Adalimumab-treated Rheumatoid Arthritis Patients Research Articles

P189 A longitudinal study of psychological predictors of response to adalimumab in patients with rheumatoid arthritis

Abstract Background/Aims The treatment of rheumatoid arthritis (RA) has improved since the introduction of targeted biological disease-modifying antirheumatic drugs (bDMARDs), such as adalimumab. However, no treatment options for RA are universally effective. Psychological factors may have an important role in treatment response. Published data reported that pre-treatment psychological variables such as an increased treatment necessity belief correlated with better adherence to adalimumab in RA patients. This current study aimed to investigate whether psychological factors correlate with change in 4V-DAS28-CRP as well as subcomponents of the score in adalimumab-treated RA patients. Methods Psychological, clinical and demographic data and DAS28 scores were collected pre-treatment, and at 3,6, and 12-months post-treatment, as part of a prospective national study, BRAGGSS. Sixteen pre-treatment clinical and psychological variables were tested for association with treatment response at 3 and 12 months. Multiple linear regression models were analysed and a Bonferroni corrected p-value of < 0.003 was applied at each interval to assess significance. Results Data was available for 501 patients at 3 months follow up. Pre-treatment Beliefs about Medicine Questionnaire (BMQ) scores with regards to treatment necessity (P = 0.001), and two domains of the Illness Perception Questionnaire (IPQ), which were treatment belief and treatment control (P = 0.0001), correlated with the change in DAS28 by 3 months (Table 1). At 12 months, data were available for 362 patients. The treatment belief domain of the pre-treatment Illness Perception Questionnaire correlated with the change in tender joint count (P = 0.001) (Table 1). At 12 months no other sub-components correlated with the psychological variables. Conclusion Pre-treatment scores with regards to Illness Perception and Beliefs about Medicine correlated with 4V-DAS28-CRP response at 3 months. Of the subcomponents of DAS28, the psychological variables showed the highest correlation with tender joint count; as the tender joint count receives the highest weighting in the 4 variable DAS28 score, this may confound the assessment of treatment response. It will be necessary to undertake further analyses to assess the predictive value of these potentially modifiable psychological variables identified, but to also understand factors contributing to these psychological scores, such as the role of severe disease itself on psychological beliefs. Disclosure N. Raza: None. N. Nair: None. D. Plant: None. K. Hyrich: None. A.W. Morgan: None. J. Isaacs: None. A.G. Wilson: None. A. Barton: None.

Systematic comparison of drug-tolerant assays for anti-drug antibodies in a cohort of adalimumab-treated rheumatoid arthritis patients

Drug interference complicates assessment of immunogenicity of biologicals and results in an underestimation of anti-drug antibody (ADA) formation. Drug-tolerant assays have the potential to overcome such limitations. However, to which extent drug-tolerant assays provide an unbiased picture of the antibody response to a biological is unknown.In this study, we compared the measurement of ADA to adalimumab in 94 consecutive adalimumab-treated rheumatoid arthritis patients using the traditional antigen binding test (ABT) and four different drug-tolerant assays, the Ph-shift anti-Idiotype Antigen binding test (PIA) and three newly developed assays for this study: an acid-dissociation radioimmunoassay (ARIA), a temperature-shift radioimmunoassay (TRIA) and an electrochemoluminescence-based assay (ECL).Our results indicate that drug-tolerant assays provide a fairly consistent view on the antibody formation: quantitatively, the results from all four assays correlate well (Spearman r>0.9). However, the percentage of ADA-positive patients ranges from 51 to 66% between assays, with the ARIA identifying the highest number of patients as positive. These differences are largely due to patients making low amounts of ADA; if ADA levels were above ca. 100AU/ml, a patient was identified as positive in all four assays. Adalimumab concentrations were significantly lower in ADA-positive samples.Taken together, the results indicate that these different drug-tolerant assays provide a similar and reasonably consistent view on ADA responses, which however, breaks down at the lower end of the detectable range, and highlight that ADA is best reported quantitatively. Furthermore, if an even more sensitive drug-tolerant assay could be developed, one would probably find additional positive samples that will predominantly contain very low levels of ADA.

FRI0147 IgG4 antibody response upon long term treatment with adalimumab

BackgroundA substantial part of the rheumatoid arthritis (RA) patients is chronically treated with adalimumab. Some of these patients produce antibodies against adalimumab, which correlate with lower serum drug levels and...

AB0455 Disease duration, but not rheumatoid factor status, impacts clinical response in adalimumab-treated rheumatoid arthritis patients with an inadequate response to standard dmard therapy: Subgroup analysis of the DE020 continuation trial

BackgroundRheumatoid factor (RF) is a prognostic marker of aggressive rheumatoid arthritis (RA); effective disease control may be more difficult in RF positive (+) patients (pts). Some biologic DMARDs have differential...

IgG4 Production Against Adalimumab During Long Term Treatment of RA Patients

A substantial part of rheumatoid arthritis (RA) patients is chronically treated with adalimumab. Some of these patients produce antibodies against adalimumab, which correlate with lower serum drug levels and reduced clinical response. Long term exposure to antigens may result in antigen specific IgG4 production as was demonstrated in studies on prolonged exposure to antigens such as different allergens, Factor VIII and IFN-β. Here, we investigate whether long term treatment of RA patients with the therapeutic monoclonal antibody adalimumab leads to the production of specific IgG4 antibodies. We developed radio immunoassays to detect total IgG or IgG4 against adalimumab and applied these in a cohort of 271 consecutive RA patients during 3 years of adalimumab treatment. In 32 % of the 271 patients antibodies against adalimumab were detectable. IgG4 antibodies were detected in 29 % of the patients. The proportion IgG4 of total IgG against adalimumab varies widely between patients, and IgG4 was found to contribute significantly to the anti drug antibody (ADA) response in some patients. In the immune response against adalimumab in adalimumab-treated RA patients a considerable part of the ADA is IgG4. Although IgG4 is often considered to be harmless due to its lack of effector function, neutralization of adalimumab by IgG4 antibodies will lead to a reduced clinical response.

Atherosclerosis in Rheumatoid Arthritis

There is a growing body of evidence supporting an increased risk of cardiovascular (CV) mortality in patients with rheumatoid arthritis (RA). This is the result of complex mechanisms leading to accelerated atherosclerosis [1]. In this regard, besides classic CV risk factors [2], chronic inflammation [3] and a genetic component [3, 4] have been proposed to influence the development of atherosclerosis in RA. This special issue encompasses different aspects of the CV disease associated to RA. With respect to this, the link between atherosclerosis and RA was discussed. Surrogate markers of atherosclerosis have been found to be useful in predicting the presence of atherosclerosis disease in subclinical stages in adults with RA [5, 6]. Data shown in this special issue also confirmed that children with juvenile idiopathic arthritis may have higher carotid intima-media wall thickness index values than controls. These observations emphasize the need for increased awareness of the risk of atherosclerosis in children with juvenile idiopathic arthritis. An exhaustive literature review on the genetic influence in the development of CV disease in patients with RA was also included. With respect to this, it is important to keep in mind that besides gene polymorphisms located within the MHC region [3, 4], variations of genes located outside this region, such as CCR5, MTHF [7, 8], are of potential relevance in the increased risk of CV disease associated to RA. Adipokines are molecules not only implicated in the development of metabolic syndrome but also in inflammatory mechanisms that may play a role in the pathogenesis of different autoimmune diseases [9, 10]. A timely review on the implication of adipokines in the development of the atherosclerotic disease not only focusing on RA but also discussing the link between these molecules and the presence of atherosclerosis in other chronic inflammatory rheumatic diseases was included in the special issue. The mechanisms associated with endothelial dysfunction, an early step in the atherogenesis process, in patients with RA are far from being completely understood. In this special issue an assessment of the potential role of asymmetric dimethylarginine and apelin as biomarkers to detect early data of endothelial dysfunction in patients with RA was included. Anti-TNF-α drugs constitute the mainstay of therapy in RA patients with severe disease that is refractory to conventional disease modifying antirheumatic drugs. One of the articles included in the special issue confirmed the previously reported short-term beneficial effect of the fully human-anti-TNF-α monoclonal antibody adalimumab on endothelial function [11]. In addition, new data showing persistent improvement of endothelial function in adalimumab-treated RA patients without progression of the carotid intima-media thickness are reported. This is of potential relevance as the use of anti-TNF-α therapy has been associated with a decrease of mortality in RA patients, mainly due to a reduction in the incidence of CV events [12]. In line with the above, Popa et al. had previously assessed the effects of the anti-TNF-α therapy on the HDL antiatherogenic function. They observed that infliximab, a chimeric anti-TNF-α monoclonal IgG1 antibody was able to improve HDL antioxidative capacity. This effect was sustained 6 months after anti-TNF-α therapy had been initiated [13]. In this special issue the same group conducted an extensive review on the effect that different biologic therapies exert on the atherogenic index and HDL cholesterol in patients with RA. Taken together, these studies confirm the presence of complex mechanisms that influence the development of atherosclerosis in RA. Nevertheless, further studies are needed to shed light on the problem of augmented risk of CV disease in patients with RA. Miguel A. Gonzalez-Gay Zoltan Szekanecz Calin D. Popa Patrick Dessein

Venous and arterial thromboembolic events in adalimumab‐treated patients with antiadalimumab antibodies: A case series and cohort study

We observed 3 patients who developed severe venous and arterial thromboembolic events during treatment with adalimumab, 2 of whom had rheumatoid arthritis (RA) and 1 of whom had psoriatic arthritis. Antiadalimumab antibodies were detected in all 3 patients. We undertook this study to determine whether the development of antiadalimumab antibodies was associated with thromboembolic events during adalimumab treatment. A retrospective search (with blinding with regard to antiadalimumab antibody status) for thromboembolic events was performed in a prospective cohort of 272 consecutively included adalimumab-treated RA patients. Incidence rates were calculated and hazard ratios (HRs) were estimated using Cox regression. None of the index patients were part of the cohort. Antiadalimumab antibodies were detected in 76 of 272 patients (28%). Eight thromboembolic events were found, 4 of which had occurred in patients with antiadalimumab antibodies. The incidence rate was 26.9/1,000 person-years for patients with antiadalimumab antibodies and 8.4/1,000 person-years for patients without those antibodies (HR 3.8 [95% confidence interval 0.9-15.3], P = 0.064). After adjustment for duration of followup, age, body mass index, erythrocyte sedimentation rate, and prior thromboembolic events, the HR was 7.6 (95% confidence interval 1.3-45.1) (P = 0.025). These findings suggest that the occurrence of venous and arterial thromboembolic events during adalimumab treatment is higher in patients with antiadalimumab antibodies than in those without antiadalimumab antibodies. Patient numbers were relatively small; therefore, validation in other cohorts is mandatory.

No overall progression and occasional repair of erosions despite persistent inflammation in adalimumab-treated rheumatoid arthritis patients: results from a longitudinal comparative MRI, ultrasonography, CT and radiography study

AimTo monitor joint inflammation and destruction in rheumatoid arthritis (RA) patients receiving adalimumab/methotrexate combination therapy using MRI and ultrasonography. To assess the predictive value of MRI and ultrasonography for erosive...

A novel method for the detection of antibodies to adalimumab in the presence of drug reveals “hidden” immunogenicity in rheumatoid arthritis patients

Production of anti drug antibodies (ADA) in adalimumab treated RA patients is associated with reduced serum adalimumab levels and less clinical response. However, most current assays to measure ADA are unable to detect ADA in complex with adalimumab. Thus, ADA is only measured if antibody production exceeds drug levels in the serum, meaning that ADA formation is underestimated. The aim of this study is to develop a method to detect ADA in the presence of drug. A pH-shift-anti-idiotype Antigen binding test (PIA) was used to enable ADA measurement in the presence of adalimumab. ADA–adalimumab complexes were dissociated by acid treatment and addition of excess rabbit anti-idiotype-F(ab) before neutralization. Rabbit anti-idiotype-F(ab) blocks reformation of ADA–drug complexes by competing with patient ADA for adalimumab binding. Released ADA are measured by an antigen binding test (ABT). The PIA enabled detection of ADA in the presence of large excess of adalimumab and was used to measure ADA in 30 adalimumab treated rheumatoid arthritis (RA) patients during the first 28weeks of treatment. It revealed ADA in 21 out of 30 tested patients, while the ABT detected ADA in only 5 patients. Indicating that an immunogenic reaction towards adalimumab is present in the majority of adalimumab treated patients.

Autoimmunity and Anti-TNF-α Agents

Treatment of rheumatoid arthritis (RA) patients with anti-tumor necrosis factor-alpha (anti-TNF-alpha) biologic agents has been associated with a reduction in the levels of specific autoantibodies, such as rheumatoid factor (RF) and anticyclic citrullinated peptide (anti-CCP), and the induction of non- organ-specific autoantibodies (antinuclear antibodies [ANAs], anti-dsDNA, and antiphospholipid antibodies [aPLs]). The mechanisms by which the blockade of anti-TNF-alpha decreases the generation of specific autoantibodies, such as anti-CCP and RF, are not yet known. However, it has been shown that these agents can downregulate the production of several inflammatory cytokines and mediators and that these anti-inflammatory effects may account for reduced autoantibody generation, particularly in the synovial compartment. Infliximab treatment leads to the induction of ANAs in 63.8% of RA patients and 49.1% of Crohn's disease (CD) patients, and anti-dsDNA antibodies in 13% of RA patients and 21.5% of CD patients, respectively. The development of ANAs and anti-dsDNA antibodies has also been described after etanercept therapy in 11% and 15% of RA patients, respectively. In the controlled trials, increases in ANA and anti-dsDNA titers were observed in 5.3% and in 12.9% of adalimumab-treated RA patients. Only limited data on the induction of aPL antibodies during TNF-alpha blocking treatment are available.