Outcome of COVID-19 in patients with autoimmune bullous diseases

Plain Language Summary

It is unknown whether COVID-19 infection outcomes differ in AIBD patients compared to the general population. In this survey-based study, we enquired about the outcomes of COVID-19 infections from patients registered in our AIBD clinic at a tertiary care centre in Northern India. All registered patients were contacted between June and October 2021. Out of 1389 registered patients, 409 completed the survey. Patients who received rituximab after the onset of pandemic were at higher risk of acquiring COVID-19 infection. Patients with advanced age, active disease and concomitant comorbidities were at higher risk COVID-19 related mortality.

Introduction

As severe COVID-19 indicates a hyper-inflammatory state, there is concern that the presence of pre-existing autoimmune disease or the use of immunosuppressants may increase the risk of severe COVID-19 infection.¹ AIBD, especially pemphigus vulgaris and bullous pemphigoid, are potentially life-threatening. The management of AIBD is exigent and often needs the administration of high-dose systemic corticosteroids and other immunosuppressants.² Optimisation of AIBD treatment during the COVID-19 pandemic requires clinicians to identify factors associated with poorer disease outcomes in COVID-19-positive AIBD patients and to understand whether these treatment modalities impact the overall prognosis of COVID-19 infection.

This telephonic survey was aimed to determine the impact of AIBDs on the susceptibility and outcome of COVID-19 infection.

Materials and Methods

Results

We attempted to contact all patients registered with our AIBD clinic telephonically (n = 502). Among them, 42 patients refused to answer our survey as they were in remission off therapy for a long duration; 19 patients refused informed consent, and 32 patients had died of various causes prior to the onset of pandemic. The remaining 409 patients or their attendants answered our survey [Figure 1]. We failed to contact the other patients due to incorrect phone numbers in their clinic files, or they failed to answer our calls (at least twice, on 2 different days).

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Figure 1

Number of patients at each step

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Discussion

Data on COVID-19 outcomes among patients with AIBD is not robust. Such patients may be at an added risk of acquiring infection due to chronic disease courses, requirement of frequent travel to healthcare facilities, and immunosuppression for the management of their primary disease.

A recent systematic review including a pooled total of 732 AIBD patients documented COVID-19 symptoms in 70 patients (9.5%), while the diagnosis of COVID-19 was confirmed in 16 (2.1%) patients.³ Six (0.8%) patients developed severe symptoms requiring hospital admission and three patients (0.4%) died of COVID-19, all being elderly with/ without comorbidities.³ In our study, the frequency of confirmed COVID-19 infection (12.2%) and mortality (2.2%) were over five times higher. This may be attributed to the timing of our survey in October 2021, after the spread of the delta variant of COVID-19, which had higher transmissibility and mortality compared to the initial Alpha variant.^{4 ,5}

The rate of infection with coronavirus in AIBD patients in our study was 12.2%, with a case-fatality ratio of 18%, compared to the incidence rate of 2.7% and case fatality ratio of 1.87% in the general population of our region (states of Punjab, Haryana, Himachal Pradesh and union territory of Chandigarh) during a similar time period (calculated as the total number of cases observed in these four states from March 2020 to 31^st October 2021, divided by the total population of these states as per the last population census).⁶ Our data projects an unfavourable prognosis of COVID-19 in AIBD patients compared to normal population. Attributable risk could not be calculated due to the observational nature of the current study.

Advanced age, active disease during the lockdown, andpresence of comorbidities were significantly associated with death due to COVID-19 infection. Association of mortality with disease activity may be explained by a higher risk of exposure to infection due to frequent hospital visits and a higher likelihood of receiving immunosuppressants. Comorbidities such as cardiovascular disease, diabetes, obesity, reduced kidney function, and chronic liver disease are well-established risk-factors for death due toCOVID-19.^7,8 Seven of nine patients who died in the present study had at least one comorbidity; while the remaining two patients received rituximab for the active disease.

Administration of rituximab after the onset of pandemic in India was significantly associated with COVID-19 infection in our study. Similar observations were made by Joly et al. who noted a more than five-fold higher incidence of COVID-19 infection in AIBD patients who received rituximab compared to those not receiving rituximab.⁹ Observational outcome statistics have been encouraging for several immunosuppressants, however, data pertaining to rituximab is not as reassuring.¹⁰ Worsened primary disease and mortality after COVID-19 infection in patients receiving rituximab have been documented in rheumatological diseases.^{11 ,12} The most plausible mechanism by which rituximab impacts COVID-19 outcomes is blunting of humoral immunity. A study by Anderson et al. observed that after adjusting for comorbidities and various other confounding factors, the use of most immunosuppressant drugs was not associated with increased mortality.¹³ Rituximab, whether used for autoimmune conditions or cancer, however, increased the risk of COVID-19 mortality.¹³ The association between rituximab treatment and adverse COVID-19 outcomes did not reach statistical significance in our study, likely due to the limited number of patients receiving rituximab and very low number of observed mortality. Two out of nine patients who died due to COVID-19-related complications had received rituximab for AIBD.

Rituximab has been advocated as the first-line treatment for pemphigus by several international guidelines and a recent surge in the availability of affordable biosimilars immensely increased its use.^{2 ,14} A safe approach to rituximab therapy for AIBD during the pandemic must be formulated.

Our study has some limitations. The relative risk of COVID-19 infection and complications among AIBD patients could not be estimated due to lack of a control group. The incidence of COVID-19 in AIBD could not be determined due to lack of denominator (source population) data.

Despite the ongoing pandemic for last two years, the formulation of evidence-based guidelines for the management of AIBD during the pandemic has been difficult due to the scarcity of data on COVID-19 outcomes in this population. This study has a clear relevance in this context as it is among the largest studies of COVID-19 in AIBD patients and is the only such study from the Indian subcontinent.

Conclusion

Use of rituximab increases the odds of acquiring COVID-19 infection, while advanced age, active disease status for AIBD, and presence of comorbidities may increase the risk of mortality due to COVID-19.