Evolution of monoclonal gammopathy of undetermined significance in patients treated with JAK inhibitors for rheumatic diseases: data from the MAJIK-SFR registry.

OBJECTIVE: Monoclonal gammopathy of undetermined significance (MGUS) is common, but there are scarce data regarding the effect of DMARDs on this premalignant condition. We aimed to evaluate the impact of JAK inhibitors (JAKis) on MGUS when initiated for an active rheumatic disease. METHODS: Patients with monoclonal abnormality prior to JAKi initiation for an active rheumatic disease were identified through the MAJIK-SFR Registry, a French multicentre prospective study. Clinical and biological data were collected using a standardized case report form. RESULTS: Twenty patients were identified with a mean age of 65 years and a diagnosis of RA (n = 15), PsA (n = 3), and axial SpA (n = 2). The JAKi prescribed was baricitinib (n = 9), tofacitinib (n = 6) or upadacitinib (n = 5), with a mean duration of 15.5 months. Seventeen patients had individualized serum monoclonal protein (IgG kappa n = 9; IgG lambda n = 4; IgM kappa n = 3; IgA lambda n = 1) ranging from 0.16 to 2.3 g/dl, and three patients did not have an initial measurable spike but they had a positive serum immunofixation. With a follow-up of 4-28 months, the serum monoclonal protein level decreased in 8 of 17 patients (47%), remained stable in 8 patients (47%) and increased in 1 patient (6%). The maximal decrease observed was an initial IgG kappa of 2.3 g/dl, decreasing to 0.2 g/dl at month 14. CONCLUSION: This study provides reassuring and promising data on MGUS evolution in patients treated with JAKis for rheumatic diseases, which may guide the choice of treatment in patients with both conditions.

Effects of disease-modifying anti-rheumatic drugs on sacroiliac MRI score in axial spondyloarthritis: a systematic review and meta-analysis.

INTRODUCTION: Sacroiliac bone marrow edema is an important factor in the diagnosis and management of axial spondyloarthritis (axSpA). The aim of this meta-analysis is to assess the effect of the different bDMARDs and tsDMARDs on the SPARCC score at 12-16 and 48-52 weeks. METHODS: A systematic review, performed on PubMed (including Medline), Cochrane (CENTRAL) and DOAJ databases, included randomized controlled studies evaluating the sacroiliac joint (SIJ) SPARCC score at 12-16 or 48-52 weeks in patients with axSpA meeting the ASAS 2009 criteria or the modified New York criteria. We included studies evaluating the effects of the different treatments on the SPARCC score of SIJ in axial spondyloarthritis in comparison to a control group. RESULTS: Eighteen studies were included in the meta-analysis. Nine studies evaluated the effect of TNFα inhibitors (TNFi), three for IL-17 inhibitors, and four for JAK inhibitors. At 12 and 16 weeks, SIJ SPARCC score was significantly improved by TNFi (WMD: - 3.29 [95% CI - 4.25; - 2, 34]), by IL-17 inhibitors (WMD: - 4.66 [95% CI - 6.22; - 3.09]), and by JAK inhibitors (JAKi) (WMD: - 3.06 [95% CI - 3.24; - 2.89]). There was no difference between the molecule subgroups. At 48-52 weeks, TNFα inhibitors reduced more SIJ SPARCC, but not significantly (WMD: - 2.26 [95% CI - 4.94; 0.42]), than placebo groups who began a TNFi treatment with delay. CONCLUSION: Our meta-analysis shows a comparable improvement of the SIJ SPARCC score regarding TNFi, JAKi, and IL-17 inhibitors at three months and suggests the presence of an opportunity window. Key Points • Anti-TNF Ab, anti-IL17 Ab, and JAK inhibitor treatments reduce the sacroiliac joint SPARCC scores. • There is no difference between the different treatments in the reduction of the sacroiliac joint SPARCC score after 3 months in axial spondyloarthritis.

Difficult-to-treat axial spondyloarthritis is associated with psoriasis, peripheral involvement and comorbidities: results of an observational nationwide study.

OBJECTIVES: To determine the cumulative incidence and identify the factors associated with difficult-to-treat axial spondyloarthritis (D2T-axSpA) in French patients newly benefiting from the French 'long-term illness' (LTI) social security scheme for axial spondyloarthritis (axSpA). METHODS: This national cohort study was based on the French National Medico-Administrative Database, SNDS, which contains data on hospitalisation, LTI and outpatient care consumption. All French patients newly receiving LTI benefits for ankylosing spondylitis (AS) between 2010 and 2013 were included in the study. In France, LTI is required to access biological/targeted synthetic DMARDs (b/tsDMARDs). The follow-up period ended on 31 December 2018. So-called D2T-axSpA was defined as the failure of three b/tsDMARDs or of two b/tsDMARDs with different modes of action. Comorbidities and extra-musculoskeletal manifestations were identified using previously described algorithms. Characteristics were compared between patients with D2T-axSpA and patients with non-D2T-axSpA who had received at least one b/tsDMARD with bivariate and multivariate analysis using logistic regression. Incidence rates of major cardiovascular event (MACE) and death were compared using competitive risk analysis. RESULTS: 22 932 patients were included. 10 798 (47.08%) patients received at least one bDMARD. None received tsDMARD. During follow-up, 2115 patients were classified as having D2T-axSpA, representing 19.59% of patients who received at least one bDMARD. In multivariate analysis, D2T-axSpA was significantly associated with female gender, peripheral involvement, psoriasis, hypertension and depression (p<0.001 for each case). There was no difference in the incidence of MACE (p=0.92) or death (p=0.87). CONCLUSION: D2T-axSpA affects one in five patients exposed to bDMARDs in this national cohort. D2T-axSpA is more common in women and patients with peripheral involvement and/or comorbidities.

Comparison of sacroiliac CT findings in patients with and without ankylosing spondylitis aged over 50 years.

Diagnosis of axial spondyloarthritis (axSpA) is nowadays commonly made with the help of pelvic radiography or magnetic resonance imaging (MRI). However, there is an important inter-observer variability in radiography, and MRI is subject to possible false positives and is not the best modality for studying structural lesions. Conversely, pelvic computed tomography (CT) has excellent specificity and appears to be more effective than radiography for the diagnosis of ankylosing spondylitis (AS). However, its findings in patients over 50 years of age have not yet been studied. The objectives of this study were to describe the CT characteristics of sacro-iliac joints (SIJ) and the presence of intra-articular gas in patients with AS aged over 50 years and to compare them with controls of the same age and sex. This two-center, cross-sectional, observational study was performed using the medical records of the rheumatology departments of two University Hospitals. We included patients with a clinical diagnosis of axSpA, who had both definite radiographic sacroiliitis according to the modified New York criteria and met the ASAS 2009 criteria for axSpA (that is, AS), and who had undergone any CT scan including the whole SIJ. Each patient was matched for age and sex to a control randomly selected on the Picture Archiving and Communication System (PACS), symptomatic or asymptomatic, and without spondyloarthritis. For each individual, CT scans were interpreted blindly by two independent rheumatologists and scored for joint space narrowing (JSN), erosions, sclerosis, intra-articular gas, and diffuse idiopathic skeletal hyperostosis (DISH). Ninety patients and 90 controls were included in the study. The rates of positive JSN, erosion, and sclerosis scores were higher in the AS group (91% vs. 21%, p < 0.0001; 31% vs. 2%, p < 0.0001; 27% vs. 13%, p = 0.03, respectively), but the rates of intra-articular gas and DISH were higher in the control group (24% vs. 68%, p < 0.0001; 7% vs. 33%, p < 0.0001, respectively). 58% of patients had complete bilateral ankylosis. A total of 83 (92.2%) patients had a CT scan considered positive for AS, compared with only seven controls (7.8%). Sclerosis and erosions were predominantly on the anterosuperior part and iliac side of the joint in controls and were more diffuse in patients with AS. CT findings in patients with AS over 50 years of age are mostly represented by changes in the joint space; patients with AS have more erosions and sclerosis changes, but less intra-articular gas than controls.

Increased gut permeability and intestinal inflammation precede arthritis onset in the adjuvant-induced model of arthritis.

BACKGROUND: Intestinal inflammation, dysbiosis, intestinal permeability (IP), and bacterial translocation (BT) have been identified in patients with spondyloarthritis but the time at which they appear and their contribution to the pathogenesis of the disease is still a matter of debate. OBJECTIVES: To study the time-course of intestinal inflammation (I-Inf), IP, microbiota modification BT in a rat model of reactive arthritis, the adjuvant-induced arthritis model (AIA). METHODS: Analysis was performed at 3 phases of arthritis in control and AIA rats: preclinical phase (day 4), onset phase (day 11), and acute phase (day 28). IP was assessed by measuring levels of zonulin and ileal mRNA expression of zonulin. I-inf was assessed by lymphocyte count from rat ileum and by measuring ileal mRNA expression of proinflammatory cytokines. The integrity of the intestinal barrier was evaluated by levels of iFABP. BT and gut microbiota were assessed by LPS, soluble CD14 levels, and 16S RNA sequencing in mesenteric lymph node and by 16S rRNA sequencing in stool, respectively. RESULTS: Plasma zonulin levels increased at the preclinical and onset phase in the AIA group. Plasma levels of iFABP were increased in AIA rats at all stages of the arthritis course. The preclinical phase was characterized by a transient dysbiosis and increased mRNA ileal expression of IL-8, IL-33, and IL-17. At the onset phase, TNF-α, IL-23p19, and IL-8 mRNA expression were increased. No changes in cytokines mRNA expression were observed at the acute phase. Increased CD4+ and CD8+ T cell number was measured in the AIA ileum at day 4 and day 11. No increase in BT was observed. CONCLUSION: These data show that intestinal changes precede the development of arthritis but argue against a strict "correlative" model in which arthritis and gut changes are inseparable.

Effects of an Exercise Program and Cold-Water Immersion Recovery in Patients with Rheumatoid Arthritis (RA): Feasibility Study.

Rheumatoid Arthritis (RA) patients present is an increased cardiovascular risk (CVR) linked to systemic inflammatory manifestations. A physical activity program with known positive effects on CVR, followed by cryotherapy because of its analgesic and anti-inflammatory effects, may be interesting. However, there are no reports in the literature of such a program. This study aimed to determine the feasibility (acceptability, safety, and effectiveness) of an individualized Intermittent Exercise Program followed by cold-water immersion as a recovery for RA patients. The program was conducted three times per week by eighteen RA patients (one man) with means of age and BMI of 55 (11.9) years and 25.5 (4.7) kg·m-2. Outcomes were assessed before and after nine and seventeen sessions and included evaluation of acceptability by perceived exertion (Borg) and water temperature (VAS) measures at each session; safety by a number of painful and swollen joints (echography); physical function (health assessment questionnaire); general health status (Short Form-36) measures; and effectiveness by arterial stiffness (pulse wave velocity, or PWV) measures. The results showed good acceptability of the program; no patient dropped out of the protocol or even presented difficulties or perceived pain. The HR and PWV values decreased significantly (70.2 ± 8.4 to 66 ± 5.5; p < 0.05 and 8.9 ± 1.2 to 7.0 ± 0.8; p < 0.001) after nine exercise sessions. No aggravation of symptoms has been noted. This program is acceptable, safe, and effective; consider tailoring it for supervised home-based use.

Novel insights into the anatomy and histopathology of the sacroiliac joint and correlations with imaging signs of sacroiliitis in case of axial spondyloarthritis.

For a better understanding of the pathophysiology of spondyloarthropathy (SpA), a detailed anatomical description of the sacroiliac joint is required because sacroiliitis is the earliest and most common sign of SpA and an essential feature for the diagnosis of ankylosing spondylitis. Beyond the anatomy, the histopathology of sacroiliac entheses and immunological mechanisms involved in sacroiliitis are crucial for a better understanding of disease causation. In this narrative review, we discuss the core anatomical, histological, and immunohistological observations involved in the development of sacroiliitis, focusing particularly on imaging-based information associated with sacroiliitis. Finally, we try to answer the question of whether at the sacroiliac joint, enthesitis precedes synovitis and subchondral bone changes in SpA.

Recommendations for assessing the risk of cardiovascular disease and venous thromboembolism before the initiation of targeted therapies for chronic inflammatory rheumatic diseases.

BACKGROUND: Patients with rheumatoid arthritis (RA) and other chronic inflammatory rheumatic disorders have increased risk of cardiovascular disease (CVD) and venous thromboembolism (VTE) compared with the general population. Moreover, recent data have raised concerns around a possible increased risk of major CV events (MACE) and VTE in patients treated with JAK inhibitors (JAKi). In October 2022, the PRAC has recommended measures to minimize the risk of serious side effects, including CV conditions and VTE, associated with all approved in chronic inflammatory diseases. OBJECTIVE: To provide an adequate and feasible strategy to evaluate, at the individual level, the risk of CVD and VTE in patients with chronic inflammatory rheumatic diseases. METHODS: A multidisciplinary steering committee comprised 11 members including rheumatologists, a cardiologist, a hematologist expert in thrombophilia and fellows. Systematic literature searches were performed and evidence was categorized according to standard guidelines. The evidence was discussed and summarized by the experts in the course of a consensus finding and voting process. RESULTS: Three overarching principles were defined. First, there is a higher risk of MACE and VTE in patients with chronic inflammatory rheumatic diseases compared with the general population. Second, the rheumatologist has a central role in the evaluation of the risk of CVD and VTE in patient with chronic inflammatory rheumatic diseases. Third, the risk of MACE and VTE should be regularly assessed in patients with chronic inflammatory rheumatic diseases, particularly before initiating targeted therapies. Eleven recommendations were defined to prevent potentially life-threatening complications of CVD and VTE in patients with chronic inflammatory rheumatic diseases, providing practical assessment of CVD and VTE before considering the prescription of targeted therapies, and especially JAKi. CONCLUSION: These practical recommendations based on expert opinion and scientific evidence provide consensus for the prevention and the assessment of CVD and VTE.

Cytokines and intestinal epithelial permeability: A systematic review.

BACKGROUND: The intestinal mucosa is composed of a well-organized epithelium, acting as a physical barrier to harmful luminal contents, while simultaneously ensuring absorption of physiological nutrients and solutes. Increased intestinal permeability has been described in various chronic diseases, leading to abnormal activation of subepithelial immune cells and overproduction of inflammatory mediators. This review aimed to summarize and evaluate the effects of cytokines on intestinal permeability. METHODS: A systematic review of the literature was performed in the Medline, Cochrane and Embase databases, up to 01/04/2022, to identify published studies assessing the direct effect of cytokines on intestinal permeability. We collected data on the study design, the method of assessment of intestinal permeability, the type of intervention and the subsequent effect on gut permeability. RESULTS: A total of 120 publications were included, describing a total of 89 in vitro and 44 in vivo studies. TNFα, IFNγ or IL-1ß were the most frequently studied cytokines, inducing an increase in intestinal permeability through a myosin light-chain-mediated mechanism. In situations associated with intestinal barrier disruption, such as inflammatory bowel diseases, in vivo studies showed that anti-TNFα treatment decreased intestinal permeability while achieving clinical recovery. In contrast to TNFα, IL-10 decreased permeability in conditions associated with intestinal hyperpermeability. For some cytokines (e.g. IL-17, IL-23), results are conflicting, with both an increase and a decrease in gut permeability reported, depending on the study model, methodology, or the studied conditions (e.g. burn injury, colitis, ischemia, sepsis). CONCLUSION: This systematic review provides evidence that intestinal permeability can be directly influenced by cytokines in numerous conditions. The immune environment probably plays an important role, given the variability of their effect, according to different conditions. A better understanding of these mechanisms could open new therapeutic perspectives for disorders associated with gut barrier dysfunction.

ChatGPT: when artificial intelligence replaces the rheumatologist in medical writing.

In this editorial we discuss the place of artificial intelligence (AI) in the writing of scientific articles and especially editorials. We asked chatGPT « to write an editorial for Annals of Rheumatic Diseases about how AI may replace the rheumatologist in editorial writing ¼. chatGPT's response is diplomatic and describes AI as a tool to help the rheumatologist but not replace him. AI is already used in medicine, especially in image analysis, but the domains are infinite and it is possible that AI could quickly help or replace rheumatologists in the writing of scientific articles. We discuss the ethical aspects and the future role of rheumatologists.

Impact of NSAIDs on 8-year cumulative incidence of major cardiovascular events in patients with ankylosing spondylitis: a nationwide study.

OBJECTIVES: The objectives of this study were to describe the incidence of major adverse cardiovascular events (MACEs) in French patients newly benefiting from the French Long-term Illness scheme (LTI) for AS and to evaluate the effect of various treatments on the risk of MACE occurrence. METHODS: This national cohort study was based on the French national medico-administrative database SNDS containing data on hospitalization, the LTI, and outpatient care consumption. All French patients newly receiving LTI benefits for AS from 2010 to 2013 were included. The final follow-up date was 31 December 2018. The occurrences of MACEs [stroke and myocardial infarction (MI)] and comorbidities were identified from algorithms previously described in the literature. Competitive risk analysis using propensity score and inverse weighting was performed to calculate cumulative incidence functions and to determine subhazard ratios (SHRs) for the various treatments of interest. RESULTS: Between 2010 and 2013, 22 929 patients were included [mean age 43.0 (s.d. 13.9) years, 44.9% mal]. The 8-year cumulative incidences of MACE, stroke, and MI were 1.81% (1.61-2.05), 0.97% (0.83-1.14), and 0.85% (0.71-1.04), respectively. NSAIDs [SHR: 0.39 (0.32-0.50), P < 0.001] and anti-TNF [SHR 0.61 (0.46-0.80), P < 0.001], but not anti-IL17 [2.10 (0.79-5.57)] were associated with a lower risk of MACE occurrence. CONCLUSION: MACE incidence rates at 8 years are low in patients newly benefiting from LTI for AS. Our results support the hypothesis of a protective role of NSAIDs and anti-TNF in cardiovascular risk in these patients.