Pattern of infliximab utilization in rheumatoid arthritis patients at an academic medical center.код для вставкиСкачать
Arthritis & Rheumatism (Arthritis Care & Research) Vol. 53, No. 6, December 15, 2005, pp 872– 878 DOI 10.1002/art.21582 © 2005, American College of Rheumatology ORIGINAL ARTICLE Pattern of Inﬂiximab Utilization in Rheumatoid Arthritis Patients at an Academic Medical Center SANDEEP K. AGARWAL,1 AGNES L. MAIER,1 LORI B. CHIBNIK,1 JONATHAN S. COBLYN,1 ANNE FOSSEL,1 RYAN LEE,1 JOHN FANIKOS,2 KAREN FIUMARA,2 COLLEEN LOWRY,2 AND MICHAEL E. WEINBLATT1 Objective. To investigate the pattern of use of inﬂiximab with an emphasis on treatment escalation and the durability of inﬂiximab use in the management of rheumatoid arthritis (RA) in an academic setting. Methods. We conducted a retrospective review of pharmacy and medical records of 183 patients with RA who received at least 1 inﬂiximab infusion at the infusion centers of the Brigham and Women’s Hospital. Treatment escalation was deﬁned as an increase in the dosage of inﬂiximab to >3 mg/kg and/or a decrease in the dosing interval to <7 weeks between infusions. Results. A total of 183 patients with RA received inﬂiximab infusions for a mean ⴞ SD duration of 58.2 ⴞ 56.6 weeks. Inﬂiximab was discontinued in 48% of the patients during the ﬁrst year of therapy and in 67% of the patients overall. A total of 126 patients had a treatment escalation, including 25 patients with a dose increase, 35 patients with a decrease in the interval, and 66 patients with both. Inﬂiximab treatment was associated with a decrease in corticosteroid and methotrexate doses. Patients who had a treatment escalation were more likely to continue inﬂiximab infusions compared with patients without a treatment escalation (odds ratio 2.0, 95% conﬁdence interval 1.0 – 4.1). Conclusion. The use of inﬂiximab may be an effective treatment for RA; however, a substantial number of patients will discontinue its use. Treatment escalation is commonly used in the management of RA with inﬂiximab and is associated with longer duration of inﬂiximab use. KEY WORDS. Rheumatoid arthritis; Inﬂiximab; Dose; Interval. INTRODUCTION Biologic response modiﬁers targeting tumor necrosis factor ␣ (TNF␣) have profoundly transformed the management of rheumatoid arthritis (RA) and dramatically improved the outlook for patients with RA. Clinical trials with inﬂiximab, a chimeric (mouse-human) monoclonal antibody targeting human TNF␣, in combination with methotrexate Supported by an unrestricted grant from Bristol Myers Squibb. Dr. Agarwal is recipient of the Abbott Scholar Award in Rheumatology Research. 1 Sandeep K. Agarwal, MD, Agnes L. Maier, MD, Lori B. Chibnik, MD, Jonathan S. Coblyn, MD, Anne Fossel, MD, Ryan Lee, MD, Michael E. Weinblatt, MD: Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts; 2John Fanikos, MD, Karen Fiumara, MD, Colleen Lowry, MD: Brigham and Women’s Hospital, Boston, Massachusetts. Address correspondence to Michael E. Weinblatt, MD, Brigham and Women’s Hospital, Division of Rheumatology, Immunology, and Allergy, 75 Francis Street, Boston, MA 02115. E-mail: [email protected] Submitted for publication March 1, 2005; accepted in revised form June 16, 2005. 872 have demonstrated an impressive improvement in clinical signs and symptoms, functional and general health status, and the prevention of radiographic progression in patients with established and early RA (1–3). Accordingly, inﬂiximab was approved in 1999 for the treatment of RA, in combination with methotrexate, at a starting dosage of 3 mg/kg administered by intravenous infusion at 0, 2, and 6 weeks followed by every 8 weeks thereafter. Despite the impressive clinical response to inﬂiximab in RA clinical trials, many in the rheumatology community perceive that a substantial number of patients do not respond adequately when inﬂiximab is administered using the standard dosing protocol. Pharmacokinetic modeling suggests that treatment escalation, a decrease in the interval between infusions and/or an increase in the dose at each infusion, may result in better clinical outcomes (4). Indeed, data from the Anti–Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy (ATTRACT) and Active Controlled Study of Patients Receiving Inﬂiximab for Treatment of Rheumatoid Arthritis of Early Onset (ASPIRE) studies have demonstrated that higher dosages (6 mg/kg and 10 mg/kg) were more effective than 3 mg/kg in treating both the clinical signs and symp- Inﬂiximab Use in Patients With Rheumatoid Arthritis toms of RA and reducing radiographic progression (1,3). Accordingly, the US Food and Drug Administration (FDA) approved an expanded label for inﬂiximab in combination with methotrexate for the management of moderate to severe RA at dosages up to 10 mg/kg and intervals as frequent as every 4 weeks. Randomized clinical trials are the gold standard to determine the clinical efﬁcacy of emerging therapies. However, these trials may not reﬂect actual clinical practice due to differences in patient selection and monitoring and are often brief compared with the duration of treatment required for chronic illnesses such as RA. Furthermore, clinical practice is inﬂuenced by patient and physician perceptions of effectiveness and adverse events. The extent to which the beneﬁts of inﬂiximab observed in the clinical trials have translated into sustained clinical beneﬁts for patients with RA in routine clinical care remains unclear. A recent observational study using 2 large rheumatology practices in Dallas, Texas and the National Data Bank for Rheumatic Diseases demonstrated that dose escalations were common and that patients had a durable efﬁcacious response to inﬂiximab consistent with data from clinical trials (5). These patients are from a variety of clinical settings and largely reﬂect the practices of community rheumatologists, which may differ from the practices in the academic setting. Fitzcharles et al (6) also reported that inﬂiximab dose escalations were common in a small cohort from a Canadian academic center. However, this study only had short-term followup, and inﬂiximab was used in patients with RA as well as other rheumatic diseases. The pattern of inﬂiximab use in the management of RA has not been reported using large cohorts of patients with RA with long duration of followup in the academic setting. A better understanding of inﬂiximab use in these patients would be an important complement to the published randomized clinical trials and would be useful for physicians who use inﬂiximab in the management of RA. Therefore, we conducted a retrospective analysis of patients with RA treated with inﬂiximab at the Brigham and Women’s Center for Arthritis and Joint Diseases. The objective of the current study was to investigate the pattern of use of inﬂiximab with an emphasis on treatment escalation and the durability of inﬂiximab use in the management of RA. PATIENTS AND METHODS Patients. Patients receiving at least 1 infusion of inﬂiximab were initially identiﬁed by reviewing the pharmacy records at Brigham and Women’s Hospital and Faulkner Hospitals from September 1999 to September 2003. The Brigham and Women’s Center for Arthritis and Joint Diseases is a large academic rheumatology practice with ⬎30 practicing board certiﬁed rheumatologists engaged in clinical care with ⬎31,000 patient visits per year. Patients who are prescribed inﬂiximab receive their infusions at either an infusion center at Brigham and Women’s Hospital or the Faulkner Hospital, an off-campus afﬁliated site. Neither infusion center is directly afﬁliated with the rheuma- 873 tologists, and revenues generated from infusion therapies are credited solely to the hospital pharmacy departments. Pharmacy and medical records of 387 patients who were given inﬂiximab between 1999 and 2003 were reviewed. Of these 387 patients, 202 patients diagnosed with RA were identiﬁed using the International Classiﬁcation of Diseases, Ninth Revision (ICD-9) code for RA (714.00) to screen the pharmacy records. Using the 1987 American College of Rheumatology (ACR; formerly the American Rheumatism Association) criteria for RA (7), the diagnosis of RA was conﬁrmed in 183 patients. The dates of infusion and dose administered were obtained from the pharmacy records. Medical records were reviewed to obtain clinical, laboratory, and radiographic data. The laboratory data and radiographic data were gathered at Brigham and Women’s Hospital per usual clinical practice. The Institutional Review Board at Brigham and Women’s Hospital approved this study. Treatment escalation. Based on data from the ATTRACT trial, inﬂiximab is usually started at a dosage of 3 mg/kg administered by intravenous infusion at 0, 2, and 6 weeks followed by every 8 weeks thereafter. An interval decrease was deﬁned as a decrease in the weekly interval to less than the prior interval. If patients were receiving inﬂiximab every 8 weeks, the interval was only considered decreased if it was changed to 7 weeks or less. This was done to capture intentional interval decreases due to medical reasons and to minimize the effect of logistical variables encountered in real-life situations such as slight variations in scheduling of infusions. A dose increase was deﬁned as an increase in the dose of inﬂiximab from the previous dose administered. Treatment escalation of inﬂiximab was deﬁned as a dose increase and/or a decrease in the interval between infusions. Statistical analyses. All analyses were performed using the SAS system version 9.1 (SAS Institute, Cary, NC). Doses were recorded as either milligrams or mg/kg. In cases where doses were recorded as milligrams, mg/kg were calculated based on the patient’s weight. All continuous variables were tested for normality using the D’Agostino-Pearson test. We used t-tests (if normally distributed), Wilcoxon’s rank sum tests (if non-normal), and chi-square tests to assess differences in baseline characteristics and risk factors between subgroups (dose escalation versus no dose escalation, and discontinuation versus no discontinuation). All statistical tests were performed at a signiﬁcance level of 5%. RESULTS Patient characteristics. A total of 387 patients received at least 1 inﬂiximab dose at the infusion centers at Brigham and Women’s Hospital and the Faulkner Hospital between 1999 and 2003. Using the ICD-9 code for RA (714.00) to screen the pharmacy records, 202 patients diagnosed with RA were initially identiﬁed. Using the 1987 ACR criteria for RA (7), the diagnosis of RA was conﬁrmed in 183 of 202 874 Agarwal et al Table 1. Diagnosis of all patients who received inﬂiximab Diagnosis Rheumatoid arthritis Rheumatoid arthritis (not conﬁrmed by authors) Crohn’s disease Psoriatic arthritis Juvenile rheumatoid arthritis Ankylosing spondylitis/spondylarthropathy Reactive arthritis Adult Still’s disease Sjögren’s syndrome Vasculitis Undifferentiated polyarthritis Raynaud’s phenomenon Unclear diagnosis Systemic lupus erythematosis, sarcoidosis, Behçet’s disease, dermatomyositis, mixed connective tissue disease No. of patients 183 19 99 33 20 7 4 2 3 3 3 2 4 1 of each patients. The 19 patients initially coded as having RA who did not meet the ACR criteria for RA were excluded from the study. The coded diagnoses for the remaining patients, including psoriatic arthritis, Crohn’s disease, and other rheumatic diseases, are presented in Table 1. Our cohort of patients with RA was 87% female with a mean ⫾ SD age of 59.3 ⫾ 14.4 years (Table 2). The majority Table 2. Baseline demographics and disease characteristics* Characteristic Value Total number of patients Sex Female Male Age, mean ⫾ SD years Weight, mean ⫾ SD kg Disease duration, years ⬍2 2–10 ⬎10 RF status Negative Positive Unknown Erosive disease No Yes Unknown Prior joint arthroplasty No Yes Unknown ESR, mean ⫾ SD mm/hour (n ⫽ 63) CRP, mean ⫾ SD mg/liter (n ⫽ 26) 183 159 (87) 24 (13) 59.3 ⫾ 14.4 60.8 ⫾ 27.0 19 (11) 68 (38) 92 (51) 42 (23) 111 (61) 29 (16) 43 (23) 113 (62) 27 (15) 126 (70) 51 (28) 3 (2) 50.5 ⫾ 29.4 10.3 ⫾ 17.5 * Unless otherwise indicated, values are the number (percentage). RF ⫽ rheumatoid factor; ESR ⫽ erythrocyte sedimentation rate; CRP ⫽ C-reactive protein level. of patients in our cohort had long-standing RA (51% ⬎10 years, 38% 2–10 years). Consistent with the long duration of disease, patients had received multiple disease-modifying antirheumatic drugs (DMARDs) prior to initiating inﬂiximab treatment (Table 3). The most common reason for discontinuation of DMARD therapy was lack of efﬁcacy, although a substantial number of patients discontinued DMARD therapy due to toxicity. Methotrexate was conﬁrmed to be part of the past therapeutic regimen in 87 patients. Of those patients who had previously taken methotrexate, 47 patients discontinued methotrexate due to lack of sustained clinical beneﬁt and 41 stopped due to toxicity or intolerance. Etanercept was used in 42 patients and adalimumab was used in 1 patient prior to receiving inﬂiximab. At the time of initiation of inﬂiximab, 143 patients were taking concomitant DMARDs and continued their use during the inﬂiximab treatment (Table 3). Of note, only 101 patients were taking methotrexate at the time of inﬂiximab initiation, despite recommendations for use of concomitant methotrexate with inﬂiximab. The mean ⫾ SD dosage of methotrexate at the time of inﬂiximab initiation was 16.2 ⫾ 5.9 mg (range 7.5–25 mg) per week. Corticosteroids were part of the therapeutic regimen in 112 of 183 patients, with a mean daily prednisone equivalent dosage of 7.9 ⫾ 5.2 mg (range 2–50 mg). Duration of inﬂiximab therapy and adverse events. In total, 183 patients with RA received at least 1 inﬂiximab infusion. The mean ⫾ SD duration of inﬂiximab use for the entire cohort was 58.2 ⫾ 56.6 weeks (range 0 –246 weeks). The loading doses at weeks 0, 2, and 6 were completed in 147 patients. During the study period, 123 (67%) of 183 patients discontinued inﬂiximab infusions at our center. As seen in Table 4, patients were more likely to discontinue inﬂiximab in the ﬁrst year of use (48%) compared with patients receiving inﬂiximab infusions for a longer duration. The mean ⫾ SD duration of inﬂiximab therapy in patients who remained on treatment was 97.7 ⫾ 63.1 weeks (range 2–246 weeks) compared with a mean of 41.0 ⫾ 41.5 weeks (range 0 –182 weeks) for patients who discontinued inﬂiximab infusions (P ⬍ 0.0001). The reasons for discontinuation of inﬂiximab are listed in Table 5. Forty-ﬁve (25%) of 123 patients stopped inﬂiximab infusions due to lack of efﬁcacy, and 40 patients stopped inﬂiximab infusions due to toxicity. Furthermore, 8 patients stopped inﬂiximab infusions due to lack of remaining clinical activity as determined by the treating physician. Patients who discontinued inﬂiximab within the ﬁrst 3 doses (i.e., during the loading protocol) were more likely to stop due to toxicity (odds ratio [OR] 6.8, 95% conﬁdence interval [95% CI] 2.3–19.8; P ⬍ 0.001) and were less likely to stop due to continued disease activity (OR 0.2, 95% CI 0.1– 0.4; P ⬍ 0.001) than patients who continued to receive inﬂiximab after the loading doses. There were 31 patients (17%) who reported a nonserious adverse event, including 25 mild infusion reactions. Inﬂiximab was discontinued in 24 patients as a result of these mild adverse events. Serious adverse events, deﬁned as adverse events requiring hospitalization, intravenous an- Inﬂiximab Use in Patients With Rheumatoid Arthritis 875 Table 3. Prior disease-modifying antirheumatic drug (DMARD) exposure and concomitant DMARD therapy Prior exposure Concomitant therapy Discontinuation reason Drug No. Toxicity Ineffective Other No. Hydroxychloroquine Sulfasalazine Methotrexate Leﬂunomide Etanercept Adalimumab Anakinra Azathioprine Gold Cyclosporine 116 67 87 60 42 1 2 15 56 12 6 17 41 29 9 0 0 4 6 0 102 48 47 33 26 1 0 9 42 10 8 2 0 0 7 0 2 2 8 2 10 6 101 22 0 0 0 3 0 1 tibiotics, new medical diagnosis, or resulting in death, were observed in 23 (13%) patients. These included 3 serious infusion reactions and 7 infections (4 pneumonia, 1 cellulitis, 1 osteomyelitis, and 1 aspergillus infection). Inﬂiximab was discontinued in 16 patients due to these serious adverse events. Two of the 7 patients with infections died as a result of pneumonia complicated by sepsis and disseminated aspergillus infection. No cases of demyelination, lupus-like syndrome, lymphoma, or tuberculosis were observed. Conﬁrmation of tuberculin skin testing was documented in 145 (79%) of the 183 medical records prior to starting inﬂiximab therapy. Ten of these patients had a positive tuberculin skin test result, and conﬁrmation of isoniazid therapy was observed in the medical records of 5 of these patients. Escalation of treatment. Treatment escalation was deﬁned as an increase in the dose per kilogram of weight to ⬎3 mg/kg, a decrease in the interval between infusions to ⬍7 weeks, or both. Using these criteria, 126 (69%) of 183 patients had a treatment escalation of inﬂiximab. Of these patients, 66 patients had a change in both the dose and interval, 25 patients had only an increase in the dose, and 35 patients had only a decrease in the interval between infusions. In total, 91 patients (50%) had a dose increase and 101 patients (55%) had an interval decrease. Of note, 5 patients had a decrease in the dose of inﬂiximab and 25 patients had an increase in the interval between infusions. In patients who had a dose increase, the inﬂiximab dose was increased a mean ⫾ SD of 1.6 ⫾ 1.1 times per patient Table 4. Number of inﬂiximab discontinuations by year of patient treatment Year of treatment Total no. patients No. patients discontinued (%) 1 2 3 4 5 Total 183 79 32 16 5 183 88 (48) 26 (33) 5 (16) 4 (25) 0 (0) 123 (67) (median 1.0, range 1– 8). The ﬁrst dose change usually occurred in the ﬁrst 22 weeks of treatment, as seen in Figure 1 (mean ⫾ SD 33 ⫾ 29, median 25.1 weeks; range 2–126 weeks). The dosage was increased to 5 mg/kg in 91 patients and 10 mg/kg in only 10 patients. The frequency of speciﬁc inﬂiximab doses given to patients as a result of dose escalation is shown in Figure 2. Evidence for the dose escalation was apparent in both the entire cohort and the dose escalation group. In the entire cohort, inﬂiximab was started at a mean ⫾ SD dosage of 3.15 ⫾ 0.53 mg/kg (median 3.0 mg/kg, range 3.0 –5.0 mg/kg), and at the end of the study the mean dosage was 4.39 ⫾ 1.81 mg/kg (median 3.5 mg/kg, range 3.0 –10.0 mg/kg; P ⬍ 0.0001). In patients with a dose increase, inﬂiximab was started at a mean dosage of 3.11 ⫾ 0.46 mg/kg (median 3.00 mg/kg, range 3–5 mg/kg), and at the end of the study the mean dosage was 5.46 ⫾ 1.76 mg/kg (median 5.00 mg/kg, range 3–10 mg/kg; P ⬍ 0.0001). In patients who had an interval decrease, the interval between inﬂiximab infusions was decreased a mean of 4.2 ⫾ 4.1 times per patient (median 1, range 0 –19). As seen in Figure 1, the ﬁrst interval decrease occurred at a mean ⫾ SD 30.7 ⫾ 27.2 weeks (median 20.0 weeks, range 2–153 weeks). In patients who had an interval decrease, the mean Table 5. Reasons for withdrawal of inﬂiximab Reason No. patients who withdrew* % of total patients (n ⴝ 183) Continued disease activity Toxicity Health insurance/cost Other Positive response Infusions done elsewhere Moved or lost to followup Family issue Patient request Planning pregnancy Unknown 45 40 5 35 8 7 9 1 5 1 4 25 22 3 19 4 4 5 ⬍1 3 ⬍1 2 * Some patients had more than one reason listed. 876 Agarwal et al Fifty-four (48%) of 112 patients had a change in their corticosteroid dose, including 18 discontinuations, 27 decreases, 5 increases, and 4 initiations. The mean ⫾ SD prednisone dosage in these 54 patients decreased from 7.94 ⫾ 6.91 mg/day (range 0 –50 mg/day) at the time of inﬂiximab initiation to 3.56 ⫾ 3.57 mg/day (range 0 –15 mg/day; P ⬍ 0.0001) at the end of the study. The reason for a change in the prednisone dose was a positive clinical response in 42 patients. In contrast to the trend seen with methotrexate, patients who had a treatment escalation were not more likely to have a change in their prednisone dose. Figure 1. Time to inﬂiximab dose escalation or interval decrease. interval throughout the study was 7.0 ⫾ 1.9 weeks (range 2–14 weeks) compared with 8.7 ⫾ 1.8 weeks (range 6 –16 weeks; P ⫽ 0.0001) in patients without an interval decrease. The mean ⫾ SD ﬁnal interval between the last 2 infusions (either at the end of the study or prior to discontinuation) in patients without an interval decrease was 8.5 ⫾ 1.9 weeks (range 6 –16 weeks). In contrast, the mean ﬁnal interval in patients who had an interval decrease was 6.3 ⫾ 2.4 weeks (range 2–14 weeks; P ⬍ 0.0001). Three patients from the interval decrease group were not included in this particular analysis because they had an interval ⬎3 SDs above the group mean. Change in methotrexate and prednisone dose. As noted above, at the time of inﬂiximab initiation, 101 patients were taking weekly methotrexate and 112 patients were taking daily prednisone. Thirty-eight (38%) patients had a change in their methotrexate dose, including 7 discontinuations, 19 decreases, 9 increases, and 3 initiations. The mean ⫾ SD methotrexate dosage in these 38 patients decreased from 15.0 ⫾ 7.21 mg/week (range 0 –25 mg/week) at the time of inﬂiximab initiation to 10.53 ⫾ 6.61 mg/ week (range 0 –22.5 mg/week; P ⫽ 0.009) at the end of the study. The reason for a change in the methotrexate dose was a positive clinical response in 21 patients. Figure 2. Frequency of inﬂiximab doses administered to patients with rheumatoid arthritis. Factors associated with treatment escalation and discontinuation. Risk factor analysis was performed to determine factors associated with treatment escalation and discontinuing inﬂiximab. Sex, rheumatoid factor status, presence of erosions on radiographs, duration of disease, prior joint arthroplasty, and baseline erythrocyte sedimentation rate or C-reactive protein level were not found to be associated with a higher risk of dose escalation or rates of discontinuation. Furthermore, there were no differences in rates of treatment escalation or inﬂiximab discontinuation in patients who were taking either methotrexate or corticosteroids compared with those not taking either medication. Interestingly, patients who had a treatment escalation were more likely to continue receiving inﬂiximab infusions compared with patients who did not have a treatment escalation (OR 2.0, 95% CI 1.0 – 4.1; P ⫽ 0.05). DISCUSSION Inﬂiximab, an intravenous biologic response modiﬁer targeting TNF-␣, in combination with methotrexate has been demonstrated to effectively improve clinical outcomes in patients with RA. Clinical trials have demonstrated a sustained clinical response with minimal adverse events (1,2). Pharmacokinetic modeling has suggested that treatment escalation, either decreasing the interval between infusions or increasing the dose of inﬂiximab, may result in improved clinical efﬁcacy (4). The extent to which a durable clinical response to inﬂiximab and the use of treatment escalation have become part of routine clinical practice in the management of RA has not been clearly identiﬁed in the literature. Therefore, we conducted a retrospective analysis to characterize the pattern of inﬂiximab use in the management of RA by rheumatologists in an academic center. In our cohort, 183 patients with RA were treated with inﬂiximab for up to 246 weeks (mean ⫾ SD 58.3 ⫾ 56.6 weeks), but there was a surprisingly high rate of discontinuation within the ﬁrst year of treatment (48%) and within the entire study overall (67%). Treatment escalations were very common, occurring in 69% of patients treated with inﬂiximab. Treatment escalation was associated with a longer duration of inﬂiximab use and a higher likelihood of continuing inﬂiximab. Lastly, both corticosteroids and methotrexate doses were decreased in patients treated with inﬂiximab. Stern and Wolfe (5) have recently described patterns of Inﬂiximab Use in Patients With Rheumatoid Arthritis inﬂiximab use in 2 separate cohorts largely made up of patients with RA treated in the community health care setting. They reported rates of treatment escalation of inﬂiximab in the 2 cohorts (66% and 56%) similar to our cohort of patients with RA treated at an academic rheumatology center. However, the treatment escalations in these 2 cohorts were almost all dose escalations. In contrast, our cohort had similar rates of dose escalation and interval decreases. Based on pharmacokinetic modeling, it has been suggested that decreasing the interval may be more effective than increasing the dose at raising serum inﬂiximab trough levels, which correlate with clinical response; however, this has not been investigated in more formal clinical settings (4). Perhaps the most impressive difference in the use of inﬂiximab in our report compared with both clinical trials as well as other observational studies is the high rate of inﬂiximab discontinuation (1,5,8). The ATTRACT trial reported a 1-year discontinuation rate of 21%. In clinical practice, the rate of discontinuation may have been higher because an additional 18% of patients who received inﬂiximab did not meet ACR20 criteria (9). Stern and Wolfe (5) reported discontinuation rates of 14% at 1 year and 25% at 2 years, and Sidiropoulos et al (8) reported a discontinuation rate of 29% after the 12th infusion. Both of these observational studies likely had patients with similar disease duration and severity as well as a similar degree of dose escalation compared with our cohort. However, a critical difference may be that the previous reports only included patients who had completed the loading protocol at 0, 2, and 6 weeks. Consistent with this possibility is the higher rate of adverse reactions and the association of early discontinuation with adverse reactions in our cohort compared with prior studies. However, the high rate of discontinuation observed in the current study (48% at 1 year and 67% overall) can only partially be explained by including all patients with RA who have received at least 1 inﬂiximab dose. Other factors such as patient and physician perceptions and physician incentives may also be involved. Another possible explanation for the high rate of discontinuation could be the surprisingly low rate of concomitant methotrexate administration. Inﬂiximab has been approved for use in patients with RA with concomitant methotrexate administration. Despite these recommendations, only 101 of the 183 patients in our cohort were taking methotrexate. The lack of association between concomitant methotrexate use and either treatment escalation or discontinuation suggests that the high rate of discontinuation is not due to the low rate of concomitant methotrexate. However, it remains possible that in some patients, concomitant methotrexate use may help prevent the formation of antichimeric antibodies that potentially contribute to infusion reactions and/or treatment discontinuation. In May 2002, a consensus statement by 158 rheumatologists stated that physicians may consider either a dose increase or an interval decrease in patients with an incomplete response to TNF␣ antagonists (10). Also in 2002, the US FDA issued an expanded label for the use of inﬂiximab in patients with RA up to 10 mg/kg and as often as every 4 877 weeks. Although dose escalation was common in our cohort, it is rather surprising that most patients with a treatment escalation only reached 5 mg/kg. Only 10 patients reached the maximum recommended dosage of 10 mg/kg. A more aggressive approach to dose escalation may be beneﬁcial in the treatment of patients who may not be responding optimally to inﬂiximab therapy. However, the increased cost and potential increased risk of adverse events relative to an unproven clinical beneﬁt should also be considered in this medical decision (11). Although inﬂiximab treatment escalation may be commonly used, it remains to be determined if this practice has added clinical beneﬁt in the management of RA. The ATTRACT and ASPIRE studies suggest that the higher dose may be more efﬁcacious in patients who have not been previously exposed to inﬂiximab. However, it is unknown if escalating inﬂiximab treatment in a patient with an initial suboptimal response to inﬂiximab, in contrast to an inﬂiximab-naı̈ve patient, will have any added clinical beneﬁt. Two recent reports have addressed this issue and concluded that treatment escalations were not always sufﬁcient to maintain adequate disease control, and that the perceived clinical beneﬁt from treatment escalation may actually represent a regression-like effect as opposed to a real clinical response (8,12). Because the current study is a retrospective review of medical records, it is difﬁcult to accurately determine if patients received an additional clinical beneﬁt from the treatment escalation. However, it is intriguing that patients who had a treatment escalation were more likely to continue to receive inﬂiximab infusions. Furthermore, patients treated with inﬂiximab often had a decreased need for corticosteroids and methotrexate. This change in methotrexate was also associated with treatment escalation. Although not conclusive, these data suggest a beneﬁcial effect of treatment escalation of inﬂiximab. Future prospective studies are needed to address whether treatment escalation is clinically and cost effective. Inﬂiximab has been a critical advance in the management of RA, resulting in dramatic clinical improvement and the prevention of disabling radiographic damage. Despite the use of inﬂiximab with the common practice of treatment escalation in patients with RA, many patients continue to have disease activity, emphasizing the need for prospective studies that address the risks and beneﬁts of treatment escalation. Furthermore, these observations also underscore the importance of future research to identify novel therapeutic targets and develop new agents for the management of RA. REFERENCES 1. 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