|Year : 2016 | Volume
| Issue : 3 | Page : 144-148
Experience of biological agents usage in patients with rheumatoid arthritis from a Western Indian center
Anuj Singhal1, Darshan Bhakuni2, Vishal Marwaha3, Vivek Hande4, Garvit Bagga4
1 Department of Rheumatology, INHS Asvini, Mumbai, Maharashtra, India
2 Consultant Rheumatologist, UB Area, Bareilley, Uttar Pradesh, India
3 Department of Rheumatology, Command Hospital, Alipore, Kolkata, India
4 Department of Medicine, INHS Asvini, Mumbai, Maharashtra, India
|Date of Web Publication||11-Aug-2016|
Department of Rheumatology, INHS Asvini, Colaba, Mumbai - 400 005, Maharashtra
Source of Support: None, Conflict of Interest: None
Background: In this study the clinical outcomes of different biologics agents in patients with rheumatoid arthritis (RA) has been appraised.
Methods: Nineteen RA patients with DMARD failure were administered etanercept (n = 7) or infliximab (n = 12), and 17 RA patients with TNFi failure were administered rituximab (n = 13), abatacept (n = 2), or tocilizumab (n = 2) as per 2013 EULAR guidelines. Baseline demographic details, disease duration, rheumatoid factor, and anticyclic citrullinated peptide antibody were obtained. To monitor disease activity, disease activity score 28-erythrocyte sedimentation rate (DAS28-ESR) score was obtained at baseline, and after 3 months and 6 months of therapy initiation.
Results: All the groups were comparable in the baseline. Over 6 months of treatment, the reduction in disease activity, as evidenced by reduction in the mean DAS28-ESR scores was statistically significant for all patients when considered together, as well as when individual biologics were considered separately (P < 0.05 in all cases). However, there was no statistically significant difference in the magnitude of reduction in the mean DAS28-ESR scores between patients who received etanercept and infliximab in DMARD failure RA patients (P = 0.877), or between patients who received rituximab, abatacept, and tocilizumab in TNFi failure patients (P = 0.455).
Conclusions: Different biologic agents showed similar efficacy in patients with RA.
Keywords: Biologics, disease activity, rheumatoid arthritis
|How to cite this article:|
Singhal A, Bhakuni D, Marwaha V, Hande V, Bagga G. Experience of biological agents usage in patients with rheumatoid arthritis from a Western Indian center. Indian J Rheumatol 2016;11:144-8
|How to cite this URL:|
Singhal A, Bhakuni D, Marwaha V, Hande V, Bagga G. Experience of biological agents usage in patients with rheumatoid arthritis from a Western Indian center. Indian J Rheumatol [serial online] 2016 [cited 2017 Mar 28];11:144-8. Available from: http://www.indianjrheumatol.com/text.asp?2016/11/3/144/187412
| Introduction|| |
Rheumatoid arthritis (RA) is the most common inflammatory joint disease seen in clinical practice and is estimated to affect around 1% of the Indian population.  Therapy with disease-modifying antirheumatic drugs (DMARDs) should be started early for RA patients, and a delay of as less as 9 months has been reported to adversely impact clinical outcome.  The most frequently used and also the most efficacious DMARD is methotrexate (MTX). Studies have shown that in patients who fail to respond to MTX, adding another DMARD is associated with limited efficacy and that addition of a biologic therapy is clinically superior. ,
The introduction of biologic response modulators (BRMs) for the treatment of RA has brought in a significant improvement in clinical outcomes of the condition worldwide.  The approved BRMs for RA include the anti-tumor necrosis factor α (TNF) agents (infliximab, adalimumab, etanercept, golimumab, and certolizumab pegol), rituximab, tocilizumab, and abatacept (targeting CD20, interleukin [IL]-6, and CD80/86 respectively). Although the BRMs are effective, their exorbitant cost is the major hindrance for their regular usage, especially in India where most of the treatment is borne by the patient through out-of-pocket spending.  Despite the arrival of biosimilars, the cost of therapy with BRMs is still comparatively higher than that with DMARDs.
Ours is a specialist state-owned health-care organization which provides BRMs free of cost to patients with RA and other rheumatological conditions through government procurement. We were curious to know the comparative clinical outcomes of the usage of different BRMs for RA patients who have continued disease despite being treated with DMARD either as monotherapy or in combination therapy. With this background, we report our experience of BRMs usage in Asian Indian RA patients with DMARD failure and anti-TNF agent failure.
| Methods|| |
We collected data from patients with RA attending the rheumatology OPD of the INHS Asvini Hospital over 2 years between January 1, 2014, and December 31, 2015, referred from across the country since ours is a national level referral institute.
RA patients who showed continued disease activity despite on therapy with DMARD for at least 6 months disease activity score 28-erythrocyte sedimentation rate (DAS28-ESR score >4.6) were declared as cDMARD failure cases and were put on treatment with either etanercept, given as 50 mg per sitting, subcutaneously; the dosing was once a week up to 4 months, once every 2 weeks for 4 months, and once a month for 4 months, or infliximab given as 3 mg/kg intravenous infusion every 2 nd month for 8 doses. The allocation of treatment was determined by patient convenience, affordability, and physician discretion. DMARD-failure patients who could visit us on a weekly basis were started with etanercept therapy, and patients who resided at a distant place were started with infliximab therapy. TNF inhibitor (TNFi) failure patients with high anticyclic citrullinated peptide antibody (ACPAb) titers were started with rituximab, and those with low or normal ACPAb titers were started with abatacept or tocilizumab, based on 2013 EULAR recommendation in treatment of RA.  MTX therapy was continued in these patients as per the 2013 EULAR guidelines. 
The cases where disease activity continued to remain high despite on therapy with an anti-TNF BRM for at least 6-9 months (DAS28-ESR score >4.6) were declared TNFi failure cases, and alternative BRMs were considered. Patients showing high values ACPAb titers were initiated therapy with rituximab, given as 1 g intravenous infusion on days 0, 15, 180, and 195, and those with normal or low-normal ACPAb titers were initiated therapy with abatacept given as 10 mg/kg intravenous infusion monthly for 12 doses, or tocilizumab given as 8 mg/kg intravenous infusion once a month for 12 doses, based on patient convenience, affordability, and physician discretion. MTX therapy was continued in these patients. 
We used rituximab and etanercept biosimilars in all patients; we did not use biosimilars for the other three BRMs (infliximab, abatacept, and tocilizumab).
Randomization was not performed for treatment allocation in either DMARD failure patients or Anti-TNF failure patients. Further, since this was not a clinical trial but a compilation of experience with different agents, informed consent waiver was obtained from the Institutional Ethics Committee.
At the initiation of therapy, in either case, the duration of disease, baseline values of rheumatoid factor (RF) titers and ACPAb titers were collected. For the purpose of this study, normal reference values for RF and ACPAb titers were <15 IU/ml and <20 IU/ml, respectively. DAS28-ESR was calculated at baseline, after 3 months, and after 6 months of therapy was used to measure the disease severity in both cases, and a reduction in DAS28-ESR score by more than two points from initial score, or DAS28-ESR score <3.5 was considered to be a reduction in disease severity.
All data were recorded electronically and analyzed using SPSS version 22 (Armonk, NY: IBM Corp. 2013); P < 0.05 was considered to be statistically significant for all tests applied.
| Results|| |
Patient disposition is summarized in [Figure 1]. A total of 108 RA patients were administered triple DMARD therapy as per COBRA regime, out of which 36 patients did not show satisfactory reduction in DAS28-ESR scores over 6 months. These patients were declared as "RA patients with DMARD failure" and were initiated with etanercept and infliximab; 19 of these showed satisfactory reduction in DAS28-ESR scores.
Patients not showing satisfactory reduction in DAS28-ESR scores over 6-9 months (n = 17) were declared as "RA patients with TNFi failure" and were initiated with rituximab, tocilizumab, or abatacept.
Median number of infliximab infusions was 9 in DMARD failure cases and 4 in TNFi failure cases. For etanercept, the median number of infusion was 24 and 12, respectively. Four doses of rituximab (1 g each) were given over 195 days. Tocilizumab and abatacept were administered as 10-12 monthly doses.
The baseline demographic values are summarized in [Table 1].
Rheumatoid arthritis patients with disease-modifying antirheumatoid drugs failure
Out of the 19 patients, 7 patients received etanercept and 12 received infliximab. Out of the 19 patients, 13 were female (5 etanercept and 8 infliximab), and 6 were male (2 etanercept and 4 infliximab).
The mean age of patients among patients receiving etanercept and infliximab was 39.57 ± 17.56 years and 37.08 ± 11.41 years, respectively. The average duration of disease among patients receiving ETA and INF was 6.28 ± 3.59 months and 26.92 ± 39.23 months, respectively. In both cases, the difference was not statistically significant (age: P = 0.745; duration of disease: P = 0.09; independent samples t-test).
A total of 6 patients on etanercept and 11 patients on infliximab had positive RF titers, and a total of 4 patients on etanercept and 11 patients on infliximab had positive ACPAb titers. This distribution of patients was not significantly different (P = 1.00 for RF titers and P = 0.117 for ACPAb titers; Fisher's exact test).
The mean DAS28-ESR scores at baseline, 3 months, and 6 months is summarized in [Table 2]. The distribution of mean DAS28-ESR scores over 6 months among these patients is shown in [Figure 2]. Overall, the improvement in disease, as evidenced by reduction in the mean DAS28-ESR scores over 6 months of treatment was statistically significant for all patients when considered together (P < 0.0001), as well as when etanercept and infliximab were considered separately (P = 0.0011 and 0.0113, respectively). However, there was no statistically significant difference in the magnitude of reduction in the mean DAS28-ESR scores between patients who received etanercept and those who received infliximab (P = 0.877).
|Figure 2: Mean disease activity score 28-erythrocyte sedimentation rate scores over 6 months in disease-modifying antirheumatoid drugs failure rheumatoid arthritis patients receiving etanercept and infliximab|
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|Table 2: Mean disease activity score 28-erythrocyte sedimentation rate scores over 6 months in disease-modifying anti-rheumatoid drugs failure rheumatoid arthritis patients receiving Etanercept and Infliximab |
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Two patients who received etanercept reported mild, self-limited flu-like transfusion reaction, and two patients on infliximab had self-limiting cutaneous rashes. There were no serious reactions which required treatment discontinuation.
Rheumatoid arthritis patients with antitumor necrosis factor biologics failure
Out of the 17 patients, 13 patients received rituximab, 2 received abatacept, and 2 received tocilizumab. Out of the 17 patients, 14 were female (10 rituximab, 2 abatacept, and 2 tocilizumab) and 3 were male (3 rituximab).
The mean age of patients among patients receiving rituximab, abatacept, and tocilizumab was 42.38 ± 14.23 years, 29.50 ± 7.78 years, and 50.00 ± 8.49 years, respectively. The average disease duration among patients receiving rituximab, abatacept, and tocilizumab was 34.54 ± 53.66 months, 7.50 ± 6.36 months, and 43.50 ± 44.55 months, respectively. In both cases, the difference was not statistically significant (age: P = 0.329; duration of disease: P = 0.748; one-way ANOVA).
By statistical analysis, it appeared that a significantly higher number of patients who received rituximab had a higher baseline RF and ACPAb titers; however, this should be viewed with caution because there were very few observations in the abatacept and tocilizumab groups.
The mean DAS28-ESR score at baseline, 3 months, and 6 months is summarized in [Table 3]. The distribution of mean DAS28-ESR scores over 6 months among these patients is shown in [Figure 3]. Overall, the improvement in disease, as evidenced by reduction in the mean DAS28-ESR scores over 6 months of treatment was statistically significant for all patients when considered together (P = 0.0003), as well as for those patients who received rituximab (P = 0.0073); this reduction was not statistically significant in patients who received abatacept and tocilizumab (P = 0.2097 and 0.1336, respectively). This difference in response to treatment should be viewed with caution, considering the fact that there were very few observations in the abatacept and tocilizumab group. Finally, there was no statistically significant difference in the magnitude of reduction in the mean DAS28-ESR scores between patients who received any of the three biologics (P = 0.455).
|Figure 3: Mean disease activity score 28-erythrocyte sedimentation rate over 6 months in antitumor necrosis factor biologics failure rheumatoid arthritis patients receiving rituximab, abatacept, and tocilizumab|
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|Table 3: Mean disease activity score 28-erythrocyte sedimentation rate scores over 6 months in antitumor necrosis factor biologics failure rheumatoid arthritis patients receiving rituximab, abatacept, and tocilizumab |
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Two patients who received rituximab reported mild, self-limited flu-like transfusion reaction, and another patient had an abdominal wall abscess which did not require rituximab discontinuation. There were no serious reactions which required any treatment withdrawals.
| Discussion|| |
The introduction of BRMs brought in a landmark change in the treatment of RA. The success of BRMs targeting TNF-α and ILs 1 and 6 has reaffirmed the role of these cytokines in the pathogenesis of RA. 
According to the 2015 ACR guidelines, patients having established RA with moderate or high disease activity despite DMARD therapy (with or without glucocorticoids) may be treated with either a combination of DMARD or a TNFi or with a non-TNF BRM, with or without MTX. In case, the disease activity is moderate to high despite a single TNFi BRM therapy; the ACR guidelines recommend using a non-TNF biologics.  The guideline does not elaborate upon the sequence of choice among the different TNFi BRMs and the non-TNF BRMs.
We used the DAS28-ESR score to analyze the response of various biologics.  Remission, low disease activity, moderate disease activity, and high disease activity are determined based on cutoff points of 2.6, 3.2, and 5.1, respectively.  In our study, because of the restriction of the sample size, we used mean values of DAS28-ESR for analyzing the effect of different biologics on disease activity.
Comparative studies between biologics for efficacy in RA are lacking. A 2009 Cochrane review compared individual Cochrane reviews which studied the safety and efficacy of different BRMs - abatacept, adalimumab, anakinra, etanercept, infliximab, and rituximab - in RA. The authors found that almost all BRMs had similar efficacy as per the ACR50 (American College of Rheumatology criteria for 50% improvement), the exceptions being anakinra being less efficacious than etanercept and adalimumab being more efficacious than anakinra. In terms of safety, the authors concluded that the withdrawal rate was higher with adalimumab than with etanercept, higher with anakinra than with etanercept, and higher with infliximab than with etanercept. 
In our study, we found that in both the scenarios, namely, in RA patients with DMARD failure and in RA patients with anti-TNF agent failure, all the BRMs used resulted in a significant improvement in disease activity as evidenced by a reduction in the DAS28-ESR scores. In the DMARD failure group, there was no significant difference in the mean reduction of DAS28-ESR by etanercept and infliximab, and in the anti-TNF agent failure group, there was no significant difference in the mean reduction of DAS28-ESR by rituximab, tocilizumab, and abatacept.
Previous studies which have compared the efficacy of different BRMs in RA have generally concluded that the efficacy of BRMs is similar. ,,
The major limitation of this study is its inadequate sample size, and hence the results need to be interpreted with caution. However, keeping in mind, the expenditure incurred in the administration of a BRM, these results should not be discarded. Further, since randomization was not followed and allocation of drug was based on factors such as severity of disease and patient convenience, the impact of these factors on the outcome cannot be ruled out completely. Keeping in mind, the results of this study, further randomized studies are warranted with a larger sample size.
| Conclusions|| |
To conclude, for RA patients with DMARD failure, etanercept and infliximab offer similar reduction in disease severity, and for RA patients who have continued disease despite treatment with anti-TNF agents, rituximab, tocilizumab, and abatacept offer statistically similar reduction in disease severity, as evidenced by reduction in DAS28-ESR. The selection of appropriate BRM may be driven by factors such as patient convenience, affordability, and disease severity.
The authors acknowledge the assistance of MarksMan Healthcare Solutions Pvt Ltd, Mumbai, in the statistical analysis, preparation, and processing of manuscript.
Financial support and sponsorship
The Biologics used in the study were provided to the patients free of cost by the Government of India.
Conflicts of interest
There are no conflicts of interest.
| References|| |
Tsakonas E, Fitzgerald AA, Fitzcharles MA, Cividino A, Thorne JC, M′Seffar A, et al.
Consequences of delayed therapy with second-line agents in rheumatoid arthritis: A 3 year followup on the hydroxychloroquine in early rheumatoid arthritis (HERA) study. J Rheumatol 2000;27:623-9.
van der Kooij SM, de Vries-Bouwstra JK, Goekoop-Ruiterman YP, van Zeben D, Kerstens PJ, Gerards AH, et al.
Limited efficacy of conventional DMARDs after initial methotrexate failure in patients with recent onset rheumatoid arthritis treated according to the disease activity score. Ann Rheum Dis 2007;66:1356-62.
van Vollenhoven RF, Ernestam S, Geborek P, Petersson IF, Cöster L, Waltbrand E, et al.
Addition of infliximab compared with addition of sulfasalazine and hydroxychloroquine to methotrexate in patients with early rheumatoid arthritis (Swefot trial): 1-year results of a randomised trial. Lancet 2009;374:459-66.
Roshique KK, Ravindran V. Efficacy and safety of a biosimilar rituximab in biologic naïve patients with active rheumatoid arthritis. Clin Rheumatol 2015;34:1289-92.
Shahrawat R, Rao KD. Insured yet vulnerable: Out-of-pocket payments and India′s poor. Health Policy Plan 2012;27:213-21.
Smolen JS, Landewé R, Breedveld FC, Buch M, Burmester G, Dougados M, et al.
EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis 2014;73:492-509.
Scott DL. Biologics-based therapy for the treatment of rheumatoid arthritis. Clin Pharmacol Ther 2012;91:30-43.
Singh JA, Saag KG, Bridges SL Jr., Akl EA, Bannuru RR, Sullivan MC, et al.
2015 American College of rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken) 2016;68:1-25.
Inoue E, Yamanaka H, Hara M, Tomatsu T, Kamatani N. Comparison of disease activity score (DAS) 28- erythrocyte sedimentation rate and DAS28- C-reactive protein threshold values. Ann Rheum Dis 2007;66:407-9.
Fransen J, Stucki G, van Riel P. Rheumatoid arthritis measures: Disease activity score (DAS), Disease activity score-28 (DAS28), Rapid assessment of disease activity in rheumatology (RADAR), and Rheumatoid arthritis disease activity index (RADAI). Arthritis Rheum 2003;49(S5):S214-24.
Singh JA, Christensen R, Wells GA, Suarez-Almazor ME, Buchbinder R, Lopez-Olivo MA, et al
. Biologics for rheumatoid arthritis: An overview of Cochrane reviews. Cochrane Database Syst Rev 2009;(4):CD007848.
Devine EB, Alfonso-Cristancho R, Sullivan SD. Effectiveness of biologic therapies for rheumatoid arthritis: An indirect comparisons approach. Pharmacotherapy 2011;31:39-51.
Strehblow C, Haberhauer G, Fasching P. Comparison of different biologic agents in patients with rheumatoid arthritis after failure of the first biologic therapy. Wien Med Wochenschr 2010;160:225-9.
Gartlehner G, Hansen RA, Jonas BL, Thieda P, Lohr KN. The comparative efficacy and safety of biologics for the treatment of rheumatoid arthritis: A systematic review and metaanalysis. J Rheumatol 2006;33:2398-408.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]