Rheumatoid Arthritis: Keenan GF

Maini RN, Breedveld FC, Kalden JR, Smolen JS, Furst D, Weisman MH, St Clair EW, Keenan GF, van der Heijde D, Marsters PA, Lipsky PE, Anonymous00061. · Kennedy Institute of Rheumatology, Hammersmith, London, UK. · Arthritis Rheum. · Pubmed #15077287 links to  free full text

Abstract: OBJECTIVE: To evaluate the efficacy and safety of repeated administration of infliximab plus methotrexate (MTX) over a 2-year period in patients with rheumatoid arthritis (RA) who previously experienced an incomplete response to MTX. METHODS: Four hundred twenty-eight patients were randomly assigned to receive MTX plus placebo or infliximab at a dose of 3 or 10 mg/kg plus MTX for 54 weeks, with an additional year of followup. The protocol was later amended to allow for continued treatment during the second year. Of 259 patients who entered the second year of treatment, 216 continued to receive infliximab plus MTX for 102 weeks. Ninety-four of these 259 patients experienced a gap in therapy of >8 weeks before continuing therapy. Infusions were administered at weeks 0, 2, and 6, followed by treatment every 4 weeks or every 8 weeks (alternating with placebo infusions in the interim 4-week visits) at a dose of 3 or 10 mg/kg for a total of 102 weeks (including the gap in therapy). For safety and efficacy assessments, data on the patients who were randomized to receive treatment, irrespective of whether treatment was administered for 102 weeks, were evaluated using all actual observations available. The efficacy measures included the Health Assessment Questionnaire (HAQ) (physical function), Short Form 36 health survey (SF-36) (health-related quality of life), total radiographic scores (structural damage), and the American College of Rheumatology 20% improvement criteria (ACR20) (signs and symptoms). RESULTS: The infliximab plus MTX regimens resulted in significantly greater improvement in HAQ scores (P < or = 0.006) and SF-36 physical component summary scores (P < or = 0.011) compared with the MTX-only group. There also was stability in the SF-36 mental component summary score among patients who received the infliximab plus MTX regimens. Median changes from baseline to week 102 in the total radiographic score were 4.25 for patients who received the MTX-only regimen and 0.50 for patients who received the infliximab plus MTX regimen. The proportion of patients achieving an ACR20 response at week 102 varied from 40% to 48% for the infliximab plus MTX groups compared with 16% for the MTX-only group. CONCLUSION: Throughout 102 weeks of therapy, infliximab plus MTX provided significant, clinically relevant improvement in physical function and quality of life, accompanied by inhibition of progressive joint damage and sustained improvement in the signs and symptoms of RA among patients who previously had an incomplete response to MTX alone.

Shergy WJ, Isern RA, Cooley DA, Harshbarger JL, Huffstutter JE, Hughes GM, Spencer-Smith EA, Goldman AL, Roth SH, Toder JS, Warner D, Quinn A, Keenan GF, Schaible TF, Anonymous00018. · Centocor Inc., Malvern, Pennsylvania, USA. · J Rheumatol. · Pubmed #11950005 No free full text.

Abstract: OBJECTIVE: To assess the timing of onset of clinical benefit following the initial infusion of infliximab and to obtain additional safety experience of infliximab when given in an office setting to patients with rheumatoid arthritis (RA). In addition, the safety of reducing the infusion time from 2 hours to 1 hour was evaluated. METHODS: Patients (n = 553) with active RA despite receiving methotrexate (MTX) were treated with infliximab 3 mg/kg given over 2 h at baseline (Week 0), and Weeks 2, 6, and 14 in this multicenter open-label trial. Patients continued to receive a stable dose of MTX (> or = 7.5 mg/wk). At selected sites, patients tolerating the first 4 infusions were eligible to receive 2 additional infusions at twice the usual infusion rate (given over 1 h). Patients returned for efficacy assessments at 48 h following the initial infusion and several times throughout study participation. RESULTS: By 48 h following the first infusion, significant (p < 0.001) improvements were observed in duration of morning stiffness (34% mean improvement), physician's global disease assessment scores (30%), patient's global disease assessment scores (25%), and patient's pain assessment scores (30%). By Week 16, 52 to 63% mean improvements in these efficacy variables were observed (p < 0.001), the significant improvement was maintained through the end of study participation in the subset of patients who received the additional 1 h infliximab infusions. Through 16 weeks, 10% (54/553) of patients reported an adverse event associated with at least 1 of the 4 infusion procedures; the majority were mild and transient in nature. In the subset of 197 patients who received 2 additional infusions over 1 h, no increase in the frequency or severity of infusion-related adverse events was observed compared to the 2 h infusion. CONCLUSION: Infliximab administered to patients with RA in an outpatient setting resulted in significant clinical improvement within 48 h that was sustained with additional infusions. Approximately 10% of patients experienced an infusion reaction, highlighting the need for direct supervision over patient treatment. Patients who tolerated infliximab infusions given over 2 h also tolerated a 1 h infusion.

Schiff MH, Hobbs KF, Gensler T, Keenan GF. · Denver Arthritis Clinic, Denver, CO 80230, USA. · Curr Med Res Opin. · Pubmed #17519063 No free full text.

Abstract: OBJECTIVE: To assess how in-office magnetic resonance imaging (MRI) scans of the hand/wrist or feet are utilized in a rheumatology practice to make clinical evaluations regarding therapeutic options for rheumatoid arthritis (RA) patients. METHODS: In a large clinical practice, a retrospective review was conducted on the first 300 RA patients who had office-based MRI scans at baseline. Information was collected on demographics, baseline therapy, and whether any change in therapy occurred at the time of the MRI scans. MR images of the affected wrist were obtained with a low-field strength dedicated extremity unit. RESULTS: Of the 300 patients, 99 patients (33%) had MRIs that exhibited signs of erosions, joint space narrowing, or bone edema. These patients were classified as MRI-positive. The remaining 201 patients (67%) were classified as MRI-negative. A substantial majority (85%) of MRI-positive patients received a change in their therapeutic regimen, compared with only 9.5% of the MRI-negative patients (p < 0.001). In the 84 MRI-positive patients who had their therapy changed, 65% received a new prescription for a biologic or an increase in the dose of their existing biologic and 34% of the MRI-positive patients received a DMARD. In the 19 MRI-negative patients with a therapeutic change, 11% received a biologic agent and 88% received a DMARD. The major limitation of this study is that it was a retrospective analysis and the assessments of MRI findings were qualitative. CONCLUSION: In this large population of RA patients, there was an association between MRI detection of joint space narrowing, erosions, and/or bone edema and change in therapeutic management.

Visvanathan S, Keenan GF, Baker DG, Levinson AI, Wagner CL. · Clinical Pharmacology and Experimental Medicine, Medical Affairs, and Immunology, Centocor Research and Development, Inc., Malvern, Pennsylvania 19355, USA. · J Rheumatol. · Pubmed #17444589 No free full text.

Abstract: OBJECTIVE: We assessed whether the addition of anti-tumor necrosis factor (TNF) agent to methotrexate (MTX) therapy might alter the response of patients with rheumatoid arthritis (RA) to pneumococcal vaccination. METHODS: Seventy patients with early RA (n = 20, 36, and 14 in the infliximab 3 mg/kg plus MTX, infliximab 6 mg/kg plus MTX, and placebo plus MTX groups, respectively) were included in an analysis of patients enrolled in an ASPIRE substudy. Patients received 0.5 ml pneumococcal vaccine (Pneumovax) 34 weeks after initiation of study treatment; patient sera were collected 4 weeks later (week 38). Antibody responses were tested using enzyme immunoassay methods for reactivity to a panel of 12 serotypes of the pneumococcal vaccine. RESULTS: No significant difference in response to Pneumovax was observed between the infliximab plus MTX and placebo plus MTX groups. Roughly 80%-85% of patients responded to at least one serotype; however, only 20%-25% of patients in the different treatment groups responded to at least 6 different serotypes. Comparable proportions of patients in the 3 treatment groups responded to an increasing number (> or = 1 to > or = 6) of different serotypes. Patients < 45 years of age and those receiving oral corticosteroids generally appeared to respond better than those age 45 to 65 years and those not receiving oral corticosteroids. CONCLUSION: All treatment groups in this study had lower responses to vaccine than would be expected in the normal population. However, the addition of the anti-TNF agent infliximab to MTX therapy did not appear to affect the response of patients with RA to pneumococcal vaccination.

Katz JA, Antoni C, Keenan GF, Smith DE, Jacobs SJ, Lichtenstein GR. · Division of Gastroenterology, Case Western Reserve University, Cleveland, Ohio 44106-5066, USA. · Am J Gastroenterol. · Pubmed #15571587 No free full text.

Abstract: OBJECTIVES: Infliximab is approved for the treatment of rheumatoid arthritis (RA) and Crohn's disease (CD). We report the first large series of pregnancy outcomes in women with RA and CD exposed to infliximab. METHODS: The infliximab safety database was queried for all reports of pregnancy. Data were extracted regarding the indication for infliximab, timing of infliximab relative to conception, pregnancy course, and pregnancy outcome. The proportion of live births, miscarriages, and therapeutic terminations for women directly exposed to infliximab before or during confirmed pregnancy were compared to those expected for the general U.S. population of pregnant women and pregnant women with CD not exposed to infliximab. RESULTS: Of the 146 identified pregnancies, 131 involved women exposed directly to infliximab and outcome data were available for 96 of these women. Live births occurred in 67% (64/96), miscarriages in 15% (14/96), and therapeutic termination in 19% (18/96) of the pregnancies directly exposed to infliximab with available outcome data. These results are similar to those expected for the general U.S. population of pregnant women or pregnant women with CD not exposed to infliximab. CONCLUSION: Data from the infliximab safety database suggest that infliximab exposure during pregnancy results in outcomes that do not differ from those in the U.S. population of pregnant women and pregnant women with CD not exposed to infliximab. No increased risk of adverse outcome was detected, however, follow-up of larger numbers of pregnant women exposed to infliximab will be necessary to definitively exclude any fetal risk.