Effective use of TNF antagonists
© BioMed Central Ltd 2004
Received: 17 July 2003
Accepted: 6 August 2003
Published: 21 June 2004
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© BioMed Central Ltd 2004
Received: 17 July 2003
Accepted: 6 August 2003
Published: 21 June 2004
Tumor necrosis factor (TNF) antagonists are biologic response modifiers that have significantly improved functional outcomes in patients with rheumatoid arthritis (RA). RA is a progressive disease in which structural joint damage can continue to develop even in the face of symptomatic relief. Before the introduction of biologic agents, the management of RA involved the use of disease-modifying antirheumatic drugs (DMARDs) early in the course of disease. This focus on early treatment, combined with the availability of the anti-TNF agents, has contributed to a shift in treatment paradigms favoring the early and timely use of DMARDs with biologic therapies. Improvement in symptom control does not always equate to a reduction in disease progression or disability. With the emergence of structure-related outcome measures as the primary means for assessing the effectiveness of antirheumatic agents, the regular use of X-rays is recommended for the continued monitoring and evaluation of patients. In addition to the control of symptoms and improvement in physical function, a reduction in erosions and joint-space narrowing should be considered among the goals of therapy, leading to a better quality of life. Adherence to therapy is an important element in optimizing outcomes. Durability of therapy with anti-TNF agents as reported from clinical trials can also be achieved in the clinical setting. Concomitant methotrexate therapy might be important in maintaining TNF antagonist therapy in the long term. Overall, the TNF antagonists have led to improvements in clinical and radiographic outcomes in patients with RA, especially those who have failed to show a complete response to methotrexate.
Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory disease that affects approximately 1% of the world's population. It is characterized by a loss in functional capacity resulting from decreased structural integrity of the joints, diminished muscle strength and tone, and a variety of psychosocial factors. A 10-year outcomes study of 183 patients with early RA showed that most (94%) are able to manage daily life activities. On the basis of disability scores on the Health Assessment Questionnaire (HAQ), a self-reported measure of functional impairment, 20% of patients had no disability, 28% were mildly disabled, and 10% were seriously disabled .
Treatment strategies have traditionally involved the use of disease-modifying antirheumatic agents (DMARDs) and, more recently, the tumor necrosis factor (TNF) antagonists. To optimize the functional outcomes of patients with RA, it is essential to examine the role of these newer agents in preventing disease progression and, potentially, in producing a cure. This examination requires several considerations, including (1) the importance of treating patients early, (2) the fact that improvements in symptom control do not necessarily signal reduced disease progression and disability, (3) the emergence of structure-related parameters as a primary means of assessing response to therapy, (4) therapeutic alternatives for patients who do not respond satisfactorily to one anti-TNF agent, and (5) discontinuation rates and whether they influence therapy, given the desire for durable clinical responses.
The advantages of the early initiation of therapy combined with the introduction of newer antirheumatic agents (such as the TNF biologic response modifiers) have shifted treatment models toward the earlier and more timely use of DMARDs  and biologic therapy [5, 6]. A panel of rheumatic disease experts has issued a consensus report addressing the role of TNF antagonists in patients with RA; the panel stated that TNF antagonists may become first-line agents in the treatment of RA and should not be reserved for patients with advanced disease .
Improved symptom control with disease progression
Mean Larsen index
Increased structural damage
As assessment of structural damage in RA is emerging as an important method of evaluating disease outcomes, radiographs (that is, X-rays), have become essential tools not just for the diagnosis of RA but for continued monitoring. Radiographic findings can be reported with the Sharp score or the Larsen index. The total Sharp score is derived from the combination of erosion and joint-space narrowing scores. Joint-space narrowing is not a major contributor to the overall Larsen index score .
Clinical changes after a switch from etanercept to infliximab
Post-infliximab (4 doses; week 14)
Mean tender joints (n)
Mean swollen joints (n)
Mean prednisone dosage (mg/day)
Discontinuation rates of a pharmacologic agent, including antirheumatic agents, can influence therapy. Discontinuation rates can serve as a reasonable guide to the efficacy or safety of an agent. Before definitive conclusions can be made, other variables should be considered, for example the phase of therapy (such as acute, continuation, maintenance), reasons for the discontinuation (such as lack of efficacy, toxicity, adverse events [AEs]), associated symptoms or intercurrent illness, and drug profile (including previous medications and concomitant therapy). Discontinuation rates can also serve as a reflection of the chronic, aggressive course of the disease, which can require more than one therapy or can sometimes involve the switching of agents to achieve satisfactory clinical outcomes.
For a better understanding of how discontinuation rates affect therapy in the era of anti-TNF agents, a review of the discontinuation rates with DMARDs based on three large studies is presented [18–20]. According to a Markov model based on the Arthritis, Rheumatism, and Aging Medical Information System (ARAMIS) postmarketing surveillance cohort (n = 4285 consecutively enrolled patients with RA who were followed up for 17,085 patient-years), 46–60% of patients initially receiving methotrexate alone would still be on methotrexate alone or with a DMARD after 5 years . When patterns of drug use in patients with RA in a community setting were evaluated, drug discontinuation and medication switching were observed to be common . Almost 20% (1300 of 6944) of patients who took at least one antirheumatic drug during the study year used a DMARD, with methotrexate being the most frequently used. Of the DMARD users, 23% discontinued the drug during the study year, 19% were taking other concurrent DMARDs, and 16% added another DMARD. DMARDs were often used with other (that is, non-DMARD) agents, because 63% of DMARD users were also taking an NSAID and 61% were taking a corticosteroid . Aletaha and Smolen  evaluated the treatment patterns with traditional DMARDs and their changes during the two decades before the introduction of newer antirheumatic agents. The study involved 593 patients with RA who were followed from their first presentation in the clinic throughout the course of their disease, of whom 222 patients received their first DMARD during the study . Before 1985 most (65–90%) of initial DMARDs were gold compounds, whereas after 1985 methotrexate was the initial DMARD in 29% of new patients. Patients with high disease activity were more likely to be receiving methotrexate than other DMARDs, and first DMARDs in new patients were used for longer than subsequent DMARDs, because they were more effective . On the basis of an analysis of 122 controlled trials and observational studies involving 16,071 patients with RA, Hawley and Wolfe  concluded that good retention rates in studies lasting 3–12 months were not representative of long-term results, although the retention rates observed in controlled and observational studies were similar during the first treatment year.
Discontinuation rates at 1 year for anti-TNF agents in randomized clinical trials
No. of patients
Discontinuation rates (%)
Active RA despite methotrexate therapy; mean duration 9–12 years
3 mg q 4 weeks
3 mg q 8 weeks
10 mg q 4 weeks
10 mg q 8 weeks
Early RA; mean duration <1 year (i.e. 11–12 months)
25 mg twice weekly
Methotrexate (mean, 19 mg) weekly
The chronic course of RA merits long-term maintenance therapy. Efforts to lower discontinuation rates have included the administration of methotrexate together with anti-TNF agents. Support for enhanced therapeutic efficacy with this approach has been documented [22, 23]. Maini and colleagues conducted a 26-week, double-blind, placebo-controlled trial in 101 patients with active RA exhibiting an incomplete response to methotrexate(about 9–15 mg per week for the last 3 months before the study) . Patients received either infliximab 1, 3, or 10 mg/kg intravenously with or without methotrexate 7.5 mg per week, or placebo plus methotrexate 7.5 mg per week intravenously at weeks 0, 2, 6, 10, and 14; follow-up continued until week 26 . Results showed that when infliximab (at all dose regimens in the study) was administered together with infliximab and weekly methotrexate, 60–80% of patients attained a Paulus 20% response for up to 14 weeks, and 50–60% of patients sustained a response after the cessation of treatment until the end of the study . In the ATTRACT study, the combination of infliximab and methotrexate over 30, 54, and 102 weeks provided significant, clinically relevant improvement in a majority of patients with RA who had an incomplete response to methotrexate alone; however, discontinuation rate data at 102 weeks have yet to be made available [11–13]. As more data from long-term trials that involve these agents accumulate, focusing on discontinuation rates and correlating safety and efficacy parameters, the role of concomitant methotrexate in the long-term maintenance of anti-TNF therapy will be clarified further.
Aside from clinical trial data, clinical practice data report the discontinuation rates of anti-TNF agents. A 2-year Swedish study conducted in seven clinical centers evaluated the anti-TNF agents infliximab (n = 135) and etanercept (n = 166]) and a newer-generation DMARD, leflunomide (n = 103), for efficacy (based on ACR response criteria) and tolerability (based on survival and AEs) in patients with RA . Initial doses of the agents in this study were 3 mg/kg intravenously at weeks 0, 2, 6, and 12 and every 8 weeks thereafter for infliximab, and 25 mg subcutaneously twice weekly for etanercept; appropriate dose adjustments and switching to another of the three agents were allowed after withdrawal from one treatment . On the basis of ACR20 and ACR50 responses, the TNF antagonists performed significantly better than the newer DMARD, and no significant differences were noted between the efficacy of infliximab and etanercept at 0.5, 1.5, 9, and 12 months . At 3 months, ACR20 and ACR50 responses were noted in a greater percentage of patients who received infliximab than leflunomide (P < 0.01 and P < 0.05, respectively), whereas ACR20 and ACR50 responses were noted in a greater percentage of etanercept-treated and leflunomide-treated patients at 3 months (P < 0.001) and 6 months (P < 0.05) . Survival data showed that 75%, 79%, and 22% of patients continued to receive infliximab, etanercept, and leflunomide, respectively, after 20 months (for 24-month discontinuation rates of 25%, 21%, and 78%, respectively) . In the infliximab-treated and etanercept-treated patients in this study, AEs were the primary cause of drug discontinuation. There were 2.8 life-threatening AEs per 100 treatment-years (namely anaphylactoid reaction, mesothelioma, and severe pharyngitis) and 10.0 serious AEs per 100 treatment-years (namely allergic reactions, bacterial infections, Hodgkin's/non-Hodgkin's lymphoma, thrombocytopenia, lupus-like reaction, discoid lupus) with infliximab. Etanercept-treated patients experienced 1.3 fatal AEs per 100 treatment-years (namely gas-troenteritis, immunocytoma of the breast, and myocardial infarction) and 7.0 serious AEs per 100 treatment-years (namely myocardial infarction, bacterial infections, uterine cervical carcinoma, leukemia, malaise, leucopenia, Bell's paralysis, cutaneous vasculitis, discoid lupus) .
An electronic medical record system was used to review all patients seen in a university rheumatology clinic (the Arizona Arthritis Center at the University of Arizona) who had been treated with infliximab (n = 118) or etanercept (n = 90) between February 1998 and May 2002 . Data were collected on diagnosis, disease duration, dates of therapy, reasons for treatment discontinuation, and AEs and serious AEs. Most (82%) of the 208 patients in this study had a diagnosis of RA . Kaplan-Meier analysis for the discontinuation of any anti-TNF therapy showed a mean medication duration of 768 days (95% confidence interval [CI] 693–843 days) with a maximum follow-up time of 1260 days .
For infliximab, the mean time to discontinuation was 931 days (95% CI 844–1018 days), with 32 (27%) of 118 patients discontinuing infliximab. After 15 months there was a 0% rate of discontinuation with infliximab . For etanercept, the mean time to discontinuation was 595 days (95% CI 491–700 days), with 58 (64%) of 90 patients discontinuing etanercept . The log-rank test coefficient for the difference between survival curves for the two groups was 20.03 (P < 0.01) and the Gehan-Breslow coefficient was 16.01 (P < 0.001) . The investigators documented a low probability of discontinuations of infliximab after 1 year of treatment and concluded that, on the basis of the results of the survival analysis of the data from their practice, patients receiving infliximab remain on therapy significantly longer than those on etanercept .
Clinical trials and community findings support the efficacy and safety of the current TNF antagonists. To optimize comprehensive therapeutic outcomes in clinical practice, DMARDs or anti-TNF agents, or both, should be instituted early, and patient status and response to therapy should be monitored on a regular basis by using X-rays and radiographic scores. Structure-related parameters are emerging as a most important measure of outcome by which the efficacy of antirheumatic therapies are evaluated. In addition to a reduction of symptoms and improvement in physical function, optimal reductions in erosions and joint-space narrowing should be part of the goals of therapy. Patients who show an unsatisfactory response to one anti-TNF agent should be started on another. Adherence to therapy is an important element in optimizing outcomes, and durability of therapy can also be achieved in the clinical setting. Finally, the concomitant administration of methotrexate might be important in the maintenance of TNF antagonist therapy in the long term. Overall, the TNF antagonists have provided significant improvements in clinical and radiographic outcomes for patients with RA, especially those who have had an incomplete response to methotrexate therapy.
American College of Rheumatology
Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy
disease-modifying antirheumatic drugs
Early Rheumatoid Arthritis
erythrocyte sedimentation rate
Health Assessment Questionnaire
non-steroidal anti-inflammatory drug
tumor necrosis factor
The transcript of the World Class Debate for ACR 2002 has been published electronically in Joint and Bone. This article, and others published in this supplement, serve as a summary of the proceedings as well as a summary of other supportive, poignant research findings (not included in the World Class Debate ACR 2002).