CD28null CD4 T-cell expansions in autoimmune disease suggest a link with cytomegalovirus infection

Immunosenescence is thought to contribute to the increase of autoimmune diseases in older people. Immunosenescence is often associated with the presence of an expanded population of CD4 T cells lacking expression of CD28 (CD28null). These highly cytotoxic CD4 T cells were isolated from disease-affected tissues in patients with rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, or other chronic inflammatory diseases and their numbers appeared to be linked to disease severity. However, we recently demonstrated that the common herpes virus, cytomegalovirus (CMV), not ageing, is the major driver of this subset of cytotoxic T cells. In this review, we discuss how CMV might potentiate and exacerbate autoimmune disease through the expansion of CD28null CD4 T cells

Randomized trial of stopping TNF-inhibitors in rheumatoid arthrisis: patients with stable low disease activity in the Netherlands

Background/Purpose: The effectiveness of TNF-inhibitors (TNFi) in the treatment of rheumatoid arthritis has already been demonstrated in many studies. However, little is known on stopping TNFi in patients with stable lowdisease activity and the subsequent likelihood of exacerbation of rheumatoid arthritis. In addition, it is not clear whether TNFi can be restarted effectively and safely. Given the potential risk of serious side-effects and complications and the high costs of TNFi, it is important to examine whether patients in stable low disease activity can effectively stop TNFi. Methods: Multicenter open-label randomized study. Patients diagnosed with rheumatoid arthritis according to the ACR 1987 criteria were included. Patients had been treated with a TNFi for at least 1 year and with stable dose DMARDs for at least 6 months. All included patients had low disease activity in the 6 months prior to inclusion, with at least 2 DAS28 scores 3.2 in this period. Patients were randomized to discontinuing or continuing their current TNFi in a 2:1 ratio. DAS28 flare was defined as DAS283.2 with an increase 0.6 compared to the previous DAS28. Results: In total 817 patients from 47 centers were included: 531 patients (65%) in the discontinuation group and 286 patients (35%) in the continuation group. In the discontinuation group significantly more patients (30.8%) experienced a DAS28 flare within the first 6 months than in the continuation group (9.4%, P 0.0001). At 12 months, 46.9% of the patients experienced a DAS28 flare in the discontinuation group vs. 16.6% in the continuation group (P 0.0001). Median time to the first flare in the discontinuation group was 24 weeks. Survival analyses confirmed that flare free survival was significantly (P 0.0001) lower in the discontinuation group. The hazard ratio of DAS28 flare after discontinuing TNFi was 2.15 (95% CI: 1.59–2.91), after adjusting for disease duration, age, sex, and anti-CCP status. Conclusion:Flare-free discontinuation of TNF-inhibitors was possible in 53% of patients with stable low disease activity rheumatoid arthritis during a period of 12 months. Disclosure: H. E. Vonkeman, None; M. Ghiti Moghadam, None; M. A. F. J. van De Laar, None; P. M. ten Klooster, None; T. Jansen, Abbvie, 2, UCB, 2, Abbvie, 5, AstraZeneca, 5, UMS, 5, Janssen Pharmaceutica Product, L.P., 5, Menarini, 5, Novartis Pharmaceutical Corporation, 5, Pfizer Inc, 5, Roche Pharmaceuticals, 5, Abbvie, 8; P. van Riel, None

Measuring Disease Exacerbation and Flares in Rheumatoid Arthritis: Comparison of Commonly Used Disease Activity Indices and Individual Measures

OBJECTIVE: To evaluate and compare the utility of commonly used outcome measures for assessing disease exacerbation or flare in patients with rheumatoid arthritis (RA). METHODS: Data from the Dutch Potential Optimalisation of (Expediency) and Effectiveness of Tumor necrosis factor-α blockers (POET) study, in which 462 patients discontinued their tumor necrosis factor-α inhibitor, were used. The ability of different measures to discriminate between those with and without physician-reported flare or medication escalation at the 3-month visit (T2) was evaluated by calculating effect size (ES) statistics. Responsiveness to increased disease activity was compared between measures by standardizing change scores (SCS) from baseline to the 3-month visit. Finally, the incremental validity of individual outcome measures beyond the Simplified Disease Activity Score was evaluated using logistic regression analysis. RESULTS: The SCS were greater for disease activity indices than for any of the individual measures. The 28-joint Disease Activity Score, Clinical Disease Activity Index, and Simplified Disease Activity Index performed similarly. Pain and physician's (PGA) and patient's global assessment (PtGA) of disease activity were the most responsive individual measures. Similar results were obtained for discriminative ability, with greatest ES for disease activity indices followed by pain, PGA, and PtGA. Pain was the only measure to demonstrate incremental validity beyond SDAI in predicting 3-month flare status. CONCLUSION: These results support the use of composite disease activity indices, patient-reported pain and disease activity, and physician-reported disease activity for measuring disease exacerbation or identifying flares of RA. Physical function, acute-phase response, and the auxiliary measures fatigue, participation, and emotional well-being performed poorly

Measuring Disease Exacerbation and Flares in Rheumatoid Arthritis: Comparison of Commonly Used Disease Activity Indices and Individual Measures

To evaluate and compare the utility of commonly used outcome measures for assessing disease exacerbation or flare in patients with rheumatoid arthritis (RA). Data from the Dutch Potential Optimalisation of (Expediency) and Effectiveness of Tumor necrosis factor-α blockers (POET) study, in which 462 patients discontinued their tumor necrosis factor-α inhibitor, were used. The ability of different measures to discriminate between those with and without physician-reported flare or medication escalation at the 3-month visit (T2) was evaluated by calculating effect size (ES) statistics. Responsiveness to increased disease activity was compared between measures by standardizing change scores (SCS) from baseline to the 3-month visit. Finally, the incremental validity of individual outcome measures beyond the Simplified Disease Activity Score was evaluated using logistic regression analysis. The SCS were greater for disease activity indices than for any of the individual measures. The 28-joint Disease Activity Score, Clinical Disease Activity Index, and Simplified Disease Activity Index performed similarly. Pain and physician's (PGA) and patient's global assessment (PtGA) of disease activity were the most responsive individual measures. Similar results were obtained for discriminative ability, with greatest ES for disease activity indices followed by pain, PGA, and PtGA. Pain was the only measure to demonstrate incremental validity beyond SDAI in predicting 3-month flare status. These results support the use of composite disease activity indices, patient-reported pain and disease activity, and physician-reported disease activity for measuring disease exacerbation or identifying flares of RA. Physical function, acute-phase response, and the auxiliary measures fatigue, participation, and emotional well-being performed poorl

An Economic Evaluation of Stopping Versus Continuing Tumor Necrosis Factor Inhibitor Treatment in Rheumatoid Arthritis Patients With Disease Remission or Low Disease Activity: Results From a Pragmatic Open-Label Trial

Item does not contain fulltextOBJECTIVE: To evaluate, from a societal perspective, the incremental cost-effectiveness of withdrawing tumor necrosis factor inhibitor (TNFi) treatment compared to continuation of these drugs within a 1-year, randomized trial among rheumatoid arthritis patients with longstanding, stable disease activity or remission. METHODS: Data were collected from a pragmatic, open-label trial. Cost-utility analysis was performed using the nonparametric bootstrapping method, and a cost-effectiveness acceptability curve was constructed using the net-monetary benefit framework, where a willingness-to-accept threshold (WTA) was defined as the minimal cost saved that a patient accepted for each quality-adjusted life year (QALY) lost. RESULTS: A total of 531 patients were randomized to the stop group and 286 patients to the continuation group. Withdrawal of TNFi treatment resulted in a >60% reduction of the total drug cost, but led to an increase of approximately 30% in other health care expenditures. Compared to continuation, stopping TNFi resulted in a mean yearly cost saving of euro7,133 (95% confidence interval [95% CI] euro6,071, euro8,234]) and was associated with a mean loss of QALYs of 0.02 (95% CI 0.002, 0.040). Mean saved cost per QALY lost and per extra flare incurred in the stop group compared to the continuation group was euro368,269 (95% CI euro155,132, euro1,675,909) and euro17,670 (95% CI euro13,650, euro22,721), respectively. At a WTA of euro98,438 per QALY lost, the probability that stopping TNFi treatment is cost-effective was 100%. CONCLUSION: Although an official WTA is not defined, the mean saved cost of euro368,269 per QALY lost seems acceptable in The Netherlands, given existing data on willingness to pay

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

Item does not contain fulltextObjective: 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

Impact of Stopping Tumor Necrosis Factor Inhibitors on Rheumatoid Arthritis Patients' Burden of Disease

Item does not contain fulltextOBJECTIVE: To determine the impact of stopping tumor necrosis factor inhibitor (TNFi) treatment on patient-reported outcomes (PROs) of physical and mental health status, health utility, pain, disability, and fatigue in patients with established rheumatoid arthritis (RA). METHODS: In the pragmatic, 12-month POET trial, 817 RA patients with >/=6 months of remission or stable low disease activity were randomized 2:1 to stopping or continuing TNFi. In case of flare, TNFi was restarted at the discretion of the rheumatologist. PROs were assessed every 3 months. RESULTS: TNFi was restarted within 12 months in 252 of 531 patients (47.5%) in the stop group. At 3 months, mean PRO scores were significantly worse in the stop group, and a larger proportion of patients experienced a minimum clinically important difference (MCID) on all PROs. Effect sizes (ES) were strongest for health utility (ES -0.24) and pain (ES -0.30). Mean scores improved again after this point, but disability scores remained significantly different at 12 months. After 12 months, the relative risk of experiencing an MCID ranged from 1.16 for mental health status to 1.58 for fatigue. Mean PRO scores for patients restarting TNFi within 6 months were no longer significantly different from those that did not restart TNFi at 12 months. CONCLUSION: Stopping TNFi had a significant negative short-term impact on a broad range of PROs. Long-term negative consequences appeared to be limited, and outcomes in patients needing to restart TNFi within the first 6 months tended to be restored at 12 months

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