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Study l Citation: Peter E. Lipsky MD, Desiree MFM van der Heyde MD, E. William St. Clair MD, Daniel E. Furst MD, Ferdinand C. Breedveld MD, Joachim R. Kalden MD, Josef S. Smolen MD, Michael Weisman MD, Paul Emery MD, Marc Feldmann MD, BS, PhD, Gregory R. Harriman MD, Ravider N. Maini, FRCP for the Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group.

Infliximab and Methotrexate in Treatment of Rheumatoid Arthritis

The New England Journal of Medicine November 30, 2000

From the University of Texas Southwestern Medical Center at Dallas, Dallas (P.E.L.); University Hospital Maastricht, Maastricht, the Netherlands (D.M.F.M.H.); Duke University Medical Center, Durham, N.C. (E.W.S.), Virginia Mason Research Center, Seattle (D.E.F.); the University of Leiden, Leiden, the Netherlands (F.C.B.); the Institute for Clinical Immunology, Erlangen, Germany (J.R.K.); the University of Vienna, Vienna, Austria (J.S.S.); the University of California at San Diego, San Diego (M.W.); the Research School of Medicine, University of Leeds, Leeds, United Kingdom (P.E.); the Kennedy Institute of Rheumatology and the Imperial College School of Medicine at Charing Cross Hospital, London (M.F., R.N.M.); and Centocor, Malvern, Pa. (G.R.H.).

Click on the link at left to go to your desired page: Introduction Page 2 Page 3 Study 1 Study 2 Conclusion Post-Test

Abstract:

This study was conducted to determine the effect, if any, on joint damage seen in patients with long-term rheumatoid arthritis. 428 study participants were divided into five groups treated with methotrexate plus placebo, or one of two different doses of infliximab on two different frequencies of administration. Clinical responses were assessed using a standardized criteria along with radiological examination. In addition, a quality of life survey was completed by participants. Participants who received infliximab as a part of their therapy showed a reduction in symptoms (p<0.001), improved quality of life, and less joint damage (p<0.001) than seen in the group treated with methotrexate and placebo. In addition, the infliximab-treated participants had no evidence of continued joint damage regardless of their clinical response to the treatments.

Key Words:

rheumatoid arthritis, tumor necrosis factor, infliximab, methotrexate

Discussion:

Rheumatoid arthritis (RA) is a chronic disease characterized by inflammation that causes pain and can lead to progressive joint damage. Current therapy includes methotrexate to treat the disease, though it is not always effective. When treatment is not adequate other drugs have been suggested and used. Investigational shortcomings were a major motivating factor in this study, as prior studies have only tested tumor necrosis factor-alpha (TNF-α) neutralizing therapies for three to six months, which does not adequately address the potential for impact on long-term joint damage.

Infliximab binds with, and neutralizes the effects of, TNF-α. While this action reduces the signs and symptoms of RA, the ability to achieve a sustained benefit and reduce joint damage remains unknown.

This study was conducted to determine if infliximab could achieve a sustained benefit and have a positive effect on joint damage in a longer-term one-year study.

Participants were eligible for the study if they had active RA despite treatment with oral methotrexate therapy of at least 12.5 mg/week. Active RA was defined as six or more swollen joints, or the same number of tender joints, and at least two of the following criteria:

* Morning stiffness that lasted 45 minutes or more

* Erythrocyte sedimentation rate of 28 mm/hour or greater

* Serum C-reactive protein concentration of at least 2.0 mg/dL or greater

For this study, 428 participants were recruited. All had active RA despite being treated with methotrexate therapy. Participants were randomly assigned to one of five groups (as shown in Table 1 below) to receive the same amount of methotrexate as they were taking pre-trial, plus infusions of infliximab or placebo (dosed at 3 mg or 10 mg/kg body weight for 54 weeks) in order to blind both participants and researchers from the regimen they were receiving. All participants received IV infusions at the initiation of treatment, then again at weeks two and six. Two of the infliximab groups (one receiving 3 mg and the other receiving10 mg) and the placebo group received additional infusions every four weeks. The other 3 mg and 10 mg infliximab groups received infusions every eight weeks and placebo infusions on the interim four-week intervals to hide their group designations from the participants and researchers.

Table 1. Randomization, dosing schedule, and study completion information for the five study groups

Group:	1	2	3	4	5
Treatment	methotrexate	3mg/kg infliximab	3mg/kg infliximab	10mg/kg infliximab	10mg/kg infliximab
	plus placebo	every 8 weeks	every 4 weeks	every 8 weeks	every 4 weeks
		plus methotrexate	plus oral methotrexate	plus oral methotrexate	plus oral methotrexate
Participants assigned	n=88	n=86	n=86	n=87	n=81
Completers	44	63	66	75	65
Discontinuation (dc)	44	23	20	12	16
Reasons for dc*	7 AE, 32 LE, 5 O	5 AE, 17 LE, 1 O	9 AE, 10 LE, 1 O	4 AE, 6 LE, 2 O	8 AE, 7 LE, 1 O
# of documented ACR improvement evaluations	27	73	99	123	116
Patients experiencing a decreased # of swollen joints	13	37	50	60	63
Patients experiencing a decrease # of tender joints	23	49	55	56	65
Mean serum C-reactive protein (mg/dl)	2.8	1.6	1.5	1.2	1.1

*Key: AE= adverse events; LE= lack of efficacy; O=other reasons

Participants were assessed and graded according to symptoms and disease progression. Changes in swollen and tender joints were evaluated and classified according to the American College of Rheumatology (ACR) definitions. Using ACR designations, a grade of ACR 20 means a 20% reduction in the number of swollen joints along with a 20% improvement in at least three of the self-evaluated disease progression classifications listed below. These classifications included the following categories of survey items with scores that were determined by the patient or physician using a visual analog scale (VAS) or laboratory values:

· Patient global assessment of disease status

· Physician global assessment of disease status

· Patient perception of pain

· Disability by health assessment survey

· Erythrocyte sedimentation rate

· C-reactive protein concentration

In addition, general health status was evaluated using the Medical Outcomes Study Short-Form Health Survey (SF-36). Participants were tested for the development of antibodies against infliximab. Radiographic evaluations of the hands and feet were used to look for erosions and joint-space narrowing to determine progression of joint damage.

Results:

Signs and symptoms of RA decreased in more patients in the infliximab groups than in the methotrexate-alone group as judged by the numbers of participants with ACR 20, 50 and 70 responses showing improvement in the numbers of swollen and/or tender joints (p<0.001). While the higher-dose infliximab groups had better results, there was only one category (ACR 50) that did not show this significant difference between methotrexate-only and methotrexate plus lower-dose infliximab. All doses of infliximab plus methotrexate were more effective than methotrexate alone (p<0.001) for rate of erosions and joint space narrowing. The decrease in progression did not appear to be related to baseline characteristics of radiologic evaluations or biochemical evaluations. A decrease in mean C-reactive protein serum levels was significant in the infliximab-containing therapies (p<0.006 in group 2 and p<0.001 in groups 3-5). Infliximab plus methotrexate also had a greater effect on participants' arthritis-specific function (as determined by the Health Assessment Questionnaire), and the physical component of the SF-36.

Participants discontinued therapy for a variety of reasons, although more than twice as many methotrexate-alone participants discontinued therapy than did combination infliximab plus methotrexate participants. Adverse events were common and found in similar numbers among the groups, and were minor in severity. See Table 1 for a summary of participant discontinuations.

Summary of Study 1

This study suggested that despite this population’s failure to control their RA on methotrexate alone, the addition of infliximab provided benefit to the participants, including slowing the progression of their joint damage in both doses and interval groups. Adverse events were seen in all therapy groups, and were mostly minor. Some serious adverse events developed, most notably in the methotrexate-only group, and included bacterial infections, cellulitis, fungal infection, herpes zoster, peritonitis, and tuberculosis. While some cancers occurred mostly in the higher-dose infliximab plus methotrexate group, the frequency was not different from expected values predicted from the Surveillance, Epidemiology and End Results database. There were eight deaths in this trial, three in the methotrexate-alone group (three percent) and five in the infliximab groups (one percent). These deaths were not attributed to the therapy these participants were receiving or their side effects.

There was significantly more joint damage in the group given methotrexate-alone than in the infliximab plus methotrexate groups. At the conclusion of this trial (54 weeks) the infliximab plus methotrexate groups had significantly better radiographic scores concerning their joint damage and progression (39 to 55 percent versus 14 percent). Infliximab plus methotrexate therapy was effective and yielded improvement regardless of the existing damage at baseline, arresting progression and improving functional test scores.

Overall, infliximab plus methotrexate was well tolerated and achieved a sustained benefit by reducing the signs and symptoms of RA over those results using methotrexate therapy alone. Furthermore, quality of life was positively impacted in these patients, as was joint damage. Joint damage increased in the methotrexate alone group, but did not increase in the infliximab plus methotrexate groups. The researchers concluded that infliximab plus methotrexate therapy provided a definite clinical benefit that stopped, and possibly reversed, the joint damage seen in this population.

Click on the link at left to go to your desired page: Introduction Page 2 Page 3 Study 1 Study 2 Conclusion Post-Test

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