Treatment options in patients with rheumatoid arthritis failing initial TNF inhibitor therapy: a critical review

Conventional disease-modifying antirheumatic drugs such as methotrexate are the mainstay of treatment for rheumatoid arthritis. More recently, biologic agents such as etanercept, infliximab and adalimumab, which act by inhibiting tumour necrosis factor (TNF), have become available. TNF inhibitors have proved to be very effective in patients not responding to conventional disease-modifying antirheumatic drugs. However, about 20% to 40% of patients treated with a TNF inhibitor fail to achieve a 20% improvement in American College of Rheumatology criteria, and more lose response over time (secondary failure or acquired therapeutic resistance) or experience adverse events following treatment with a TNF inhibitor. In this group of patients, therapeutic options were limited until recently and an established treatment approach was to switch from one TNF inhibitor to another. In recent years, therapeutic options in these patients have increased with the introduction of biologic agents with novel mechanisms of action, such as rituximab and abatacept. This review outlines the current evidence in support of the available treatment strategies in patients with an inadequate response or intolerance to an initial TNF inhibitor

A systematic review of infliximab in the treatment of early rheumatoid arthritis

Sophie Martin Du Pan, Cem Gabay, Axel FinckhDivision of Rheumatology, Department of Internal Medicine, University of GenevaBackground: Several health authorities have recently revised the indication of infliximab (IFX) to include the treatment of early rheumatoid arthritis (RA). The aim of this systematic review of the literature was to appraise the efficacy, safety, and cost-effectiveness of early therapy with IFX.Methods: We identified published clinical trials from 1966 to May 2006. We included randomized clinical trials (RCTs) in RA with disease duration of less than 3 years comparing the treatment of methotrexate-IFX (MTX-IFX) with methotrexate-placebo (MTX-placebo).Results: A total of 8 studies met inclusion criteria. Three studies reported redundant data regarding the vdH Sharp Score. Out of the 5 remaining studies, 4 analyzed structural joint destruction (vdH Sharp Score) and demonstrated a significant reduction in radiographic damage progression in favor of the combination of MTX-IFX compared with MTX-placebo (–4.1 vdH Sharp Score units (95% CI: 3.5; 4.6). Three studies also displayed a benefit of MTX-IFX on functional outcomes of RA (HAQ score) and disease activity measures (DAS, ACR response criteria), although less markedly.Conclusions: Although data might be skewed because of only 2 existing large studies with concordant data, results from RCTs demonstrate improved efficacy of the combination MTXIFX compared with MTX-placebo in early RA. However, many early RA patients probably do not require the addition of IFX to achieve a satisfying clinical and radiological course. So far, no evidence has established the superiority of MTX-IFX over MTX-prednisone or other combinations of traditional disease-modifying anti-rheumatic agents.Keywords: rheumatoid arthritis, antirheumatic agents, inflixima

Effectiveness of biologic DMARDs in monotherapy versus in combination with synthetic DMARDs in rheumatoid arthritis: data from the Swiss Clinical Quality Management Registry

Objectives. To determine the frequency of use of biologic DMARDs (bDMARDs) in monotherapy, to describe the baseline characteristics of patients treated with bDMARDs in monotherapy and to compare the effectiveness of bDMARDs in monotherapy with that of bDMARDs in combination with synthetic DMARDs (sDMARDs). Methods. Using data from the Swiss RA (SCQM-RA) registry, bDMARD treatment courses (TCs) were classified either as monotherapy or as combination therapy, depending on the presence of concomitant sDMARDs. Prescription of bDMARD monotherapy was analysed using logistic regression. bDMARD retention was analysed using Kaplan-Meier and Cox models with the addition of time-varying covariate effects. Evolution of the DAS28 over time was analysed with mixed-effects models for longitudinal data. Results. A total of 4218 TCs on bDMARDs from 3111 patients were included, of which 1136 TCs (27%) were initiated as monotherapy. bDMARD monotherapy was preferentially prescribed to older, co-morbid patients with longer disease duration, lower BMI, more active disease and more previous bDMARDs. After adjusting for potential confounding factors, drug retention was significantly lower in monotherapy [hazard ratio 1.15 (95% CI: 1.03, 1.30)]. Other factors such as type of bDMARD and calendar year of prescription were associated with a stronger effect on drug retention. Response to treatment in terms of DAS28 evolution was also slightly but significantly less favourable in monotherapy (P = 0.04). Conclusion. Our data suggest that bDMARD monotherapy is prescribed to more complex cases and is significantly less effective than bDMARD therapy in combination with sDMARDs, but to an extent that is clinically only marginally relevan

Preferences of patients and at risk individuals for preventive approaches to rheumatoid arthritis

Effective treatments for rheumatoid arthritis (RA) are available and can lead to remission for some patients, but most patients remain on potentially toxic and expensive medications in the long term. Interest is increasingly turning to the disease phases preceding the development of RA that represent opportunities for preventive interventions. At-risk target populations include individuals with genetic and environmental risk factors, those who have developed systemic autoimmunity, and those who have developed clinically suspect symptoms (eg, arthralgias without synovitis, or an early arthritis). Ongoing prospective studies will inform the development of increasingly accurate predictive tools to identify individuals at risk of developing RA. Furthermore, a range of preventive approaches has been suggested, including lifestyle modification (eg, smoking cessation) and pharmacologic interventions (eg, hydroxychloroquine, methotrexate, abatacept, rituximab) that are currently the subject of randomized controlled trials. As prediction and prevention of RA evolve, it is increasingly likely that individuals at risk (including asymptomatic individuals) may be faced with complex decisions about whether to accept assessment of their risk status or to take a preventive intervention associated with risk of serious adverse events and uncertain benefit. Acceptance of preventive medication in other contexts can be low. For example, <25% of women at high risk of breast cancer are willing to take preventive hormonal treatments. Actual uptake is lower still. Patients' beliefs and preferences predict treatment uptake and adherence. Before the dream of preventing RA can become reality, health care providers need to understand the perspectives of individuals in the target population and to identify barriers and facilitators for this approach. This commentary reviews what is currently known about the perspectives of patients and individuals at risk about predictive and preventive approaches for RA and identifies gaps to be addressed to inform the development of efficient preventive strategies

The long-term impact of early treatment of rheumatoid arthritis on radiographic progression: a population-based cohort study

Objective. To measure the long-term rate of radiographic progression in a cohort of patients treated early vs late with conventional DMARDs. Methods. The long-term rate of radiographic progression in patients included in the Swiss clinical quality management in rheumatoid arthritis (SCQM-RA) registry who initiated treatment with conventional DMARDs within the first year of symptom onset (early DMARD) vs patients who initiated treatment 1-5 years after symptom onset (late DMARD). Radiographic progression was assessed in 38 joints using a validated score (Ratingen Score). The rate of progression was calculated using a multivariate regression model for longitudinal data, adjusting for potential confounders. Results. A total of 970 RA patients were included. The 368 patients in the early DMARD group started therapy after a median symptom duration of 6 months, whereas the 602 patients in the late DMARD group initiated therapy after median 2.5 years. RF, MTX use and other risk factors for erosive disease progression were similar between the two groups. However, the estimated rate of radiographic progression at baseline was higher in the early DMARD vs the late DMARD group (1.8 vs 0.6, P < 0.01). In spite of this, the long-term rate of radiographic progression was significantly lower in the early DMARD group after adjustment for confounding factors (−0.35 at 5 years, P = 0.012). Conclusion. This result supports the concept of a therapeutic window of opportunity early in the disease course and suggests that early initiation of DMARD therapy results in a long-lasting reduction of radiographic damag

Comparative effectiveness of biologics in patients with rheumatoid arthritis stratified by body mass index: a cohort study in a Swiss registry.

OBJECTIVES Obesity is associated with lower treatment response in patients with rheumatoid arthritis (RA). In patients with obesity, abatacept was suggested as a preferable option to tumour necrosis factor-alpha inhibitors. We aimed to assess the comparative effectiveness of etanercept, infliximab and abatacept, compared with adalimumab, in patients with RA with obesity. Secondarily, we also investigated this in patients with overweight and normal weight for completeness. DESIGN Observational cohort study. SETTING Swiss Clinical Quality Management in Rheumatic Diseases (SCQM) registry (1997-2019). PARTICIPANTS Adult patients with RA from the SCQM registry who received etanercept, infliximab, abatacept or adalimumab as their first biological or targeted synthetic disease-modifying antirheumatic drug were classified based on their body mass index (BMI) at the start of that treatment in three cohorts: obese, overweight, normal weight. They were followed for a maximum of 1 year. EXPOSURE The study exposure of interest was the patients' first biological, particularly: etanercept, infliximab and abatacept, compared with adalimumab. PRIMARY AND SECONDARY OUTCOME MEASURES The primary study outcome was remission within 12 months, defined as 28-joint Disease Activity Score (DAS28) <2.6. Missingness was addressed using confounder-adjusted response rate with attrition correction. Logistic regression was used to compare the effectiveness of etanercept, infliximab and abatacept versus adalimumab. Each BMI cohort was addressed and analysed separately. RESULTS The study included 443 obese, 829 overweight and 1243 normal weight patients with RA. There were no statistically significant differences in the odds of DAS28-remission at ≤12 months for etanercept, infliximab and abatacept, compared with adalimumab, in any of the BMI cohorts. CONCLUSIONS No differences in DAS28-remission were found between the study drugs and adalimumab as first biologic in patients with RA, independently of the BMI cohort. We did not find evidence that treatment with abatacept increased the likelihood of remission compared with adalimumab among obese patients with RA

Influence of cytokine inhibitors on concentration and activity of MMP-1 and MMP-3 in disc herniation

INTRODUCTION: Spontaneous resorption of disc herniation (DH) after sciatica is well documented. The matrix metalloproteinases (MMP)-1 and MMP-3 are enzymes potentially involved in this process. Glucocorticoid injections are commonly used for treatment, and other anti-inflammatory molecules like tumor necrosis factor (TNF) inhibitors are under clinical investigation. However, little is known about the effect of these molecules on DH resorption. METHODS: DH tissue was harvested from patients undergoing surgery for sciatica. Samples were thoroughly washed. Diced explants were cultured ex-vivo in 1) 0.5 ml Dulbecco's modified Eagle's medium (DMEM) 10% fetal calf serum (FCS), (controls), 2) recombinant interleukin 1 receptor antagonist (IL-1Ra), (100 ng/ml), 3) dexamethasone (10E-5 M), or 4) TNF inhibitor monoclonal antibody (10 microg/ml). Supernatants were harvested at 48 hours and frozen. Immunocapture activity assays determined total MMP activity, active MMP levels and pro-MMP levels. RESULTS: Fourteen DH tissue samples were analysed. Levels of all forms of MMP-3 were higher than the respective levels of MMP-1(P < 0.01). In particular, the median (interquartile range [IQR]) total MMP-3 level was 0.97 (0.47 - 2.19) ng/mg of tissue compared to 0.024 (0.01 - 0.07) ng/mg of total MMP-1 level (P < 0.01). Incubation with IL-1Ra, dexamethasone, or TNF inhibitors significantly decreased levels of all forms of MMP-3 (P < 0.05). Dexamethasone significantly decreased the ratio of active MMP-3 to total MMP-3 activity. A significant inhibitory effect of dexamethasone was observed only on active MMP-1, while IL-1 and TNF inhibitor had no significant effect on any form. CONCLUSIONS: MMP-3 appears to play a greater role than MMP-1 in DH resorption. Dexamethasone, IL-1-Ra and TNF inhibitor decreased active MMP-3, indicating that the clinical use of these drugs may affect the resorption of DH under certain conditions

Diagnostic value of anti-cyclic citrullinated peptides and association with HLA-DRB1 shared epitope alleles in African rheumatoid arthritis patients

INTRODUCTION: The purpose of this study was to examine the diagnostic performance of autoantibodies against citrullinated peptides/proteins (ACPA) and to determine the prevalence of HLA-DRB1 shared epitope alleles (SE) in African patients with rheumatoid arthritis (RA). METHODS: Serum levels of anti-cyclic citrullinated peptides antibodies (anti-CCP2, anti-CCP3), IgM and IgA rheumatoid factors (RF) were measured by enzyme-linked immunosorbent assay in the serum of 56 consecutive RA patients regularly followed in the Rheumatology Unit of the School of Medicine, University of Yaounde, Yaounde, Cameroon. Genotyping of HLA-DRB1 alleles was performed by polymerase chain reaction and hybridization with sequence-specific oligonucleotide probes on microbeads arrays. Fifty-one patients with other inflammatory rheumatic diseases and 50 healthy individuals were included as controls. RESULTS: An anti-CCP2 assay showed the best diagnosis sensitivity (82%) and specificity (98%) with high positive predictive (PPV) (96%) and negative predictive values (NPV) (91%). Thirty percent of RA patients were carrying at least one copy of the HLA-DRB1 shared epitope (SE) compared to 10% and 14% of patients with other inflammatory rheumatic diseases and healthy individuals, respectively. The presence of the SE was associated with the production of ACPA. CONCLUSIONS: Anti-CCP2 antibodies are useful markers of RA in African patients. In this cohort, the prevalence of the SE is higher in RA patients than in controls but lower than that reported in patient cohorts of European ancestry. The discrepancy between the high prevalence of ACPA-positive patients and the relatively low number of SE-positive cases suggest that, in addition to SE, other genetic factors control the development of ACPA in African RA patients

Is radiographic progression of late-onset rheumatoid arthritis different from young-onset rheumatoid arthritis? Results from the Swiss prospective observational cohort

Objective. RA can be categorized into late-onset RA (LORA, >60-65 years) and young-onset RA (YORA, 30-55 years), depending on the patient's age at disease onset. Since the average age of the population is continuously increasing, LORA will most probably gain in importance in the future. Despite this growing importance, LORA has not been the focus of much interest in the past. The aim of this study was to analyse radiographic damage progression of early disease in LORA compared with YORA patients. Methods. We included all patients from the Swiss RA registry, Swiss Clinical Quality Management in RA, with recent-onset arthritis, either RA (disease duration ≤1 year) or undifferentiated arthritis, as diagnosed by the data-entering physician. Patients were followed for 5 years. The cut-off between YORA and LORA was operationally set at 60 years of age. The primary outcome of this study was disease progression and activity, which was assessed based on the 28-joint DAS (DAS28) and the progression of joint erosions using a validated scoring system (Ratingen score). Results. A total of 592 patients with early disease were analysed. The age at disease onset had a Gaussian distribution, with a single peak at 54 years of age; 366 patients were categorized as YORA and 226 as LORA at disease onset. DAS28 scores were significantly higher among LORA as compared with YORA patients (4.8 vs 4.5, P = 0.049). Corticosteroids were used in 68% of LORA patients as a first-line treatment, compared with 25.4% in YORA patients (χ2 test: 54.58; P < 0.0001). In contrast, DMARDs were used in 100% of the YORA patients as first-line treatment, compared with 91.2% of the LORA patients. During follow-up, new glucocorticoids, synthetic DMARDs or biologic DMARDs were initiated in 32.8%, 61.1% and 14.1% of all YORA patients and 17.5%, 54.6% and 6.6% of LORA patients, respectively (χ2 test: 7.08, 22.53, 54.4; all P < 0.01). The DAS28 scores decreased in both groups during the observed time period, and the initial differences in disease activity vanished after 6 months and during the subsequent follow-up. The Ratingen score was higher in LORA than in YORA patients at inclusion (12.7 vs 5.6, P < 0.0001). The rate of radiographic progression at 5 years was similar when comparing LORA and YORA (3.3 vs 2.6, respectively, P = 0.64). The Ratingen scores at onset and during follow-up over 5 years did not clearly separate LORA and YORA into two groups, but rather, increased linearly when comparing the patients in groups per decade from 20 to 92 years of age. Conclusion. Our results did not show LORA as a separate subgroup of RA with a different prognosis with regard to radiographic progressio