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BRIEF REPORT
Ahead of print publication  

Rituximab and COVID-19 infection in patients with autoimmune rheumatic diseases – A real-world study from India


1 Department of Rheumatology, Travancore Medical College Hospital, Kollam, Kerala; Department of Clinical Immunology and Rheumatology, Christian Medical College, Vellore, Tamil Nadu, India
2 Department of Clinical Immunology and Rheumatology, Christian Medical College, Vellore, Tamil Nadu, India
3 Department of Clinical Immunology and Rheumatology, Christian Medical College, Vellore, Tamil Nadu, India; Ibn Sina Diagnostic Centre, Chittagong, Bangladesh
4 Department of Biostatistics, Christian Medical College, Vellore, Tamil Nadu, India
5 Department of Clinical Immunology and Rheumatology, Christian Medical College, Vellore, Tamil Nadu; Department of General Medicine, Division of Rheumatology, Kasturba Medical College, Manipal, Karnataka, India

Date of Submission04-Jul-2022
Date of Acceptance19-Aug-2022
Date of Web Publication07-Oct-2022

Correspondence Address:
John Mathew,
Department of Clinical Immunology and Rheumatology, Christian Medical College, Vellore - 632 004, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injr.injr_136_22

  Abstract 


Introduction: Safety of rituximab (RTX) in autoimmune rheumatic diseases (AIRDs) has been a concern during this ongoing coronavirus (COVID-19) pandemic. Delayed worsening of COVID symptoms, increased hospital stays, and mortality has been reported among those infected post-RTX. This study describes the occurrence and course of COVID-19 infection among AIRD Indian patients who received RTX during this pandemic.
Patients and Methods: Adult patients (≥18 years) with any AIRD, who received RTX between October 2019 and May 2021, were enrolled in this study. Patients satisfying the inclusion criteria were telephonically enquired about contracting confirmed COVID-19, its course, treatment, and outcome. Baseline parameters, immunoglobulin G level, vaccination, and comorbidity status before RTX were compared between the COVID-19 infected and noninfected patients to determine factors affecting the outcome.
Results: Out of 1081 patients admitted during the study period, 218 patients received RTX. The mean age of these patients was 40.1 ± 14.2 years and comprised mostly of women (81.7%). Rheumatoid arthritis followed by lupus and anti-neutrophilic cytoplasmic antibodies-associated vasculitis was the predominant AIRD. Among the patients contacted (207/218 [94.9%]), 11 (5.3%) patients reported confirmed COVID-19 infections. Out of these, three (27.3%) had severe COVID-19 and one patient succumbed to it. Others became symptom-free after a mean duration of 14.4 ± 4.7 days of onset of symptoms. No significant difference among the baseline parameters observed predicted COVID-19 susceptibility.
Conclusion: Among our AIRD patients treated with RTX, occurrence, and mortality of COVID-19 infection was low. Younger age of our patient cohort and female predominance might have contributed in reducing the severity of SARS-CoV-2 infection.

Keywords: Autoimmune rheumatic diseases, COVID-19 infection, outcome, rituximab, vaccination



How to cite this URL:
Nair AM, Chandhu A S, Zafar MT, Vinodini G, Yadav B, Padiyar S, Ganapati A, Mathew J. Rituximab and COVID-19 infection in patients with autoimmune rheumatic diseases – A real-world study from India. Indian J Rheumatol [Epub ahead of print] [cited 2022 Nov 30]. Available from: https://www.indianjrheumatol.com/preprintarticle.asp?id=358023




  Introduction Top


Rituximab (RTX) has been widely used in the treatment of autoimmune rheumatic diseases (AIRDs), owing to its pleiotropic effects on the immune system. Infections, especially within the first 3 months of infusion, remain a concern with this chimeric monoclonal anti-CD20 antibody.[1] Several factors have been associated with an increased risk of infections with RTX, namely old age, chronic lung disease, cardiac insufficiency, diabetes mellitus, renal dysfunction, and laboratory parameters such as neutropenia as well as low immunoglobulin G (IgG) level. AIRD disease activity and dose of concomitant steroid use (prednisolone equivalent of >10 mg/day) while initiating RTX can also contribute[2],[3],[4] to the risk.

During the ongoing coronavirus (COVID-19) pandemic, the use of RTX in AIRD has been a matter of discussion. Heightened infection risk and delayed recovery from infection following RTX infusion were contemplated, due to the possible compromise in the development of antiviral immunity.[5],[6] There are reports of the delayed clinical worsening of COVID-19 infection and the need for mechanical ventilation as well as mortality following RTX treatment.[7] Prolonged hospital admission for COVID-19 infection has been also noted after receiving RTX.[8],[9] Several bodies have, in fact, proposed to postpone or reduce the maintenance doses of RTX.[10]

Here, we describe our experience on the occurrence and course of COVID-19 infection among AIRD patients who received RTX therapy during the COVID pandemic at a tertiary care center in India.


  Patients and Methods Top


Patients' recruitment

Patients, aged ≥18 years, admitted under the department of clinical immunology and rheumatology at a tertiary care center from South India, to whom RTX was administered between October 2019 and May 2021 were enrolled. The study period included the time period 3 months before the first COVID patient being reported in India (on January 30, 2020), the lockdown period (from March 25, 2020, to May 31, 2020), the nine unlock phases (from June 1 to February 28, 2021), and the second wave from March 2021. Demography, details of the underlying AIRD, comorbidities, pneumococcal/influenza vaccination status, and immunoglobulin levels before RTX infusion were retrieved from the institutional electronic medical records. Steroid and immunosuppressant (IS) details following the second dose/maintenance dose of RTX infusion were noted. This study was approved by the institutional ethics committee (IRB Min No. 13800 dated February 24, 2021).

Data collection

The enrolled patients were telephonically contacted between June and July 2021. After obtaining the patient's verbal consent, details pertaining to the status of AIRD and COVID-19 infections were collected using a questionnaire. Confirmed COVID-19 infection was defined if the patient's nasopharyngeal/throat swabs were positive for SARS-CoV-2, as determined by real-time reverse transcription–polymerase chain reaction.

Outcome assessed and statistical analysis

The primary outcome assessed was the occurrence of COVID-19 infections among patients who received RTX during the study period. Other outcomes studied were the severity of COVID-19 infection and mortality among the affected patients. Baseline characteristics among those who received RTX with and without COVID-19 infection were compared to identify factors contributing to COVID-19 infection and its severity.

The severity of COVID-19 infection was designated based on the institutional protocol. Mild infection was any COVID-19-related symptoms without pneumonia or hypoxia and respiratory rate <24/min. Moderate infection was defined as pneumonia (clinical or radiological) or hypoxia and respiratory rate ≤30/min, SpO2 ≥90% on room air, and no respiratory distress. Severe infection was defined as the presence of pneumonia and ≥1 of the following: respiratory rate >30/min, severe respiratory distress, and SpO2 <90% on room air.

Data were analyzed using the SPSS version 21 IBM (SPSS version 21) (IBM SPSS Version 21, United States). Continuous data were represented using mean ± standard deviation (SD), and categorical variables were expressed as frequency and percentage. A comparison of means was done using two independent sample t-tests. Association between the categorical variables was analyzed using Chi-square/Fisher's exact test. P < 0.05 was considered to be statistically significant.


  Results Top


Clinical profile of autoimmune rheumatic diseases patients treated with rituximab

Out of 1081 patients admitted during the study period, 218 (20.2%) received RTX. The flowchart of patient selection is as presented in [Supplemental Figure 1], 218 (20.2%) received RTX. The majority of these patients were women (178 [81.7%]) with their mean ± SD age being 39.8 ± 13.7 years. The clinical and treatment profiles of all patients are outlined in [Table 1].
Table 1: Clinical and treatment profile of patients who received rituximab during the study period (n=218)

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Majority (197 [90.4%]) received RTX for disease activity/flare, and 21 (9.6%) patients received RTX as maintenance therapy. Originator RTX was administered to 46 (21.1%) patients, and the rest received biosimilar RTX. Among those 197 patients who received RTX for treatment, 169 (85.8%) patients received their first dose of RTX during the study period. Rheumatoid arthritis (RA) (76 [34.9%]) followed by systemic lupus erythematosus (SLE) (57 [26.1%]) and anti-neutrophilic cytoplasmic antibodies-associated vasculitis (AAV) (21 [9.6%]) was the predominant AIRD for whom RTX was given among our patients [Supplementary Figure 2]. The indications for administering RTX are detailed in [supplementary Table 1].



COVID-19 infection, severity, and mortality following rituximab

Out of the 218 patients who received RTX, 207 (94.9%) patients with a mean ± SD follow-up duration of 11.6 ± 6.5 months were contacted. Details of these 207 patients are mentioned in [Table 1].

Confirmed COVID-19 infection was established in 11 (5.3%) out of 207 patients contacted. Seven (63.6%) patients had an infection during the first COVID wave and four (36.4%) patients during the second COVID wave in India. COVID-19 was diagnosed after a mean duration of 4.6 ± 2.8 months of receiving RTX. Among these 11 patients, 4 (36.4%) had RA, 2 (18.2%) had AAV, and the rest 5 (45.5%) patients had undifferentiated connective tissue disease, SLE, overlap myositis, IgG4 disease, and Evan's syndrome in each.

Disease activity (8 [72.7%]), maintenance RTX (2 [18.2%]), and diffuse alveolar hemorrhage (1 [9.1%]) were the indications for given RTX during the study period. The mean IgG level of these patients was 1326.9 ± 604.1 mg/dl. Fever and cough were the predominant COVID-related symptom reported by the patients [Supplementary Table 2]. A statistically significant number of these patients had a history of contact with a COVID-19-infected person when compared to the nonCOVID-19 group (P = 0.006). No statistical difference in other patient characteristics was observed between those infected with SARS-CoV-2 and those without during the study period [Table 1]. Furthermore, a difference between the concomitant IS used, originator/biosimilar RTX, and treatment/maintenance RTX between the two groups was not seen.



Three (27.3%) patients had severe COVID-19 infections warranting intensive care, oxygen supplementation, and parenteral dexamethasone. Patients with severe infection received a lower dose of RTX (1000 ± 612.4 mg) when compared to those with mild–moderate infection (1800 ± 447.2 mg) (P = 0.046). Patients with moderate and severe disease had a shorter duration between the last RTX infusion and onset of COVID-19 infection compared to those with mild disease. However, this did not reach statistical significance (P = 0.063). Other than this, a statistical difference between the severe group and the mild–moderate group of COVID-19 patients was not seen. Majority (90.9%) recovered from COVID-19 infection after a mean duration of 14.4 ± 4.7 days of onset of symptoms. These patients were followed up for a duration of 6.8 ± 4.7 months post-COVID; two patients reported cough and breathlessness 30 and 14 days after recovering from COVID-19 infection.

Five (2.4%), out of these 207 patients, expired after a mean duration of 1.8 ± 1.3 months of receiving RTX. Of these, only one patient succumbed to COVID-19-related pneumonia during the second COVID wave. IgG level before administering RTX was low (273 mg/dl).


  Discussion Top


Several speculations have been raised globally on the use of RTX during this pandemic. In a survey done among Indian rheumatology practitioners, reduced usage of biological disease-modifying antirheumatic drugs (bDMARDs) was disclosed by 47.5% as compared to 12.2% for conventional synthetic DMARDs. Considering the possibility of disease flare, 64.2% of practitioners were less inclined to change the major IS but 58.3% deferred using RTX.[11]

An increased predisposition to COVID-19 infection among our AIRD patients who received RTX, either for treatment or for maintenance, was not observed in this study. COVID-19 infection was seen in around 5%; out of this, less than a third had severe COVID-19 infection and majority recovered uneventfully. The median age of these COVID-19-affected patients was 40 years (range 16–73) and was predominantly women (91%). Patients in our study were about two decades younger when compared to the Spanish[8] and French[9] cohorts.

Most of our patients had immunoglobulin levels above the lower limit of normal (>700 mg/dl) and were vaccinated with either pneumococcal/influenza vaccines. Low IgG levels before RTX infusion have been associated with an increased risk of infection.[12] A plausible bystander effect of influenza vaccination has been suggested in a study from Brazil to be beneficial in minimizing the severity of COVID-19 infection.[13],[14] A delayed clinical worsening (on the 18th–19th day postonset of symptoms) warranting mechanical ventilation was not observed in our patients with COVID-19 unlike that by Guilpain et al.[15] and Avouac et al.[9]

The limitation of this study would be its retrospective nature; hence, the asymptomatic/mildly symptomatic COVID-19 infection could have been missed. Inadequate access to the radiological and laboratory parameters of our patients with COVID-19 treated elsewhere and the smaller number of affected patients within the individual AIRD groups have restricted further analyses.


  Conclusion Top


Younger age, female preponderance, extensive pre-RTX influenza vaccinations, ensuring normal IgG levels, and quicker steroid tapering could have led to a lower incidence and severity of COVID-19 among our AIRD patients who received RTX. Holding back this treatment option in our patient population when tackling the AIRD activity should be reconsidered. Our study highlights the importance of appropriate patient selection while considering RTX therapy during this pandemic.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Berghen N, Vulsteke JB, Westhovens R, Lenaerts J, De Langhe E. Rituximab in systemic autoimmune rheumatic diseases: Indications and practical use. Acta Clin Belg 2019;74:272-9.  Back to cited text no. 1
    
2.
Li ZY, Chen M, Zhao MH. Severe infections following rituximab treatment in antineutrophil cytoplasmic antibody-associated vasculitis. Kidney Dis (Basel) 2021;7:50-6.  Back to cited text no. 2
    
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Gottenberg JE, Ravaud P, Bardin T, Cacoub P, Cantagrel A, Combe B, et al. Risk factors for severe infections in patients with rheumatoid arthritis treated with rituximab in the autoimmunity and rituximab registry. Arthritis Rheum 2010;62:2625-32.  Back to cited text no. 3
    
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Heusele M, Clerson P, Guery B, Lambert M, Launay D, Lefevre G, et al. Risk factors for severe bacterial infections in patients with systemic autoimmune diseases receiving rituximab. Clin Rheumatol 2014;33:799-805.  Back to cited text no. 4
    
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Schulze-Koops H, Krueger K, Vallbracht I, Hasseli R, Skapenko A. Increased risk for severe COVID-19 in patients with inflammatory rheumatic diseases treated with rituximab. Ann Rheum Dis 2021;80:e67.  Back to cited text no. 5
    
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Mehta P, Porter JC, Chambers RC, Isenberg DA, Reddy V. B-cell depletion with rituximab in the COVID-19 pandemic: Where do we stand? Lancet Rheumatol 2020;2:e589-90.  Back to cited text no. 6
    
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Favalli EG, Agape E, Caporali R. Incidence and clinical course of COVID-19 in patients with connective tissue diseases: A descriptive observational analysis. J Rheumatol 2020;47:1296.  Back to cited text no. 7
    
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Nuño L, Novella Navarro M, Bonilla G, Franco-Gómez K, Aguado P, Peiteado D, et al. Clinical course, severity and mortality in a cohort of patients with COVID-19 with rheumatic diseases. Ann Rheum Dis 2020;79:1659-61.  Back to cited text no. 8
    
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Avouac J, Drumez E, Hachulla E, Seror R, Georgin-Lavialle S, El Mahou S, et al. COVID-19 outcomes in patients with inflammatory rheumatic and musculoskeletal diseases treated with rituximab: A cohort study. Lancet Rheumatol 2021;3:e419-26.  Back to cited text no. 9
    
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4 Treatment Considerations | COVID-19 Rapid Guideline: Rheumatological Autoimmune, Inflammatory and Metabolic Bone Disorders | Guidance | NICE. NICE. Available from: https://www.nice.org.uk/guidance/ng167/chapter/4-Treatment-considerations#biological-treatments. [Last accessed on 2020 Dec 27].  Back to cited text no. 10
    
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Gupta L, Misra DP, Agarwal V, Balan S, Agarwal V. Management of rheumatic diseases in the time of COVID-19 pandemic: Perspectives of rheumatology practitioners from India. Ann Rheum Dis 2021;80:e1.  Back to cited text no. 11
    
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Buch MH, Smolen JS, Betteridge N, Breedveld FC, Burmester G, Dörner T, et al. Updated consensus statement on the use of rituximab in patients with rheumatoid arthritis. Ann Rheum Dis 2011;70:909-20.  Back to cited text no. 12
    
13.
Fink G, Orlova-Fink N, Schindler T, Grisi S, Ferrer APS, Daubenberger C, Brentani A. Inactivated trivalent influenza vaccination is associated with lower mortality among patients with COVID-19 in Brazil. BMJ Evid Based Med. 2020:bmjebm-2020-111549.  Back to cited text no. 13
    
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Salem ML, El-Hennawy D. The possible beneficial adjuvant effect of influenza vaccine to minimize the severity of COVID-19. Med Hypotheses 2020;140:109752.  Back to cited text no. 14
    
15.
Guilpain P, Le Bihan C, Foulongne V, Taourel P, Pansu N, Maria AT, et al. Rituximab for granulomatosis with polyangiitis in the pandemic of COVID-19: Lessons from a case with severe pneumonia. Ann Rheum Dis 2021;80:e10.  Back to cited text no. 15
    



 
 
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