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Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

Objective

Continuous treatment with the anti–tumor necrosis factor α (anti-TNFα) antibody infliximab is efficacious in ankylosing spondylitis (AS), whereas treatment discontinuation results in disease relapse, with variable delay. This study was undertaken to compare the efficacy of continuous treatment with infliximab with that of a treatment regimen adapted to symptom recurrence. Methotrexate (MTX) in combination with infliximab was also tested.

Methods

Patients with active AS were randomly assigned at week 0 to receive infliximab every 6 weeks (continuous treatment) or upon symptom recurrence (on-demand treatment), following infusions at weeks 4, 6, and 10. Patients in the on-demand group were randomly assigned to receive either MTX in combination with infliximab or infliximab alone. Patients were monitored for 1 year. The primary end point was the proportion of patients who met the ASsessment in AS International Working Group criteria for 20% improvement (ASAS20) at week 58.

Results

Of 247 patients, 124 were assigned to receive infliximab every 6 weeks and 123 to receive on-demand treatment. Among the latter, 62 received MTX, and 61 received infliximab alone. A greater proportion of patients receiving infliximab every 6 weeks fulfilled ASAS20 response criteria at week 58 than did patients receiving on-demand treatment (75% versus 46%; P < 0.0001). Patients in the continuous treatment group received more infliximab infusions after week 10 than did those in the on-demand group (mean ± SD 5.8 ± 2.2 versus 3.5 ± 2; P < 0.0001). Addition of MTX did not significantly affect the proportion of patients with an ASAS20 response at week 58, nor the number of infliximab infusions administered.

Conclusion

These findings indicate that continuous treatment of AS with infliximab is more efficacious than on-demand treatment, and that the addition of MTX to infliximab provides no significant benefit.

Ankylosing spondylitis (AS) is the prototypical form of a group of inflammatory rheumatic diseases, the spondylarthritides. It is characterized by the predominance of inflammation in the sacroiliac joints, spine, and anterior chest wall. Involvement of peripheral skeletal sites, consisting of arthritis, dactylitis, and enthesitis, is also frequent, and extraarticular manifestations, such as uveitis, psoriasis, or inflammatory bowel disease (IBD), may develop during the course of AS (1). The genetic predisposition to AS is strong, in large part due to the HLA–B27 allele (2). The burden of AS has recently been recognized as severe, frequently leading to invalidity, work loss, and social impairment (3, 4). There is a need for treatments that are more efficacious than nonsteroidal antiinflammatory drugs (NSAIDs), which have remained the cornerstone of AS treatment until recently (5). The classic disease-modifying antirheumatic drugs (DMARDs), such as sulfasalazine or methotrexate (MTX), which have been proven efficacious in the treatment of rheumatoid arthritis (RA), exhibit at most limited efficacy in axial AS (6).

The monoclonal antibody infliximab belongs to the family of anti–tumor necrosis factor α (anti-TNFα) biologic agents, which have been shown to be remarkably efficacious in the treatment of several disorders, such as RA, IBD, AS, and psoriasis (7). In AS, a dramatic response to an induction regimen consisting of 3 infusions of 5 mg/kg infliximab at weeks 0, 2, and 6, was first reported in open-label trials (8), then formally proven in a 3-month placebo-controlled trial (9). Another trial in AS confirmed the efficacy over placebo of an induction regimen of 5 mg/kg infliximab, followed by maintenance infusions every 6 weeks for 6 months (10). In an open-label extension trial, the initial response was sustained over 3 years in the majority of patients who received maintenance infusions every 6 weeks, whereas discontinuing infliximab predictably resulted in relapse, delay to which varied considerably from patient to patient (8, 11–13).

The approved standard of care for infliximab treatment maintenance in patients with AS is an infusion every 6–8 weeks, but this regimen has not been demonstrated to afford an optimal risk/benefit ratio in purposely designed trials (8, 12, 13). Thus, given the potential morbidity and the heavy cost associated with infliximab treatment, some patients have been treated as their symptoms recur, rather than on a systematic basis. In a 2-year observational study, there was no evidence that systematic treatment provided greater benefit than on-demand treatment (13).

In RA, MTX in combination with infliximab has been shown to improve efficacy and to reduce immunization against the chimeric monoclonal antibody (14). Thus, it is recommended that infliximab be given in association with MTX in patients with RA. In contrast, MTX generally has not been administered concomitantly with infliximab in patients with AS, mostly because of the lack of evidence of the efficacy of MTX for this indication (15). Yet, it is not known if concomitant administration of MTX could enhance the efficacy of infliximab in AS, by preventing immunization against the chimeric antibody for instance.

The primary objective of the present study was to compare 2 methods of treatment maintenance with infliximab in AS, following a standard induction regimen: systematic infusions every 6 weeks versus on-demand infusions. The benefit of adding MTX to infliximab was also evaluated.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

Patients.

Adult patients (18 years of age or older) with a diagnosis of AS were recruited via 32 rheumatology departments in France. To be eligible for the study, patients had to fulfill the clinical part of the modified New York criteria for the diagnosis of AS (16) and have evidence of active inflammation in the 3 months prior to enrollment, demonstrated by ≥1 of the following: a serum C-reactive protein (CRP) level more than twice the upper limit of normal, positive findings on magnetic resonance imaging of the spine or sacroiliac joints, or a vascularized enthesitis shown on power Doppler ultrasound (17). Additional criteria for enrollment were the presence of clinically active axial disease, as defined by a Bath AS Disease Activity Index (BASDAI) (18) score of ≥3 of 10, and a score of ≥3 of 10 for axial pain (second item on the BASDAI). Radiographic evidence of advanced sacroiliitis was not mandatory for enrollment in the study, but grading of radiographic abnormalities in the sacroiliac joints on a pelvic radiograph taken <6 months before enrollment was recorded.

DMARDs, such as sulfasalazine, MTX, hydroxychloroquine, intramuscular gold, thiol compound, cyclosporine, and intravenous bisphosphonate, had to be discontinued ≥4 weeks before enrollment. Dosages of NSAIDs and corticosteroids had to have been stable for ≥4 weeks before enrollment.

A negative pregnancy test result was required for nonmenopausal women, and use of contraception during the study period and for 6 months after the last infusion of infliximab was requested of all patients of childbearing potential. Patients were excluded from the study if they were pregnant, breastfeeding, had been vaccinated with a live organism during the month preceding study entry, had an infection at study entry or had any episode of serious infection during the 3 months prior to study entry, had an active malignancy in the 5 years prior to study entry, were addicted to drugs or alcohol, had severe chronic concomitant disease, had received an investigational drug in the 3 months prior to study entry, or had received any known TNF inhibitor therapy (such as thalidomide, infliximab, or etanercept) in the past.

Study design.

This 1-year, multicenter, prospective, randomized, comparative study was conducted in accordance with the Declaration of Helsinki (1964) and its revision (1975), and was approved by the Institutional Review Board of the Ambroise Paré Hospital (Boulogne-Billancourt, France). Written informed consent was obtained from all patients. At the enrollment visit (week 0), patients were randomly assigned to the continuous treatment group or to the on-demand treatment group. In addition, patients in the on-demand group were randomly allocated to receive infliximab alone or infliximab plus MTX. Randomization was centralized by the coordinating center and communicated to other centers by fax.

Administration of drugs.

All patients were scheduled to receive a loading regimen of infliximab consisting of 3 infusions, given at weeks 4, 6, and 10. Thereafter, patients in the continuous treatment group received infliximab infusions every 6 weeks, until week 52, whereas patients in the on-demand group received supplementary infusions only upon relapse, up to week 54, with a minimum interval of 4 weeks between infusions. For each infusion, infliximab was administered intravenously at a standard dose of 5 mg/kg in 250 ml of 0.9% NaCl, over a 2-hour period. The dose of infliximab was increased to 7.5 mg/kg per infusion in the continuous treatment group, starting not earlier than week 40, for those patients in relapse at 2 consecutive visits. Likewise, the infusion dose was increased to 7.5 mg/kg in the on-demand group, starting no earlier than the fourth on-demand infusion, if relapse occurred as early as 3 weeks after an infusion. In the group receiving MTX, this drug was given orally as a single weekly dose. A starting dose of 2.5 mg of MTX was given 4 weeks before the first infliximab infusion, and then increased weekly by 2.5 mg, up to a maximum dose of 12.5 mg, which was continued throughout the study.

Monitoring of relapse.

Starting at enrollment, all patients were required to call a toll-free automated phone server once every week until completion of the study in order to perform a guided self-evaluation as follows. First, patients gave a positive or negative answer to the following questions: “Since the last connection, do you think that your disease has remained under control?” and “Since the last connection, do you think that your disease has been worsening?” Patients then answered the questions on the French version of the BASDAI, using a numerical rating scale of 0–10. Finally, patients entered a value (from 0–10) corresponding to their global assessment of pain over the previous week. Relapse was defined as a negative answer to the first question, a positive answer to the second question, and either an increase in the BASDAI score of ≥1 of 10, or an increase in patient's assessment of pain of ≥2 of 10, compared with the lowest score reached by that patient since the first infliximab infusion. Whenever relapse was detected ≥4 weeks after the last infusion in the on-demand treatment group, the patient was urged to contact the treating center to schedule an infusion as soon as possible. Notification was also sent to the treating center so that an infusion could be planned for that patient in the coming week.

Efficacy end points.

Patient status was assessed at enrollment (week 0) and at weeks 4, 6, 10, 16, and 58 in all groups. Patients in the continuous treatment group were also assessed at other planned infusion visits, and patients in the on-demand group were assessed at additional infusion visits determined according to relapse.

The following clinical variables were evaluated at each visit: patient's assessment of pain (on a scale of 0–10), patient's global assessment (on a scale of 0–10), BASDAI, the Bath AS Functional Index (BASFI) (19), weight, Schober test, fingers-to-floor distance, occiput-to-wall distance, chest expansion, Westergren erythrocyte sedimentation rate (ESR), and serum CRP level. The Short Form 36 (SF-36) health survey (20) was used to assess quality of life at weeks 0, 16, and 58.

The primary end point was the proportion of patients with an ASsessment in Ankylosing Spondylitis International Working Group 20% response (ASAS20) at week 58 (21). An ASAS20 responder was defined as a patient showing ≥20% improvement from baseline (week 0) and absolute improvement from baseline of ≥1 unit (on a scale of 0–10), in 3 of the following 4 ASAS domains: patient's global assessment, patient's assessment of pain, BASFI, and inflammation (mean of the 2 morning stiffness–related BASDAI score questions); as well as an absence of deterioration from baseline by ≥20% and by ≥1 unit in the fourth domain.

Secondary outcome measures included achievement of an ASAS40 response (22) and achievement of partial remission (21) according to the ASAS definition. The ASAS40 response was computed in a manner similar to that used to compute the ASAS20 response, except that it required improvement of 40% in ≥3 of the 4 ASAS domains, with a positive change of ≥2 units (on a scale of 0–10) in each domain. Absence of deterioration in the remaining domain was required and was defined as for the ASAS20 response. Partial remission has been defined as a value of <2 units (on a scale of 0–10) in each of the 4 ASAS domains (patient's global assessment, pain, BASFI, and inflammation).

Other outcome measures were improvement in independent components of the ASAS response criteria, in the BASDAI, the SF-36, Schober test, fingers-to-floor distance, chest expansion, occiput-to-wall distance, acute-phase reactants (ESR and CRP level), number of infliximab infusions administered after the loading regimen, number of patients requiring an increase in the dose of infliximab, and the areas under the curves (AUCs) for the BASDAI and for patient's assessment of pain recorded on a weekly basis, calculated from week 0 through week 58.

Evaluation of safety.

Patients were monitored for adverse reactions, and their vital signs were monitored during each infusion and for 1 hour afterward. At each visit, patients were asked to describe any side effects, and a peripheral white blood cell count, hemoglobin level, and platelet count were determined. In patients receiving MTX, a peripheral white blood cell count, hemoglobin level, and platelet count were monitored weekly for 3 months and then monthly thereafter. These patients were also monitored on a monthly basis for creatininemia, bilirubinemia, serum aminotransferase levels, and albuminemia.

Statistical analysis.

Sample size determination was based on earlier trials in patients with AS (9, 23). Power calculations indicated that a sample size of 234 patients, with equal allocation to continuous treatment and on-demand treatment groups, provided 80% power to detect a 19% difference in response rate, assuming a response rate of 53% in the continuous treatment group and 34% in the on-demand treatment group and a 10% loss-to-followup rate, and using a 2-sided chi-square test with a 0.05 significance level.

All patients enrolled in the study were included in intent-to-treat analyses of efficacy and safety. The last observation carried forward approach was used to handle missing data. The AUCs of BASDAI and patient's assessment of pain, recorded on a weekly basis, were computed using a trapezoidal rule. Quality of life was assessed in each group using a quality-adjusted time without symptoms and toxicity (Q-TWIST) analysis, as previously described (24, 25), with some modifications to account for the specific purpose of this study. Whatever the length of followup, each patient's health state from week 10 through week 58 was classified as one of the following: time without symptoms and toxicity (TWIST), i.e., low disease symptoms (BASDAI ≤3.5 [26]); discomfort (DIS) related to an infusion (set to 3 days); moderate relapse (REL1; BASDAI 3.5 to ≤5.5); serious relapse (REL2; BASDAI 5.5 to ≤7.5); or very severe relapse (REL3; BASDAI >7.5). The percentage of time that patients experienced each health state was weighted by a utility coefficient (denoted as U), which was arbitrarily defined to account for distinct levels of quality of life relative to TWIST (UTWIST = 1), in the health states DIS (UDIS = 0.75, or 0.5 in case of adverse event related to the infusion), REL1 (UREL1 = 0.90), REL2 (UREL2 = 0.75), and REL3 (UREL3 = 0.50). The Q-TWIST was computed as follows: Q-TWIST = TWIST + UDIS × DIS + UREL1 × REL1 + UREL2 × REL2 + UREL3 × REL3.

Differences between groups were tested using the chi-square test (for categorical data), or Student's unpaired t-test (for numerical data). P values less than 0.05 were considered significant. All statistical analyses were performed using SAS 9.1 (SAS Institute, Cary, NC).

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

Patient characteristics.

Overall, 247 patients with active axial AS were entered into the study between April and October 2003, and randomly assigned to receive infliximab as a continuous treatment (124 patients) or only upon relapse (on-demand treatment; 123 patients), after a standard loading regimen of 3 infusions. In the on-demand treatment group, patients were randomly allocated to receive either infliximab alone (62 patients) or MTX in combination with infliximab (61 patients) throughout the study, starting 4 weeks before the first infusion of infliximab (Figure 1).

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Figure 1. Randomization, reasons for treatment discontinuation, and number of patients who completed the 58-week study of infliximab therapy for ankylosing spondylitis. Of the 247 patients who were initially enrolled, 6 received no infusions of study medication. One hundred seventy-seven patients completed the study protocol. Sixty-four patients discontinued the study, 27 because of adverse events, 13 because of lack of efficacy, and 24 because of personal reasons or noncompliance. Q6 = continuous treatment group (patients received infliximab every 6 weeks); MTX = methotrexate; W0 = week 0.

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Characteristics of the patients at entry were typical of AS (Table 1). Patients had a mean ± SD age of 41.4 ± 11.3 years and a mean ± SD disease duration of 14.9 ± 9.9 years. The majority of the patients were men (76%), most were HLA–B27 positive (80%), and most had advanced radiographic sacroiliitis (79%). The majority had previously received DMARDs (76%), mostly sulfasalazine (70%) or MTX (36%), and were receiving stable doses of NSAIDs at enrollment (82%). They had active axial disease, as shown by a mean ± SD patient's global assessment of 7.4 ± 1.6, a mean ± SD score on the BASDAI of 6.2 ± 1.4, a mean ± SD score of axial pain on the BASDAI of 7.3 ± 1.7, a mean ± SD ESR of 34.3 ± 23.3 mm/hour, and a mean ± SD CRP level of 31 ± 24.5 mg/liter. The treatment groups were well matched with regard to characteristics at baseline (Table 1).

Table 1. Characteristics of the study patients at enrollment, by treatment group*
CharacteristicContinuous treatment (n = 124)On-demand treatment
All (n = 123)Not receiving MTX (n = 61)Receiving MTX (n = 62)
  • *

    Except where indicated otherwise, values are the mean ± SD. No statistically significant between-group differences were found for any of these baseline characteristics by chi-square test (categorical data) or Student's t-test (numerical data). IBD = inflammatory bowel disease; BASDAI = Bath Ankylosing Spondylitis Disease Activity Index; BASFI = Bath Ankylosing Spondylitis Functional Index; SF-36 = Short Form 36; ESR = erythrocyte sedimentation rate; CRP = C-reactive protein.

  • Information on HLA–B27 positivity was available on 115 patients in the continuous treatment group, 52 patients in the on-demand treatment group receiving methotrexate (MTX), and 58 patients in the on-demand treatment group not receiving MTX.

  • Radiographic sacroiliitis of at least grade II bilaterally or grade III unilaterally. Radiographs were available for 118 patients in the continuous treatment group, 54 patients in the on-demand treatment group receiving MTX, and 57 patients in the on-demand treatment group not receiving MTX.

Sex, no. (%) male93 (75)95 (77)45 (74)50 (81)
Age, years41.4 ± 12.341.3 ± 10.340 ± 9.642.7 ± 10.9
Disease duration, years14.6 ± 10.515.1 ± 9.313.8 ± 7.016.4 ± 11.1
HLA–B27 positive, %80818379
Sacroiliitis, %76828183
History of peripheral arthritis, no. (%)73 (59)82 (67)46 (75)36 (58)
History of uveitis, no. (%)33 (27)43 (35)20 (33)23 (37)
History of psoriasis, no. (%)20 (16)13 (11)4 (7)9 (15)
History of IBD, no. (%)12 (10)12 (10)6 (10)6 (10)
Patient's assessment of pain, 0–10 scale6.9 ± 1.96.7 ± 1.86.9 ± 1.66.6 ± 2.0
Patient's global assessment, 0–10 scale7.4 ± 2.97.5 ± 1.57.7 ± 1.67.3 ± 1.4
BASDAI6.2 ± 1.56.2 ± 1.36.1 ± 1.46.3 ± 1.3
BASFI5.4 ± 25.8 ± 1.96.0 ± 1.85.6 ± 1.9
Physical component of the SF-3633 ± 731 ± 732 ± 730 ± 6
Mental component of the SF-3634 ± 1036 ± 1037 ± 1135 ± 9
ESR, mm/hour37 ± 2532 ± 2133 ± 1931 ± 23
CRP, mg/liter33 ± 2729 ± 2131 ± 2228 ± 22
Weight, kg73 ± 1673 ± 1473 ± 1373 ± 14
Schober test, cm2.2 ± 1.52.5 ± 1.52.3 ± 1.42.6 ± 1.7
Fingers-to-floor distance, cm28 ± 1530 ± 1631 ± 1629 ± 17
Occiput-to-wall distance, cm6.2 ± 6.96.1 ± 6.75.9 ± 7.06.3 ± 6.5
Chest expansion, cm3.6 ± 1.93.5 ± 1.93.4 ± 2.03.6 ± 1.8

All except 6 patients received ≥1 infusion of infliximab, and a majority of them (72%) completed the 1-year trial. Reasons for discontinuation are summarized in Figure 1 and were well balanced between treatment groups. The overall rate of weekly calls to the automated phone system throughout the study was 88% of the calls that were expected according to the intent-to-treat analyses. In the on-demand treatment group, 110 patients received ≥1 infusion(s) of infliximab after the loading regimen because of relapses, resulting in 432 on-demand infusions. The delay between decision and execution of on-demand infusion was 4.3 days on average, and ≤7 days in 90% of cases. In this group, only 3 of 85 patients who completed the study (3.5%) did not require any on-demand infusions (1 patient receiving infliximab alone, and 2 receiving infliximab plus MTX).

Efficacy.

At week 58, 93 of 124 patients (75%) in the continuous treatment group were ASAS20 responders, compared with 56 of 123 patients (46%) in the on-demand treatment group (P < 0.0001) (Table 2). Significantly more patients were ASAS40 responders and significantly more patients fulfilled ASAS criteria for partial remission in the continuous treatment group than in the on-demand treatment group (Table 2). In the latter group, proportions of ASAS20 responders, ASAS40 responders, and patients in partial remission did not differ significantly between the group who received MTX and the group who did not (Table 2). A subgroup analysis restricted to patients who fulfilled the modified New York criteria yielded similar results (data not shown).

Table 2. Proportion of patients in whom a response was achieved at week 58 according to the ASAS criteria, by treatment group (intent-to-treat analysis)*
ASAS criteriaContinuous treatment group (n = 124)On-demand treatment group (n = 123)POn-demand treatment group not receiving MTX (n = 62)On-demand treatment group receiving MTX (n = 61)
  • *

    Values are the number (%) of patients who met the criteria. No significant differences were found between the on-demand treatment group not receiving methotrexate (MTX) and the on-demand treatment group receiving MTX. ASAS = ASsessment in Ankylosing Spondylitis; ASAS20 = ASessment in Ankylosing Spondylitis International Working Group criteria for 20% improvement (see Patients and Methods for details).

  • By chi-square test.

ASAS2093 (75)56 (46)<0.000125 (40)31 (51)
ASAS4063 (51)37 (30)0.000915 (24)22 (36)
Partial remission34 (27)9 (7)<0.00013 (5)6 (10)

Besides ASAS criteria, intent-to-treat analysis of most other secondary criteria at week 58 revealed a significantly better response in the continuous treatment group than in the on-demand treatment group, whereas there was no statistically significant difference between patients who did and those who did not receive MTX in the on-demand treatment group (Table 3). A greater increase in weight between enrollment and week 58 was also observed in the continuous treatment group compared with the on-demand treatment group (Table 3).

Table 3. Change in clinical and biologic features from enrollment to week 58, by treatment group (intent-to-treat analysis)*
CriterionContinuous treatment group (n = 124)On-demand treatment group (n = 123)POn-demand treatment group not receiving MTX (n = 62)On-demand treatment group receiving MTX (n = 61)
  • *

    Values are the mean ± SD. No significant differences were found between the on-demand treatment group not receiving MTX and the on-demand treatment group receiving MTX. See Table 1 for definitions.

  • By Student's t-test.

Patient's assessment of pain, 0–10 scale−3.1 ± 2.8−1.4 ± 2.6<0.0001−1.3 ± 2.7−1.6 ± 2.6
Patient's global assessment, 0–10 scale−3.3 ± 2.9−2.0 ± 2.40.0003−2.1 ± 2.4−2.9 ± 2.6
BASDAI−2.9 ± 2.4−1.7 ± 2.0<0.0001−1.8 ± 1.8−1.6 ± 2.1
BASFI−2.4 ± 2.3−1.2 ± 2.0<0.0001−1.0 ± 1.9−1.5 ± 2.0
Physical component of the SF-366.0 ± 9.15.7 ± 8.10.855.8 ± 8.35.7 ± 8.0
Mental component of the SF-367.8 ± 10.24.8 ± 9.40.025.8 ± 10.03.9 ± 8.8
ESR, mm/hour−18.6 ± 24.9−10.4 ± 17.80.003−9.1 ± 17.7−11.7 ± 17.9
CRP, mg/liter−20.2 ± 25.4−8.1 ± 28.00.0004−6.7 ± 30.6−9.4 ± 25.1
Weight, kg2.4 ± 4.60.9 ± 4.20.0090.9 ± 3.90.9 ± 4.5
Schober test, cm0.6 ± 1.10.3 ± 1.50.060.2 ± 1.50.3 ± 1.5
Fingers-to-floor distance, cm−6.7 ± 10.7−2.9 ± 14.50.02−1.6 ± 15.8−4.2 ± 13.0
Occiput-to-wall distance, cm−1.4 ± 3.30 ± 4.40.0060.1 ± 5.0−0.2 ± 3.8
Chest expansion, cm0.7 ± 1.60.7 ± 1.70.960.7 ± 1.70.7 ± 1.7

The AUCs of the weekly BASDAI and patient's assessment of pain were lower in the continuous treatment group than in the on-demand group (mean ± SD 3.5 ± 1.8 versus 4.2 ± 2.1 [P = 0.004] and mean ± SD 4.0 ± 1.8 versus 4.6 ± 2.1 [P = 0.02], respectively). In contrast, the AUCs for these 2 measures did not differ between patients who did and those who did not receive MTX in the on-demand group (mean ± SD 4.2 ± 2.1 versus 4.2 ± 2 [P = 0.95] and mean ± SD 4.6 ± 2.2 versus 4.5 ± 2.1 [P = 0.91], respectively).

After the loading regimen, a greater number of infliximab infusions were administered in the continuous treatment group than in the on-demand group throughout the study period (mean ± SD 5.8 ± 2.2 versus 3.5 ± 2.3, P < 0.0001) (Table 4). No difference in number of infusions was observed between patients who did and those who did not receive MTX in the on-demand group (3.3 ± 2.0 versus 3.7 ± 2.6, P = 0.38) (Table 4). An increase in infliximab dose to 7.5 mg/kg per infusion because of insufficient response was required in 6 patients in the continuous treatment group (4.8%) and 6 patients in the on-demand group (4.9%) (P = 0.99) (Table 4). In the latter group, 2 of the patients were receiving MTX (3.3%), and 4 were not (6.5%) (P = 0.41) (Table 4).

Table 4. Reactions to infliximab infusions (intent-to-treat analysis)*
 Continuous treatment group (n = 124)On-demand treatment group (n = 123)POn-demand treatment group not receiving MTX (n = 62)On-demand treatment group receiving MTX (n = 61)
  • *

    No significant differences were found between the on-demand treatment group not receiving methotrexate (MTX) and the on-demand treatment group receiving MTX.

  • By Student's t-test.

  • By chi-square test.

  • §

    The infusion dose was increased to 7.5 mg/kg.

No. of infusions after week 10, mean ± SD5.8 ± 2.23.5 ± 2.3<0.00013.7 ± 2.63.3 ± 2.0
No. (%) of patients who had a reaction to infusion18 (14.5)8 (6.5)<0.046 (9.7)2 (3.3)
Mean ± SD % of infusions complicated by reactions2.8 ± 8.71.4 ± 5.70.121.8 ± 6.40.9 ± 5.0
No. (%) of patients requiring an increased dose§6 (4.8)6 (4.9)0.994 (6.5)2 (3.3)

Safety.

A total of 218 patients (88.3%) experienced adverse events, with no significant difference between groups. Sixty-six serious events occurred in 57 patients, including 1 sudden death attributed to likely myocardial infarction in the on-demand group receiving MTX and 2 solid cancers (1 in the continuous treatment group, and 1 in the on-demand group receiving MTX). There were 3 cases of serious infection in the continuous treatment group and 4 in the on-demand group (3 were receiving MTX and 1 was not). Other, nonserious infections affected significantly more patients in the continuous treatment group than in the on-demand group (59.7% versus 45.5%; P = 0.03), and their overall frequency was increased in the continuous treatment group as compared with the on-demand group (mean ± SD 1.47 ± 1.85 versus 0.86 ± 1.22; P = 0.003), with no difference between the patients who were receiving MTX and those who were not. Notably, there were no cases of lymphoma, tuberculosis, or opportunistic infection.

Reaction to infusion was observed in a greater proportion of patients in the continuous treatment group than in the on-demand group (Table 4), but the proportion of infusions complicated with reactions did not differ between the 2 groups. In the on-demand group, there was no statistically significant difference in either the proportion of patients who experienced reactions or the proportion of infusions complicated by reactions, between patients receiving MTX and those not receiving MTX (Table 4).

Q-TWIST.

The percentage of time spent without symptoms and toxicity was higher in the continuous treatment group than in the on-demand group (Figure 2). The Q-TWIST value was significantly greater in the continuous treatment group than in the on-demand group (91.7 ± 8.9 versus 87.6 ± 12.5; P = 0.003).

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Figure 2. Percentage of time between week 10 and week 58 that patients in the 2 infliximab maintenance groups (continuous treatment [Q6] and on-demand treatment) experienced very severe relapse (REL3; Bath Ankylosing Spondylitis Disease Activity Index [BASDAI] >7.5), serious relapse (REL2; BASDAI 5.5 to ≤7.5), moderate relapse (REL1; BASDAI 3.5 to ≤5.5), discomfort related to an infusion (DIS), or time without symptoms and toxicity (TWIST; BASDAI ≤3.5).

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DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

Despite the great efficacy of infliximab in the treatment of AS, it has not yet been shown that the treatment modality recommended for this drug as a standard of care (i.e., an induction regimen consisting of 3 infusions of 5 mg/kg of infliximab, followed by infusions every 6–8 weeks) yields the best ratio of efficacy to safety. Disadvantages of infliximab therapy include safety concerns, discomfort related to the infusion procedure, and cost (27). It is therefore of interest to examine which dose and/or schedule of infliximab infusions affords optimal treatment in each patient.

Several studies have evaluated the efficacy of a reduced infusion dose of 3 mg/kg of infliximab, administered as a standard loading regimen, followed by additional infusions every 8 weeks, as recommended for RA (28–31). A reduced infliximab dose was shown to adequately control disease in a subset of patients (28–30), but in 1 of these studies, the dosage of infliximab and/or the frequency of infusions had to be increased to maintain sufficient efficacy, so that there was no real gain at the end of the followup period as compared with a standard regimen (31). Furthermore, in none of those studies was low-dose infliximab compared with a standard regimen. Aside from lowering the cost of treatment, there is no proven advantage, either in terms of efficacy or safety, of reducing the dose of infliximab.

In AS, the patient's perception of major disease symptoms (i.e., fatigue, pain, and stiffness) is considered to be a very good indicator of disease activity. Self-administered questionnaires, such as the BASDAI, are routinely used to evaluate the efficacy of anti-TNF therapy in AS (32). Thus, considering the rapid kinetics of infliximab and the variability of its effects among patients, both during the induction phase of treatment and during relapse, we reasoned that it could be beneficial if intervals between infusions could be adapted to the patients' symptoms, rather than to modify the dose administered per infusion (8, 13). This could offer the advantage of adjusting the amount of infliximab delivered in order to meet the exact needs of each patient.

To achieve this goal, we created a survey based on 2 indicators of disease activity, the patient's assessment of pain and the BASDAI, which allowed us to detect a worsening of disease activity as early as possible. Cutoff values used to identify a relapse were very similar to those recently recognized as the minimum clinically relevant level of change in these outcome measures (33). Furthermore, the delay between detection of a relapse and administration of infliximab infusion was notably short, i.e., 4 days on average. Thus, suitable conditions were achieved to assess the advantage of adapting the schedule of infusions to each patient.

Previous studies have shown that relapse occurs upon infliximab discontinuation in most, if not all, AS patients (12, 13). Indeed, in the present study, the vast majority of patients in the on-demand treatment group required ≥1 additional infusion after the loading regimen. During the same period of time, however, the number of infusions was reduced by 40% in the on-demand group as compared with the continuous treatment group. Accordingly, the proportion of patients experiencing a reaction to infusion and the rate of nonserious infections were 55% and 41.5% lower, respectively, in the on-demand group than in the continuous treatment group. However, the rate of serious adverse events, including infections, and the overall frequency of adverse events were not significantly different between groups.

A major finding of this study was the greater effectiveness of infliximab given at fixed intervals compared with infliximab given on demand. This result involved all parameters studied after 1 year of treatment (except for the physical component of the SF-36), including the percentage of patients classified as responders based on the ASAS criteria, the results of physical examination, and biologic markers of inflammation. Between-group differences were observed not only at the end of the study, but also in the weekly evaluation of parameters, such as the BASDAI and the global assessment of pain. Increases in these parameters were considered to be confirmations of relapse, and the occurrence of such increases in patients who did not report relapse suggests that patients either failed to properly identify relapses or deliberately delayed reporting relapses, presumably to minimize the inconvenience of infusions.

Whatever the reason, there was a progressive divergence of the weekly BASDAI between the continuous treatment group and the on-demand treatment group over 1 year (data not shown), resulting in a rather poor response rate in the on-demand group at the end of the trial. We used the Q-TWIST method to estimate a balance between the advantage of sparing infusions and the disadvantage of reduced efficacy associated with on-demand infusions. This calculation allowed us to conclude that infliximab given at fixed intervals was more effective than infliximab given on demand. Notably, patients in the on-demand group spent almost twice as much time overall in serious or very severe relapse as did those in the continuous treatment group.

MTX or other immunosuppressive agents, such as azathioprine, are routinely combined with infliximab for the treatment of diseases such as RA and Crohn's disease. This combination treatment results in greater efficacy because of additional action on the disease and/or prevention of immunization against infliximab chimeric antibody (14, 34). Thus, we also tested MTX in combination with infliximab in the treatment of AS. Given that MTX alone is not efficacious in the treatment of AS, even at dosages as high as 20 mg/week (15, 35), we used an intermediate dosage of MTX. This dosage was progressively reached in order to minimize the risk of side effects due to MTX (36), while trying to prevent immunization and reaction to infliximab, which are often associated with a loss of efficacy (37–39). Hence, adverse events were not increased among patients taking MTX.

Furthermore, there was a trend toward fewer reactions to infusions in the on-demand treatment group receiving MTX as compared with the on-demand treatment group not receiving MTX. This finding could indicate that the addition of MTX actually prevented immunization against infliximab, but the difference between groups was not statistically significant. Nevertheless, efficacy was not improved by adding MTX to the treatment, as judged by disease parameters or by the number of on-demand infusions received by patients. Thus, in this study, MTX in combination with infliximab provided no demonstrable benefit. Such a negative result could be explained, however, by a lack of power to demonstrate limited efficacy of MTX, since the sample size was not determined primarily to answer this question.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

Dr. Breban had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study design. Breban, Ravaud, Claudepierre, Henry, Wendling, Trape, Dougados.

Acquisition of data. Breban, Claudepierre, Hudry, Euller-Ziegler, Pham, Solau-Gervais, Chary-Valckenaere, Marcelli, Perdriger, Le Loët, Wendling, Fautrel, Fournié, Combe, Gaudin, Jousse, Mariette, Baleydier, Dougados.

Analysis and interpretation of data. Breban, Ravaud, Claudepierre, Baron, Dougados.

Manuscript preparation. Breban, Ravaud, Baron, Henry, Combe, Trape, Dougados.

Statistical analysis. Ravaud, Baron.

Monitoring of data. Baleydier.

Acknowledgements

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

We acknowledge the following investigators for their contributions to patient enrollment: Dr. E. Houvenagel (Lomme), Dr. T. Schaeverbeke (Bordeaux), Dr. P. Fardellone (Amiens), Dr. C. Zarnitsky (Le Havre), Dr. E. Lespessailles (Orléans), Dr. T. Thomas (St. Etienne), Dr. P. Hilliquin (Corbeil Essonnes), Dr. G. Falgarone (Bobigny), Dr. M. Alcalay (Poitiers), Dr. P. Goupille (Tours), Dr. J. F. Maillefert (Dijon), Dr. S. Martinon (Lyon), Dr. R. Trèves (Limoges), and Dr. J. Sibilia (Strasbourg). We also thank Schering-Plough for supplying the study drug.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES
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