aware of available resources to signpost patients. CONCLUSION: These recommendations support the inclusion of self-management advice and resources in the routine management of people with IA and aim to empower and support patients and encourage a more holistic, patient-centred approach to care which could result in improved patient experience of care and outcomes.

Detrimental Impact of Microbiota-Accessible Carbohydrate-Deprived Diet on Gut and Immune Homeostasis: An Overview.

Dietary fibers are non-digestible polysaccharides functionally known as microbiota-accessible carbohydrates (MACs), present in inadequate amounts in the Western diet. MACs are a main source of energy for gut bacteria so the abundance and variety of MACs can modulate gut microbial composition and function. This, in turn, impacts host immunity and health. In preclinical studies, MAC-deprived diet and disruption of gut homeostasis aggravate the development of inflammatory diseases, such as allergies, infections, and autoimmune diseases. The present review provides a synopsis on the impact of a low-MAC diet on gut homeostasis or, more specifically, on gut microbiota, gut epithelium, and immune cells.

Non-pharmacological and pharmacological interventions in patients with early arthritis: a systematic literature review informing the 2016 update of EULAR recommendations for the management of early arthritis.

OBJECTIVE: To perform a systematic literature review (SLR) on pharmacological and non-pharmacological treatments, in order to inform the European League Against Rheumatism (EULAR) recommendations for the management of early arthritis (EA). METHODS: The expert committee defined research questions concerning non-pharmacological interventions, patient information and education, non-steroidal anti-inflammatory drug, glucocorticoid (GC) and disease-modifying antirheumatic drugs (DMARDs) use, as well as on disease monitoring. The SLR included articles published after the last EULAR SLR until November 2015 found in the MEDLINE, EMBASE and Cochrane databases and abstracts from the 2014 and 2015 American College of Rheumatology and EULAR conferences. RESULTS: Exercise programmes may improve pain and physical function in patients with EA. Patients with EA treated within the first 3 months of symptoms have better clinical and radiological outcomes than those treated beyond 3 months. The clinical and radiological efficacy of GCs is confirmed, with similar efficacy of oral and parenteral administrations. Long-term data raise concerns regarding cardiovascular safety when using GCs. Step-up DMARD therapy is as effective as intensive DMARD therapy 'ab initio' for the long-term outcome of EA. Short-term superiority of intensive therapy with bDMARDs is not maintained on withdrawal of bDMARD. Patients with early psoriatic arthritis have better skin and joint outcomes when tight control is used compared to standard care. CONCLUSIONS: The findings confirm the beneficial effect of exercise programmes and the importance of early drug therapy and tight control. They support the use of methotrexate and GCs as first-line drugs, although the long-term use of GCs raises safety concerns.

High levels of natural killer cells are associated with response to tocilizumab in patients with severe rheumatoid arthritis.

OBJECTIVES: We aimed to assess the effect of tocilizumab (TCZ), an IL-6 receptor inhibitor, on B, T, NK and NKT cells in patients with RA and to study the cell type predictors of remission. We also compared NK cells in patients with RA and in controls. METHODS: RA patients included in the study met the 2010 ACR/European League Against Rheumatism (EULAR) criteria, were receiving stable doses of steroids and had not received rituximab in the previous year. Different B and T cell subsets, NK cells and NKT cells were assessed by flow cytometry along with perforin A and granzyme B to estimate NK cell cytotoxicity. RESULTS: We included 92 RA patients, including 20 requiring TCZ treatment and 15 requiring anti-TNF drugs, and 25 controls. At baseline, the proportion of CD56(dim)CD16(+)CD3(-) NK cells was inversely correlated with the 28-joint DAS (DAS28). In TCZ-treated patients, the baseline proportion of CD3(-)CD56(+) NK cells was inversely correlated with the change in DAS28 at 3 months and the proportion was 3-fold greater for patients with DAS28 remission at 3 months than other patients. Change in the proportion of CD56(bri)CD16(-) NK cells was linearly correlated with change in the DAS28 at 3 months. The baseline proportion of NK cells did not predict change in disease activity at 3 months with anti-TNF therapy. The perforin content in NK cells increased with TCZ treatment. CONCLUSION: This study supports NK cell involvement in RA and in the TCZ mechanism of action. NK cells at baseline could be a predictive factor of TCZ response if results are confirmed.

Etanercept normalises left ventricular mass in patients with rheumatoid arthritis.

BACKGROUND: Cardiovascular mortality is increased in patients with rheumatoid arthritis (RA). RA is associated with an increased left ventricular mass index (LVMI), a strong marker of cardiovascular mortality, and vessel abnormalities. Experimental studies have suggested that tumour necrosis factor α (TNFα) may induce LV hypertrophy. OBJECTIVE: To study the effect of medium-term (3- and 6-months) treatment with the TNFα inhibitor etanercept (ETN) and synthetic disease-modifying antirheumatic drugs (sDMARDs) on LV morphological features and arterial stiffness in patients with RA. METHODS: Consecutive female patients with active RA requiring treatment with ETN (n=28) or sDMARDs (n=20) were included. Clinical and biological monitoring, echocardiography and pulse wave velocity (PWV) assessment were performed at inclusion and at 3 and 6 months after the start of treatment. Paired t tests and multivariate linear regression analysis were used. RESULTS: Mean LVMI tended to be higher at baseline in the ETN group than in the sDMARD group (96.5±19.8 vs 84.3±26.8 g/m2; p=0.11 for the ETN and sDMARD groups, respectively). In patients with ETN treatment, mean LVMI was significantly decreased at 3 and 6 months (-6.3±7.6 and -14.2±9.3 g/m2; p<0.001), with no change from baseline for patients with sDMARD treatment (-2.2±10.9 and -2.7±10.2 g/m2, respectively). Blood pressure (BP) and aortic PWV were not changed by either treatment. CONCLUSIONS: ETN induced a significant decrease in LVMI with medium-term treatment with no change in BP or PWV. TNFα may be an important factor of LV hypertrophy, which may explain the benefit of TNF inhibitors on cardiovascular morbidity and mortality in RA. These results need to be confirmed by larger studies and with other TNF inhibitors.

Etanercept concentration in patients with rheumatoid arthritis and its potential influence on treatment decisions: a pilot study.

OBJECTIVE: For patients with rheumatoid arthritis (RA), recommendations are inconclusive about whether tumor necrosis factor-α (TNF-α)-blocker therapy should be evaluated at 3 or 6 months. Biomarkers are needed to predict at 3 months which patients would benefit from further treatment because of nonoptimal response. Our objective was to investigate whether serum etanercept (ETN) concentrations and anti-ETN antibodies at 3 months are predictors of clinical response to ETN at 6 months in patients with RA in terms of European League Against Rheumatism criteria and Disease Activity Score in 28 joints (DAS28). METHODS: Between 2009 and 2010, we included 19 women with active RA who were candidates for ETN therapy. Response criteria were evaluated at 3 and 6 months. Serum concentrations of ETN and anti-ETN antibodies were measured by ELISA at baseline and at 3 and 6 months. RESULTS: Eighteen patients completed followup. Three-month ETN concentrations were lower for 6-month nonresponders than responders (p = 0.03). Three-month ETN levels correlated significantly with change in DAS28 between baseline and 6 months (r = -0.62, p = 0.006). The best predictor of response at 6 months was observed with an ETN threshold of 3.1 µg/ml at 3 months. No anti-ETN antibodies were found. CONCLUSION: ETN concentrations at 3 months predict response to ETN therapy at 6 months. Low ETN concentrations could explain the absence of response to ETN, suggesting that patients with low ETN levels could benefit from increased ETN dose or earlier interruption of treatment.

Effect of TNF inhibitors on lipid profile in rheumatoid arthritis: a systematic review with meta-analysis.

BACKGROUND: Patients with rheumatoid arthritis (RA) are at increased risk of cardiovascular disease. Lipid changes related to inflammation have been described in RA. Tumour necrosis factor α (TNFα) inhibitor (TNFi) treatment is effective in controlling inflammation and decreasing the number of cardiovascular events. OBJECTIVE: To assess the change in lipid levels with TNFi treatment in patients with RA by systematic review and meta-analysis. METHODS: A Medline search was performed for articles published up to March 2011. Reports describing values for total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides (TGs), atherogenic index (AI) and apolipoprotein B/A (apoB/A) collected before and after TNFi initiation were included. Data were analysed according to short-, mid- and long-term treatment. Statistical analysis of pre-post data was performed by comprehensive meta-analysis. A random effects model was used when there was evidence of heterogeneity. RESULTS: The search retrieved 32 articles, of which 13 prospective before/after studies were analysed. Long-term TNFi treatment was associated with increased levels of HDL (+0.27 mmol/l, p<0.0001) and TC (+0.27 mmol/l, p=0.03), whereas LDL levels and AI remained unchanged. After long-term treatment, TG levels increased (+0.28 mmol/l, p<0.001) and apoB/A decreased (-0.3, p<0.0001). CONCLUSION: The presumed cardioprotective effects of TNFi in RA do not seem to be explained by quantitative lipid changes since long-term treatment has no effect on LDL levels or on AI. Increased HDL levels could have some beneficial effects, but this needs to be confirmed by prospective studies with long-term follow-up.

TGF beta1 polymorphisms are candidate predictors of the clinical response to rituximab in rheumatoid arthritis.

OBJECTIVE: To evaluate the association between several candidate single-nucleotide polymorphisms (SNPs) and responsiveness to rituximab in patients with rheumatoid arthritis (RA). METHODS: Sixty-three RA patients were included. Nine genes (13 SNPs) were subsequently analyzed, including those coding for cytokines involved in synovitis (IL10, LTA, TGFß1, TNF-α, TNF receptor II) and genes associated with RA susceptibility (-C5 TRAF1, STAT4, TNFAIP3 and PTPN22). RESULTS: Forty-four patients were defined as responders and 19 as nonresponders. TGFß1 Codon 10 and TGFß1 Codon 25 SNPs were both associated with clinical response (probability to respond to treatment with the Codon 10C/T genotype: OR = 1.6; P = 0.002, and with the Codon 25 G/C genotype: OR = 1.6; P = 0.025). The probability to be a responder when the TGFß Codon10 C/T and TGFß Codon 25 G/C genotypes were co-inherited, doubled (OR = 2.6; P = 0.008). CONCLUSION: The TGFß1 SNPs are associated with a good response to rituximab therapy and as such could be useful genetic biomarkers in predicting therapy outcome.

Sarcoid-like granulomatosis in patients treated with tumor necrosis factor blockers: 10 cases.

OBJECTIVE: TNF blockers have been recently evaluated for treating refractory sarcoidosis and could be efficient. However, several cases of sarcoidosis have been diagnosed during anti-TNF therapy. Here, we report the largest series of sarcoid-like granulomatosis following TNF blocker treatment. METHODS: A call for observations of sarcoid-like granulomatosis following TNF blocker treatment was sent to the members of the French 'Club Rhumatismes et Inflammation'. Histological evidence of granulomatosis was required. RESULTS: Observations of 10 patients [seven females; median age 50.5 (range 27-72) years] with sarcoid-like granulomatosis while on anti-TNF treatment were collected: five were treated with etanercept and five with monoclonal antibodies; four patients received TNF blockers for RA and six for SpA. The median delay between anti-TNF agent introduction and granulomatosis diagnosis was 18 (range 1-51) months. Clinical symptoms were mainly pulmonary and cutaneous. Angiotensin-converting enzyme activity was increased in six cases. Lymph-node and/or lung involvement were observed by CT scan of the chest for eight patients. The median delay between drug discontinuation and remission was 6 (range 1-11) months for clinical signs and 6 (range 2-12) months for biological and radiographic findings. Improvement was observed in all patients after drug discontinuation with or without steroids. CONCLUSIONS: Sarcoid-like granulomatosis is rare but not exceptional in patients treated with TNF blockers (approximately 1/2800) and does not seem to be related to gender, rheumatic disease or in our series the type of anti-TNF drug used (monoclonal antibodies or soluble receptor). Discontinuation of anti-TNF usually leads to recovery.