Identification of Risk Factors for COVID-19 Hospitalization in Patients With Anti-Rheumatic Drugs: Results From a Multicenter Nested Case Control Study.

Patients with inflammatory rheumatic diseases (IRDs) do not have an increased risk for coronavirus disease 2019 (COVID-19) compared with the general population. However, it remains uncertain whether subgroups of patients with IRD using different immunosuppressive antirheumatic drugs carry a higher risk for severe COVID-19 compared with other patients with IRD. The aim of this study is to identify risk factors for severe COVID-19, requiring hospitalization in patients with IRD. This is a multicenter nested case control study conducted in the Netherlands. Cases are hospital known patients with IRD requiring hospitalization for COVID-19 between March 1, 2020, and May 31, 2020. Controls are hospital known patients with IRD not requiring hospitalization for COVID-19 in this period, included at a 4:1 ratio. Patient, disease, and treatment characteristics were extracted from electronic medical records and a questionnaire. Potential risk factors were analyzed using unconditional logistic regression, corrected for confounders and multiple testing. Eighty-one cases and 396 controls were included. General risk factors of older age and obesity apply to patients with IRD as well (odds ratio (OR) for age ≥ 75 3.5, 95% confidence interval (CI) 1.9-6.3, OR for body mass index ≥ 40 4.5, 95% CI 1.5-14). No significantly increased ORs for COVID-19 hospitalization were found for any antirheumatic agent or IRD. A protective effect was found for use of methotrexate (OR 0.53, 95% CI 0.31-0.92). In conclusion, similar to the general population, elderly and obese patients with IRD have a higher risk for hospitalization for COVID-19. We did not identify a specific antirheumatic agent or IRD to increase the risk of COVID-19 hospitalization in patients with IRD, except for a possible protective effect of methotrexate.

Predictors of biologic-free disease control in patients with rheumatoid arthritis after stopping tumor necrosis factor inhibitor treatment.

BACKGROUND: The aim of this study was to identify predictors of prolonged disease control after discontinuation of tumor necrosis factor inhibitor (TNFi) treatment in patients with rheumatoid arthritis (RA). METHODS: Post-hoc analysis of 439 RA patients (67.3% rheumatoid factor positive) with longstanding RA in remission or with stable low disease activity, randomized to stopping TNFi treatment in the multicenter POET trial. Prolonged acceptable disease control was defined as not restarting TNFi treatment within 12 months after stopping. Baseline demographic and disease-related variables were included in univariate and multivariate logistic regression analysis for identifying predictors of relapse. RESULTS: One year after baseline, 220 patients (50.1%) had not restarted TNFi treatment. Use of an anti-TNF monoclonal antibody (versus a receptor antagonist, OR = 2.41; 95% CI: 1.58-3.67), ≤10 yrs. disease duration (OR = 2.15; 95% CI: 1.42-3.26) and low or moderate multi-biomarker disease activity (MBDA) scores (OR = 2.00; 95% CI: 1.10-3.64) at baseline were independently predictive of successful TNFi discontinuation (area under the receiver operating characteristic curve = 0.66; 95% CI: 0.61-0.71). Results were similar when using no physician-reported flare as the criterion. TNFi-free survival was significantly different for patient groups based on the number of predictors present, ranging from 21.4% of patients with no predictor present to 66.7% of patients with all three predictors present. CONCLUSION: Patients using an anti-TNF monoclonal antibody, with shorter disease duration and low or moderate baseline MBDA score are most likely to achieve prolonged disease control after TNFi discontinuation. TRIAL REGISTRATION: Netherlands Trial Register NTR3112, 21 October 2011.

Adalimumab drug and antidrug antibody levels do not predict flare risk after stopping adalimumab in RA patients with low disease activity.

OBJECTIVE: To establish whether serum adalimumab (ADA) trough level (ADA-TL) and antidrug antibody (ADA-ab) level predict flare after stopping ADA in established RA patients with long-standing low disease activity. METHODS: From the clinical trial Potential Optimalisation and Effectiveness of TNF-blockers, 210 RA patients stopping ADA, who had been using ADA (40 mg/2 weeks) for >1 year with conventional synthetic DMARDs and who had low disease activity (DAS28 < 3.2, or the rheumatologist's assessment of low disease activity with CRP < 10 mg/l) for at least 6 months prior to stopping, were followed for 1 year. The ADA-TL was measured (by ELISA) 12-17 days after the last ADA injection; if it was low, ADA-abs were measured (by an antigen-binding test). Association between time-to-flare and ADA-TL was evaluated by area under the receiver operating characteristic curve and Cox regression. RESULTS: A total of 106 (51%) patients flared within 1 year after stopping ADA. The area under the receiver operating characteristic curve for flare and ADA-TL was 0.50 (95% CI 0.42-0.58), P = 0.92. The hazard ratio for flare for ADA-TL ⩾ 5 µg/ml (adequate level) vs <5 µg/ml was 0.93 (95% CI: 0.63-1.36) (not significant). Of the 4 patients with high ADA-ab levels, 2 patients (50%) experienced a flare. CONCLUSION: Flare risk within the year following stopping ADA is not predicted by the ADA-TL or ADA-abs assessed at the moment of stopping. TRIAL REGISTRATION: Netherlands Trial Register, http://www.trialregister.nl, NTR3112.

Multi-biomarker disease activity score as a predictor of disease relapse in patients with rheumatoid arthritis stopping TNF inhibitor treatment.

OBJECTIVE: Successfully stopping or reducing treatment for patients with rheumatoid arthritis (RA) in low disease activity (LDA) may improve cost-effectiveness of care. We evaluated the multi-biomarker disease activity (MBDA) score as a predictor of disease relapse after discontinuation of TNF inhibitor (TNFi) treatment. METHODS: 439 RA patients who were randomized to stop TNFi treatment in the POET study were analyzed post-hoc. Three indicators of disease relapse were assessed over 12 months: 1) restarting TNFi treatment, 2) escalation of any DMARD therapy and 3) physician-reported flare. MBDA score was assessed at baseline. Associations between MBDA score and disease relapse were examined using univariate analysis and multivariate logistic regression. RESULTS: At baseline, 50.1%, 35.3% and 14.6% of patients had low (<30), moderate (30-44) or high (>44) MBDA scores. Within 12 months, 49.9% of patients had restarted TNFi medication, 59.0% had escalation of any DMARD and 57.2% had ≥1 physician-reported flare. MBDA score was associated with each indicator of relapse. At least one indicator of relapse was observed in 59.5%, 68.4% and 81.3% of patients with low, moderate or high MBDA scores, respectively (P = 0.004). Adjusted for baseline DAS28-ESR, disease duration, BMI and erosions, high MBDA scores were associated with increased risk for restarting TNFi treatment (OR = 1.85, 95% CI 1.00-3.40), DMARD escalation (OR = 1.99, 95% CI 1.01-3.94) and physician-reported flare (OR = 2.00, 95% 1.06-3.77). CONCLUSION: For RA patients with stable LDA who stopped TNFi, a high baseline MBDA score was independently predictive of disease relapse within 12 months. The MBDA score may be useful for identifying patients at risk of relapse after TNFi discontinuation.

Limited value for ultrasonography in predicting flare in rheumatoid arthritis patients with low disease activity stopping TNF inhibitors.

Objective: Ultrasonography (US) can be used for treatment decisions in RA patients. This study investigated the added value of US to clinical variables in predicting flare in RA patients with longstanding low disease activity when stopping TNF inhibitors (TNFi). Methods: Cox models with and without using US added to clinical variables were developed in the Potential Optimization of Expediency of TNFi-UltraSonography study. RA patients (n = 259), using >1 year TNFi and csDMARD with DAS28 < 3.2 for 6 months prior to inclusion, were followed for 52 weeks after stopping TNFi. The added value of US was assessed in two ways: first, by the extent to which individual predictions for flare at 52 weeks with and without US differed; and second, by comparing how US information improved the prediction to classify patients at 52 weeks in the low risk (<33% flare), intermediate risk (33-50%) and high risk (50-100%) groups. Results: Although US was predictive of flare at group level (multivariate hazard ratio = 1.7; 95% CI: 1.1, 2.5), individual predictions for flare at 52 weeks with and without US differed little (median difference 3.7%; interquartile range: -7.8 to 6.5%). With US, 15.9% of patients were designated low risk; without US, 14.6%. In fact, 12.0% of patients were US-classified as low risk with/without knowing US. Conclusion: In RA patients with longstanding low disease activity, at time of stopping TNFi, US is a predictor for flare at group level, but at the patient level, US has limited added value when common clinical parameters are used already, though the predictive value of clinical predictors is modest as well.

An OMERACT reliability exercise of inflammatory and structural abnormalities in patients with knee osteoarthritis using ultrasound assessment.

OBJECTIVE: To assess whether ultrasonography (US) is reliable for the evaluation of inflammatory and structural abnormalities in patients with knee osteoarthritis (OA). METHODS: Thirteen patients with early knee OA were examined by 11 experienced sonographers during 2 days. Dichotomous and semiquantitative scoring was performed on synovitis characteristics in various aspects of the knee joint. Semiquantitative scoring was done of osteophytes at the medial and lateral femorotibial joint space or cartilage damage of the trochlea and on medial meniscal damage bilaterally. Intra- and interobserver reliability were computed by use of unweighted and weighted κ coefficients. RESULTS: Intra- and interobserver reliability scores were moderate to good for synovitis (mean κ 0.67 and 0.52, respectively) as well as moderate to good for the global synovitis (0.70 and 0.50, respectively). Mean intra- and interobserver reliability κ for cartilage damage, medial meniscal damage and osteophytes ranged from fair to good (0.55 and 0.34, 0.75 and 0.56, 0.73 and 0.60, respectively). CONCLUSIONS: Using a standardised protocol, dichotomous and semiquantitative US scoring of pathological changes in knee OA can be reliable.

Impaired Porphyromonas gingivalis-Induced Tumor Necrosis Factor Production by Dendritic Cells Typifies Patients With Rheumatoid Arthritis.

OBJECTIVE: The prevalence of periodontitis is increased in patients with rheumatoid arthritis (RA), and the severity of periodontitis can affect the level of arthritis. Porphyromonas gingivalis is one of the main bacteria involved in periodontitis. Our aim was to determine if there are differences in the innate immune response against P gingivalis between healthy controls and RA patients. METHODS: Monocyte-derived dendritic cells (DCs) from healthy controls, RA patients, and patients with psoriatic arthritis (PsA) were stimulated with P gingivalis, a range of other bacteria, and Toll-like receptor agonists. Cytokine production was determined, and blocking studies were performed to determine which receptors were involved in differential recognition of P gingivalis. Effects on T cell cytokines were also determined in cultures of peripheral blood mononuclear cells (PBMCs). RESULTS: Upon stimulation with P gingivalis, RA patient DCs produced less tumor necrosis factor as compared to healthy control DCs, which was not observed in PsA patients or upon stimulation with other bacteria. In addition, P gingivalis-mediated activation of RA patient PBMCs showed a clear reduction of interferon-γ production. Among the various possible underlying mechanisms investigated, only blockade of CR3 abolished the difference between RA patients and healthy controls, suggesting the involvement of CR3 in this process. CONCLUSION: Immune cells from RA patients display a reduced response to P gingivalis, which has functional consequences for the immune response. This may result in prolonged survival of P gingivalis, possibly driving autoantibody formation and a self-perpetuating loop of chronic inflammation. The possible role of CR3 in this process warrants further investigation.

Flare Rate in Patients with Rheumatoid Arthritis in Low Disease Activity or Remission When Tapering or Stopping Synthetic or Biologic DMARD: A Systematic Review.

OBJECTIVE: To evaluate the risk of having a disease flare in patients with rheumatoid arthritis (RA) with low disease activity (LDA) or in remission when deescalating (tapering or stopping) disease-modifying antirheumatic drug (DMARD) therapy. METHODS: A search in medical databases including publications from January 1950 to February 2015 was performed. Included were trials and observational studies in adults with RA who were in LDA or remission, evaluating ≥ 20 patients tapering or stopping DMARD. Flare rates had to have been reported. A metaanalysis was performed on studies deescalating tumor necrosis factor (TNF) blockers. RESULTS: Four studies evaluated synthetic DMARD. Flare rates ranged from 8% at 24 weeks to 63% at 4 months after deescalation. Fifteen studies reported on TNF blockers. Estimated flare rates by metaanalysis on studies tapering or stopping TNF blockers were 0.26 (95% CI 0.17-0.39) and 0.49 (95% CI 0.27-0.73) for good-quality and moderate-quality studies, respectively. Flare rates in 3 studies stopping tocilizumab were 41% after 6 months, 55% at 1 year, and 87% at 1 year. Flare rates in 3 studies deescalating abatacept were 34% at 1 year, 41% at 1 year, and 72% at 6 months. Five studies evaluating radiographic progression in patients deescalating treatment all found limited to no progression. CONCLUSION: Results suggest that more than one-third of patients with RA with LDA or in remission may taper or stop DMARD treatment without experiencing a disease flare within the first year. Dose reduction of TNF blockers results in lower flare rates than stopping and may be noninferior to continuing full dose. Radiological progression after treatment deescalation remains low, but may increase slightly.

Optimizing the expediency of TNFi in rheumatoid arthritis: offering a TNFi holiday in patients having reached low-disease activity in the maintenance phase.

INTRODUCTION: The treatment of rheumatoid arthritis (RA) has been revolutionized since the introduction of biological disease-modifying antirheumatic drugs such as tumour necrosis factor alpha inhibitors (TNFi), and clinical remission has become a realistic target in the treatment strategy. Discontinuation strategies of TNFi therapy after reaching sustained remission or low-disease activity (LDA) have been emerging. These strategies are important considering the risk-benefit profile of TNFi, as well as looking at them from a cost-economic point of view. AREAS COVERED: This article presents an overview of recent major studies on TNFi withdrawal, and tapering and about the safety of doing so. EXPERT OPINION: Although data are still limited, tapering or discontinuing TNFi in some RA patients may well be possible, especially in the early RA patients who are methotrexate naive. Also, a substantial group of longer established RA patients can stop or taper TNFi, particularly when ultrasonography signals are negative. However, before making the decision of implementing it in the routine care for RA patients, more predictors for successful discontinuation are desired.

Impaired dendritic cell proinflammatory cytokine production in psoriatic arthritis.

OBJECTIVE: The pathogenesis of psoriatic arthritis (PsA) remains poorly understood. The underlying chronic inflammatory immune response is thought to be triggered by unknown environmental factors potentially arising from a defective immune function. We undertook this study to determine whether an impaired acute inflammatory response by dendritic cells (DCs) might compromise the clearance of bacteria and predispose to chronic inflammation. METHODS: We determined cytokine production by DCs from healthy controls and from patients with rheumatoid arthritis, PsA, and psoriasis in response to Mycobacterium tuberculosis, Mycobacterium avium paratuberculosis, and a range of other bacteria and Toll-like receptor (TLR) ligands. Phenotypic differences involved in cellular responses against (myco)bacteria were determined by quantitative polymerase chain reaction and flow cytometry. RESULTS: The secretion of proinflammatory cytokines by PsA DCs was impaired upon in vitro challenge with mycobacteria and TLR-2 ligands. This impairment was associated with elevated serum levels of C-reactive protein. The expression of TLR-2 and other receptors known to mediate mycobacterial recognition was unaltered. In contrast, the intracellular TLR inhibitors suppressor of cytokine signaling 3 and A20 were more highly expressed in DCs from PsA patients. PsA DCs further demonstrated up-regulated levels of ATG16L1, NADPH oxidase 2, and LL37, which are molecules implicated in the immune response against intracellular bacteria. CONCLUSION: Our findings indicate that DCs from PsA patients have a disordered immune response toward some species of (myco)bacteria. This might predispose to impaired immune responses to, and in turn impaired clearance of, these bacteria, setting the stage for the chronic inflammation of joints, entheses, skin, and the gut.