Factors associated with COVID-19 severity in patients with spondyloarthritis: Results of the French RMD COVID-19 cohort.

OBJECTIVES: The objective of the current study was to evaluate the severity of COVID-19 and identify factors associated with severe disease outcomes in patients with spondyloarthritis (SpA), a chronic inflammatory rheumatic and musculoskeletal disease (RMD). METHODS: We utilized patient data from the French national multicenter RMD COVID-19 cohort (NCT04353609). The primary outcome was to describe COVID-19 characteristics in patients with SpA based on disease severity of COVID-19 (mild, moderate or severe) with serious infection including moderate and severe cases. The secondary outcome was to identify the factors associated with serious COVID-19 classification. RESULTS: Among the 626 patients with SpA (56% female, mean age 49±14 years) from the French RMD cohort, COVID-19 severity was mild in 508 (81%), moderate in 93 (15%), and severe in 25 (4%) patients. Clinical signs and symptoms of COVID-19 were reported in 587 (94%) patients, with the most frequent presented symptom of fever (63%) and cough (62%), followed by flu-like symptoms (53%), agueusia (39%), anosmia (37%), dyspnea (32%) and diarrhea (19.9%). COVID-19 severity was associated with corticosteroid therapy (OR=3.08 [95% CI: 1.44-6.58], P=0.004) and age (OR=1.06 [95% CI: 1.04-1.08], P<0.001) while use of tumor necrosis factor inhibitor (TNFi, OR=0.27 [95% CI: 0.09-0.78], P=0.01) was associated with less severe disease. We did not identify an association between NSAID use and COVID-19 severity. CONCLUSIONS: In this study, the majority of patients with SpA had a favorable COVID-19 outcome. We confirmed age and corticosteroids therapy had a negative impact on disease outcomes while TNFi use was protective.

Adherence to and patient's knowledge of self-management of subcutaneous biologic therapy in chronic inflammatory rheumatic diseases: results of a multicentre cross-sectional study.

OBJECTIVES: Non-adherence to biologic therapy is an issue in chronic inflammatory rheumatic diseases (CIRDs) and might be related to poor patient knowledge of the risk of these therapies. Our aim here was to evaluate the level of patient adherence to and knowledge of self-care safety skills for biologic therapy. METHODS: This was a multicentre, cross-sectional study in which out-patients visited an office- or hospital-based rheumatologist. All the patients received subcutaneous biologic therapy for CIRDs. We collected data on: 1. the level of CIRD patient adherence to current subcutaneous biologic therapy using both the self-administered Compliance Questionnaire Rheumatology 5 items (CQR5) and a simple adherence question; 2. patients' knowledge of self-management of biologic therapy by the self-administered BIOSECURE questionnaire; 3. sources of information related to biologic therapy. RESULTS: In all, 285 patients (rheumatoid arthritis, n=103; spondyloarthritis, n=153; psoriatic arthritis, n=25) were enrolled by 19 rheumatologists. The mean (SD) biologic therapy duration was 5.9 (4.9) years. Adherence to the current biologic therapy was high (79.3% and 57.5% according to the CQR5 questionnaire and the adherence question, respectively). Level of knowledge of self-care safety skills (median BIOSECURE score 71) was in the acceptable range. Level of adherence and level of knowledge of self-care safety skills for biologic therapy were not associated. Patients declared that the main sources of information were their rheumatologist (92.6%) and the rheumatology team (30.5%). CONCLUSIONS: According to the patients' estimation, adherence to biologic therapy and the level of knowledge of self-care safety skills related to biologic therapy are acceptable, and these domains are not related (e.g. level of adherence and level of knowledge of risks).

Uveitis occurrence in early inflammatory back pain. Five years data from the prospective French nationwide DESIR cohort.

OBJECTIVE: Uveitis is a frequent extra rheumatological manifestation in axial Spondyloarthritis (SpA). The aim of study was to evaluate the prevalence and incidence of uveitis over the first five years of a prospective nationwide cohort of patients with high suspicion of early axial SpA, and to evaluate its associated factors. METHODS: DESIR is a prospective observational cohort of patients with recent onset inflammatory back pain (more than 3 months, less than 3 years), suggestive of axial SpA, All available factors in the database were compared between patients with and without uveitis at 5 years, by uni and then multivariate analysis. Baseline factors associated with new cases of uveitis occurrence over the 5 years were also analyzed. SIGNIFICANCE: P less than 0.05. RESULTS: After 5 years, 91 patients (out of 480 with complete follow-up) had at least one uveitis episode, giving an estimated prevalence of 18.9% [95% CI: 15.4-22.4]. In multivariate analysis, uveitis was significantly associated with dactylitis, and elevated ESR. New incident uveitis occurred in 31 cases over 5 years, giving an estimated incidence rate of 1.29 [0.84-1.74]/100 patient-years. Incidence of new uveitis was associated in multivariate analysis with baseline factors: diagnosis of SpA, sacro iliac MRI inflammatory SPARCC score, dactylitis, syndesmophyte score. No significant association was found with HLA-B27, DMARDs, BASDAI, ASDAS, BASFI. CONCLUSION: Five-years data of the DESIR cohort allowed an estimation of incidence rate of uveitis of 1.3/100p-y; over five years, uveitis was associated with dactylitis, biologic and sacro iliac MRI inflammation.

Spondyloarthritis-Associated IgA Nephropathy.

INTRODUCTION: IgA nephropathy (IgAN) can be associated with spondyloarthritis (SpA). The course of SpA-associated IgAN remains largely unknown due to the absence of large cohorts. METHODS: This retrospective study included patients with biopsy-proven IgAN and definite SpA. Kidney biopsies were centrally examined and scored according to the IgAN Oxford Classification. Thirty-two patients fulfilled the inclusion criteria, with a male:female ratio of 9:1 and median age of 27 and 37 years at SpA and IgAN diagnosis, respectively. HLA-B27 was positive in 90% of cases, and most patients (60%) presented with ankylosing spondylitis. The mean baseline estimated glomerular filtration rate (eGFR) was 84 ± 26 ml/min per 1.73 m2, and the urine protein-to-creatinine ratio was 0.19 g/mmol. RESULTS: Renal biopsy revealed frequent presence of crescents (33%) and interstitial inflammation (18%). Despite almost constant use of renin-angiotensin system inhibitors, combined with steroids in 13 of 32 patients, renal outcome was particularly poor. After a median follow-up of 5.9 years, 4 patients (12.5%) reached end-stage renal disease and 41% of patients experienced a >50% decrease of eGFR. The mean annual eGFR decline rate was -4.3 ± 6.7 ml/min per 1.73 m2. The risk of reaching class IV or V chronic kidney disease (CKD) stage during follow-up was associated with the presence of hypertension, level of proteinuria, and baseline S- and T-scores of the Oxford. CONCLUSION: SpA-associated IgAN is associated with a poor renal outcome, despite frequent use of steroids. Tumor necrosis factor (TNF)-α blockade did not appear to influence the rate of eGFR decline in this setting.

Genome-wide association study and gene expression analysis identifies CD84 as a predictor of response to etanercept therapy in rheumatoid arthritis.

Anti-tumor necrosis factor alpha (anti-TNF) biologic therapy is a widely used treatment for rheumatoid arthritis (RA). It is unknown why some RA patients fail to respond adequately to anti-TNF therapy, which limits the development of clinical biomarkers to predict response or new drugs to target refractory cases. To understand the biological basis of response to anti-TNF therapy, we conducted a genome-wide association study (GWAS) meta-analysis of more than 2 million common variants in 2,706 RA patients from 13 different collections. Patients were treated with one of three anti-TNF medications: etanercept (n = 733), infliximab (n = 894), or adalimumab (n = 1,071). We identified a SNP (rs6427528) at the 1q23 locus that was associated with change in disease activity score (ΔDAS) in the etanercept subset of patients (P = 8 × 10(-8)), but not in the infliximab or adalimumab subsets (P>0.05). The SNP is predicted to disrupt transcription factor binding site motifs in the 3' UTR of an immune-related gene, CD84, and the allele associated with better response to etanercept was associated with higher CD84 gene expression in peripheral blood mononuclear cells (P = 1 × 10(-11) in 228 non-RA patients and P = 0.004 in 132 RA patients). Consistent with the genetic findings, higher CD84 gene expression correlated with lower cross-sectional DAS (P = 0.02, n = 210) and showed a non-significant trend for better ΔDAS in a subset of RA patients with gene expression data (n = 31, etanercept-treated). A small, multi-ethnic replication showed a non-significant trend towards an association among etanercept-treated RA patients of Portuguese ancestry (n = 139, P = 0.4), but no association among patients of Japanese ancestry (n = 151, P = 0.8). Our study demonstrates that an allele associated with response to etanercept therapy is also associated with CD84 gene expression, and further that CD84 expression correlates with disease activity. These findings support a model in which CD84 genotypes and/or expression may serve as a useful biomarker for response to etanercept treatment in RA patients of European ancestry.

Dissociated responses to newer antimyeloma drugs identify a subset of refractory patients with an extremely poor prognosis.

We describe the striking and unexpected evolution of 10 patients with de novo multiple myeloma treated with novel-agent based induction therapy, who displayed a dissociated evolution characterised by an apparent good response contrasting with the concomitant development of aggressive non-secreting plasmocytomas immediately before, or just after, autologous stem cell transplantation. Patients did not respond to salvage therapies. Eight of them died from progression less than 12 months after diagnosis. This unusual evolution in the era of novel agents warrants further scrutiny.

Genome-wide association analysis of anti-TNF drug response in patients with rheumatoid arthritis.

BACKGROUND: Treatment strategies blocking tumour necrosis factor (anti-TNF) have proven very successful in patients with rheumatoid arthritis (RA). However, a significant subset of patients does not respond for unknown reasons. Currently, there are no means of identifying these patients before treatment. This study was aimed at identifying genetic factors predicting anti-TNF treatment outcome in patients with RA using a genome-wide association approach. METHODS: We conducted a multistage, genome-wide association study with a primary analysis of 2 557 253 single-nucleotide polymorphisms (SNPs) in 882 patients with RA receiving anti-TNF therapy included through the Dutch Rheumatoid Arthritis Monitoring (DREAM) registry and the database of Apotheekzorg. Linear regression analysis of changes in the Disease Activity Score in 28 joints after 14 weeks of treatment was performed using an additive model. Markers with p<10(-3) were selected for replication in 1821 patients from three independent cohorts. Pathway analysis including all SNPs with p<10(-3) was performed using Ingenuity. RESULTS: 772 markers showed evidence of association with treatment outcome in the initial stage. Eight genetic loci showed improved p value in the overall meta-analysis compared with the first stage, three of which (rs1568885, rs1813443 and rs4411591) showed directional consistency over all four cohorts studied. We were unable to replicate markers previously reported to be associated with anti-TNF outcome. Network analysis indicated strong involvement of biological processes underlying inflammatory response and cell morphology. CONCLUSIONS: Using a multistage strategy, we have identified eight genetic loci associated with response to anti-TNF treatment. Further studies are required to validate these findings in additional patient collections.

Emerging patterns of genetic overlap across autoimmune disorders.

Most of the recently identified autoimmunity loci are shared among multiple autoimmune diseases. The pattern of genetic association with autoimmune phenotypes varies, suggesting that certain subgroups of autoimmune diseases are likely to share etiological similarities and underlying mechanisms of disease. In this review, we summarize the major findings from recent studies that have sought to refine genotype-phenotype associations in autoimmune disease by identifying both shared and distinct autoimmunity loci. More specifically, we focus on information from recent genome-wide association studies of rheumatoid arthritis, ankylosing spondylitis, celiac disease, multiple sclerosis, systemic lupus erythematosus, type 1 diabetes and inflammatory bowel disease. Additional work in this area is warranted given both the opportunity it provides to elucidate pathogenic mechanisms in autoimmunity and its potential to inform the development of improved diagnostic and therapeutic tools for this group on complex human disorders.

Combination of the Schirmer I and phenol red thread tests as a rescue strategy for diagnosis of ocular dryness associated with Sjögren's syndrome.

PURPOSE: To define a combination of the Schirmer I and phenol red thread (PRT) tests that improves the screening of patients with ocular sicca syndrome. METHODS: The PRT test was performed before (PRT1) and after (PRT2) the Schirmer I test, in both eyes of 143 patients complaining of ocular dryness secondary to Sjögren's syndrome or sicca asthenia polyalgia syndrome (SAPS; 72 and 71 patients, respectively), and in 40 control patients. Groups were matched by age and sex. After determining the best cutoff values using the receiver operating characteristic procedure, several combinations of PRT and Schirmer I were assessed to improve the predictive values of the procedure. RESULTS: The best cutoff value for PRT2, estimated at 15 mm, provided a satisfying match between sensitivity and specificity indexes (68% and 90%, respectively), similar to those obtained with the Schirmer I test. If PRT1 alone was ineffective to screen SGS from control patients, the comparison between PRT1 and PRT2 (so-called "DeltaPRT") was found as a good marker to detect patients with persistent tear reflex. Interestingly, the combination of positive Schirmer I, PRT 2, and/or ΔPRT tests was found to be highly predictive of severe ocular sicca syndrome. CONCLUSIONS: The combination of the Schirmer I and PRT tests strongly improves the screening procedure to detect patients with ocular dryness related to Sjögren's syndrome or SAPS. It could be more widely used in daily clinical practice, aside from the Schirmer I test, to optimize the work-up of patients presenting with dry-eye subjective signs.

Critical care management and outcome of severe Pneumocystis pneumonia in patients with and without HIV infection.

BACKGROUND: Little is known about the most severe forms of Pneumocystis jiroveci pneumonia (PCP) in HIV-negative as compared with HIV-positive patients. Improved knowledge about the differential characteristics and management modalities could guide treatment based on HIV status. METHODS: We retrospectively compared 72 patients (73 cases, 46 HIV-positive) admitted for PCP from 1993 to 2006 in the intensive care unit (ICU) of a university hospital. RESULTS: The yearly incidence of ICU admissions for PCP in HIV-negative patients increased from 1993 (0%) to 2006 (6.5%). At admission, all but one non-HIV patient were receiving corticosteroids. Twenty-three (85%) HIV-negative patients were receiving an additional immunosuppressive treatment. At admission, HIV-negative patients were significantly older than HIV-positive patients (64 [18 to 82] versus 37 [28 to 56] years old) and had a significantly higher Simplified Acute Physiology Score (SAPS) II (38 [13 to 90] versus 27 [11 to 112]) but had a similar PaO2/FiO2 (arterial partial pressure of oxygen/fraction of inspired oxygen) ratio (160 [61 to 322] versus 183 [38 to 380] mm Hg). Ventilatory support was required in a similar proportion of HIV-negative and HIV-positive cases (78% versus 61%), with a similar proportion of first-line non-invasive ventilation (NIV) (67% versus 54%). NIV failed in 71% of HIV-negative and in 13% of HIV-positive patients (p < 0.01). Mortality was significantly higher in HIV-negative than HIV-positive cases (48% versus 17%). The HIV-negative status (odds ratio 3.73, 95% confidence interval 1.10 to 12.60) and SAPS II (odds ratio 1.07, 95% confidence interval 1.02 to 1.12) were independently associated with mortality at multivariate analysis. CONCLUSION: The yearly incidence of ICU admissions for PCP in HIV-negative patients in our unit increased from 1993 to 2006. The course of the disease and the outcome were worse in HIV-negative patients. NIV often failed in HIV-negative cases, suggesting that NIV must be watched closely in this population.

Association of transforming growth factor beta1 and tumor necrosis factor alpha polymorphisms with anti-SSB/La antibody secretion in patients with primary Sjögren's syndrome.

OBJECTIVE: To determine whether cytokine gene polymorphisms of interferon-gamma (IFNgamma), interleukin-6 (IL-6), IL-10, tumor necrosis factor alpha (TNFalpha), and transforming growth factor beta1 (TGFbeta1) predispose subjects to the development of primary Sjögren's syndrome (SS). METHODS: Single-base-exchange cytokine gene polymorphisms were analyzed in 129 French patients with primary SS who fulfilled the American-European Consensus Group criteria, as well as in 96 unrelated healthy subjects. RESULTS: The frequency of the TNF-308A (TNF2) allele was significantly higher in the SS patients (26% versus 11%). This TNF2 association was restricted to patients with anti-SSB (37% versus 11% in controls). Stratification did not reveal an independent effect of TNF2 and HLA-DRB1*03 on disease or on anti-SSB antibody secretion. The frequency of allele C at codon 10 of TGFbeta1 was strongly increased in the subgroup of patients with anti-SSB; this allele acted synergistically with DRB1*03 to predispose patients to the secretion of anti-SSB. The IL-10 GCC haplotype carrier rate was significantly higher in SS patients than in controls (67% versus 48%), but the IL-10 allele and genotype frequencies were not significantly different. No association was found between IL-6 or IFNgamma polymorphisms and primary SS. CONCLUSION: TNF2 was associated with anti-SSB antibody secretion, although this association was not independent of the association with DRB1*03. Allele C at codon 10 of TGFbeta1 was found to act synergistically with DRB1*03 in predisposing patients to the secretion of anti-SSB. These results therefore suggest that most of the known genetic predisposition to primary SS might concern the pattern of autoantibody diversification.