International Journal of Rheumatic Diseases 2014
ORIGINAL ARTICLE
Good response to infliximab in rheumatoid arthritis following failure of interleukin-1 receptor antagonist Jun BAO,1,2 Tao YUE,3 Ting LI,2 Dong-Yi HE3 and Yi-Xiao BAO1 1 Department of Pediatrics, Xinhua Hospital Shanghai Jiaotong University School of Medicine, 2Department of Rheumatology & Immunology, Shanghai Changzheng Hospital, Second Military Medical University, and 3Department of Rheumatology, Shanghai Guanghua Hospital, Shanghai, China
Abstract Aim: To evaluate the efficacy of tumor necrosis factor inhibitor infliximab in patients with rheumatoid arthritis (RA) who were disease-resistant to recombinant human interleukin-1 receptor antagonist (IL-1Ra). Methods: A total of 104 patients with active RA despite methotrexate (MTX) treatment were enrolled in the open trial. Among them, 27 IL-1Ra nonresponders ‘Switchers’ and 51 biologic-naive patients ‘Naivers’ received an infusion of 3 mg/kg infliximab at weeks 0, 2, 6 and 14, combined with concurrent MTX therapy, while the other 26 patients who had never received any biologics ‘Controls’ continued MTX monotherapy. Clinical outcomes and safety were assessed at weeks 0, 2 and every 4 weeks thereafter for 18 weeks with the American College of Rheumatology (ACR) core set criteria, the Disease Activity Score in 28 joints, and records of adverse events (AEs) and abnormal laboratory findings. Results: At week 18, an ACR20 response was achieved in 56% of Switchers and 61% of Naivers, compared with 23% of Controls (P = 0.0013 and 0.0126, respectively). Compared with Controls, both Switchers and Naivers achieved a significant improvement in tender-joint count, swollen-joint count, patient’s assessment of pain, patient’s and physician’s global assessment of disease activity, erythrocyte sedimentation rate and C-reactive protein. Switchers even achieved a greater benefit from health assessment questionnaire (HAQ) scores than Naivers. Infliximab was well tolerated, with a similar incidence of AEs across all study groups. Conclusion: Switching from IL-1Ra to infliximab is effective in improving disease activity and maintaining joint function. Key words: arthritis rheumatoid, biological agents, infliximab, interleukin-1 blocker, tumor necrosis factor-a blocker.
INTRODUCTION Chronic inflammation of the synovial membrane is a hallmark characteristic of rheumatoid arthritis (RA). Correspondence: Professor Yi-Xiao Bao, Department of Pediatrics, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China. Email: [email protected] Professor Dong-Yi He, Department of Rheumatology, Shanghai Guanghua Hospital, 540 Xinhua Road, Shanghai 200052, China. Email: [email protected]. Drs Jun Bao and Tao Yue contributed equally to this work.
Pro-inflammatory cytokines, especially tumor necrosis factor (TNF)-a and interleukin 1 (IL-1), play a crucial role in the pathogenesis of rheumatoid synovitis. The introduction of selective anti-cytokine therapies has dramatically improved the treatment of refractory RA. Infliximab, one of the most-used TNF-a inhibitors, is a chimeric immunoglobulin G1 (IgG1) monoclonal antibody that contains murine variable regions targeted to TNF-a. Recombinant human IL-1 receptor antagonist (IL-1Ra) which prevents the binding of IL-1 to its receptor is solely the currently commercially available IL-1 blocker. The results of clinical trials show that
© 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
J. Bao et al.
infliximab and IL-1Ra can significantly improve the clinical signs and symptoms of active RA, improve function and retard radiologic evidence of joint damage in RA.1,2 However, approximately 30% of RA patients withdraw from treatment due to adverse events (AEs), lack of response to anti-TNF-a or anti-IL-1 therapies. Thus initiating therapy with a second biologic agent is advocated when the first has failed.3 No direct evidence has been raised to illustrate a clinical benefit and risk from secondary anti-TNF therapy in RA patients who do not tolerate or do not respond to IL-1Ra. Here, we assessed the efficacy and tolerability of TNF inhibitor infliximab in patients who had not responded to previous IL-1Ra treatment, compared with those naive to any biologic agents.
METHODS Study protocol A total of 104 patients were enrolled in the open trial which was conducted at Shanghai Changzheng Hospital and Shanghai Guanghua Hospital in China from
December 2008 to August 2010 (Fig. 1). Eligible patients were 18–65 years of age, fulfilled the revised 1987 American Rheumatism Association criteria for the classification of RA, and had active disease despite consecutive treatment with methotrexate (MTX) at a stable dosage of 10–25 mg/week for at least 12 weeks before enrollment. Active RA was defined as four or more swollen joints, six or more tender joints and at least one of the following: a serum C-reactive protein (CRP) level of at least 10 mg/L or an erythrocyte sedimentation rate (ESR) of at least 28 mm/h, or morning stiffness lasting longer than 45 min. Patients were excluded if they had a recent history of significant infection, evidence of laboratory abnormalities, or significant systemic disease or autoimmune disease other than RA. All patients provided written informed consent. The study protocol was approved by the institutional review committee and was conducted in accordance with the Declaration of Helsinki and all subsequent revisions. Of the 104 enrolled patients, 77 had never received any biologics treatment and 27 were non-responders to IL-1Ra who did not achieve an American College of
Figure 1 Trial profile. MTX, methotrexate.
2
International Journal of Rheumatic Diseases 2014
Switching from IL-1Ra to infliximab for RA
Rheumatology (ACR) 20% improvement criteria response2 following at least 3-month IL-1Ra therapy. After 4 weeks of washout period, the 27 IL-1Ra failing patients ‘Switchers’ were assigned to switch to 3 mg/kg infliximab at weeks 0, 2, 6 and 14, combined with concurrent MTX therapy. The other 77 biologic-naive patients were double-blindly randomized in a 2 : 1 ratio to receive infliximab (n = 51, ‘Naivers’) or placebo (n = 26, ‘Controls’) plus MTX treatment. Patients were allowed to take non-steroidal anti-inflammatory drugs or oral corticosteroids (≤ 10 mg/day of prednisone or equivalent) if the dose had been stable for at least 4 weeks prior to entry. No patients had previously received any disease-modifying antirheumatic drug other than MTX and IL-1Ra, or any intra-articular or parenteral administration of corticosteroid within the past 4 weeks.
Clinical outcomes Efficacy and safety were assessed at weeks 0, 2 and every 4 weeks thereafter for 18 weeks. The efficacy endpoint was the proportion of patients with an ACR20 response4 at week 18. An ACR20 response was defined according to the ACR definition of a 20% improvement from baseline in tender joint count and swollen joint count, as well as in three of the following: patient’s assessment of pain, patient’s global assessment of disease activity, physician’s global assessment of disease activity, health assessment questionnaire (HAQ) estimate of physical function, and ESR or serum CRP levels. Other endpoints included ACR50 and ACR70 responses (50% and 70% improvement of the ACR core set, respectively), the modified Disease Activity Score in 28 joints (DAS28)5 and a change in DAS28 from baseline. Safety assessment was based on AEs, abnormal signs and laboratory findings.
Statistical analysis The proportion of patients who had ACR responses and adverse events was analyzed by chi-square test. Continuous variables and DAS28 were analyzed using Student’s paired t-test or analysis of variance (parametric) or Wilcoxon’s rank sum test (nonparametric) as appropriate. Two-tailed P-values of 0.05 or less were considered to be statistically significant.
RESULTS Characteristics of the patients The three treatment groups were well balanced in demographic and baseline characteristics (Table 1). Of
International Journal of Rheumatic Diseases 2014
the 51 Naivers, 46 (90.2%) completed the study, one withdrew due to lack of efficacy at week 6, and four withdrew due to AEs at weeks 2, 6 and 10, respectively. Twenty-two (81.5%) of the 27 Switchers completed the study, one discontinued infliximab due to lack of efficacy at week 2, and four discontinued infliximab due to AEs at week 2 and 10, respectively. Only one (3.8%) of the 26 Controls withdrew from the study due to disease worsening at week 14 (Fig. 1).
Therapeutic responses At week 18, an ACR20 response was achieved in 56% of Switchers and 61% of Naivers versus 23% of Controls (P = 0.0013 and 0.0126, respectively) (Fig. 2a). Compared with Controls, the greater ACR20 response rates were sustained in both infliximab-treated groups throughout the study (Fig. 2b). No difference was shown in the ACR20 response between the two infliximab-treated groups (P > 0.05). At week 18, the ACR50 response rate of Naivers was significantly greater than Switchers or Controls. Switchers had no significant difference in ACR50 response rate from Controls. As to ACR70 response rates, no significant differences were found among the three groups (Fig. 2a). Compared with Controls, both Switchers and Naivers achieved a significant improvement in tender-joint count, swollen-joint count, patient’s assessment of pain and ESR by week 2. A significant decrease in CRP level was also achieved in both infliximab groups until week 14. Naivers achieved a greater improvement in patient’s and physician’s global assessment of disease activity by week 2, earlier than Switchers did by week 6. However, a greater improvement in HAQ was shown in Switchers rather than Naivers (Fig. 3a–h). Compared with the baseline values, mean DAS28 scores in both infliximab-treated groups were significantly decreased by week 2 (Fig. 3i). The mean DAS28 scores in both infliximab-treated groups were also significantly decreased than the Control group throughout the study, but no significant difference was noted between Switchers and Naivers during the period (Fig. 3i).
Safety During the 18-week study, a total of 21 (27%) patients receiving infliximab developed AEs, and eight (10%) them withdrew due to AEs. The incidences of total AEs, serious AEs and AEs leading to withdrawal were similar between infliximab-treated patients and patients receiving MTX monotherapy. However, significantly more
3
J. Bao et al.
Table 1 Characteristics of patients at baseline
Age (years) Sex, female (%) Weight (kg) RF positivity (%) ANA positivity (%) Corticosteroid use (%) MTX dose (mg/week) Swollen joint count (0–66) Tender or painful joint count (0–68) Physician’s global assessment of disease activity (0–100 mm) Patient’s global assessment of disease activity (0–100 mm) Patient’s assessment of pain (0–100 mm) HAQ score (0–3) CRP (mg/L) ESR (mm/h) Duration of morning stiffness (min/day) DAS28
Naivers (n = 51)
Controls (n = 26)
Switchers (n = 27)
48 44 (86) 56.8 37 (73) 15 (29) 12 (24) 10.3 9.2 10.2 57.4 59.2 54.2 0.6 21.8 45.8 76.9 5.0
42 21 (81) 56.4 19 (73) 8 (31) 6 (23) 11.3 8.4 9.9 53.7 57.5 50.9 0.6 19.7 48.7 64.6 5.4
49 22 (81) 58.9 20 (74) 9 (33) 7 (26) 11.3 8.8 10.3 62.2 63.2 53.0 0.5 17.9 40.0 55.4 5.4
9.6 9.6
1.8 7.0 6.7 15.7 18.8 19.8 0.7 26.6 36.8 96.1 2.5
12.7 8.1
2.7 4.5 5.4 20.4 19.6 21.3 0.5 20.0 34.0 72.9 1.1
10.2 9.8
2.7 4.9 5.7 110.7 112.5 20.4 0.4 24.9 24.3 54.7 1.0
Data are mean SD or number (%) unless other indicated. No significant differences between groups for any characteristic. ANA, anti-nuclear antibodies; CRP, C-reactive protein (normal < 10 mg/L); DAS28, disease activity score in 28 joints; ESR, erythrocyte sedimentation rate; HAQ, health assessment questionnaire; RF, rheumatoid factor; MTX, methotrexate.
(a)
(b)
Switchers had AEs than Naivers or Controls, and more withdrew from the study due to AEs than Controls (Table 2). The most common AEs associated with infliximab were infusion-related reactions (IRRs). Patients receiving infliximab had a similar incidence of IRRs (8%) and IRRs leading to withdrawal (5%) compared with the Controls. However, a significantly greater incidence of IRRs (15%) was noted in Switchers versus Controls (Table 2). IRRs occurred most frequently with the second or third infusion of infliximab, clinically presenting with chilling, fever, rash, chest distress and even anaphylactic shock. Infections occurred with a similar frequency in all study groups. However, serious infections such as pneumonia were the second reason for discontinuation in the study (Table 2). Other AEs, including abnormal liver function, leucopenia and cardiac events were mild, and no significant difference was found among the three groups.
DISCUSSION Figure 2 Therapeutic responses in patients with active rheumatoid arthritis. (a) percentage of patients achieving an American College of Rheumatology (ACR)20, ACR50, and ACR70 response at week 18. (b) changes in the percentage of patients achieving an ACR20 response during the 18-week study.
4
This open trial confirms that therapy with infliximab plus MTX provides a rapid clinical remission in patients with active RA despite MTX treatment. Furthermore, data from the study demonstrate that a previous failure with IL-Ra does not influence the response to
International Journal of Rheumatic Diseases 2014
Switching from IL-1Ra to infliximab for RA
(a)
(b)
(c)
(d)
(e)
(f)
(g)
(h)
Figure 3 Mean changes from baseline in the American College of Rheumatology (ACR) score criteria components, and DAS28 throughout the study. Other abbreviations as designated in Table 1 and Fig. 2. Compared with Controls, a significant improvement in (a) tender joint count; (b) swollen joint count; (c) patient’s assessment of pain (VAS); (d) patient’s global assessment of disease activity; (e) physician’s global assessment of disease activity; (f) health assessment questionnaire (HAQ); (g) erythrocyte sedimentation rate (ESR); (h) C-reactive protein (CRP) and (i) DDAS28 (Disease Activity Score of 28 joints). Compared with Controls, - - - -, Compared with Naivers, - - - -.
infliximab, with a similar ACR20 response as biologicnaive patients. Indirect comparisons between cytokine antagonists indicate that anti-TNF-a agents, including infliximab, seem to be more effective in improving disease activity than the IL-1 blocker.6–9 Our findings
International Journal of Rheumatic Diseases 2014
(i)
further indicate a predominant role of TNF-a in the pathogenesis of RA. However, the patients switching from IL-1Ra to infliximab in our study achieved a greater improvement in HAQ score than the biologic-naive patients and the
5
J. Bao et al.
AUTHORS CONTRIBUTIONS
Table 2 Adverse events Patients with AEs, n (%)
Naivers (n = 51)
Controls (n = 26)
Switchers (n = 27)
Any AE Deaths Serious AEs AEs leading to withdrawal Infusion-related reactions (IRRs) IRRs leading to withdrawal Infection Any Serious Abnormal liver function Leukopenia Premature ventricular contraction Post-trauma fraction
10 (20) 0 1 (2) 4 (9) 2 (4)
3 (12) 0 0 0 0
11 (41)*$ 0 3 (11) 4 (15)* 4 (15)*
1 (2)
0
3 (11)
2 (4) 1 (2) 2 (4) 2 (4) 1 (2)
1 (4) 0 1 (4) 1 (4) 0
3 (11) 1 (4) 1 (4) 3 (11) 0
1 (2)
0
0
Values are expressed as number of patient and percentages in parentheses. Compared with Controls, *P < 0.05. Compared with Naivers, $ P < 0.05.
Drs J Bao, Yue and Li carried out the clinical studies and collected data. Drs J Bao and He conceived of the study, participated in its design and coordination. And Dr YX Bao performed the statistical analysis and drafted the manuscript. All authors read and approved the final version to be published.
ACKNOWLEDGEMENT This study was supported in part by grants from National Natural Science Foundation of China (No. 81172782).
CONFLICTS OF INTEREST STATEMENT The authors declare that they have no conflict of interest.
TRIAL REGISTRY Chinese Clinical Trial Register ChiCTR-TRC-10001060.
placebo group. IL-1 is recognized as one of the most crucial cytokines in mediating bone and cartilage destruction.10 Clinical trials showed that the IL-1Ra reduced radiologic progressive joint damage in patients with RA.11 So we suppose that IL-Ra might partly improve joint function by blocking the role of IL-1. When the IL-Ra-failing patients in our study switched to infliximab treatment, infliximab not only reduced manifestations of arthritis, but also sustained joint function obtained with IL-Ra. In the present study, infliximab was well tolerated. Infusion reactions were the most common AEs of infliximab, which is consistent with previous reports.7,12,13 However, patients who were treated with IL-Ra were prone to develop infusion-related reactions following switching treatments. Biological agents are large proteins targeting a specific protein, antibody or receptor, so antibodies against the drug could be assessed after a period of therapy.14 In this study, ILRa may further promote the development of autoantibodies against infliximab, causing more infusionrelated reactions. In conclusion, our study first provides evidence for the efficacy and tolerance of switching from IL-Ra to infliximab in patients with RA. When patients fail IL-Ra, switching to infliximab may be effective in improving disease activity and maintaining joint function. Caution regarding infusion-related reactions should be taken during switching treatment.
6
REFERENCES 1 St. Clair EW (2002) Tides of inflammation: impact of biologics. J Rheumatol 29 (Suppl 65), 22–6. 2 Felson DT, Anderson JJ, Boers M et al. (1995) American College of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum 38, 727–35. 3 Hyrich KL, Lunt M, Watson KD, Symmons DPM, Silman AJ (2007) Outcomes after switching from one anti–tumor necrosis factor a agent to a second anti–tumor necrosis factor a agent in patients with rheumatoid arthritis. Arthritis Rheum 56, 13–20. 4 Felson DT, Anderson JJ, Boers M et al. (1993) The American College of Rheumatology preliminary core set of disease activity measures for rheumatoid arthritis clinical trials. Arthritis Rheum 36, 729–40. 5 Van Gestel AM, Prevoo ML, van’t Hof MA, van Rijswijk MH, van de Putte LB, van Riel PL (1996) Development and validation of the European League Against Rheumatism response criteria for rheumatoid arthritis: comparison with the preliminary American College of Rheumatology and the World Health Organization/International League Against Rheumatism criteria. Arthritis Rheum 39, 34–40. 6 Nixon R, Bansback N, Brennan A (2007) The efficacy of inhibiting tumour necrosis factor a and interleukin 1 in patients with rheumatoid arthritis: a meta-analysis and adjusted indirect comparisons. Rheumatology 46, 1140–7.
International Journal of Rheumatic Diseases 2014
Switching from IL-1Ra to infliximab for RA
7 Gartlehner G, Hansen RA, Jonas BL, Thieda P, Lohr KN (2006) The comparative efficacy and safety of biologics for the treatment of rheumatoid arthritis: a systematic review and metaanalysis. J Rheumatol 33, 2398–408. 8 Blumenauer B, Judd M, Wells G et al. (2002) Infliximab for the treatment of rheumatoid arthritis. Cochrane Database Systematic Rev, C003785. 9 Lipsky PE, van der Heijde DM, St. Clair EW et al. (2000) Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. Infliximab and methotrexate in the treatment of rheumatoid arthritis. N Engl J Med 343, 1594–602. 10 Gravallese EM, Goldring SR (2000) Cellular mechanisms and the role of cytokines in bone erosions in rheumatoid arthritis. Arthritis Rheum 43, 2143–51.
International Journal of Rheumatic Diseases 2014
11 Jiang Y, Genant HK, Watt I et al. (2000) A multicenter, double-blind, dose-ranging, randomized, placebo-controlled study of recombinant human interleukin-1 receptor antagonist in patients with rheumatoid arthritis: radiologic progression and correlation of Genant and Larsen scores. Arthritis Rheum 43, 1001–9. 12 Cheifetz A, Smedley M, Martin S et al. (2003) The incidence and management of infusion reactions to infliximab: a large center experience. Am J Gastroenterol 98, 1315–24. 13 Schaible TF (2000) Long term safety of infliximab. Can J Gastroenterol 14(Suppl C), 29C–32C. 14 Anderson PJ (2005) Tumor necrosis factor inhibitors: clinical implications of their different immunogenicity profiles. Semin Arthritis Rheum 34 (Suppl 1), 19–22.
7
ORIGINAL ARTICLE
Good response to infliximab in rheumatoid arthritis following failure of interleukin-1 receptor antagonist Jun BAO,1,2 Tao YUE,3 Ting LI,2 Dong-Yi HE3 and Yi-Xiao BAO1 1 Department of Pediatrics, Xinhua Hospital Shanghai Jiaotong University School of Medicine, 2Department of Rheumatology & Immunology, Shanghai Changzheng Hospital, Second Military Medical University, and 3Department of Rheumatology, Shanghai Guanghua Hospital, Shanghai, China
Abstract Aim: To evaluate the efficacy of tumor necrosis factor inhibitor infliximab in patients with rheumatoid arthritis (RA) who were disease-resistant to recombinant human interleukin-1 receptor antagonist (IL-1Ra). Methods: A total of 104 patients with active RA despite methotrexate (MTX) treatment were enrolled in the open trial. Among them, 27 IL-1Ra nonresponders ‘Switchers’ and 51 biologic-naive patients ‘Naivers’ received an infusion of 3 mg/kg infliximab at weeks 0, 2, 6 and 14, combined with concurrent MTX therapy, while the other 26 patients who had never received any biologics ‘Controls’ continued MTX monotherapy. Clinical outcomes and safety were assessed at weeks 0, 2 and every 4 weeks thereafter for 18 weeks with the American College of Rheumatology (ACR) core set criteria, the Disease Activity Score in 28 joints, and records of adverse events (AEs) and abnormal laboratory findings. Results: At week 18, an ACR20 response was achieved in 56% of Switchers and 61% of Naivers, compared with 23% of Controls (P = 0.0013 and 0.0126, respectively). Compared with Controls, both Switchers and Naivers achieved a significant improvement in tender-joint count, swollen-joint count, patient’s assessment of pain, patient’s and physician’s global assessment of disease activity, erythrocyte sedimentation rate and C-reactive protein. Switchers even achieved a greater benefit from health assessment questionnaire (HAQ) scores than Naivers. Infliximab was well tolerated, with a similar incidence of AEs across all study groups. Conclusion: Switching from IL-1Ra to infliximab is effective in improving disease activity and maintaining joint function. Key words: arthritis rheumatoid, biological agents, infliximab, interleukin-1 blocker, tumor necrosis factor-a blocker.
INTRODUCTION Chronic inflammation of the synovial membrane is a hallmark characteristic of rheumatoid arthritis (RA). Correspondence: Professor Yi-Xiao Bao, Department of Pediatrics, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China. Email: [email protected] Professor Dong-Yi He, Department of Rheumatology, Shanghai Guanghua Hospital, 540 Xinhua Road, Shanghai 200052, China. Email: [email protected]. Drs Jun Bao and Tao Yue contributed equally to this work.
Pro-inflammatory cytokines, especially tumor necrosis factor (TNF)-a and interleukin 1 (IL-1), play a crucial role in the pathogenesis of rheumatoid synovitis. The introduction of selective anti-cytokine therapies has dramatically improved the treatment of refractory RA. Infliximab, one of the most-used TNF-a inhibitors, is a chimeric immunoglobulin G1 (IgG1) monoclonal antibody that contains murine variable regions targeted to TNF-a. Recombinant human IL-1 receptor antagonist (IL-1Ra) which prevents the binding of IL-1 to its receptor is solely the currently commercially available IL-1 blocker. The results of clinical trials show that
© 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
J. Bao et al.
infliximab and IL-1Ra can significantly improve the clinical signs and symptoms of active RA, improve function and retard radiologic evidence of joint damage in RA.1,2 However, approximately 30% of RA patients withdraw from treatment due to adverse events (AEs), lack of response to anti-TNF-a or anti-IL-1 therapies. Thus initiating therapy with a second biologic agent is advocated when the first has failed.3 No direct evidence has been raised to illustrate a clinical benefit and risk from secondary anti-TNF therapy in RA patients who do not tolerate or do not respond to IL-1Ra. Here, we assessed the efficacy and tolerability of TNF inhibitor infliximab in patients who had not responded to previous IL-1Ra treatment, compared with those naive to any biologic agents.
METHODS Study protocol A total of 104 patients were enrolled in the open trial which was conducted at Shanghai Changzheng Hospital and Shanghai Guanghua Hospital in China from
December 2008 to August 2010 (Fig. 1). Eligible patients were 18–65 years of age, fulfilled the revised 1987 American Rheumatism Association criteria for the classification of RA, and had active disease despite consecutive treatment with methotrexate (MTX) at a stable dosage of 10–25 mg/week for at least 12 weeks before enrollment. Active RA was defined as four or more swollen joints, six or more tender joints and at least one of the following: a serum C-reactive protein (CRP) level of at least 10 mg/L or an erythrocyte sedimentation rate (ESR) of at least 28 mm/h, or morning stiffness lasting longer than 45 min. Patients were excluded if they had a recent history of significant infection, evidence of laboratory abnormalities, or significant systemic disease or autoimmune disease other than RA. All patients provided written informed consent. The study protocol was approved by the institutional review committee and was conducted in accordance with the Declaration of Helsinki and all subsequent revisions. Of the 104 enrolled patients, 77 had never received any biologics treatment and 27 were non-responders to IL-1Ra who did not achieve an American College of
Figure 1 Trial profile. MTX, methotrexate.
2
International Journal of Rheumatic Diseases 2014
Switching from IL-1Ra to infliximab for RA
Rheumatology (ACR) 20% improvement criteria response2 following at least 3-month IL-1Ra therapy. After 4 weeks of washout period, the 27 IL-1Ra failing patients ‘Switchers’ were assigned to switch to 3 mg/kg infliximab at weeks 0, 2, 6 and 14, combined with concurrent MTX therapy. The other 77 biologic-naive patients were double-blindly randomized in a 2 : 1 ratio to receive infliximab (n = 51, ‘Naivers’) or placebo (n = 26, ‘Controls’) plus MTX treatment. Patients were allowed to take non-steroidal anti-inflammatory drugs or oral corticosteroids (≤ 10 mg/day of prednisone or equivalent) if the dose had been stable for at least 4 weeks prior to entry. No patients had previously received any disease-modifying antirheumatic drug other than MTX and IL-1Ra, or any intra-articular or parenteral administration of corticosteroid within the past 4 weeks.
Clinical outcomes Efficacy and safety were assessed at weeks 0, 2 and every 4 weeks thereafter for 18 weeks. The efficacy endpoint was the proportion of patients with an ACR20 response4 at week 18. An ACR20 response was defined according to the ACR definition of a 20% improvement from baseline in tender joint count and swollen joint count, as well as in three of the following: patient’s assessment of pain, patient’s global assessment of disease activity, physician’s global assessment of disease activity, health assessment questionnaire (HAQ) estimate of physical function, and ESR or serum CRP levels. Other endpoints included ACR50 and ACR70 responses (50% and 70% improvement of the ACR core set, respectively), the modified Disease Activity Score in 28 joints (DAS28)5 and a change in DAS28 from baseline. Safety assessment was based on AEs, abnormal signs and laboratory findings.
Statistical analysis The proportion of patients who had ACR responses and adverse events was analyzed by chi-square test. Continuous variables and DAS28 were analyzed using Student’s paired t-test or analysis of variance (parametric) or Wilcoxon’s rank sum test (nonparametric) as appropriate. Two-tailed P-values of 0.05 or less were considered to be statistically significant.
RESULTS Characteristics of the patients The three treatment groups were well balanced in demographic and baseline characteristics (Table 1). Of
International Journal of Rheumatic Diseases 2014
the 51 Naivers, 46 (90.2%) completed the study, one withdrew due to lack of efficacy at week 6, and four withdrew due to AEs at weeks 2, 6 and 10, respectively. Twenty-two (81.5%) of the 27 Switchers completed the study, one discontinued infliximab due to lack of efficacy at week 2, and four discontinued infliximab due to AEs at week 2 and 10, respectively. Only one (3.8%) of the 26 Controls withdrew from the study due to disease worsening at week 14 (Fig. 1).
Therapeutic responses At week 18, an ACR20 response was achieved in 56% of Switchers and 61% of Naivers versus 23% of Controls (P = 0.0013 and 0.0126, respectively) (Fig. 2a). Compared with Controls, the greater ACR20 response rates were sustained in both infliximab-treated groups throughout the study (Fig. 2b). No difference was shown in the ACR20 response between the two infliximab-treated groups (P > 0.05). At week 18, the ACR50 response rate of Naivers was significantly greater than Switchers or Controls. Switchers had no significant difference in ACR50 response rate from Controls. As to ACR70 response rates, no significant differences were found among the three groups (Fig. 2a). Compared with Controls, both Switchers and Naivers achieved a significant improvement in tender-joint count, swollen-joint count, patient’s assessment of pain and ESR by week 2. A significant decrease in CRP level was also achieved in both infliximab groups until week 14. Naivers achieved a greater improvement in patient’s and physician’s global assessment of disease activity by week 2, earlier than Switchers did by week 6. However, a greater improvement in HAQ was shown in Switchers rather than Naivers (Fig. 3a–h). Compared with the baseline values, mean DAS28 scores in both infliximab-treated groups were significantly decreased by week 2 (Fig. 3i). The mean DAS28 scores in both infliximab-treated groups were also significantly decreased than the Control group throughout the study, but no significant difference was noted between Switchers and Naivers during the period (Fig. 3i).
Safety During the 18-week study, a total of 21 (27%) patients receiving infliximab developed AEs, and eight (10%) them withdrew due to AEs. The incidences of total AEs, serious AEs and AEs leading to withdrawal were similar between infliximab-treated patients and patients receiving MTX monotherapy. However, significantly more
3
J. Bao et al.
Table 1 Characteristics of patients at baseline
Age (years) Sex, female (%) Weight (kg) RF positivity (%) ANA positivity (%) Corticosteroid use (%) MTX dose (mg/week) Swollen joint count (0–66) Tender or painful joint count (0–68) Physician’s global assessment of disease activity (0–100 mm) Patient’s global assessment of disease activity (0–100 mm) Patient’s assessment of pain (0–100 mm) HAQ score (0–3) CRP (mg/L) ESR (mm/h) Duration of morning stiffness (min/day) DAS28
Naivers (n = 51)
Controls (n = 26)
Switchers (n = 27)
48 44 (86) 56.8 37 (73) 15 (29) 12 (24) 10.3 9.2 10.2 57.4 59.2 54.2 0.6 21.8 45.8 76.9 5.0
42 21 (81) 56.4 19 (73) 8 (31) 6 (23) 11.3 8.4 9.9 53.7 57.5 50.9 0.6 19.7 48.7 64.6 5.4
49 22 (81) 58.9 20 (74) 9 (33) 7 (26) 11.3 8.8 10.3 62.2 63.2 53.0 0.5 17.9 40.0 55.4 5.4
9.6 9.6
1.8 7.0 6.7 15.7 18.8 19.8 0.7 26.6 36.8 96.1 2.5
12.7 8.1
2.7 4.5 5.4 20.4 19.6 21.3 0.5 20.0 34.0 72.9 1.1
10.2 9.8
2.7 4.9 5.7 110.7 112.5 20.4 0.4 24.9 24.3 54.7 1.0
Data are mean SD or number (%) unless other indicated. No significant differences between groups for any characteristic. ANA, anti-nuclear antibodies; CRP, C-reactive protein (normal < 10 mg/L); DAS28, disease activity score in 28 joints; ESR, erythrocyte sedimentation rate; HAQ, health assessment questionnaire; RF, rheumatoid factor; MTX, methotrexate.
(a)
(b)
Switchers had AEs than Naivers or Controls, and more withdrew from the study due to AEs than Controls (Table 2). The most common AEs associated with infliximab were infusion-related reactions (IRRs). Patients receiving infliximab had a similar incidence of IRRs (8%) and IRRs leading to withdrawal (5%) compared with the Controls. However, a significantly greater incidence of IRRs (15%) was noted in Switchers versus Controls (Table 2). IRRs occurred most frequently with the second or third infusion of infliximab, clinically presenting with chilling, fever, rash, chest distress and even anaphylactic shock. Infections occurred with a similar frequency in all study groups. However, serious infections such as pneumonia were the second reason for discontinuation in the study (Table 2). Other AEs, including abnormal liver function, leucopenia and cardiac events were mild, and no significant difference was found among the three groups.
DISCUSSION Figure 2 Therapeutic responses in patients with active rheumatoid arthritis. (a) percentage of patients achieving an American College of Rheumatology (ACR)20, ACR50, and ACR70 response at week 18. (b) changes in the percentage of patients achieving an ACR20 response during the 18-week study.
4
This open trial confirms that therapy with infliximab plus MTX provides a rapid clinical remission in patients with active RA despite MTX treatment. Furthermore, data from the study demonstrate that a previous failure with IL-Ra does not influence the response to
International Journal of Rheumatic Diseases 2014
Switching from IL-1Ra to infliximab for RA
(a)
(b)
(c)
(d)
(e)
(f)
(g)
(h)
Figure 3 Mean changes from baseline in the American College of Rheumatology (ACR) score criteria components, and DAS28 throughout the study. Other abbreviations as designated in Table 1 and Fig. 2. Compared with Controls, a significant improvement in (a) tender joint count; (b) swollen joint count; (c) patient’s assessment of pain (VAS); (d) patient’s global assessment of disease activity; (e) physician’s global assessment of disease activity; (f) health assessment questionnaire (HAQ); (g) erythrocyte sedimentation rate (ESR); (h) C-reactive protein (CRP) and (i) DDAS28 (Disease Activity Score of 28 joints). Compared with Controls, - - - -, Compared with Naivers, - - - -.
infliximab, with a similar ACR20 response as biologicnaive patients. Indirect comparisons between cytokine antagonists indicate that anti-TNF-a agents, including infliximab, seem to be more effective in improving disease activity than the IL-1 blocker.6–9 Our findings
International Journal of Rheumatic Diseases 2014
(i)
further indicate a predominant role of TNF-a in the pathogenesis of RA. However, the patients switching from IL-1Ra to infliximab in our study achieved a greater improvement in HAQ score than the biologic-naive patients and the
5
J. Bao et al.
AUTHORS CONTRIBUTIONS
Table 2 Adverse events Patients with AEs, n (%)
Naivers (n = 51)
Controls (n = 26)
Switchers (n = 27)
Any AE Deaths Serious AEs AEs leading to withdrawal Infusion-related reactions (IRRs) IRRs leading to withdrawal Infection Any Serious Abnormal liver function Leukopenia Premature ventricular contraction Post-trauma fraction
10 (20) 0 1 (2) 4 (9) 2 (4)
3 (12) 0 0 0 0
11 (41)*$ 0 3 (11) 4 (15)* 4 (15)*
1 (2)
0
3 (11)
2 (4) 1 (2) 2 (4) 2 (4) 1 (2)
1 (4) 0 1 (4) 1 (4) 0
3 (11) 1 (4) 1 (4) 3 (11) 0
1 (2)
0
0
Values are expressed as number of patient and percentages in parentheses. Compared with Controls, *P < 0.05. Compared with Naivers, $ P < 0.05.
Drs J Bao, Yue and Li carried out the clinical studies and collected data. Drs J Bao and He conceived of the study, participated in its design and coordination. And Dr YX Bao performed the statistical analysis and drafted the manuscript. All authors read and approved the final version to be published.
ACKNOWLEDGEMENT This study was supported in part by grants from National Natural Science Foundation of China (No. 81172782).
CONFLICTS OF INTEREST STATEMENT The authors declare that they have no conflict of interest.
TRIAL REGISTRY Chinese Clinical Trial Register ChiCTR-TRC-10001060.
placebo group. IL-1 is recognized as one of the most crucial cytokines in mediating bone and cartilage destruction.10 Clinical trials showed that the IL-1Ra reduced radiologic progressive joint damage in patients with RA.11 So we suppose that IL-Ra might partly improve joint function by blocking the role of IL-1. When the IL-Ra-failing patients in our study switched to infliximab treatment, infliximab not only reduced manifestations of arthritis, but also sustained joint function obtained with IL-Ra. In the present study, infliximab was well tolerated. Infusion reactions were the most common AEs of infliximab, which is consistent with previous reports.7,12,13 However, patients who were treated with IL-Ra were prone to develop infusion-related reactions following switching treatments. Biological agents are large proteins targeting a specific protein, antibody or receptor, so antibodies against the drug could be assessed after a period of therapy.14 In this study, ILRa may further promote the development of autoantibodies against infliximab, causing more infusionrelated reactions. In conclusion, our study first provides evidence for the efficacy and tolerance of switching from IL-Ra to infliximab in patients with RA. When patients fail IL-Ra, switching to infliximab may be effective in improving disease activity and maintaining joint function. Caution regarding infusion-related reactions should be taken during switching treatment.
6
REFERENCES 1 St. Clair EW (2002) Tides of inflammation: impact of biologics. J Rheumatol 29 (Suppl 65), 22–6. 2 Felson DT, Anderson JJ, Boers M et al. (1995) American College of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum 38, 727–35. 3 Hyrich KL, Lunt M, Watson KD, Symmons DPM, Silman AJ (2007) Outcomes after switching from one anti–tumor necrosis factor a agent to a second anti–tumor necrosis factor a agent in patients with rheumatoid arthritis. Arthritis Rheum 56, 13–20. 4 Felson DT, Anderson JJ, Boers M et al. (1993) The American College of Rheumatology preliminary core set of disease activity measures for rheumatoid arthritis clinical trials. Arthritis Rheum 36, 729–40. 5 Van Gestel AM, Prevoo ML, van’t Hof MA, van Rijswijk MH, van de Putte LB, van Riel PL (1996) Development and validation of the European League Against Rheumatism response criteria for rheumatoid arthritis: comparison with the preliminary American College of Rheumatology and the World Health Organization/International League Against Rheumatism criteria. Arthritis Rheum 39, 34–40. 6 Nixon R, Bansback N, Brennan A (2007) The efficacy of inhibiting tumour necrosis factor a and interleukin 1 in patients with rheumatoid arthritis: a meta-analysis and adjusted indirect comparisons. Rheumatology 46, 1140–7.
International Journal of Rheumatic Diseases 2014
Switching from IL-1Ra to infliximab for RA
7 Gartlehner G, Hansen RA, Jonas BL, Thieda P, Lohr KN (2006) The comparative efficacy and safety of biologics for the treatment of rheumatoid arthritis: a systematic review and metaanalysis. J Rheumatol 33, 2398–408. 8 Blumenauer B, Judd M, Wells G et al. (2002) Infliximab for the treatment of rheumatoid arthritis. Cochrane Database Systematic Rev, C003785. 9 Lipsky PE, van der Heijde DM, St. Clair EW et al. (2000) Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. Infliximab and methotrexate in the treatment of rheumatoid arthritis. N Engl J Med 343, 1594–602. 10 Gravallese EM, Goldring SR (2000) Cellular mechanisms and the role of cytokines in bone erosions in rheumatoid arthritis. Arthritis Rheum 43, 2143–51.
International Journal of Rheumatic Diseases 2014
11 Jiang Y, Genant HK, Watt I et al. (2000) A multicenter, double-blind, dose-ranging, randomized, placebo-controlled study of recombinant human interleukin-1 receptor antagonist in patients with rheumatoid arthritis: radiologic progression and correlation of Genant and Larsen scores. Arthritis Rheum 43, 1001–9. 12 Cheifetz A, Smedley M, Martin S et al. (2003) The incidence and management of infusion reactions to infliximab: a large center experience. Am J Gastroenterol 98, 1315–24. 13 Schaible TF (2000) Long term safety of infliximab. Can J Gastroenterol 14(Suppl C), 29C–32C. 14 Anderson PJ (2005) Tumor necrosis factor inhibitors: clinical implications of their different immunogenicity profiles. Semin Arthritis Rheum 34 (Suppl 1), 19–22.
7
