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Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
  8. APPENDIX A: THE START STUDY GROUP

Objective

To assess the risk of serious infections following 22 weeks of infliximab therapy, and to further characterize the safety profile of infliximab in combination with background treatments during 1 year in patients with rheumatoid arthritis (RA) with various comorbidities.

Methods

Patients with active RA despite receiving methotrexate (MTX) were randomly assigned to receive infusions of placebo (group 1, n = 363), 3 mg/kg infliximab (group 2, n = 360), or 10 mg/kg infliximab (group 3, n = 361) at weeks 0, 2, 6, and 14. At week 22, patients in placebo group 1 began receiving 3 mg/kg infliximab, and patients in group 3 continued to receive an infliximab dose of 10 mg/kg. Patients in group 2 who failed to meet predefined response criteria received increasing doses of infliximab in increments of 1.5 mg/kg.

Results

At week 22, the relative risk of developing serious infections in groups 2 and 3, compared with group 1, was 1.0 (95% confidence interval [95% CI] 0.3–3.1, P = 0.995) and 3.1 (95% CI 1.2–7.9, P = 0.013), respectively. The incidence of serious adverse events was 7.8% in groups 2 and 3 compared with 7.5% in group 1. From week 22 to week 54, 11.8%, 9.9%, and 10.3% of patients in groups 1, 2, and 3, respectively, reported occurrences of serious adverse events. Through week 54, 1 patient in group 1, 2 patients in group 2, and 4 patients in group 3 developed active tuberculosis.

Conclusion

The risk of serious infections in patients receiving the approved infliximab dose of 3 mg/kg plus MTX was similar to that in patients receiving MTX alone. Patients receiving the unapproved induction regimen of 10 mg/kg infliximab plus MTX followed by a 10 mg/kg maintenance regimen had an increased risk of serious infections through week 22.

The development of anti–tumor necrosis factor α (anti-TNFα) therapy has been a major advance in the treatment of patients with rheumatoid arthritis (RA) (1). Infliximab is a monoclonal antibody specific for TNFα that, when administered in combination with methotrexate (MTX), has been shown to be effective in treating patients with active RA. In the Anti–Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy (ATTRACT) study, repeated treatment with 3 mg/kg or 10 mg/kg infliximab was more effective than MTX alone in reducing the signs and symptoms of RA, inhibiting the progression of structural damage, and improving physical function and quality of life (2–4).

The results of the ATTRACT study also showed that infliximab was well tolerated by most patients who participated in the trial. After 2 years of treatment, similar proportions of patients who received MTX alone (33%) and infliximab plus MTX (29%) reported experiencing serious adverse events, with serious infections developing in 13% and 12% of patients, respectively. However, the ATTRACT study cohort consisted of a select population of 428 patients ages ≤75 years who were not receiving disease-modifying antirheumatic drugs (DMARDs) other than MTX. Furthermore, patients with significant comorbidities, such as renal, hepatic, hematologic, gastrointestinal, endocrine, pulmonary, cardiac, neurologic, or cerebral disease, were excluded from the ATTRACT study. In actual clinical practice, rheumatologists often encounter such patients.

The present study was therefore undertaken to better characterize the safety profile of infliximab in combination with MTX in a population of RA patients who were not highly selected, including those who may have existing comorbidities or may be receiving concomitant medications. The primary objective of this study was to assess the risk of serious infections within the first 22 weeks of treatment in patients who received induction and maintenance regimens of infliximab at a dose of 3 mg/kg or 10 mg/kg. In addition, the effect of escalating doses in those patients who exhibited an incomplete response to the lowest approved dose, 3 mg/kg, was evaluated.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
  8. APPENDIX A: THE START STUDY GROUP

Patients.

The first patient was enrolled in the Safety Trial for Rheumatoid Arthritis with Remicade (infliximab) Therapy (START) study (see Appendix A) in September 2001, and the last patient completed the study in November 2003. Adults were considered eligible for the study if they had a diagnosis of RA according to the revised criteria of the American College of Rheumatology (ACR; formerly, the American Rheumatism Association) (5), and had active disease despite receiving MTX; patients may or may not have been treated with other concomitant DMARDs. Active RA was defined as the presence of 6 swollen joints and 6 tender joints. At screening, patients were required to have a chest radiograph that showed no evidence of malignancy, infection, fibrosis, or active tuberculosis. Patients were excluded from the study if they had opportunistic infections, serious infections during the 2 months prior to screening, known human immunodeficiency virus infection, active tuberculosis or history of active tuberculosis with inadequate documentation of treatment, evidence of latent tuberculosis (according to a positive finding on the purified protein derivative of tuberculin [PPD] test in the US, and as defined by local guidelines outside the US) and an inability to receive prophylaxis with isoniazid, a history of lymphoproliferative disease or malignancy, or a diagnosis of congestive heart failure.

All patients must have been receiving MTX for at least 3 months prior to randomization. The MTX dose must have been stable for at least 4 weeks prior to randomization. Patients were permitted to continue receiving stable doses (for at least 4 weeks prior to randomization) of ongoing antirheumatic therapy, including the following medications: chloroquine, azathioprine, penicillamine, oral or intramuscular gold, hydroxychloroquine, sulfasalazine, leflunomide, cyclosporine, oral corticosteroids, or nonsteroidal antiinflammatory drugs. Patients were excluded from the study if they had been treated with an investigational drug (within 3 months or 5 half-lives from the time of screening, whichever was greater), with cyclophosphamide, nitrogen mustard, chlorambucil, or other alkylating agents, with more than 5 mg/kg of cyclosporine, or with any approved or investigational biologic agent (including infliximab) at any time prior to the study, with the exception of approved vaccines for the purpose of immunization.

Study agent and design.

Both infliximab and placebo were supplied as sterile, white, lyophilized powders in single-use 20-ml vials. Patients were randomly assigned to receive infusions of placebo (group 1), 3 mg/kg infliximab (group 2), or 10 mg/kg infliximab (group 3) at weeks 0, 2, 6, and 14. At week 22, patients in group 1 crossed over from the placebo group to receive 3 mg/kg infliximab at weeks 22, 26, and 30, followed by infusions every 8 weeks through week 46. Patients in group 2 received infusions of at least 3 mg/kg infliximab every 8 weeks from week 22 through week 46, with an additional infusion of placebo at week 26 to maintain the treatment blind. Beginning at week 22, patients in group 2 received a dose increase in increments of 1.5 mg/kg if their combined tender joint count (TJC) and swollen joint count (SJC) was above the threshold of response (the combined TJC and SJC value that would constitute a 20% improvement from baseline) or above the threshold of flare (the combined TJC and SJC value that would constitute a 50% worsening in the improvement from baseline for those patients whose combined TJC and SJC value was below the threshold of response). Patients were evaluated for the possibility of dose escalations at weeks 22, 30, 38, and 46. Patients in group 3 continued to receive infusions of 10 mg/kg infliximab every 8 weeks through week 46 without any dose adjustment, with an infusion of placebo at week 26 to maintain the treatment blind. All patients continued to receive stable doses of MTX (up to 25 mg/week) and other study-approved antirheumatic drugs throughout the study.

Patients were assigned to the treatment groups using adaptive allocation, with stratification according to the investigational site and concomitant oral corticosteroid use at baseline (none, up to and including 15 mg/day, or more than 15 mg/day of prednisone equivalent). Patients, investigators, and other study personnel, except for pharmacists, were blinded to the study treatment assignments.

The study was conducted in accordance with the Declaration of Helsinki, US Food and Drug Administration regulations, and the International Conference on Harmonization guidelines. All patients provided written informed consent. The protocol and informed consent form were reviewed and approved by each site's institutional review board or ethics committee.

Evaluations.

Safety evaluations included assessments of adverse events, measurements of vital signs, and the results of routine laboratory tests. A serious infection was defined as any infection identified by the investigator on the basis of clinical judgment or the results of culture, microscopy, serology, biopsy, or imaging that also met the definition of a serious adverse event. A serious adverse event (as defined by the International Conference on Harmonization guidelines) was any adverse event that resulted in death, was life threatening, resulted in hospitalization or prolongation of hospitalization, caused persistent or substantial disability, or resulted in a congenital anomaly or birth defect. Any medical event could have been designated as serious when, based on appropriate medical judgment, it was deemed to potentially have jeopardized the patient or required medical or surgical intervention to prevent one of the outcomes listed above. Adverse events were coded using the World Health Organization Adverse Reaction Term dictionary.

Clinical response was evaluated at baseline and at weeks 0, 2, 6, 14, and 22, using the ACR criteria for an improvement response (6). Sixty-eight joints were evaluated for tenderness, and 66 joints were evaluated for swelling. From week 22 through the end of the study, the TJCs and SJCs were used to determine the need for dose escalation in group 2, as described above, and to assess the clinical response in all groups. Disease activity at week 22 was assessed using the Disease Activity Score in 28 joints (DAS28). Disease remission was defined as a DAS28 of less than 2.6. Serum infliximab concentrations and the presence of antibodies to infliximab, antinuclear antibodies (ANAs), and antibodies to double-stranded DNA (anti-dsDNA) in patients positive for ANAs were also evaluated, using previously described protocols (7–11).

Statistical analysis.

A 1-sided equivalence test model supported a sample size of 334 patients in the placebo group and 666 patients evenly distributed in the 2 infliximab groups. Thus, with 1,000 patients, the study had ∼80% power, at a 5% significance level, to rule out a 2-fold increase in serious infections based on the assumption that the rates are the same in the placebo group and the combined infliximab group. The presumed rate of infection for the placebo group was 6%, which was the rate reported in patients receiving placebo plus MTX for 30 weeks in a previous trial (2).

The primary end point of the study was the proportion of patients who reported experiencing a serious infection within the first 22 weeks after initiating therapy. The Mantel-Haenszel chi-square test, stratified by baseline corticosteroid use (no corticosteroid use or any corticosteroid use), was used to analyze the data for serious infections. Other categorical data were analyzed using the chi-square test. Continuous variables were compared using an analysis of variance on the van der Waerden normal scores. All statistical tests were 2-sided, with α = 0.05.

Data on all patients who received at least 1 infusion of study medication were included in the safety analysis, including the primary end point analysis, and were included in the treatment group that most closely corresponded to the infliximab dosage actually received. All efficacy analyses were performed using the intention-to-treat convention. Prior to week 22, patients who began a new DMARD or corticosteroid, had the dose of a DMARD or corticosteroid increased above the baseline level, or received corticosteroid injections in more than 2 sites were considered to be nonresponders in the efficacy analysis at week 22. For patients who had a joint injection or a therapeutic surgical procedure, the affected joints were counted as both tender and swollen from the date of the procedure onward in the efficacy analysis. However, the procedure did not affect the clinical evaluation of the joint for determination of dose escalation. The last observation was carried forward for missing data points.

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
  8. APPENDIX A: THE START STUDY GROUP

Integrity of data.

To ensure the integrity of the data set, efficacy and quality of life data from 1 site (including 5 patients in the placebo group, 6 patients in the 3 mg/kg infliximab group, and 7 patients in the 10 mg/kg infliximab group) were excluded from the analysis. Sensitivity analyses (results not shown) indicated that the inclusion of these patients would not have significantly changed the efficacy and quality of life results. All safety and study population analyses, except for summaries using efficacy data (e.g., baseline efficacy parameters), included data from all of the study sites.

Patient disposition and baseline characteristics.

The study population was typical of patients with moderate-to-severe RA. Most patients were women (80.4%), and the median age was 52.0 years (interquartile range [IQR] 44–61 years). The median score on the Health Assessment Questionnaire (12) at baseline was 1.5 (IQR 1–2), indicating that most patients had moderate-to-severe disability. Patients generally had established disease, with a median duration of 7.5 years (IQR 3–15 years) since receiving a diagnosis of RA. The median baseline C-reactive protein level was 1.5 mg/dl (IQR 1–3 mg/dl).

The treatment groups were well matched with regard to the patients' baseline characteristics (Table 1). Patients in group 1 (receiving placebo plus MTX) had a numerically longer disease duration (a median of 8.4 years) than did those in group 2 (receiving 3 mg/kg infliximab) and group 3 (receiving 10 mg/kg infliximab) (median disease durations of 7.8 years and 6.3 years, respectively); however, this difference between the treatment groups was not statistically significant (P = 0.083). Diseases that could increase the risk of infection included chronic renal infection (0.1%), chronic sinusitis (1.3%), osteomyelitis (0.1%), chronic chest infection with bronchiectasis (0.4%), diabetes (5.4%), and chronic renal failure (0.2%), and were equally distributed among the treatment groups (8.0%, 8.1%, and 5.5% had these diseases in treatment groups 1, 2, and 3, respectively).

Table 1. Baseline characteristics of the study patients*
CharacteristicPlacebo + MTXInfliximab + MTX
3 mg/kg10 mg/kg
  • *

    Except where indicated otherwise, values are the median (interquartile range). MTX = methotrexate; VAS = visual analog scale; CRP = C-reactive protein; HAQ = Health Assessment Questionnaire; SF-36 = Short Form 36; DMARDs = disease-modifying antirheumatic drugs; NSAIDs = nonsteroidal antiinflammatory drugs.

  • Possible conditions included chronic renal infection (0.1%), chronic sinusitis (1.3%), osteomyelitis (0.1%), chronic chest infection with bronchiectasis (0.4%), diabetes (5.4%), and chronic renal failure (0.2%). Data on other possible conditions that may predispose a patient to infection were not collected.

  • Dosages are based on the prednisone equivalent.

No. of patients randomized363360361
Sex, no. (%) women302 (83.2)288 (80.0)281 (77.8)
Age, years52.0 (44–61)53.0 (45–61)52.0 (43–60)
Disease duration, years8.4 (4–15)7.8 (3–15)6.3 (3–14)
Concomitant conditions predisposing to infection, no. (%)29 (8.0)29 (8.1)20 (5.5)
Rheumatoid factor positive, no. (%)284 (80.7)293 (82.8)271 (76.8)
No. of swollen joints (of 66)15 (10–21)15 (11–21)15 (10–21)
No. of tender joints (of 68)22 (15–32)22 (15–31)22 (15–30)
Pain on 0–10-cm VAS5.9 (5–7)6.1 (5–8)5.9 (4–7)
Physician's global assessment on 0–10-cm VAS6.3 (5–7)6.2 (5–7)6.2 (5–7)
Patient's global assessment on 0–10-cm VAS5.7 (4–7)5.6 (5–7)5.7 (4–7)
CRP, mg/dl1.2 (1–3)1.6 (1–3)1.6 (1–3)
HAQ disability index (scale 0–3)1.5 (1–2)1.5 (1–2)1.5 (1–2)
SF-36   
 Physical component summary scale (scale 0–100)29.2 (24–35)29.1 (24–34)29.2 (24–35)
 Mental component summary scale (scale 0–100)44.7 (36–54)45.0 (35–54)45.7 (36–55)
DMARDs, no. (%)   
 MTX only254 (70.0)255 (70.8)252 (69.8)
 MTX + 1 other92 (25.3)88 (24.4)90 (24.9)
 MTX + 2 or more others16 (4.4)17 (4.7)19 (5.3)
Weekly MTX dose, mg15.0 (10–15)15.0 (10–18)15.0 (10–18)
Oral corticosteroids, no. (%)   
 None148 (40.8)147 (40.8)148 (41)
 ≤5 mg/day107 (29.5)125 (34.7)117 (32.4)
 >5 and ≤10 mg/day91 (25.1)74 (20.6)85 (23.6)
 >10 mg/day16 (4.4)14 (3.9)11 (3.1)
NSAIDs, no. (%)143 (39.4)156 (43.3)149 (41.3)
Narcotics/opioid analgesics, no. (%)22 (6.1)21 (5.8)24 (6.6)

Overall, 1,084 patients were randomly assigned to a treatment group, as shown in Figure 1. Two patients were assigned to group 1 (placebo plus MTX) but did not receive treatment (1 patient withdrew consent, and 1 patient was lost to followup). By week 22, 23 patients (6.3%) in group 1, 26 patients (7.2%) in group 2, and 32 patients (8.9%) in group 3 had discontinued treatment. From week 22 to week 54, similar numbers of patients in each group discontinued treatment (36 [9.9%], 33 [9.2%], and 33 [9.1%] in groups 1, 2, and 3, respectively). Before week 22, treatment was discontinued because of the occurrence of serious infections in 2 patients in group 1, 3 patients in group 2, and 9 patients in group 3. After week 22, 3 patients in group 1, 1 patient in group 2, and 6 patients in group 3 discontinued treatment because of serious infections.

thumbnail image

Figure 1. Randomization scheme and distribution of patients in the safety study of infliximab. All patients received concomitant methotrexate (MTX).

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The majority of patients were from North America (130 patients in the placebo group and 262 patients in the infliximab groups combined) and Europe (116 in the placebo group and 233 patients in the infliximab groups combined). However, patients from Australia and New Zealand (48 patients in the placebo group and 97 patients in the infliximab groups combined, respectively) and Argentina (67 and 129 patients, respectively) were also enrolled.

Occurrence of serious infections as primary end point through week 22.

The primary study end point was the occurrence of a serious infection within the first 22 weeks after initiating therapy. At week 22, the relative risk (compared with the placebo plus MTX group) of developing a serious infection, stratified by corticosteroid use, was 2.0 (95% confidence interval [95% CI] 0.8–5.0, P = 0.116) in the combined group of patients receiving infliximab plus MTX. In patients treated with 3 mg/kg infliximab plus MTX up to week 22, the relative risk of serious infection was 1.0 (95% CI 0.3–3.1, P = 0.995), and in those receiving 10 mg/kg infliximab plus MTX, the relative risk was 3.1 (95% CI 1.2–7.9, P = 0.013). Overall, 6 patients (1.7%) in the placebo plus MTX group, 6 patients (1.7%) in the 3 mg/kg infliximab group, and 18 patients (5.0%) in the 10 mg/kg infliximab group reported developing serious infections through week 22. The most common serious infections reported by patients in the infliximab plus MTX groups were pneumonia (7 patients), tuberculosis (4 patients), cellulitis (2 patients), and urinary tract infection (2 patients) (Table 2). In the placebo plus MTX group, the most common serious infection was bronchitis (2 patients). In addition, 1 patient receiving placebo plus MTX had newly detected latent tuberculosis.

Table 2. Serious infections through week 22*
CategoryPlacebo + MTXInfliximab + MTX
3 mg/kg10 mg/kgCombined
  • *

    Except where indicated otherwise, values are the number (%) of patients. MTX = methotrexate.

  • Verbatim term: cellulitis right upper arm secondary to intravenous line.

No. of patients treated361360361721
Weeks of followup, mean21.721.921.721.8
Weeks of treatment, mean13.613.613.313.5
Patients with ≥1 serious infection6 (1.7)6 (1.7)18 (5.0)24 (3.3)
Serious infections reported    
 Pneumonia0 (0.0)3 (0.8)4 (1.1)7 (1.0)
 Active tuberculosis0 (0.0)0 (0.0)3 (0.8)3 (0.4)
 Newly detected latent tuberculosis1 (0.3)1 (0.3)0 (0.0)1 (0.1)
 Cellulitis0 (0.0)1 (0.3)1 (0.3)2 (0.3)
 Urinary tract infection0 (0.0)0 (0.0)2 (0.6)2 (0.3)
 Bronchitis2 (0.6)1 (0.3)0 (0.0)1 (0.1)
 Corneal ulceration0 (0.0)0 (0.0)1 (0.3)1 (0.1)
 Viral infection0 (0.0)0 (0.0)1 (0.3)1 (0.1)
 Influenza0 (0.0)0 (0.0)1 (0.3)1 (0.1)
 Injection site inflammation0 (0.0)0 (0.0)1 (0.3)1 (0.1)
 Otitis media0 (0.0)0 (0.0)1 (0.3)1 (0.1)
 Pleurisy0 (0.0)0 (0.0)1 (0.3)1 (0.1)
 Pneumocystis carinii infection0 (0.0)0 (0.0)1 (0.3)1 (0.1)
 Sepsis0 (0.0)0 (0.0)1 (0.3)1 (0.1)
 Sinusitis0 (0.0)0 (0.0)1 (0.3)1 (0.1)
 Septic arthritis1 (0.3)0 (0.0)0 (0.0)0 (0.0)
 Diverticulitis1 (0.3)0 (0.0)0 (0.0)0 (0.0)
 Pyelonephritis1 (0.3)0 (0.0)0 (0.0)0 (0.0)

The relative risk of serious infections among the patients in the combined infliximab plus MTX group compared with the placebo plus MTX group was similar in those from North America (relative risk 3.5, 95% CI 0.4–28.8, P = 0.212), Europe (relative risk 3.4, 95% CI 0.7–15.1, P = 0.095), and Australia/New Zealand (relative risk 1.7, 95% CI 0.2–15.9, P = 0.641). The relative risk of serious infections in patients from Argentina was lower (relative risk 0.3, 95% CI 0.02–2.9) than that in patients from the other countries (P = 0.236).

Efficacy results at week 22.

Patients receiving infliximab showed significant improvement in the signs and symptoms of RA, as assessed by the ACR response criteria. At week 22, 58% of patients in group 2 and 61% of patients in group 3 achieved a 20% improvement response (ACR20), compared with 26% of patients in group 1 (P < 0.0001) (Table 3). Furthermore, significantly more patients in the infliximab plus MTX groups exhibited an ACR50 or ACR70 response as compared with those in the placebo plus MTX group (Table 3).

Table 3. Efficacy results at week 22*
 Placebo + MTXInfliximab + MTX
3 mg/kg10 mg/kgCombined
  • *

    MTX = methotrexate; ACR = American College of Rheumatology; ACR20 = ACR 20% improvement criteria; DAS28 = Disease Activity Score in 28 joints.

ACR response, no. (%)    
 ACR2087 (25.5)199 (58.0)205 (61.0)404 (59.5)
  P versus placebo <0.001<0.001<0.001
 ACR5033 (9.7)110 (32.1)119 (35.4)229 (33.7)
  P versus placebo <0.001<0.001<0.001
 ACR7016 (4.7)48 (14.0)54 (16.1)102 (15.0)
  P versus placebo <0.001<0.001<0.001
DAS28 response    
 Mean ± SD DAS284.4 ± 1.43.5 ± 1.43.3 ± 1.33.4 ± 1.3
  P versus placebo <0.001<0.001<0.001
 Remission (DAS28 <2.6), no. (%)48 (14)106 (31)110 (32)216 (32)
  P versus placebo <0.001<0.001<0.001
 High disease activity (DAS28 >5.1), no. (%)110 (33)41 (12)35 (10)76 (11)
  P versus placebo <0.001<0.001<0.001
 Good or moderate response, no. (%)146 (44)250 (75)263 (79)513 (77)
  P versus placebo <0.001<0.001<0.001

At baseline, the mean DAS28 was 5.1, with 52% of patients in the infliximab groups and 48% of patients in the placebo group having a high level of disease activity (DAS28 >5.1). At week 22, the mean DAS28 in patients receiving infliximab plus MTX was significantly lower than that in patients receiving placebo plus MTX (P < 0.001) (Table 3). Furthermore, 31% of patients in group 2 and 32% of patients in group 3 achieved remission compared with 14% of patients in group 1 (P < 0.001).

Dose escalation.

Of the 334 patients who entered the dose-escalation phase of the study, 110 patients (32.9%) received a dose escalation because they did not meet the criteria for response at week 22 or because they initially met the response criteria at week 22 but later met the criteria for a disease flare. Sixty-seven patients (20.1%) received 1 dose increase for a total dose of 4.5 mg/kg, 23 patients (6.9%) received 2 increases for a total dose of 6.0 mg/kg, 13 patients (3.9%) received 3 increases for a total dose of 7.5 mg/kg, and 7 patients (2.1%) received 4 increases for a total dose of 9 mg/kg, the latter being the maximum allowed by the study protocol.

Improved efficacy was observed in the patients in group 2 who received dose escalations (13). Nevertheless, patients in group 2 who continued to receive 3 mg/kg infliximab in combination with MTX had similar frequencies of infections, serious infections, or other adverse events compared with those who received the dose escalations. Of the 110 patients in group 2 who received a dose escalation, 94 (85%) reported experiencing an adverse event, 19 (17%) reported experiencing a serious adverse event, 57 (52%) reported developing an infection, and 2 (2%) reported developing a serious infection between baseline and week 54. Of the 244 patients in group 2 who did not receive a dose escalation, 211 (86%) reported experiencing an adverse event, 39 (16%) reported experiencing a serious adverse event, 119 (49%) reported developing an infection, and 11 (5%) reported developing a serious infection between baseline and week 54. The mean duration of treatment was 46.2 weeks for patients with a dose escalation and 46.3 weeks for patients without a dose escalation.

Adverse events.

By week 22, adverse events had been reported by 239 patients (66.2%) receiving placebo plus MTX, 251 patients (69.7%) receiving 3 mg/kg infliximab plus MTX, and 261 patients (72.3%) receiving 10 mg/kg infliximab plus MTX (Table 4). The most frequently reported adverse events through week 22 were upper respiratory tract infection, headache, nausea, and pharyngitis, all of which were reported to occur in at least 4.7% of patients receiving infliximab plus MTX (Table 4). The adverse events that were reported in at least 2% of patients receiving infliximab plus MTX while occurring at a rate more than twice that among patients receiving placebo plus MTX were rash (4.6% versus 1.7%, respectively) and pruritus (2.4% versus 1.1%, respectively). The adverse events that were reported in at least 2% of patients receiving placebo plus MTX while occurring at more than twice the rate of that in patients receiving infliximab plus MTX were involuntary muscle contractions (2.2% versus 0.7%, respectively), pain (8.6% versus 3.5%, respectively), and worsening of RA (8.0% versus 2.9%, respectively). The overall rates of serious adverse events through week 22 were similar between the treatment groups (Table 4).

Table 4. Summary of most frequent adverse events and serious adverse events reported by infliximab-treated patients (3 mg/kg and 10 mg/kg) through week 22*
CategoryPlacebo + MTXInfliximab + MTX
3 mg/kg10 mg/kgCombined
  • *

    Values are the number (%) of patients. MTX = methotrexate; ALT = alanine aminotransferase.

Patients with ≥1 adverse event239 (66.2)251 (69.7)261 (72.3)512 (71.0)
Adverse events reported by ≥4% of patients in combined infliximab group    
 Upper respiratory tract infection38 (10.5)35 (9.7)43 (11.9)78 (10.8)
 Headache22 (6.1)35 (9.7)37 (10.2)72 (10.0)
 Nausea29 (8.0)23 (6.4)23 (6.4)46 (6.4)
 Pharyngitis12 (3.3)11 (3.1)23 (6.4)34 (4.7)
 Rash6 (1.7)17 (4.7)16 (4.4)33 (4.6)
 Diarrhea12 (3.3)9 (2.5)23 (6.4)32 (4.4)
 ALT level increased10 (2.8)13 (3.6)19 (5.3)32 (4.4)
 Hypertension12 (3.3)13 (3.6)18 (5.0)31 (4.3)
 Sinusitis14 (3.9)13 (3.6)18 (5.0)31 (4.3)
 Coughing10 (2.8)14 (3.9)16 (4.4)30 (4.2)
Patients with ≥1 serious adverse event27 (7.5)28 (7.8)27 (7.5)55 (7.8)
Serious adverse events reported by ≥2 patients in combined infliximab group    
 Pneumonia0 (0.0)2 (0.6)4 (1.1)6 (0.8)
 Active tuberculosis0 (0.0)0 (0.0)3 (0.8)3 (0.4)
 Cellulitis0 (0.0)1 (0.3)1 (0.3)2 (0.3)
 Fever1 (0.3)0 (0.0)2 (0.6)2 (0.3)
 Chest pain0 (0.0)1 (0.3)1 (0.3)2 (0.3)
 Nausea0 (0.0)0 (0.0)2 (0.6)2 (0.3)
 Vomiting0 (0.0)0 (0.0)2 (0.6)2 (0.3)
 Bone development abnormality0 (0.0)0 (0.0)2 (0.6)2 (0.3)
 Osteoarthritis1 (0.3)2 (0.6)0 (0.0)2 (0.3)
 Cardiac failure0 (0.0)1 (0.3)1 (0.3)2 (0.3)
 Myocardial infarction0 (0.0)1 (0.3)1 (0.3)2 (0.3)
 Uterine fibroid0 (0.0)2 (0.6)0 (0.0)2 (0.3)
 Urinary tract infection0 (0.0)0 (0.0)2 (0.6)2 (0.3)
 Rheumatoid arthritis4 (1.1)1 (0.3)1 (0.3)2 (0.3)

A summary of adverse events reported in those receiving infliximab plus MTX from week 22 to week 54 is provided in Table 5. The types of adverse events and serious adverse events that occurred during the second phase of the study did not differ substantially from those reported through week 22. The most common serious infections between week 22 and week 54 were pneumonia, tuberculosis, abscess, urinary tract infection, and pyelonephritis (Table 5).

Table 5. Summary of adverse events from week 22 to week 54*
CategoryInfliximab + MTX
Group 1, 3 mg/kg (n = 338)Group 2, 3–9 mg/kg (n = 334)Group 3, 10 mg/kg (n = 329)
  • *

    Values are the number (%) of patients. MTX = methotrexate.

Any adverse event244 (72.2)234 (70.1)236 (71.7)
Serious adverse event40 (11.8)33 (9.9)34 (10.3)
Any infection110 (32.5)119 (35.6)125 (38.0)
Serious infection12 (3.6)7 (2.1)12 (3.6)
Serious infections in ≥3 patients   
 Pneumonia5 (1.5)3 (0.9)4 (1.2)
 Active tuberculosis1 (0.3)2 (0.6)1 (0.3)
 Abscess1 (0.3)5 (1.5)0 (0.0)
 Pyelonephritis2 (0.6)1 (0.3)0 (0.0)

The overall rates of serious infections between weeks 22 and 54 were similar between the 3 treatment groups. This is attributable to a general decrease in the risk of serious infections over time in patients who received infliximab from baseline to week 54, particularly those in group 3. Eighteen patients in group 3 reported developing serious infections during the first 22 weeks of the study. At this rate, 26 patients with serious infections would have been expected between weeks 22 and 54. However, only 12 patients in group 3 reported serious infections during this period. In group 2, 6 patients reported developing serious infections during the first 22 weeks of the study. Nine patients would have been expected between weeks 22 and 54, but 7 patients in group 2 reported serious infections during this period.

A total of 5 patients died during the study. In group 1 (placebo plus MTX), 1 patient died of septic shock 173 days after the last placebo infusion at week 14. Among patients who received infliximab plus MTX, 1 patient from group 1 died because of a probable cervical subluxation 6 days after the week-38 infliximab infusion (3 mg/kg), 1 patient in group 3 died of a cerebrovascular accident 82 days after the last infliximab infusion (10 mg/kg) at week 46, 1 patient in group 3 died of septic shock 82 days after the last infliximab infusion (10 mg/kg) at week 22, and 1 patient died of tuberculosis 17 days after the week-14 infliximab infusion (10 mg/kg).

In this study, patients received a total of 7,592 infliximab infusions through week 54, of which 195 (2.6%) were associated with an infusion reaction. Typically, infusion reactions were mild or moderate and involved headache, nausea, hypertension, or dizziness. Five infliximab-treated patients reported serious infusion reactions during the study, comprising anaphylactoid reaction (1 patient in group 1 receiving 3 mg/kg, and 1 patient in group 2 receiving 3 mg/kg), allergic reaction (1 patient in group 3 receiving 10 mg/kg), circulatory failure (1 patient in group 2 receiving 3 mg/kg), and infusion syndrome (1 patient in group 3 receiving 10 mg/kg). One patient in group 1 receiving placebo plus MTX developed a gastric ulcer that was discovered within 1 hour of infusion and, therefore, met the predefined criteria for a serious infusion reaction.

Overall, 9 patients reported positivity for tuberculosis through week 54. Two of these cases were newly detected latent tuberculosis (1 patient in group 1 reported newly detected latent tuberculosis 8 days after the week-14 infusion of placebo, and latent tuberculosis was detected in 1 patient in group 2 at 1 day after the week-14 infliximab infusion of 3 mg/kg). These patients were enrolled in the trial using an inappropriate tuberculosis skin test (the tuberculin skin test [TST]). Although they were determined to be negative for tuberculosis by the inappropriate TST, they were found to be positive when retested using an appropriate tuberculosis test (the PPD test). Both of these patients received prophylaxis with isoniazid and did not develop active tuberculosis. Of the remaining 7 cases of tuberculosis, 1 was reported by a patient in group 1 (58 days after receiving the week-30 infliximab infusion of 3 mg/kg), 2 were reported by patients in group 2 receiving 3 mg/kg infliximab (43 days after the week-22 infusion and 51 days after the week-46 infusion, respectively), and 4 were reported by patients in group 3 receiving 10 mg/kg infliximab (63 days after the week-14 infusion, 46 days after the week-6 infusion, 28 days after the week-22 infusion, and 17 days after the week-14 infusion, respectively). Six of the cases of active tuberculosis occurred in Europe, and 1 case occurred in South America. Five of the 7 patients with active tuberculosis had extrapulmonary tuberculosis; the other 2 patients had pulmonary infection.

Before receiving any infusions of study medication, all patients underwent screening for tuberculosis according to local guidelines. All 7 patients who developed active tuberculosis had baseline PPD test results that were negative according to local guidelines. One patient had a PPD test result of 6-mm induration, which was considered to be a negative result according to the local guidelines. However, the patient also had evidence of abnormality on chest radiograph at baseline and did not receive prophylaxis, which was a violation of the study protocol. According to the protocol, patients with a history of active tuberculosis were required to have received a full course of antitubercular therapy 2 years prior to the baseline study visit. Patients with latent tuberculosis at screening were allowed to enter the trial if they also started isoniazid prophylaxis before receiving the first study infusion. Of the 80 patients who received prophylactic treatment for latent tuberculosis, none developed active tuberculosis during the study. Furthermore, none of the 15 patients with a history of appropriately treated active tuberculosis developed active tuberculosis during the study.

A total of 314 patients had a history of receiving the bacilli Calmette-Guérin vaccine. Of these, only 53 patients (16.8%) had a PPD test result at screening that was >5 mm, and only 27 (8.5%) met the criteria for latent tuberculosis by local guidelines (>10 mm on PPD) and received isoniazid prophylaxis. None of these patients had adverse reactions to the PPD test.

A total of 26 patients reported the development of 30 tumors during the trial. Nineteen of the 30 reported malignancies were nonmelanoma skin cancers, benign neoplasms, or carcinoma in situ and were reported by none of the patients receiving placebo (group 1), 5 patients receiving 3 mg/kg infliximab (group 1), 9 patients receiving 3–9 mg/kg infliximab (group 2), and 5 patients receiving 10 mg/kg infliximab (group 3). Nine patients reported having 11 noncutaneous malignancies, which included 1 patient with renal cell carcinoma, leiomyosarcoma, and liposarcoma 22 days after receiving placebo at week 6, 1 patient with prostate carcinoma 55 days after receiving 3 mg/kg infliximab (group 1) at week 38, 1 patient with ovarian carcinoma 49 days after receiving 3 mg/kg infliximab (group 2) at week 38, 1 patient with non-Hodgkin's lymphoma 1 day after receiving 3 mg/kg infliximab (group 2) at week 6, 1 patient with pancreatic cancer 54 days after receiving 3 mg/kg infliximab (group 2) at week 14, 1 patient with carcinoma of the colon 88 days after receiving 4.5 mg/kg infliximab (group 2) at week 38, 1 patient with ovarian cancer 7 days after receiving 3 mg/kg infliximab (group 2) at week 30, 1 patient with squamous cell carcinoma of the lung 80 days after receiving 10 mg/kg infliximab at week 6, and 1 patient with spinocellular carcinoma (pulmonary) 43 days after receiving 10 mg/kg infliximab at week 6. The single case of lymphoma occurred after the week-6 infusion of 3 mg/kg infliximab, and was considered by the investigator to be unrelated to study treatment. None of the other malignancies are considered to be commonly associated with immunosuppressive therapy.

A total of 369 infliximab-treated patients (37.3%) became newly positive for ANAs at some time during the study. Of 169 patients evaluated for anti-dsDNA, 53 patients (31.4%) were found to be newly positive for these antibodies. Four of the patients who tested positive for ANAs and antibodies to dsDNA at some time during the study also reported experiencing adverse events consistent with an autoimmune disorder (1 patient in group 1 had a worsening of lichen planus, and 3 patients in group 3 had lupus syndrome).

Seventy patients (22.2%) in group 1, 74 patients (22.0%) in group 2, and 38 patients (11.4%) in group 3 were found to be positive for antibodies to infliximab at any time during the study through week 54. After the last infusion, 165 patients (52.2%) in group 1, 162 patients (48.2%) in group 2, and 166 patients (50%) in group 3 were found to be negative for antibodies to infliximab. Eighty-one patients (25.6%) in group 1, 100 patients (29.8%) in group 2, and 128 patients (38.6%) in group 3 had detectable levels of infliximab in the serum; therefore, the antibody status for these patients was inconclusive.

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
  8. APPENDIX A: THE START STUDY GROUP

The present study was conducted to further characterize the safety profile of infliximab in patients with RA in the context of a large, international, randomized controlled trial. The study population consisted of patients who are more representative of those encountered in a typical rheumatologist's practice than the study cohorts of previous large, randomized controlled trials of infliximab. Patients receiving stable doses of concomitant DMARDs in addition to MTX were eligible to participate in the study. Only patients with specific comorbidities that were contraindications in the product label were excluded from the study. In fact, patients with conditions that may predispose them to infection, such as diabetes and chronic renal failure, were allowed to participate in the trial. Patients with these and other important comorbidities were excluded from previous large clinical trials of infliximab. Moreover, patients with a history of active tuberculosis that was adequately treated, or those with latent tuberculosis who were willing and able to receive prophylactic treatment, were also allowed to participate in the START study.

The results of this study show that in this patient population, the approved 3 mg/kg dose of infliximab in combination with MTX has an efficacy and safety profile similar to that demonstrated in the ATTRACT cohort. The relative risk of serious infections through week 22 for the 3 mg/kg infliximab plus MTX group compared with the placebo plus MTX group was 1.003 (P = 0.995). The incidence of serious infections was the same between the 3 mg/kg infliximab plus MTX group and the placebo plus MTX group (1.7%). Moreover, the incidences of serious adverse events (7.8% and 7.5%, respectively) and all adverse events (69.7% and 66.2%, respectively) were similar between the 3 mg/kg infliximab plus MTX and placebo plus MTX groups. In the ATTRACT study, the incidence of serious infections at week 30 in the group of patients who received 3 mg/kg infliximab every 8 weeks was 1%, while the incidence of serious adverse events was 9% (2).

In the present study, the relative risk of serious infections at week 22 in patients receiving 10 mg/kg infliximab plus MTX (group 3) was increased relative to that in patients receiving placebo (relative risk 3.1, P = 0.013), with 5.0% of patients reporting a serious infection. This was similar to the rate reported for the corresponding ATTRACT cohort at week 30, in which 6% of patients receiving 10 mg/kg infliximab (every 8 weeks) plus MTX and 6% of patients receiving placebo plus MTX reported a serious infection (2).

Importantly, the dosing regimen assigned to patients in group 3, a 3-dose induction regimen of 10 mg/kg infliximab followed by maintenance dosing every 8 weeks, has not been approved, according to the product labeling for infliximab (Remicade) (14). The product labeling does allow for a regimen consisting of a 3-dose induction of 3 mg/kg infliximab followed by dose increases up to 10 mg/kg for patients who do not adequately respond to the initial dose. This is similar to the regimen evaluated in group 2, in which patients received 3 mg/kg infliximab during the first 22 weeks of the study followed by dose increases up to 9 mg/kg if they met the criteria for nonresponse or disease flare. Dose escalations did not appear to be associated with an increase in the risk of adverse events, including serious infections, relative to the patients in group 2 who did not receive dose escalations. However, these results should be interpreted with caution, because patients were not assigned randomly to receive dose escalations. Further study may be necessary to confirm these results.

The relative risk of serious infections for the combined infliximab group compared with the placebo group was numerically similar between those from North America, those from Europe, and those from Australia/New Zealand, while the risk appeared to be numerically less in those from Argentina. Although noteworthy, this latter finding was not statistically significant and should be interpreted with caution, since the study was not powered to assess the relative risk of serious infection by region.

It is important to note that this study was conducted, in part, to satisfy a regulatory mandate from the US Food and Drug Administration. Thus, regulatory definitions were used to determine whether an adverse event was serious. However, some events that were categorized as serious using the regulatory definition may not have been considered serious by a rheumatologist in normal clinical practice. Clinically relevant serious infections that were reported in this trial were pneumonia, tuberculosis, Pneumocystis carinii pneumonia, sepsis, septic arthritis, pyelonephritis, and diverticulitis.

During this study, active tuberculosis was diagnosed in 7 patients receiving infliximab, and latent tuberculosis was newly detected in 1 patient receiving placebo and 1 patient receiving infliximab. One of the deaths in this study was considered by the investigator to be due to active tuberculosis. All cases of tuberculosis occurred in patients outside of the US. Most of the patients with active tuberculosis had extrapulmonary disease. The infliximab product label includes a warning about tuberculosis and a recommendation to screen patients for tuberculosis prior to initiating infliximab therapy (14). All patients who developed active tuberculosis had negative PPD test results according to local guidelines. All but 1 of these patients also had normal findings on chest radiography at baseline. The development of active tuberculosis was potentially avoidable in the patient who had a PPD test result of 6 mm and a radiographic abnormality at baseline that was misread. It is possible that patients with negative PPD test results who later developed active tuberculosis were anergic. Nevertheless, none of the patients with a history of active tuberculosis or evidence of latent tuberculosis at screening, who were appropriately screened and treated, developed active tuberculosis during the study.

The efficacy results of this trial were also similar to those reported in ATTRACT. Patients receiving infliximab plus MTX had a significant reduction in the signs and symptoms of RA compared with those receiving placebo plus MTX. In addition, significantly more patients in the infliximab groups achieved remission according to the DAS28, compared with those receiving placebo plus MTX. There was no clinically relevant difference in efficacy between the 3 mg/kg and 10 mg/kg infliximab doses. The percentage of patients achieving an ACR20 response at week 22 was 26% in the placebo group, 58% in the 3 mg/kg infliximab plus MTX group, and 61% in the 10 mg/kg infliximab plus MTX group. These response values at week 30 for the corresponding treatment groups in ATTRACT were 21%, 50%, and 52%, respectively (2).

The incidences of adverse events over the course of the 1-year treatment and followup period were consistent with the known safety profile of infliximab. Patients in group 1 crossed over from placebo to receive 3 mg/kg infliximab, while continuing to receive MTX. Although there were slight increases in the incidences of adverse events, serious adverse events, and serious infections in this group after week 22, there was also a longer observation period from week 22 to week 54.

The overall rates of serious infections during the second part of the study were similar between the treatment groups. In a previous study (15), peak serum infliximab concentrations were directly proportional to dose, and among the range of serum infliximab concentrations, the maximum peak concentration increased after each dose of the induction regimen at weeks 0, 2, and 6. In the present START study, high peak serum infliximab concentrations during the induction regimen of 10 mg/kg may have led to the increased risk of serious infections during the first 22 weeks. During the maintenance period, when infusions were administered every 8 weeks, peak serum infliximab concentrations may not have reached the same level as they did during the induction period, and thus the risk of serious infections was reduced. However, other factors may have caused the decreased rate of serious infections after week 22. For example, patients who were vulnerable to infection may have been selected out during the early part of the study.

Several potential limitations of this study should be considered when interpreting the results. First, although the study population was large, it was not powered for detecting rare adverse events or evaluating serious infection rates in subgroups of patients, such as the previously mentioned analysis by region. Second, comorbidity information was collected for only a prespecified list of diseases (see footnote in Table 1). Data for other comorbidities that could increase the risk of infection were not collected. Finally, while the study entry criteria were less selective than those of previous randomized controlled trials of infliximab, the data were collected in the context of a clinical trial in which patients returned at regularly scheduled intervals for study-specific procedures and followup. Patient contact and followup may be different under usual clinical practice. However, regular followup and careful observation by expert clinicians who are knowledgeable about the risks associated with treatment are advisable for any patient who is receiving immunomodulatory therapy.

The results of this large, randomized, controlled trial demonstrate that an induction and maintenance regimen of 3 mg/kg infliximab in combination with MTX was well tolerated in a population of patients representative of those encountered in a typical rheumatology practice. The results also demonstrate that an induction and maintenance regimen of 10 mg/kg infliximab in combination with MTX was associated with an increased risk of serious infections, including tuberculosis. There was no evidence of a corresponding increase in efficacy with the 10 mg/kg induction and maintenance regimen. Therefore, the results of this study suggest that patients with RA should not receive a 10 mg/kg infliximab induction regimen. However, the approved 3 mg/kg infliximab induction regimen with subsequent dose escalation was well tolerated and was not associated with an increased rate of serious infections.

Acknowledgements

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
  8. APPENDIX A: THE START STUDY GROUP

We are grateful to Scott Newcomer, MS, of Centocor, Inc., for his assistance in preparing the manuscript, and Frederick Wolfe, MD, for his expert advice and critical review of the manuscript.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
  8. APPENDIX A: THE START STUDY GROUP
  • 1
    Furst DE, Breedveld FC, Kalden JR, Smolen JS, Burmester GR, Dougados M, et al. Updated consensus statement on biological agents for the treatment of rheumatoid arthritis and other immune mediated inflammatory diseases. Ann Rheum Dis 2003; 62 Suppl II: II219.
  • 2
    Maini R, St Clair EW, Breedveld F, Furst D, Kalden J, Weisman M, et al. Infliximab (chimeric anti-tumour necrosis factor α monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. Lancet 1999; 354: 19329.
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    Lipsky PE, van der Heijde DM, St Clair EW, Furst DE, Breedveld FC, Kalden JR, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. N Engl J Med 2000; 343: 1594602.
  • 4
    Maini RN, Breedveld FC, Kalden JR, Smolen JS, Furst D, Weisman MH, et al. Sustained improvement over two years in physical function, structural damage, and signs and symptoms among patients with rheumatoid arthritis treated with infliximab and methotrexate. Arthritis Rheum 2004; 50: 105165.
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    Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988; 31: 31524.
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    Felson DT, Anderson JJ, Boers M, Bombardier C, Furst D, Goldsmith C, et al. American College of Rheumatology preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum 1995; 38: 72735.
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    Maini RN, Breedveld FC, Kalden JR, Smolen JS, Davis D, Macfarlane JD, et al. Therapeutic efficacy of multiple intravenous infusions of anti–tumor necrosis factor α monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum 1998; 41: 155263.
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    LoBuglio AF, Wheeler RH, Trang J, Haynes A, Rogers K, Harvey EB, et al. Mouse/human chimeric monoclonal antibody in man: kinetics and immune response. Proc Natl Acad Sci U S A 1989; 86: 42204.
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    McCarty GA, Rice JR. Characterization and comparison of commercially available antinuclear antibody kits using single pattern index sera. J Rheumatol 1980; 7: 33947.
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    Crowe W, Kushner I. An immunofluorescent method using Crithidia luciliae to detect antibodies to double-stranded DNA. Arthritis Rheum 1977; 20: 8114.
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    Wold RT, Young FE, Tan EM, Farr RS. Deoxyribonucleic acid antibody: a method to detect its primary interaction with deoxyribonucleic acid. Science 1968; 161: 8067.
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    Fries JF, Spitz PW, Kraines RG, Holman HR. Measurement of patient outcome in arthritis. Arthritis Rheum 1980; 23: 13745.
  • 13
    Westhovens R, Wolfe F, Rahman MU, Han J, Yocum D. Infliximab dose escalation in patients with rheumatoid arthritis: results from the START trial [abstract]. Arthritis Rheum 2004; 50 Suppl 9: S1856.
  • 14
    Remicade [package insert]. Malvern, PA: Centocor; 2004.
  • 15
    St Clair EW, Wagner CL, Fasanmade AA, Wang B, Schaible T, Kavanaugh A, et al. The relationship of serum infliximab concentrations to clinical improvement in rheumatoid arthritis: results from ATTRACT, a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2002; 46: 14519.

APPENDIX A: THE START STUDY GROUP

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
  8. APPENDIX A: THE START STUDY GROUP

In the United States: Daniel Wallace, Los Angeles, CA; Evan Siegel, Wheaton, MD; Michael Burnette, Tampa, FL; Jeffrey Kaine, Sarasota, FL; Joel Kremer, Albany, NY; Margaret Michalska, Chicago, IL; Bernard Rubin, Fort Worth, TX; David Yocum, Tucson, AZ; Arthur Kavanaugh, La Jolla, CA; Eugene Boling, Upland, CA; Charles Ludivico, Bethlehem, PA; Marlin Wenger, Lancaster, PA; Joan Bathon, Baltimore, MD; Stephen Bookbinder, Ocala, FL; Norman Gaylis, Aventura, FL; Jeffrey Poiley, Orlando, FL; Sanford Roth, Phoenix, AZ; Paul Caldron, Paradise Valley, AZ; Frederick Dietz, Rockford, IL; Andrew Baldassare, St. Louis, MO; Justus Fiechtner, Lansing, MI; Gary Fink, North Charleston, SC; Daniel Norden, Norristown, PA; Adam Rosen, Largo, FL; Robert Valente, Lincoln, NE; Sohrab Fallahi, Montgomery, AL; Maria Greenwald, Rancho Mirage, CA; William Shergy, Huntsville, AL; Michael Stack, Indianapolis, IN; Mark Stern, Springfield, IL; Robert Zurier, Worcester, MA; Charles Birbara, Worcester, MA; Joseph Forstot, Boca Raton, FL; Charles Pritchard, Willow Grove, PA; Henry Malin Prupas, Reno, NV; John Harshbarger, Wilmington, NC; Mitchell Lowenstein, Palm Harbor, FL; Kenneth Nies, Torrance, CA; Robert Ettlinger, Tacoma, WA; Jay Scott Toder, Johnston, RI; Sheldon Solomon, Voorhees, NJ; John Condemi, Rochester, NY; Jose Del Giudice, Lubbock, TX. In Canada: Carter Thorne, Newmarket, Ontario; William Bensen, Hamilton, Ontario; Mary Ann Fitzcharles, Montreal, Quebec; Ben Lasko, Toronto, Ontario; Wojciech Olszynski, Saskatoon, Saskatchewan; Kam Shojania, Richmond, British Columbia; Alfred Cividino, Hamilton, Ontario; Rafat Faraawi, Kitchener, Ontario; Tim McCarthy, Winnipeg, Mannitoba. In Belgium: Rene Westhovens, Leuven; Piet Geusens, Diepenbeek; Jean Pierre Devogelaer, Brussels; Anne Peretz, Brussels; Michel Malaise, Liège; Eric Veys, Ghent. In Germany: Jurgen Wollenhaupt, Hamburg; Andrea Rubbert, Koln; Hans-Peter Tony, Wurzburg; Rieke Alten, Berlin; Rolf Walter Hauer, Berlin. In Hungary: Laszlo Hodinka, Budapest; Bela Gomor, Budapest; Antal Insperger, Veszprem. In Finland: Marjatta Leirisalo-Repo, Helsinki; Terhi Uotila, Pikonlinna; Pekka Hannonen, Jyvaskyla. In Spain: Alicia Garcia Lopez, Seville; Luis Carreno Perez, Madrid; Jose Luis Marenco de la Fuente, Seville; Vincente Rodriguez-Valverde, Santander; Jose Andres Roman Ivorra, Valencia. In the United Kingdom: Michael Plant, Middlesborough; Tom Sheeran, Cannock; Phillip Platt, Newcastle Upon Tyne; Bruce Kirkham, London; David Michael Grennan, Lancashire. In Australia: Leslie Barnsley, Concord, New South Wales; Laurence Clemens, Fitzroy, Victoria; Stephen Hall, Malvern, Victoria; Daniel R. Langlands, Nedlands, Western Australia; Graeme Jones, Hobart, Tasmania; Geoffrey McColl, Parkville, Victoria; Kevin Pile, Woodville, South Australia; Phillip Vecchio, Woollongabba, Queensland. In New Zealand: Chula Rajapakse, Lower Hutt; Peter Jones, Rotorua; Hamish Hart, Takapuna; Daniel Ching, Timaru; Nigel Gilchrist, Christchurch; Peter Gow, Auckland. In Argentina: Guillermo Tate, Eduardo Mysler, Cecilia Pisoni, Osvaldo Hubscher, Alicia Eimon, José Maldonado Cocco, and Juan Barreira, Buenos Aires; Alberto Berman, Alberto Spindler, and Eleonora Lucero, Tucumán; Alberto Strusberg, Ana Bertoli, and Gonzalo Fierro, Córdoba; Bernado Pons-Estel, Guillermo A. Berbotto, and Carlos A. Battagliotti, Rosario. In Poland: Marek Brzosko, Szczecin; Stanislaw Sierakowski, Bialystok; Jacek Pazdur, Warsaw; Leszek Szczepanski, Lublin; Jacek Szechinski, Wroclaw; Maria Maciejowska-Roge, Wloszczowa.