Predicting response to anti-TNF treatment in rheumatoid arthritis patients☆
Introduction
The anti-tumour necrosis factor (anti-TNF) agents infliximab (INF), etanercept (ETA) and adalimumab (ADA)] have been found to be safe in large placebo-controlled trials involving patients with established or early disease, and effective in controlling disease signs and symptoms and improving the quality of life [1], [2], [3], [4], [5], [6], [7]. They have now been administered to more than one million patients and a recent review using the American College of Rheumatology 50% response (ACR50) after 12 months found that all three drugs are equally effective in patients with established rheumatoid arthritis (RA) taking concomitant methotrexate (MTX) [8]. However, none of these drugs has led to a 100% patient response, and responses are normally 50–70% [9], [10].
Before the introduction of anti-TNF agents, a number of studies investigated the clinical predictors of response to traditional disease-modifying anti-rheumatic drugs (DMARDs) [11]. A meta-analysis of clinical trials of DMARDs, including MTX, in RA found that the factors decreasing the rate of response to treatment included a longer disease duration, any prior use of a DMARD, a higher Steinbrocker functional class, low disease activity (according to patient global assessment), and female gender [12]. Since then, the British Society for Rheumatology (BSR) Biologics Register has reported an improved outcome among patients receiving MTX in combination with anti-TNF therapies and non-steroidal anti-inflammatory drugs (NSAIDs), and that the most disabled patients were less likely to respond despite concurrent MTX; the poor outcomes with IFN were associated with smoking, and females were less likely to achieve remission [13].
At the time of the European introduction of anti-TNF agents for the treatment of RA patients with active disease who are refractory to conventional treatments (including MTX), the Lombardy Rheumatology Group started a database for the registration and active follow-up of anti-TNF-treated patients with rheumatic diseases (Lombardy Rheumatology Network [LORHEN] clinical registry) [14]. We have now assessed the 3-year efficacy and safety of all three currently available anti-TNF agents in a large cohort of RA patients, and the aim of this study was to identify the positive and negative predictors of response.
Section snippets
Patients
The patients for this analysis were selected from the large, prospective, observational LORHEN registry, the characteristics of which are described in detail elsewhere. The analysis only included the patients who fulfilled the 1987 American College of Rheumatology (ACR) criteria for RA [15] and had been treated with at least one dose of an anti-TNF agent (INF, ETA, ADA) at one of four Rheumatology Centres in Lombardy (Italy) with at least six months' follow-up. The Italian Society of
Predictors of a DAS28 response of < 2.6 (DAS28 remission)
The analysis included 1005 of 1114 patients with established RA: 228 (22.7%) treated with ETA, 282 (28.1%) with ADA, and 495 (49.3%) with INF. At the start of therapy, their mean age was 55.72 years (range 18–88), and their mean baseline DAS28 and HAQ scores respectively 5.91 ± 0.95 and 1.46 ± 0.61.
Eight hundred and fifty-eight patients (85.4%) were receiving MTX (mean dose 10 mg, range 7.5–20 mg) and 32 (3.2%) other DMARDs (Table 1); half of the cohort was currently receiving corticosteroids.
Discussion
To the best of our knowledge, this is the largest regional registry observational study of TNF inhibitors used in the clinical management of RA [14], [21], [22]. The patients in our cohort are covered by the Italian National Health System, which provides all-inclusive care at no end-user cost to almost 100% of the population and includes free access to clinical specialists; this is important because the cost of medications and follow-up specialist care in some countries may contribute to the
Conclusions
In a clinical practice setting, only a minority of patients with long-standing RA achieve a good clinical response or remission. We found that a poorer EULAR response was significantly associated with the number of DMARDs previously used, and baseline ESR and tender joint count. A high level of disability and a daily corticosteroid dose of > 5 mg at baseline strongly predicted a EULAR non-response, whereas concomitant MTX and higher DAS28 scores were associated with a EULAR response. Finally,
Take-home messages
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In a clinical practice setting, only a minority of patients with long-standing RA achieve a good clinical response or remission.
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EULAR response was significantly associated with the number of DMARDs previously used, baseline ESR and tender joint count.
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A high level of disability and a daily corticosteroid dose of > 5 mg at baseline strongly predicted an EULAR non-response.
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Males were more likely to achieve remission than females.
References (36)
- et al.
Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial
Lancet
(2004) - et al.
Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial
Lancet
(2004) - et al.
Infliximab and methotrexate in the treatment of rheumatoid arthritis
N Engl J Med
(2000) Infliximab treatment for rheumatic disease: clinical and radiological efficacy
Ann Rheum Dis
(2002)- et al.
Etanercept therapy in rheumatoid arthritis. A randomized, controlled trial
Ann Intern Med
(1999) - et al.
Tumour necrosis factor-alpha blockade: a new era for effective management of rheumatoid arthritis
Expert Opin Pharmacother
(2000) - et al.
Efficacy and safety of adalimumab (HUMIRA) in European clinical practice: the ReAct trial
Ann Rheum Dis
(2004) - et al.
Long term efficacy and safety of adalimumab plus methotrexate in patients with rheumatoid arthritis: ARMADA 4 year extended study
Ann Rheum Dis
(2005) - et al.
The comparative efficacy and safety of biologics for the treatment of rheumatoid arthritis: a systematic review and metaanalysis
J Rheumatol
(2006) - et al.
The RADIUS Investigators: real-world effectiveness of select biologic and DMARD monotherapy and combination therapy in the treatment of rheumatoid arthritis: results from the RADIUS observational registry
Curr Med Res Opin.
(2006)
Retention rates of tumor necrosis factor blockers in daily practice in 770 rheumatic patients
J Rheumatol
Poor outcome and non-response to DMARD therapy. A study of 6870 rheumatoid arthritis patients
Arthritis Rheum
Factors predicting response to treatment in rheumatoid arthritis: the importance of disease duration
Arthritis Rheum
British Society for Rheumatology Biologics Register Predictors of response to anti-TNF-alpha therapy among patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register
Rheumatology (Oxford)
Efficacy and safety of anti-TNF agents in the Lombardy rheumatoid arthritis network (LORHEN)
Reumatismo
The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis
Arthritis Rheum
Anti-TNF treatment for rheumatoid arthritis
Clin Exp Rheum
on behalf of the EULAR standing committee for international clinical studies including therapeutic trials
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2018, European Journal of Integrative MedicineCitation Excerpt :In between, a reduction > 1.2 with present DAS28 > 3.2 or a reduction between 0.6 and 1.2 with present DAS28 < 5.1 was specified as a moderate response. Since both good-and moderate responders achieve sufficient response, they were combined as responders in the following data analysis [24]. Firstly, univariate analyses including independent student’s t-tests, chi-square tests, and Kruskal wallis H tests were applied to compare the differences of baseline clinical and demographic data between responders and non-responders.
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All of the authors have received consultancy fees or Congress invitations from Schering-Plough, Wyeth, and Abbott.