|Year : 2018 | Volume
| Issue : 3 | Page : 163-167
Safety and efficacy of abatacept among patients with refractory rheumatoid arthritis: Experience from a North Indian Tertiary Care Hospital
MN Arjun1, Arun Hegde1, Krishnan Shanmuganandan2, Darshan S Bhakuni3, Kavita Singh4, Abhishek Kumar5
1 Department of Rheumatology, Army Hospital (Research and Referral), New Delhi, India
2 Department of Rheumatology, Miot Hospital, Chennai, Tamil Nadu, India
3 Department of Rheumatology, Command Hospital, Lucknow, Uttar Pradesh, India
4 Centre for chronic disease control, PHFI, Gurgaon, Haryana, India
5 Department of Rheumatology, Command Hospital, Kolkata, West Bengal, India
|Date of Web Publication||21-Aug-2018|
Dr. Arun Hegde
Department of Rheumatology, Army Hospital (Research and Referral), Delhi Cantt, New Delhi - 110 010
Source of Support: None, Conflict of Interest: None
Background: T-cells are pathogenic in rheumatoid arthritis (RA) and have an important role in persistent synovitis, even in established disease. Modulation of T-cell activity by blocking of costimulatory signals has been known to suppress inflammation and improves prognosis in RA. This study aims to assess the effect of costimulation blockade with Abatacept in patients with RA who were refractory to conventional synthetic/biological disease modifying anti-rheumatoid drugs (csDMARDs, bDMARDs).
Methods: In this prospective study, 63 patients with active disease, measured by the European League Against Rheumatism (EULAR) disease activity score (DAS28-erythrocyte sedimentation rate [ESR]) ≥3.2, who had failed conventional therapy with at least 2 csDMARDs and/or antitumour necrosis factor (anti-TNF) agents (Infliximab/Etanercept) either standalone, or in combination, were initiated on Abatacept in fixed doses, which was given on days 1,15, and 29 and repeated every 28 days for 11 months, after taking informed consent. Biomarkers comprising ESR and DAS28-ESR score were measured at baseline and repeated at the end of 3, 6, and 12 months. The primary end-point was the achievement of remission as defined by DAS28-ESR score ≤ 2.6.
Results: Sixty-three patients completed 6 monthly follow-up whereas 57 patients completed 12 months follow-up (90% follow-up rate). DAS28-ESR declined significantly at 3 months (P = 0) and improvements were sustained at 6th and 12th month. Treatment was discontinued in three patients due to inadequate response, and three patients were lost to follow-up. Nearly 52.6% patients achieved primary end-point. Most common adverse effects reported during the study period were headache (14.2%) and upper respiratory tract infection (9.5%).
Conclusions: Abatacept is an effective and well-tolerated treatment option for Indian RA patients with an inadequate response to csDMARDs and TNF antagonists.
Keywords: Abatacept, costimulation, efficacy, refractory, rheumatoid arthritis, safety
|How to cite this article:|
Arjun M N, Hegde A, Shanmuganandan K, Bhakuni DS, Singh K, Kumar A. Safety and efficacy of abatacept among patients with refractory rheumatoid arthritis: Experience from a North Indian Tertiary Care Hospital. Indian J Rheumatol 2018;13:163-7
|How to cite this URL:|
Arjun M N, Hegde A, Shanmuganandan K, Bhakuni DS, Singh K, Kumar A. Safety and efficacy of abatacept among patients with refractory rheumatoid arthritis: Experience from a North Indian Tertiary Care Hospital. Indian J Rheumatol [serial online] 2018 [cited 2019 Aug 17];13:163-7. Available from: http://www.indianjrheumatol.com/text.asp?2018/13/3/163/234005
| Introduction|| |
The use of tumor necrosis factor antagonists (anti-TNFs) revolutionized the treatment and prognosis of rheumatoid arthritis (RA) ever since their advent 20 years back. However, there still existed a subset of patients (20%–40%), who showed either no response or inadequate response to these agents, or in addition develop antibodies against the anti-TNF inhibitors, thereby reducing clinical responses. In such patients, T-cell costimulation blockade provided an alternative mechanism of action in these patients, as was depicted early on from a study by Moreland et al. in 2002.
Abatacept is a soluble, fully human, recombinant fusion protein consisting of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen-4 linked to the Fc (hinge, CH2 and CH3 domains) portion of human immunoglobulin G1, which has been modified to prevent complement fixation. This selectively modulates the CD80/CD86:CD28 costimulatory signal, as a result disrupting the activation of T-cells, resulting in reduced proinflammatory cytokine production and downstream immune modulation.
After Moreland et al. in 2002, the effectiveness of Abatacept has been well proven in various subset of patients, like in methotrexate (MTX) and other conventional synthetic disease modifying anti-rheumatoid drugs (csDMARDs) refractory RA, in Phase IIb studies,, Phase III studies (AIM study, ATTEST study, and ASSURE study ), in anti-TNF refractory RA patients (ATTAIN study, ARRIVE study, and ASSURE study ), in DMARD-naive early RA patients. Safety of Abatacept has also been assessed in patients with various comorbidities by Weinblatt et al. in the ASSURE study  and ARRIVE study.
Studies involving biologics on Indian patients have shown differences in clinical responses in Indian versus the Western population, as well as a difference in the side effect profile, a case in point being a recently published study on the safety and efficacy of B-cell depletion in RA by Hegde et al., wherein the authors found that fewer patients achieved a European League Against Rheumatism (EULAR) good response after 24 weeks of rituximab as compared to landmark Western studies along with a lesser fall in immunoglobulin M levels with fewer incidence of infusion reactions. Few studies in literature have also studied pain tolerance and perception in various ethnic groups, with none finding any significant difference in the Indian population, contrary to common belief.
The aim of our study thus was to assess the safety and efficacy of Abatacept in Indian patients with moderate to severe RA who showed inadequate response or intolerance to conventional and/or biological DMARDs (csDMARDs and bDMARDs).
| Methods|| |
We conducted a prospective observational open-label study evaluating the safety and efficacy of Abatacept in Indian patients with RA refractory to csDMARDs/bDMARDs.
Patients and data collection
A total of 63 patients with moderate to severe RA, classified as per 2010 ACR/EULAR criteria, who were attending a tertiary care hospital in North India, were recruited, both from the rheumatology outpatient clinic and the inpatient ward. Patients were recruited for the study over a period of 36 months from August 2013 to July 2016. All patients recruited were above 18 years of age, had active disease, defined by a disease activity score in 28 joints (DAS28-erythrocyte sedimentation rate [ESR]) ≥3.2, despite having been on at least 2 csDMARDs in optimal doses (MTX 20 mg/weeks or leflunomide 20 mg OD or sulfasalazine 1 g BD or hydroxychloroquine 300 mg OD) for a period of at least 3 months. Steroids (prednisolone or equivalent, <10 mg/day) and nonsteroidal anti-inflammatory drugs were permitted if their doses had remained stable for at least 4 and 2 weeks respectively, before enrollment. Patients who had inadequate response to one or more anti-TNF agents at approved doses, after at least 3 months of treatment were also included in the study group. Exclusion criteria included patients with active infection and pregnant/lactating women.
A questionnaire was used to collect the data of all 63 patients enrolled in the study, to collect information regarding demographic factors and past and present health status of the patients. The baseline history was recorded to include features as enumerated in 2010 ACR/EULAR classification criteria for RA. Clinical evaluation included the estimation of the tender joint count and the swollen joint count.
All patients were screened for latent tuberculosis (TB) using a TB QuantiFERON Gold test and a X-ray Chest. Patients who were positive for TB QuantiFERON, received prophylaxis for latent TB with isoniazid and rifampicin for 4 months. All had normal X-ray chest.
Abatacept was administered 4 weeks after starting prophylaxis for latent TB.
The study group received a fixed dose of Abatacept approximately 10 mg/Kg body wt (Pt weighing <60 kg received 500 mg, 60–100 kg received 750 mg). The study drug was administered by a trained physician in a 30-min intravenous infusion on days 1, 15, and 29 and repeated every 28 days.
ESR was done at baseline/3/6/12 months using the Westergren method. Rheumatoid factor was done by nephelometry with cutoff 20 IU/mL and anti-citrullinated peptide antibody titres by enzyme-linked immunosorbent assay with cut off 10 U/ml. Treatment efficacy was evaluated by estimation of disease activity using the EULAR DAS28-ESR. For the DAS28, cutoff points for high-disease activity, moderate disease activity, low-disease activity (LDA) and remission were 5.1, 3.2, 2.6, and <2.6, respectively. DAS28 scores were analyzed at baseline, 3rd, 6th, and 12th month. The primary outcome was defined as achievement of a DAS28-ESR score ≤2.6.
All results were reported as mean and 95% confidence intervals.
Statistical analysis was performed using the STATA/SE software, version 12 (College Station, TX, USA: StataCorp LP). Appropriate testing was performed according to the results of normality tests. Student's t-test was used to analyze continuous and normally distributed data, and the Chi-square statistic was used to analyze qualitative data. P < 0.05 was considered statistically significant.
The study was approved by the ethics committee of the institute. Informed written consent was obtained from all patients prior to their enrollment in this study.
| Results|| |
The age group of patients varied from 26 to 59 years. The mean age of study participants was 43.7 years (standard deviation-8.61). The male: female ratio was 1:3.5. The median duration of RA was 5 years (2–21 years). Other baseline characteristics are summarized in [Table 1]. All 63 patients completed 6 months follow-up whereas 57 (90.47%) were followed up till 12 months. Six patients (9.53%) discontinued the study prematurely. Treatment discontinuation was attributed to inadequate response (n = 3, 4.7%) and lost to follow-up (n = 3). Five (7.93%) patients had prior history of pulmonary TB and had completed at least 6 months of antitubercular treatment before recruitment in the study.
The pattern of csDMARD at baseline is as shown in [Figure 1].
Abatacept was administered as the first biological agent in 82.5% of the patients (n = 52), whereas an anti-TNF-α agent had been used before the use of Abatacept in 11 patients (17.46%). Ten (15.87%) patients had received infliximab, whereas 1 (1.58%) received Etanercept.
Screening for latent TB revealed that 5 (7.93%) patients were positive by TB QuantiFERON Gold. All had a normal X-ray Chest.
The mean DAS28-ESR scores at baseline were 6.01 (5.86, 6.13). Mean DAS scores declined significantly to 4.46 (4.28,4.63, P = 0) at 3 months, 3.61 (3.29, 3.71, P = 0) at 6 months and 2.52 at 12 months (2.37, 2.67, P = 0). Thus, the DAS28 scores declined by 58.3% from baseline. At 6 months, a total of 7 (11.1%), and 14 (22.2%) achieved remission and LDA whereas 39 (61.9%) and 3 (4.7%) continued to have moderate- and high-disease activity, respectively. At 12 months, a total of 30 (52.6%) and 17 (29.8%) achieved remission and LDA whereas 10 (17.5%) patients continued to have moderate disease activity. [Figure 2] demonstrates the DAS28-ESR response to Abatacept over the treatment period.
|Figure 2: Mean change in disease activity score 28 joint-erythrocyte sedimentation rate over the study period|
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Subgroup analysis of the csDMARDs + anti-TNF group (n = 11) versus the csDMARDs only group (n = 52) who received Abatacept, revealed baseline mean DAS-28 scores to be 5.6 and 6.1 respectively. At 6 monthly follow up, the DAS28 scores declined to 3.4 and 3.6 respectively (P = 0.5), and at 12 monthly follow-up, to 2.3 and 2.6 (P = 0.2). There was no statistically significant difference in response among both groups. The above findings are summarized in [Table 2].
|Table 2: Comparison of disease activity score in 28 joints erythrocyte sedimentation rate values over 12 months for patients taking conventional synthetic disease modifying anti-rheumatoid drugs * anti-tumour necrosis factor agents versus patients taking conventional synthetic disease modifying anti-rheumatoid drugs only|
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Treatment-related adverse events
The most frequently reported adverse effects (AEs) during this period were headache (14.2%) and upper respiratory tract infection (URTI) (9.5%). There were no serious infusion reactions, reports of opportunistic infections or reactivation of TB. The AEs are summarized in [Table 3]. There were no discontinuations due to AEs.
| Discussion|| |
Abatacept is a well-tolerated biological response modifier with a unique mode of action with an acceptable safety profile. It has been already tested in clinical trials involving nearly 3000 patients with RA who had an inadequate response to MTX or other csDMARDs, or who had failed treatment with anti-TNF agents. The safety profile of Abatacept is supported by high rates of patient retention in the open-label studies, suggesting a combined efficacy and safety profile that is acceptable to both patients and treating rheumatologists. However, there exists a paucity of data regarding its safety and efficacy in Indian patients with refractory RA.
We evaluated the efficacy and safety of Abatacept in Indian patients with active RA who had an inadequate clinical response to csDMARDs and/or anti-TNF inhibitors, given either alone or in combination. All patients had long-standing disease (mean duration-5 years) which was comparable with the patients recruited across the landmark Abatacept studies, AIM (8.5 years), and ATTEST (7.9 years). All patients had high-disease activity with DAS28 scores (DAS28-ESR-6) comparable to patients in the AIM (6.4), ATTAIN (6.5) and ATTEST (6.9) studies. We found clinically meaningful and statistically significant improvements in this refractory population. Nearly 11.1% and 52.6% patients achieved the primary outcome of remission at 6 and 12 months, respectively, as compared with 14.8% and 23.8% in AIM study, 10% at 6 months in the ATTAIN study, and 11.3% and 18.7% in the ATTEST studies. Our study reveals a higher percentage of patients achieving remission at the end of 12 months. Various reasons could account for this difference, such as variations in pain perception among patients. In addition, Indians are a racially different population when compared to other ethnic populations and could be manifesting a totally different response. This aspect requires further study. In addition, patients in our study had disease duration lesser than the other studies at recruitment, which could have led to a better response. The DAS28 responses across 12 months in our study and other studies is summarized in [Figure 3]. Subgroup analysis in our study did not reveal a statistically significant difference in DAS28 responses at 6 and 12 months in the csDMARDs/Anti-TNF agents combination group compared to the csDMARDs group. The reason for this could be due to smaller sample size in the anti-TNF group compared to the csDMARDs group.
|Figure 3: Percentage of patients attaining low disease activity and remission across various studies|
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Our safety findings were consistent with other studies. Headache (14.2%) and URTI (9.5%), were the most common AEs noted, the occurrence of which was similar to the AIM (URTI-10.9%) and ATTAIN (Headache-12.4%, URTI-5.8%) study. In addition, none had opportunistic infections or reactivation of TB. The reason for this could have been a better screening protocol preinfusion and proper periodic follow-up of these patients. In addition, we had used the TB QuantiFERON Gold test instead of the tuberculin test, for the screening of latent TB, which could have accounted for an early and accurate diagnosis of latent TB. Discontinuation due to AEs or inadequate response occurred in 9.4% of our patients which was higher than in the AIM (4.2%) study. The possible reason for this could be slow onset of efficacy as perceived by patients and possible use of alternative therapies.
These findings should be interpreted within the context of the limitations of our study. It carries all weaknesses of an open-label study design. The trial duration of 1 year precludes the determination of whether long-term treatment will be associated with the emergence of other potential toxicities. A larger study population will be required to detect a wider range of toxicities. Our current study assessed the effects of Abatacept in patients with established RA and was not designed to investigate the effects in Early RA. We did not collect data pertaining to impact on patient's health-related quality of life and radiographic progression, which prevents us from assessing these important aspects of efficacy.
In conclusion, the present study with a large number of patients and excellent adherence to the treatment protocol strengthens the case for long-term use of Abatacept as an effective, safe, and well-tolerated therapeutic option for difficult-to-treat subset of Indian patients who are MTX and other csDMARDs nonresponders or in those wherein previous anti-TNF therapy had failed.
Financial support and sponsorship
The biologics used in this study were provided free to the patients by the Government of India, and all laboratory investigations were carried out in the hospital laboratory free of cost.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]