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Insensitivity versus poor response to tumour necrosis factor inhibitors in rheumatoid arthritis: a retrospective cohort study.

ABSTRACT: BACKGROUND:With advancement in the treatment options of rheumatoid arthritis (RA), optimising the outcomes of difficult-to-treat patients has become increasingly important in clinical practice. In particular, insensitivity to first-line biologic disease-modifying anti-rheumatic drugs (bDMARD) is becoming a significant problem because it may decrease the treatment adherence of patients. This study aimed to compare RA patients with an insensitivity and those with a poor response to initial treatment with tumour necrosis factor inhibitors (TNFis), which are the most frequently used bDMARDs. METHODS:This is a retrospective cohort study using clinical data from the FIRST registry. bDMARD-naïve RA patients treated with tumour necrosis factor inhibitors (TNFis) from August 2003 to May 2019 were included and categorised into three groups: TNFi insensitivity, poor response to TNFis and controls. TNFi insensitivity was defined as follows: (1) discontinuation of TNFi treatment within 22?weeks due to lack of any response, or (2) an increase in the disease activity score in 28 joints-C-reactive protein (DAS28-CRP) of >?0.6 at week 22 compared with week 0. Among the remaining patients, those with a DAS28-CRP >?2.6 at week 22 were categorised in the poor response group. RESULTS:Of the included patients, 94 were classified in the insensitivity, 604 in the poor response and 915 in the control. A higher DAS28-CRP before treatment was a risk factor for a poor response but not for insensitivity. In contrast, dose escalation of infliximab decreased the risk of a poor response but not that of insensitivity. CONCLUSIONS:In future research, poor and insensitivity to bDMARDs should be assessed separately to fully elucidate the aetiology of, and risk factors for, bDMARD refractoriness.

SUBMITTER: Ochi S

PROVIDER: S-EPMC7057565 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Insensitivity versus poor response to tumour necrosis factor inhibitors in rheumatoid arthritis: a retrospective cohort study.

Ochi Sae S Saito Kazuyoshi K Mizoguchi Fumitaka F Kato Shigeaki S Tanaka Yoshiya Y

Arthritis research & therapy 20200304 1

<h4>Background</h4>With advancement in the treatment options of rheumatoid arthritis (RA), optimising the outcomes of difficult-to-treat patients has become increasingly important in clinical practice. In particular, insensitivity to first-line biologic disease-modifying anti-rheumatic drugs (bDMARD) is becoming a significant problem because it may decrease the treatment adherence of patients. This study aimed to compare RA patients with an insensitivity and those with a poor response to initial ...[more]

PMID: 32131890

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Project description:ObjectiveTo determine whether intensive combinations of synthetic disease modifying drugs can achieve similar clinical benefits at lower costs to high cost biologics such as tumour necrosis factor inhibitors in patients with active rheumatoid arthritis resistant to initial methotrexate and other synthetic disease modifying drugs.DesignOpen label pragmatic randomised multicentre two arm non-inferiority trial over 12 months.Setting24 rheumatology clinics in England.ParticipantsPatients with rheumatoid arthritis who were eligible for treatment with tumour necrosis factor inhibitors according to current English guidance were randomised to either the tumour necrosis factor inhibitor strategy or the combined disease modifying drug strategy.InterventionsBiologic strategy: start tumour necrosis factor inhibitor; second biologic in six month for non-responders. Alternative strategy: start combination of disease modifying drugs; start tumour necrosis factor inhibitors after six months in non-responders.Main outcome measurePrimary outcomereduction in disability at 12 months measured with patient recorded heath assessment questionnaire (range 0.00-3.00) with a 0.22 non-inferiority margin for combination treatment versus the biologic strategy.Secondary outcomesquality of life, joint damage, disease activity, adverse events, and costs. Intention to treat analysis used multiple imputation methods for missing data.Results432 patients were screened: 107 were randomised to tumour necrosis factor inhibitors and 101 started taking; 107 were randomised to the combined drug strategy and 104 started taking the drugs. Initial assessments were similar; 16 patients were lost to follow-up (seven with the tumour necrosis factor inhibitor strategy, nine with the combined drug strategy); 42 discontinued the intervention but were followed-up (19 and 23, respectively). The primary outcome showed mean falls in scores on the health assessment questionnaire of -0.30 with the tumour necrosis factor inhibitor strategy and -0.45 with the alternative combined drug strategy. The difference between groups in unadjusted linear regression analysis favoured the alternative strategy of combined drugs. The mean difference was -0.14, and the 95% confidence interval (-0.29 to 0.01) was below the prespecified non-inferiority boundary of 0.22. Improvements at 12 months in secondary outcomes, including quality of life and erosive progression, were similar with both strategies. Initial reductions in disease activity were greater with the biologic strategy, but these differences did not persist beyond six months. Remission was seen in 72 patients (44 with biologic strategy; 36 with alternative strategy); 28 patients had serious adverse events (18 and 10, respectively); six and 10 patients, respectively, stopped treatment because of toxicity. The alternative strategy reduced health and social care costs per patient by £3615 (€4930, $5585) for months 0-6 and £1930 for months 6-12.ConclusionsIn patients with active rheumatoid arthritis who meet English criteria for biologics an alternative strategy with combinations of intensive synthetic disease modifying drugs gives non-inferior outcomes to treatment with tumour necrosis factor inhibitors. Costs are reduced substantially.Trial Registration ISRCTN 37438295.

Project description:IntroductionThe elevated risk of ischaemic heart disease in patients with rheumatoid arthritis (RA) has been linked to inflammation and disease severity. Treatment with tumour necrosis factor inhibitors (TNFis) is often effective in reducing disease activity and could possibly modify cardiovascular risk. Our objective in the study was to evaluate the risk of acute coronary syndrome (ACS) in patients with RA treated with TNFis compared with the risk among biologic-naïve RA patients and the general population.MethodsBy linkage of the Swedish National Patient Register and the Swedish Biologics Register, we identified a cohort of patients who were started on their first biologic, a TNFi, between 2001 and 2010 (N?=?7,704), and a cohort comprising matched biologic-naïve RA patient referents at a 3:1 ratio. Furthermore, a matched comparator cohort (5:1 ratio) was extracted from the Swedish population register. The incidence rates of a first ACS event were calculated and compared between cohorts using Cox proportional hazards regression in three different risk windows: 'ever-exposed', 'actively on TNFi' and 'short-term exposure' (active treatment maximized to 2 years). The models were adjusted for disease duration, joint surgery, comorbidity and socioeconomic factors, and, in a sensitivity analysis including a subpopulation started on therapy beginning 1 January 2006 or later, for dispensed drugs.ResultsBased on 221 events in 7,704 patients (comprising 32,621 person-years) treated with TNFi biologics, the hazard ratio ((HR); ever-exposed) for ACS among the TNFi-exposed RA patients compared with biologic-naïve RA patients was 0.8 (95% confidence interval (CI)?=?0.7 to 0.95). In comparison with the general population referents, statistical analysis using fully adjusted models resulted in a HR of 2.0 (95% CI?=?1.8 to 2.3) for biologic-naïve RA patients and a HR of 1.6 (95% CI?=?1.4 to 1.9) for the TNFi-exposed group. Similar risk estimates were obtained using the other two risk windows. A sensitivity analysis in which we compared the TNFi-exposed patients included from 1 January 2006 onward with biologic-naïve patients resulted in a HR (ever-exposed) of 0.7 (95% CI?=?0.5 to 1.0).ConclusionsRA patients treated with TNFi had a lower risk of ACS compared with biologic-naïve RA patients. Compared with the general population, the risk among patients with RA was elevated, although the difference was less pronounced among the TNFi-exposed patients. This finding could be attributable to the TNFi as such, or it could correspond to a lower degree of inflammation in the TNFi-treated group.

Dataset Information

Insensitivity versus poor response to tumour necrosis factor inhibitors in rheumatoid arthritis: a retrospective cohort study.

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Insensitivity versus poor response to tumour necrosis factor inhibitors in rheumatoid arthritis: a retrospective cohort study.

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