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ORIGINAL ARTICLE
Ahead of print publication  

Clinical efficacy and safety of tocilizumab in the treatment of seropositive rheumatoid arthritis patients in India


1 Department of Rheumatology, Command Hospital (Eastern Command), Kolkata, West Bengal, India
2 Department of Rheumatology, Manipal Hospital, New Delhi, India
3 Department of Rheumatology, Sree Balaji Medical College and Hospital, Chrompet, Chennai, Tamil Nadu, India
4 Department of Rheumatology, Command Hospital (Southern Command), Pune, Maharashtra, India
5 Department of Rheumatology, Command Hospital (Central Command), Lucknow, Uttar Pradesh, India
6 Department of Rheumatology, Command Hospital (Western Command), Chandigarh, India

Date of Submission19-Apr-2020
Date of Acceptance13-Jul-2020

Correspondence Address:
Arun Hegde,
Department of Rheumatology, Command Hospital (Southern Command), Pune - 411 040, Maharashtra
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injr.injr_98_20

  Abstract 


Background: Tocilizumab (TCZ) is a human interleukin (IL)-6 receptor (IL-6R) antibody which competitively inhibits IL-6 signal transduction. Clinical efficacy and safety of TCZ in the treatment of rheumatoid arthritis (RA) and other autoimmune conditions have been established. However, there is a lack of data on its use in the Indian population.
Objective: The objective was to study the clinical efficacy and safety of TCZ in Indian patients with seropositive RA.
Patients and Methods: This was a prospective, observational single-center study conducted at a tertiary care rheumatology center. All patients were more than 16 years of age, fulfilled the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria for RA, and had at least moderate disease activity as measured by disease activity score-28 joints erythrocyte sedimentation rate (DAS28-ESR) ≥3.2 at enrollment while on at least two disease-modifying antirheumatic drugs. Patients with latent tuberculous infection were excluded from the study. Six doses of TCZ were administered at 8 mg/kg body weight dose at four weekly interval and clinical response was assessed at each visit.
Results: All 30 patients enrolled completed the study. Baseline DAS28-ESR was 5.03 (SD0.39) which improved to 2.4 (△-2.6; 95% confidence interval: 2.30–3.04; P < 0.005) after 24 weeks. A total of 19 (63.3%) patients achieved remission (DAS-28 ESR < 2.6) at 24 weeks, while 25 (83.3%) patients showed a good EULAR response. No serious adverse effect was noted in any of the patients.
Conclusions: TCZ is an effective and safe option for the treatment of seropositive RA.

Keywords: Biological disease-modifying antirheumatic drug, IL-6 receptor antagonist, interleukin-6, rheumatoid arthritis, tocilizumab



How to cite this URL:
Kumar A, Bhakuni DS, Shanmuganandan K, Hegde A, Vasdev V, Arjun M N, Kishore K. Clinical efficacy and safety of tocilizumab in the treatment of seropositive rheumatoid arthritis patients in India. Indian J Rheumatol [Epub ahead of print] [cited 2020 Oct 27]. Available from: https://www.indianjrheumatol.com/preprintarticle.asp?id=297407




  Introduction Top


Rheumatoid arthritis (RA) is the most common form of chronic inflammatory arthritis characterized by persistent synovitis and symmetric, peripheral, erosive polyarthritis and often leads to joint deformities in inadequately treated patients.[1],[2] The advent of biological disease-modifying antirheumatic drugs (bDMARDs) in the past few decades has transformed this debilitating disease into a chronic manageable condition. These bDMARDs target the various cytokines involved in the pathogenesis of RA and interleukin-6 (IL-6) is one of them.[3] IL-6 is a pro-inflammatory cytokine produced by several types of cells including fibroblasts and monocytes.[4] It has been found to exert multifaceted immunogenic effects including T-cell activation, B-cell proliferation, and antibody production.[5] It is one of the principal cytokines for the induction of osteoclast differentiation which contributes to erosive arthritis in RA.[6]

Tocilizumab (TCZ) is a human IL-6 receptor (IL-6R) antibody which competitively inhibits IL-6 signal transduction by binding with the membrane-bound as well as soluble IL-6R.[3] Clinical efficacy and safety of TCZ in the treatment of RA in patients who have failed to respond to conventional synthetic DMARDs (csDMARD) as well as other classes of bDMARD have been established.[7],[8],[9] However, there is a lack of data on its use in the Indian population. This study was conducted to assess the clinical efficacy and safety of TCZ in Indian patients.

Objectives

The objective was to study the clinical efficacy and safety of TCZ in the Indian patients of seropositive RA.


  Patients and Methods Top


This was a prospective, observational single-center study done at a tertiary care rheumatology center. Thirty patients with seropositive RA fulfilling ACR/EULAR classification criteria 2010 and more than 16 years of age were recruited from the rheumatology outpatient department as well as from inpatients admitted to the rheumatology ward of the hospital from December 2014 to February 2017.[10] All patients had active disease, defined by a disease activity score in 28 joints – erythrocyte sedimentation rate (DAS 28-ESR) ≥3.2 despite having been on at least two csDMARDs in optimal doses (methotrexate (20 mg) once weekly or leflunomide (20 mg) daily or sulfasalazine (1 g) twice daily or hydroxychloroquine (200 mg) daily) for at least 3 months. Glucocorticoids (prednisolone or equivalent [<10 mg/day]) and nonsteroidal anti-inflammatory drugs were permitted if their doses had remained stable for at least 4 weeks and 2 weeks, respectively, before enrollment. Patients on any other class of bDMARD who had the active disease after at least 3 months of treatment at approved doses were also included in the study.

Patients with an active infection, cytopenia (absolute neutrophil count <2000 cells/mm3 and platelet count <100,000/mm3), pregnancy, and lactation were excluded from the study. Any patient with evidence of hepatitis B or hepatitis C infection, alanine transaminase, or aspartate transaminase (AST) levels >1.5 times the upper level of normal (ULN) or any evidence of liver disease were also not enrolled. Patients who were found to have latent tuberculosis as assessed by TB QuantiFERON Gold test or evidence of active tuberculous infection on plain chest skiagram were also excluded from the study.

Treatment efficacy was evaluated by estimation of disease activity using the DAS28-ESR score: Ranges of DAS28-ESR scores and the corresponding stratification of disease severity used were high disease activity (HDA) ≥5.1, moderate disease activity (MDA) <5.1, low disease activity (LDA) <3.2, and remission <2.6.[11],[12] The EULAR response rate was analyzed at 24 weeks.[13]

All the patients underwent baseline clinical and laboratory evaluations. Patients were given injection TCZ (8 mg/kg) through intravenous route every month for 6 consecutive doses without any premedications. Clinical and laboratory evaluation (ESR, C-reactive protein [CRP], complete blood count, liver function test, and lipid profile) was done at baseline, 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, and 24 weeks. Rheumatoid factor (RF) and CRP were done using nephelometry (Beckman-Coulter system). The cutoff for the normal value of RF and CRP was 20 IU/ml and 10 mg/L, respectively. Anti-citrullinated protein antibodies (ACPAs) level was measured using enzyme-linked immunosorbent assay (DRG Instruments, GmbH, Germany). The cutoff level for the normal value of ACPA was 10 U/mL.

Patients were screened for possible adverse effects by clinical evaluation and laboratory tests at four weekly intervals from the first dose of TCZ until 24 weeks. They were screened for infections and symptoms of hepatotoxicity. Absolute neutrophil count, platelet count, serum bilirubin, alanine transaminase (ALT), aspartate transaminase (AST), total cholesterol, triglyceride, and high-density lipoprotein and low-density lipoprotein (LDL) levels were determined. Hematological parameters were measured using Siemens Advia® 2120i Autoanalyzer and biochemical parameters were measured using Siemens Dimension® RxL Max® Autoanalyzer. Approval of the institutional ethical committee and the scientific committee was obtained and written informed consent for participation in the study was obtained from all enrolled subjects.

Statistical analysis

Univariate analyses, such as frequency, mean, standard deviation (SD), and range (minima and maxima) were performed to summarize the baseline characteristics of the study participants. Kurtosis was used to define the normality of the variable. Paired t-test was used for continuous variables and Chi-square test for categorical variables. All analyses were performed using (STATA version 12.0 SE; StataCorp, TX, USA) and two-sided P < 0.05 was used to indicate statistical significance for all tests.


  Results Top


This was an observational study in which clinical response to TCZ was evaluated in csDMARD refractory seropositive RA patients. A total of 34 patients were screened. Four of them were screened out, of which two had evidence of latent tuberculosis infection, one had baseline raised transaminases, and another patient was HBsAg positive. The remaining 30 patients were enrolled and all of them completed the study. The mean age of the patient was 44.53 years (SD: 13.6). Patients had a mean duration of disease of 9.4 years (SD: 7.1). There were 21 (70%) female patients and 9 (30%) male patients with a female-to-male ratio of 2.3:1. Twenty-eight (93.3%) patients were RF positive and 13 (43.3%) patients were ACPA positive. Details of csDMARDs and bDMARDs used by the patients are given in [Table 1].
Table 1: Baseline characteristics of the study participants (n=30)

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Mean ESR and CRP at baseline were 65 mm (SD 27) and 31.2 mg/L (SD 19.7), respectively. Mean DAS28-ESR at baseline was 5.03 (SD 0.39).

There was a statistically significant improvement in disease activity after the first dose of TCZ. The mean DAS28-ESR reduced from the baseline value of 5.0 to 3.5 at 4 weeks (△-1.5; 95% confidence interval [CI]: 1.18–1.77; P < 0.005). Further decrease in the mean DAS28 ESR was noted, and at week 24, it had reduced to 2.4, as shown in [Figure 1] (△-2.6; 95% CI: 2.30–3.04; P < 0.005).
Figure 1: Clinical response to tocilizumab: Mean TJC, SJC, and DAS28-ESR score of the study patients at baseline and during follow-up (DAS28-ESR: Disease activity score 28 joints-erythrocyte sedimentation rate; SJC: Swollen joint count; TJC: Tender joint count)

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[Figure 2] represents the number of patients in different strata of disease activity at baseline and during follow-up. After the first dose of TCZ, 4 (13.3%) patients achieved remission and 5 (16.7%) patients attained LDA. However, after the second dose of TCZ, 14 (46.7%) patients attained remission and 7 (20.3%) patients had LDA. At the end of 24 weeks, 19 (63.3%) patients achieved remission, 6 (20%) patients had attained LDA, while 5 (16.7%) had MDA. Twenty-five (83.3%) patients achieved EULAR good response at 24 weeks. One patient achieved a moderate response, while four patients did not show a significant response.
Figure 2: Number of patients in different strata of DAS28-ESR disease activity at baseline and during therapy (DAS28-ESR: Disease activity score 28 joints-erythrocyte sedimentation rate; HDA: High disease activity; LDA: Low disease activity; MDA: Moderate disease activity)

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Four patients in this study had earlier received bDMARD therapy of different classes. These patients had the active disease after at least 3 months of bDMARD use and they received the last dose of bDMARD at least 6 months before enrollment. Two of these patients, previously on antitumor necrosis factor (TNF) therapy, had a good EULAR response with a mean decrease in the DAS28 score from 5.3 to 2.1 and achieved DAS28 remission. Another two patients who previously received Abatacept showed moderate EULAR response with a mean decline in DAS28 from 4.9 to 3.3.

There were no serious adverse effects requiring withdrawal of therapy in study patients. Four patients (13.3%) suffered nonserious infections: two had a skin infection, one had upper respiratory tract infection, and another patient had herpes zoster. Six (20%) patients had raised ALT level and 8 (26.6%) had raised AST noted during the follow-up. All of them had ALT and AST levels less than three times the upper limit of normal. There were no symptoms of hepatitis reported in any of these patients. AST and ALT levels returned to normal after TCZ was stopped. None of the patients suffered significant leukopenia or thrombocytopenia. The mean LDL level at baseline was 103 mg/dl (SD: 29.3 mg/dl) which increased to 118 mg/dl (SD: 22.5 mg/dl) at 24 weeks. However, 7 (23.3%) patients had raised LDL levels beyond the normal level of 130 mg/dl after the use of TCZ. The mean serum total cholesterol showed rise from the baseline level 181 mg/dl (SD: 41 mg/dl) to 201 mg/dl (SD: 49 mg/dl) and mean serum triglycerides increased from 129 mg/dl (SD: 60 mg/dl) to 141 mg/dl (SD: 83.5 mg/dl) at 24 weeks. Hypersensitivity or infusion reactions were not observed in any patient.


  Discussion Top


TCZ has already been established as an efficacious bDMARD for the treatment of RA in patients with inadequate response to csDMARDs as well as bDMARD of a different class.[14] However, there is a lack of data on the use of TCZ in India. This study was conducted to assess the clinical efficacy and safety of TCZ in the Indian scenario.

Clinical efficacy

In various studies on the clinical efficacy of TCZ in RA, response rates have not remained uniform. In previous studies, DAS28 remission response has varied from as low as 30% to 87.9% of patients.[15],[16],[17],[18],[19],[20],[21],[22],[23] Comparative assessment of clinical efficacy in terms of DAS28 remission rate attainment in various clinical trials is shown in [Figure 3]. In the RADIATE study, good or moderate EULAR response was achieved by 67% of the patients who received TCZ at a similar dose of 8 mg/kg.[17] In our study, after 24 weeks of TCZ therapy, 19 (63.3%) patients achieved DAS28 remission (DAS28 < 2.6), while 6 (20%) patients had attained LDA. A EULAR good response was achieved by 25 (83.3%) and a moderate response by 4 (13.3%) patients in our study at 24 weeks. Thus, the clinical response in our study is comparable to those reported in various studies conducted previously [Figure 3].
Figure 3: Percentage of patients achieving DAS28 remission response as compared to other studies (DAS28: Disease activity score 28 joints)

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In a recent comparison of various bDMARDs used in RA from the Swedish data registry, TCZ was found to have better efficacy than anti-TNF agents, abatacept and rituximab, whereas drug survival was noticed to be better with rituximab as compared to other groups of bDMARDs.[24] There are inadequate data available for comparative analysis of clinical efficacy of different bDMARDs in the Indian scenario which has been summarized in [Table 2].[25],[26],[27],[28] However, due to small sample sizes and lack of randomized controlled trials, a conclusion cannot be drawn on the comparative clinical efficacy of bDMARDs.
Table 2: Indian data on the use of Biological disease-modifying anti-rheumatic drugs in rheumatoid arthritis

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In this study, four patients had earlier received bDMARD therapy of different class 6 months or more before enrollment which was discontinued due to inadequate response. Two of these patients, preiously on anti-TNF therapy, had a good EULAR response and achieved DAS28 remission. Another two patients who previously received abatacept showed moderate EULAR response with a mean decline in DAS28-ESR from 4.9 to 3.3. In RADIATE trial, DAS28 remission and ACR 20 response at 24 weeks were achieved in 30.6% and 50% patients, respectively, in anti-TNF inadequate responders.[17] In the ADACTA trial, DAS28-ESR improvement was greater in the TCZ treatment group (△-3.3) than in the abatacept group (△-1.8) which was statistically significant (△-1.5; 95% CI: −1.8–−1.1; P < 0.001).[23] Thus, TCZ may be a suitable option for the switch in therapy in anti-TNF inadequate responder RA patients.

Clinical response to TCZ was remarkably rapid, and 14 (73.7%) of 19 patients who attained remission in the study were in remission after the very second dose of TCZ, as elaborated in [Figure 2]. Thus, TCZ also appears to be useful in the scenario where a rapid clinical response is desired.

Safety

The safety profile of TCZ in our study has been remarkable. Serious and fatal adverse effects have been reported with the use of TCZ in other studies.[8] However, in our study, there was no serious adverse effect noted in the study patients which could require hospitalization or withdrawal of therapy. As compared to other studies which have reported even fatal infections, our patients suffered only nonserious infections.[29] The rise in the level of serum transaminases is a known adverse effect of TCZ, and the modification of TCZ is recommended if the ALT level increases to more than three times the ULN.[29] However, severe hepatic injury has been rare, and transaminases generally revert to normal levels on withdrawal of therapy.[30] In our study also, patients were found to have raised transaminases; however, levels remained less than three times the ULN and transaminases normalized after adjustment in the dose of concomitant hepatotoxic DMARD or discontinuation of TCZ at the end of the study. In this study, patients did not receive any premedication for the prevention of infusion reactions. None of our patients encountered any infusion reaction. However, severe anaphylaxis has been reported with the use of TCZ.[31] TCZ is known to increase the levels of serum total cholesterol, LDL, and triglycerides and the same have been observed in this study.[32] The patients on TCZ therapy should undergo periodic monitoring of serum lipid levels.

Our study is unique for being one of the first studies to report the clinical efficacy and safety profile of TCZ in Indian patients. This study corroborates with the clinical efficacy of TCZ in RA in various other countries and substantiates the usefulness of TCZ for RA patients requiring bDMARD therapy due to its clinical efficacy, rapid onset of clinical response, and safety profile. However, larger sample size and longer follow-up period are desired to extrapolate the findings to the larger population of RA patients.


  Conclusion Top


TCZ is a useful bDMARD for use in the csDMARD refractory RA patient on account of remarkable clinical efficacy and safety profile.

Financial support and sponsorship

No financial support was taken from any institution. TCZ was made available free to all the patients, and all investigations were carried out at the hospital laboratory, which is completely government funded.

Conflicts of interest

There are no conflicts of interest.



 
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