Repurposing the Fibrosis-4 Score in Rheumatoid Arthritis: Data from the ESPOIR Cohort.

Background: We aimed to evaluate the value of the Fibrosis-4 (FIB-4) score as a prognostic factor in RA in the prospective ESPOIR cohort. Methods: We included patients from the ESPOIR cohort with a diagnosis of RA according to ACR/EULAR criteria. The formula for the FIB-4 score is as follows: [age (years) × aspartate transaminase level (U/L)]/[platelet count (109/L) × alanine aminotransferase level (U/L)1/2]. We used a linear mixed-effects model with a random effect of patient to account for repeated measures over time. Results: Overall, 647 of the 813 patients included met the ACR/EULAR criteria for RA, with no differential diagnosis during the first 10 years of follow-up. Of these patients, at baseline, 633 had a calculable FIB-4 score. Median FIB-4 score was 0.75 (interquartile range 0.53-0.99). On multivariate analysis, FIB-4 score was not independently associated with progression of Disease Activity Score in 28 joints over 10 years of follow-up, unlike baseline C-reactive protein level and SJC. Baseline FIB-4 score was not associated with the modified Sharp score at 5-year follow-up, unlike age and ACPAs. FIB-4 score was not associated with mortality (hazard ratio 1.1 [95% CI 0.46; 2.8], p = 0.77) or major adverse cardiovascular events (0.46 [0.13; 1.6], p = 0.22) over the 10-year follow-up. No significant change in FIB-4 score over time was related to treatments. Conclusions: The present prospective cohort study did not find a prognostic role of FIB-4 score in RA. Reassuringly, FIB-4 score was not increased with DMARD treatment after 10 years of follow-up.

A prospective survey on therapeutic inertia in psoriatic arthritis (OPTI'PsA).

OBJECTIVES: Clinical inertia, or therapeutic inertia (TI), is the medical behaviour of not initiating or intensifying treatment when recommended by clinical recommendations. To our knowledge, our survey is the first to assess TI around psoriatic arthritis (PsA). METHODS: Eight hundred and twenty-five French rheumatologists were contacted via email between January and March 2021 and invited to complete an online questionnaire consisting of seven clinical vignettes: five cases ('oligoarthritis', 'enthesitis', 'polyarthritis', 'neoplastic history', 'cardiovascular risk') requiring treatment OPTImization, and two 'control' cases (distal interphalangeal arthritis, atypical axial involvement) not requiring any change of treatment-according to the most recent PsA recommendations. Rheumatologists were also questioned about their routine practice, continuing medical education and perception of PsA. RESULTS: One hundred and one rheumatologists completed this OPTI'PsA survey. Almost half the respondents (47%) demonstrated TI on at least one of the five vignettes that warranted treatment optimization. The complex profiles inducing the most TI were 'oligoarthritis' and 'enthesitis' with 20% and 19% of respondents not modifying treatment, respectively. Conversely, clinical profiles for which there was the least uncertainty ('polyarthritis in relapse', 'neoplastic history' and 'cardiovascular risk') generated less TI with 11%, 8% and 6% of respondents, respectively, choosing not to change the current treatment. CONCLUSION: The rate of TI we observed for PsA is similar to published data for other chronic diseases such as diabetes, hypertension, gout or multiple sclerosis. Our study is the first to show marked clinical inertia in PsA, and further research is warranted to ascertain the reasons behind this inertia.

In inflammatory myopathies, dropped head/bent spine syndrome is associated with scleromyositis: an international case-control study.

BACKGROUND: Some myopathies can lead to dropped head or bent spine syndrome (DH/BS). The significance of this symptom has not been studied in inflammatory myopathies (IM). OBJECTIVES: To assess the significance of DH/BS in patients with IM. METHODS: Practitioners from five IM networks were invited to report patients with IM suffering from DH/BS (without other known cause than IM). IM patients without DH/BS, randomly selected in each participating centre, were included as controls at a ratio of 2 to 1. RESULTS: 49 DH/BS-IM patients (DH: 57.1%, BS: 42.9%) were compared with 98 control-IM patients. DH/BS-IM patients were older (65 years vs 53 years, p<0.0001) and the diagnosis of IM was delayed (6 months vs 3 months, p=0.009). Weakness prevailing in the upper limbs (42.9% vs 15.3%), dysphagia (57.1% vs 25.5%), muscle atrophy (65.3% vs 34.7%), weight loss (61.2% vs 23.5%) and loss of the ability to walk (24.5% vs 5.1%) were hallmarks of DH/BS-IM (p≤0.0005), for which the patients more frequently received intravenous immunoglobulins (65.3% vs 34.7%, p=0.0004). Moreover, DH/BS-IM patients frequently featured signs and/or complications of systemic sclerosis (SSc), fulfilling the American College of Rheumatology/European Alliance of Associations for Rheumatology criteria for this disease in 40.8% of the cases (vs 5.1%, p<0.0001). Distribution of the myopathy, its severity and its association with SSc were independently associated with DH/BS (p<0.05). Mortality was higher in the DH/BS-IM patients and loss of walking ability was independently associated with survival (p<0.05). CONCLUSION: In IM patients, DH/BS is a marker of severity and is associated with SSc (scleromyositis).

Mind-body practices in chronic inflammatory arthritis.

Mind-body practices are complementary approaches recognized by the World Health Organization (WHO). While these practices are very diverse, they all focus on the interaction between mind and body. These include mindful meditation, yoga, Tai Chi, sophrology, hypnosis and various relaxation techniques. There is growing interest in incorporating these strategies in the management of chronic rheumatic diseases including rheumatoid arthritis. The aim of this review is to describe the main mind-body practices and analyze the existing evidence in chronic rheumatic diseases. In rheumatoid arthritis, the Mindfulness-Based Stress Reduction program, yoga, Tai Chi and relaxation may improve patient-reported outcomes, but the benefit on inflammation and structural progression is unclear. In spondyloarthritis, very few studies are available but similar evidence exist. Further evaluations of these practices in chronic rheumatic diseases are needed since their risk/benefit ratio appears excellent.

Can efficacy and safety data from clinical trials of rituximab in RA be extrapolated? Insights from 1984 patients from the AIR-PR Registry.

OBJECTIVES: To investigate whether the efficacy and safety data from drug-registration trials can be extrapolated to real-life RA patients receiving RTX. METHODS: The AIR-PR registry is a French multicentre, prospective cohort of RA patients treated with RTX in a real-life setting. We compared treatment responses at 12 months and serious AEs between eligible and non-eligible patients, by retrieving the eligibility criteria of the three rituximab-registration trials. We determined critical eligibility criteria and modelled the benefit-risk ratio according to the number of fulfilled critical eligibility criteria. RESULTS: Among 1984 RA patients, only 9-12% fulfilled all eligibility criteria. Non-eligible patients had less EULAR response at 12 months (40.3% vs 46.9%, p= 0.044). Critical inclusion criteria included SJC ≥ 4, TJC ≥ 4, CRP ≥ 15 mg/l, and RF positivity. Critical exclusion criteria were age >80 years, RA-associated systemic diseases, ACR functional class IV, other DMARD than methotrexate, and prednisone > 10 mg/day. Only 20.8% fulfilled those critical eligibility criteria. During the first year, serious AEs occurred for 182 (9.2%) patients, (70.3% serious infections) and patients with ≥1 critical exclusion criterion were at higher risk (HR 3.03; 95%CI 2.25-4.06; for ≥ 3 criteria vs 0). The incremental risk-benefit ratio decreased with the number of unmet critical inclusion criteria and of fulfilled exclusion criteria. CONCLUSION: Few real-life RA patients were eligible for the drug-registration trials. Non-eligible patients had lower chance of response, and higher risk of serious AEs. Efficacy and safety data obtained from those trials may not be generalizable to RA patients receiving RTX in real-world clinical practice.

Validity Evidence of A Screening Tool for Early Detection of Clinical Crisis-Related Anxiety Amongst Medical Students.

Construct: Psychological distress among students is a growing concern in medical education, even more so with the advent of COVID-19 pandemic. Anxiety is among students' mental health issues. High and persistent anxiety has many negative impacts on students' academic and personal life. Early detection is essential for timely intervention. Background: Currently, medical student anxiety is assessed using tools primarily designed for psychiatric purposes. Despite their excellent validity evidence, these tools contain sensitive items and do not explore stressors related to clinical activities. There is a need for contextualized tools to better identify anxiety-provoking factors specific to the medical education environment. Approach: We previously developed the Crisis Experience Rating Scale (CERS-7), a short screening tool to identify early on anxious students participating in clinical activities during the first wave of the COVID-19 pandemic. The present study sought to produce further validity evidence for the CERS-7. Medical students in their clinical years at two Swiss and one French medical school, all involved in COVID-19 clinical activity during the second wave of the pandemic, completed the CERS-7 and the State Anxiety Inventory (STAI-A), the best known and widely used tool to measure for general anxiety. We evaluated internal structure using confirmatory factor analysis (CFA) and relation to other variables using linear regression (LR) and receiver operating characteristic (ROC) curves with thresholds defined using the Youden index. Findings: There were 372 participants. CFA confirmed the two-factor structure of the CERS-7 scale from first-wave dataset. The CERS-7 total scale and subscales demonstrated validity evidence in relationship to the STAI-A scores and categories. A CERS-7 total scale score < 27.5 identified 93% of severely anxious students. Conclusion: The CERS-7 produces reliable scores to use for monitoring anxiety status when assigning students to clinical settings as well as for improving training conditions during clinical crisis.

Refining Incidence and Characteristics of Inflammatory Myopathies: A Quadruple-Source Capture-Recapture Survey Using the 2017 European League Against Rheumatism/American College of Rheumatology Classification Criteria.

OBJECTIVE: Inflammatory myopathies (IM), characterized by muscle inflammation and weakness, are rare systemic diseases. Our previous study estimated an IM incidence rate of 7.98 cases per million people per year (95% confidence interval 7.38-8.66) and highlighted important variations that were likely because of methodologic issues rather than true epidemiologic differences. In this study, we aimed to refine the incidence of IM, using the 2017 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) classification criteria for IM and a quadruple-source capture-recapture method during a 6-year period in Alsace, France, a region with a population of 2 million having benefits of good access to health care and accredited IM referral centers. METHODS: Clinical data of potential IM patients were obtained from 4 sources (general practitioners and community specialists, public and private hospital records, public and private laboratories, and archives from the pathology department). Patients residing in Alsace and who fulfilled the 2017 EULAR/ACR criteria for IM between January 1, 2006, and January 1, 2013, were included. We corrected potentially incomplete ascertainment of cases with capture-recapture analyses. We studied both spatial and temporal distributions of incidence of IM. We also assessed systemic manifestations of the disease. RESULTS: Our review of 1,742 potential cases identified 106 patients with IM. No spatial or temporal heterogeneity was observed. Use of log-linear models showed an estimated 14.9 additional missed cases. Thus, the incidence rate of IM was 8.22 new cases per million inhabitants per year (95% confidence interval 6.76-9.69). Extramuscular manifestations other than dermatomyositis rash were frequently recorded. CONCLUSION: The stringent methodology used in our study provides an accurate estimation of the incidence of IM. This study also demonstrates, in a population-based cohort, the systemic nature of IM.

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.

Identification of new candidate drugs for primary Sjögren's syndrome using a drug repurposing transcriptomic approach.

OBJECTIVES: To date, no immunomodulatory drug has demonstrated its efficacy in primary SS (pSS). We sought to analyse potential commonalities between pSS transcriptomic signatures and signatures of various drugs or specific knock-in or knock-down genes. METHODS: Gene expression from peripheral blood samples of patients with pSS was compared with that of healthy controls in two cohorts and three public databases. In each of the five datasets, we analysed the 150 most up- and downregulated genes between pSS patients and controls with regard to the differentially expressed genes resulting from the biological action on nine cell lines of 2837 drugs, 2160 knock-in and 3799 knock-down genes in the Connectivity Map database. RESULTS: We analysed 1008 peripheral blood transcriptomes from five independent studies (868 patients with pSS and 140 healthy controls). Eleven drugs could represent potential candidate drugs, with histone deacetylases and PI3K inhibitors among the most significantly associated. Twelve knock-in genes were associated with a pSS-like profile and 23 knock-down genes were associated with a pSS-revert profile. Most of those genes (28/35, 80%) were interferon-regulated. CONCLUSION: This first drug repositioning transcriptomic approach in SS confirms the interest of targeting interferons and identifies histone deacetylases and PI3K inhibitors as potential therapeutic targets.

Chronic stimulation with SARS-CoV-2 spike protein does not trigger autoimmunity.

Autoimmune manifestations were reported in people infected with SARS-CoV-2. Repetitive exposure of mice to foreign antigen may lead to the onset of autoimmunity. We therefore investigated whether repetitive exposure to the SARS-CoV-2 spike protein could result in autoimmunity. To address this hypothesis, we repeatedly immunized C57Bl/6 mice with spike protein injected intraperitoneally. At the end of the immunization, mice which received spike protein produced anti-spike IgG but none of them developed anti-dsDNA antibodies or proteinuria. In conclusion, repetitive immunization with SARS-CoV-2 spike protein does not induce autoimmunity in the present mice model. Albeit reassuring, these results need to be confirmed by large epidemiological study evaluating the incidence of autoimmune diseases in individuals with repetitive SARS-CoV-2 antigen exposure.

Sex influence on outcomes of patients with systemic sclerosis-associated interstitial lung disease: a EUSTAR database analysis.

OBJECTIVE: Interstitial lung disease (ILD) is the leading cause of morbidity and mortality in systemic sclerosis (SSc) patients. We aimed to investigate the impact of sex on SSc-ILD. METHODS: EUSTAR SSc patients with radiologically confirmed ILD and available percentage predicted forced vital capacity (%pFVC) were included. Demographics and disease features were recorded. A change in %pFVC over 12 months (s.d. 6) (cohort 1) was classified into stable (≤4%), mild (5-9%) and large progression (≥10%). In those with 2-year longitudinal %pFVC (cohort 2), the %pFVC change at each 12-month (s.d. 6) interval was calculated. Logistic regression analyses [odds ratio (OR) and 95% CI] and Cox proportional hazards models adjusted for age and %pFVC were applied. RESULTS: A total of 1136 male and 5253 female SSc-ILD patients were identified. Males were significantly younger, had a shorter disease duration, had a higher prevalence of CRP elevation and frequently had diffuse cutaneous involvement. In cohort 1 (1655 females and 390 males), a higher percentage of males had stable ILD (74.4% vs 69.4%, P = 0.056). In multivariable analysis, disease duration and %pFVC [OR 0.99 (95% CI 0.98, 0.99) and OR 0.97 (95% CI 0.95, 0.99), respectively] in males and age, %pFVC and anti-centromere [OR 1.02 (95% CI 1.00, 1.04), OR 0.97 (95% CI 0.96, 0.98) and OR 0.39 (95% CI 0.245, 0.63), respectively] in females were associated with large progression. The 1-year mortality rate was higher in males (5.1% vs 2.5%, P = 0.013). In cohort 2 (849 females and 209 males), a higher percentage of females showed periods of large progression (11.7% vs 7.7%, P = 0.023), the percentage of patients with none, one or two periods of worsening was not different. The overall death rate was 30.9% for males and 20.4% in females (P < 0.001). In the survival analysis, male sex was a predictor of mortality [OR 1.95 (95% CI 1.66, 2.28)]. CONCLUSIONS: Male SSc-ILD patients have a poorer prognosis and sex-specific predictors exist in SSc-ILD.

Tolerance and efficacy of targeted therapies prescribed for off-label indications in refractory systemic autoimmune diseases: data of the first 100 patients enrolled in the TATA registry (TArgeted Therapy in Autoimmune Diseases).

OBJECTIVES: To assess the tolerance and efficacy of targeted therapies prescribed off-label in refractory low-prevalence autoimmune and inflammatory systemic diseases. METHODS: The TATA registry (TArgeted Therapy in Autoimmune Diseases) is a prospective, observational, national and independent cohort follow-up. The inclusion criteria in the registry are as follows: age >18 years; low-prevalence autoimmune and inflammatory systemic disease treated with off-label drugs started after 1 January 2019. RESULTS: Hundred (100) patients (79 women) were enrolled. The median age was 52.5 years (95% CI 49 to 56) and the median disease duration before enrolment was 5 years (3 to 7). The targeted therapies at enrolment were as follows: Janus kinase/signal transducers and activators of transcription inhibitors (44%), anti-interleukin (IL)-6R (22%), anti-IL-12/23, anti-IL-23 and anti-IL-17 (9%), anti-B cell activating factor of the tumour necrosis factor family (5%), abatacept (5%), other targeted treatments (9%) and combination of targeted treatments (6%). 73% of patients were receiving corticosteroid therapy at enrolment (median dose 10 mg/day). The current median follow-up time is 9 months (8 to 10).Safety: 11 serious infections (incidence rate of 14.8/100 patient-years) and 1 cancer (1.3 cancers/100 patient-years) were observed. Two patients died from severe COVID-19 (2.7 deaths/100 patient-years).Efficacy: the targeted treatment was considered effective by the clinician in 56% of patients and allowed, in responders, a median reduction of oral corticosteroids of 15 (9 to 21) mg/day, below 7.5 mg/day in 76% of patients, while 28% discontinued. CONCLUSION: These initial results of the TATA registry confirm the diversity of targeted treatments prescribed off-label in refractory autoimmune diseases and their corticosteroid-sparing effect when effective. Tolerance was acceptable in these refractory patients with a long history of treatment with immunosuppressive drugs.

Fatigue is independently associated with disease activity assessed using the Physician Global Assessment but not the SLEDAI in patients with systemic lupus erythematosus.

OBJECTIVES: To analyse whether reported fatigue, one of the most challenging manifestations of systemic lupus erythematosus (SLE), may bias the assessment of disease activity in SLE according to the Physician Global Assessment (PGA). METHODS: Patients from the Lupus BioBank of the upper Rhein database, a cross-sectional multicentre collection of detailed clinical and biological data from patients with SLE, were included. Patients had to fulfil the 1997 American College of Rheumatology criteria for SLE and the PGA (0-3 scale) at the time of inclusion had to be available. Fatigue was assessed according to the Fatigue Scale for Motor and Cognitive Functions. Univariate and multivariate regression models were built to determine which variables were associated with the PGA. RESULTS: A total of 350 patients (89% female; median age: 42 years, IQR: 34-52) were included. The median Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score was 4 (IQR: 2-6). Of these 350 patients, 257 (73%) reported significant fatigue. The PGA (p=0.004) but not the SELENA-SLEDAI (p=0.43) was significantly associated with fatigue. Both fatigue and SELENA-SLEDAI were independently associated with the PGA in two different multivariate models. CONCLUSION: Fatigue is independently associated with disease activity assessed using the PGA but not the SLEDAI. These findings highlight the fact that the PGA should capture only objectively active disease manifestations in order to improve its reliability.

Excess of Post-Acute Sequelae of COVID-19 After the First Wave of the Pandemic.

INTRODUCTION: To compare the time distribution of initial COVID-19 among patients with self-reported post-acute sequelae of COVID-19 (PASC). METHODS: We compared the distribution of the date of the reported initial COVID-19 among patients with self-reported PASC and the COVID-19 cases in France between the first wave (January 1-May 11, 2020) and the later period (May 12, 2020-June 30, 2021) using the chi-squared test. COVID-19 cases in France were assessed using previous modeling of COVID-19 burden in France for the first time period, and positive RT-PCR testing for the second time period. RESULTS: The study included 567 individuals with PASC (median age 44, [IQR 37-50]; 83.4% women). A total of 293 (51.7%) patients reported an initial COVID-19 infection during the first period while 272 (48%) reported it during the later period (missing data, n = 2; 0.3%). Patients with PASC were 82% more likely to report initial COVID-19 during the first pandemic wave than afterward (OR 1.82, 95% CI [1.55-2.15]; p < 0.0001). CONCLUSIONS: The incidence of self-reported PASC wave was significantly higher when initial COVID-19 happened during the first pandemic wave than afterward, suggesting the importance of non-viral factors in PASC development.

Variability of Primary Sjögren's Syndrome Is Driven by Interferon-α and Interferon-α Blood Levels Are Associated With the Class II HLA-DQ Locus.

OBJECTIVE: Primary Sjögren's syndrome (SS) is the second most frequent systemic autoimmune disease, affecting 0.1% of the general population. To characterize the molecular and clinical variabilities among patients with primary SS, we integrated transcriptomic, proteomic, cellular, and genetic data with clinical phenotypes in a cohort of 351 patients with primary SS. METHODS: We analyzed blood transcriptomes and genotypes of 351 patients with primary SS who were participants in a multicenter prospective clinical cohort. We replicated the transcriptome analysis in 3 independent cohorts (n = 462 patients). We determined circulating interferon-α (IFNα) and IFNγ protein concentrations using digital single molecular arrays (Simoa). RESULTS: Transcriptome analysis of the prospective cohort showed a strong IFN gene signature in more than half of the patients; this finding was replicated in the 3 independent cohorts. Because gene expression analysis did not discriminate between type I IFN and type II IFN, we used Simoa to demonstrate that the IFN transcriptomic signature was driven by circulating IFNα and not by IFNγ protein levels. IFNα protein levels, detectable in 75% of patients, were significantly associated with clinical and immunologic features of primary SS disease activity at enrollment and with increased frequency of systemic complications over the 5-year follow-up. Genetic analysis revealed a significant association between IFNα protein levels, a major histocompatibility (MHC) class II haplotype, and anti-SSA antibody. Additional cellular analysis revealed that an MHC class II HLA-DQ locus acts through up-regulation of HLA class II molecules on conventional dendritic cells. CONCLUSION: We identified the predominance of IFNα as a driver of primary SS variability, with IFNα demonstrating an association with HLA gene polymorphisms.