COVID outcome in pemphigus: Does rituximab make pemphigus patients susceptible to more severe COVID‐19?

The COVID‐19 pandemic has raised some concerns regarding the management of chronic skin diseases, especially in patients on immunosuppressive therapy including patients with pemphigus vulgaris (PV). Literature review reveals conflicting results about the effect of monoclonal antibodies such as rituximab on clinical outcome of COVID‐19.


| INTRODUC TI ON
The coronavirus disease 2019 (COVID-19) pandemic has affected many fields of medicine including dermatology.The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has various dermatologic manifestations. 1 Moreover, this infection has led to exacerbation of many dermatoses, including psoriasis, lichen planus, and pemphigus. 2,3Therapeutics chosen to manage the infection have also had dermatologic adverse events. 4Finally, COVID vaccines have given rise to many new-onset or flares of dermatologic disorders. 5,6 the contrary, patients with pre-existing cutaneous disorders might be at increased risk of severe SARS-CoV-2 infection due to multiple reasons; many of the dermatoses are controlled and kept in remission by intensive therapy such as high-dose corticosteroids or biologic agents.These therapeutics defect the host's humoral and cell-mediated immunity, which leads to impaired defense against infections.Therefore, more severe SARS-CoV-2 infection and higher mortality rate are expected. 7mphigus vulgaris (PV) is an autoimmune dermatologic disorder which is manifested by mucocutaneous blisters.The pathophysiologic mechanism for this cutaneous disorder consists of autoantibodies production against desmoglein-1 and desmoglein-3 antigens, which leads to impaired adhesion of keratinocytes and the resultant development of blisters. 8With newly introduced therapeutic regimens, great advance has been made in controlling the disease.In recent years, rituximab has shown promising outcome in the treatment of pemphigus, so as it has become the first-line treatment for this dermatosis. 9With the beginning of the COVID-19 pandemic, concerns have arisen about the prognostic effects of rituximab on SARS-CoV-2 infection.In fact, efficient viral clearance is dependent on the synchrony of humoral and cell-mediated immunity.Rituximab is a monoclonal antibody targeting the CD-20 antigen on B cells, leads to B-cell depletion and lymphopenia with a prolonged duration of hypogammaglobulinemia.This condition can result in an increased risk of infections such as SARS-CoV-2. 10mphigus patients, like any other individual, have been at risk of COVID-19.Yet, those on biologics such as rituximab have been believed to be at further increased risk of SARS-CoV-2 infection and its related morbidity and mortality. 11In contrast, some authorities believe that since rituximab affects B-cell counts and antibody production, and not the cell-mediated immunity, it is safe and may not influence COVID outcome, and even might be associated with less severe SARS-CoV-2 infection. 12Due to these conflicting concepts, we carried out a study to assess the severity of COVID-19 in Iranian patients with pemphigus vulgaris receiving immunosuppressive therapies.The impact of SARS-CoV-2 infection on pemphigus course was also dealt with.

| MATERIAL S AND ME THODS
We conducted a cross-sectional study on adult patients with pemphigus and a history of receiving rituximab, who were infected with SARS-CoV-2 in 2020.The following inclusion criteria were used: The following exclusion criteria were applied during patient recruitment: patients without enough baseline information and who did not get COVID-19 during 2020.
Subjects were selected from the registered data in the registry system of Autoimmune Bullous Disease Research Center (Dermatry.ir).After obtaining informed consent, their clinical and demographic characteristics were collected, which included age, sex, pemphigus type, pemphigus scoring scale, duration of the disease, treatment modalities, total dosage of rituximab, dosage of prednisolone, and presence of comorbidities (e.g., hypertension, diabetes mellitus, and hyperlipidemia).Pemphigus patients who had SARS-CoV-2 symptoms were interviewed in serial medical appointments and their condition and clinical course was recorded, which included whether the infection was confirmed (PCR, serology, antigenic test, or chest CT scan) or highly suspected, type and duration of symptoms (e.g., cough, shortness of breath, myalgia, and fever) if symptomatic, degree of lung involvement, hospitalization and duration of hospital stay, the need to complementary oxygen support and intensive care unit (ICU) admission.We also collected data on the evolution of the pemphigus after COVID-19 infection, namely worsening or a change in phenotype and the continuation or discontinuation of treatment including rituximab.
Data were analyzed by SPSS software; chi-square test, Fisher's exact test, and independent t-test were used to determine the associations between the variables; p-value of <0.05% was considered significant.

| Demographic and clinical characteristics
Thirty-six adults with pemphigus vulgaris and SARS-CoV-2 infection were included.Baseline characteristics of the patients are listed in Table 1.The male consisted 47.2% of the study population.The mean age of patients was 48.43 years.The severity of pemphigus was estimated according to PDAI total activity score, which showed mild to moderate disease (PDAI <15) in all of patients (Table 1).All the patients received prednisolone in combination with rituximab.The average dose of prednisolone was 13.33 mg among the patients, ranged from 2.5 to 60 mg/day.Adverse events associated with rituximab were reported in five patients (13.9%).
The mean duration of COVID symptoms was 9.36 days in these patients.This duration was not significantly different among patients receiving >2000 versus <2000 mg of rituximab in total (8.3 days vs.  2).Table 3 demonstrated the prevalence of COVID-19 symptoms in pemphigus patients in terms of different variables.
Regarding the impact of COVID-19 on pemphigus, the majority of patients did not experience any changes in their pemphigus regarding clinical phenotype (100%) or severity (83.3%), but PV was worsened in six (16.9%) patients which was controlled with increasing the prednisolone dosage.There was not any report of multiple COVID-19 sessions in the same patient.

| DISCUSS ION
In the present study, we evaluated the clinical manifestations and outcome of pemphigus patients who had been on rituximab and became involved with SARS-CoV-2 infection.Our study showed that the patients' sex had a significant impact on cough and gastrointestinal symptoms as the manifestations of COVID.These presentations were more common in women than men.Accordingly, many studies have shown that sex has a significant effect on the severity of SARS-CoV-2 infection, as males are more prone to severe infection and mortality. 13,14However, the results of our study do not seem to be in conflict with other studies since the presence of cough and gastrointestinal symptoms do not reflect the severity of the disease.In fact, the severity is manifested by the extent of lung involvement, oxygen desaturation, and increased inflammatory biomarkers. 15,16 observed a statistically significant effect of average prednisolone dosage on headache and myalgia in pemphigus patients infected with SARS-CoV-2 (p-value = 0.008).As a matter of fact, corticosteroids impair cell-mediated immunity and hinder body defense in patients who are on high dose or prolonged duration of these agents.Therefore, these patients might be involved with more severe forms of COVID-19.On the contrary, corticosteroids may be life-saving in the inflammatory stage of SARS-CoV-2 infection. 17However, again it should be mentioned that constitutional symptoms like headache and myalgia are not indicators of disease severity in COVID patients.Therefore, there is no explanation for this observation in our study.On the contrary, age and comorbidities did not have significant effect on COVID outcomes in our study.[20] Although we aimed to investigate the impact of pemphigus severity on COVID-19 outcome, we could not get a conclusive result due to lack of enough diversity among patients regarding PDAI scores.However, we used the index of "head and neck" involvement, which was reported as another predictor of pemphigus severity in our previous study. 21Further analysis revealed that though the COVID-19 symptom duration, number of hospitalized patients, and percentage of lung involvement were all greater in patients with head and neck involvement, none of these differences reached to the significance level (Table 2).
Our study also showed no statistically significant impact of rituximab cycles on clinical manifestations, severity, degree of lung involvement, and mortality of COVID patients.This was in contrast with some previous studies which acknowledged that rituximab therapy was related to severe SARS-CoV-2 infection and increased mortality. 22,23o previous studies conducted on Iranian patients with autoimmune bullous dermatoses including pemphigus vulgaris and COVID-19, found that each passing month from the last rituximab dose, decreased the severity of COVID-19. 24,25This discrepancy might be due to the fact that other immune bullous dermatoses were also included.Moreover, in one of this studies, the number of suspicious cases of COVID-19 was even more than confirmed one, which necessitate more discretion in interpreting their results.
[12] Shahidi-dadras et al. 23 reported no one with COVID-19 among 45 patients who had received rituximab within 1 year of the pandemic and concluded that treatment with rituximab may not impair memory responses against known pathogens and might not make patients susceptible to SARS-CoV-2 infection which is in line with our results.
Another recent study reviewed current data on the clinical courses of patients with different underlying disorders receiving rituximab who got infected by SARS-CoV-2 virus and reported that the use of RTX did not increase morbidity and mortality in most patients. 26ile monoclonal antibodies such as rituximab can lead to hypogammaglobulinemia and consequently impaired humoral response against SARS-CoV-2, resulted in severe forms of infection, increased hospitalization, ICU admission and mortality, 27,28 some authors believe in even protective effect of biologic therapeutics on COVID-19 outcome. 29,30It has been shown that cytokine storm following an excessive stimulation of immune system has an important role in predicting the severity and prognosis of COVID-19. 31Thus, suppressing this over-activation of immune system by the use of biologic agents would be resulted in a milder benign clinical course of disease. 313][34] These reassuring findings of the use of new biologic therapeutics agents are congruent with our findings in patients All adult patients (age ≥18 years) who had confirmed diagnosis of pemphigus vulgaris and confirmed or highly suspected COVID-19 with or without symptoms and experienced treatment with rituximab (RTX) during last 6 months since SARS-CoV-2 infection during January 2020 to December 2020.Highly suspected cases were included if characteristic symptoms were present in the subject but not confirmed by testing and the presence of any identified COVID-19 case in the family household or contact cases (in school for example) with highly suggestive symptoms.

9. 9
days, p = 0.23).More than half of the patients received O 2 therapy (55.8%), and the mean percentage of lung involvement was 19.94% in COVIDinfected patients.Nineteen patients (52.8%) were hospitalized for SARS-CoV-2 infection and 17 (47.2%)received remdesivir.However, no one was admitted to ICU.The average duration of hospital stay was 3.26 days in the admitted patients, and the mean Quarantine duration was about 3 weeks (19.05 ± 8.42 days) among patients.Only one patient (2.8%) who was suffered from esophageal squamous cell carcinoma, under treatment with fluorouracil and cisplatin, passed away because of SARS-CoV-2 infection due to severe thrombocytopenia after chemotherapy.Of note, gender, total dose of rituximab, number of rituximab cycles, and involvement of head and neck were not associated to duration of COVID-19 symptoms (p values: 0.32, 0.23, 0.84, and 0.51, respectively), severity of disease (hospitalization) (p values: 0.46, 0.39, 0.23, and 0.72, respectively), or the percentage of lung involvement on CT scan (p values: 0.07, 0.36, 0.38, and 0.09, respectively) (Table

a
received rituximab.However, further studies are needed to shed more lights in this issue.Therefore, it is still recommended to delay rituximab therapy in individuals who become infected with SARS-CoV-2 because of the vital role of humoral immune defense in late stages of COVID-19.Moreover, in the peaks of SARS-CoV-2 infection, it is reasonable to cease rituximab therapy until the peak flattens; however, rituximab might still be initiated or continued for managing moderate to severe forms of pemphigus during the pandemic. 35-365 | CON CLUS ION Despite the presence of evidence that rituximab has the capacity to increase the severity and mortality rate of COVID patients, there are many controversies on this issue.In this study, we found no increased risk of a severe form of COVID-19 in pemphigus patients receiving rituximab.Nevertheless, taking caution seems to be the most reasonable strategy and this therapeutic agent should only be administered to those patients with critical conditions like severe pemphigus vulgaris.Moreover, those patients already on rituximab or with a history of rituximab treatment should take preventive measures like adhering to hygienic protocols and getting vaccinated in the COVID era.Independent sample t-test.b Chi-square or Fisher's exact test.TA B L E 3 (Continued)

TA B L E 1
Baseline characteristics of patient with Pemphigus Vulgaris and COVID-19.

duration (day) p-Value Hospitalized patients (N) p-Value Percentage of lung involvement on CT scan (%) p-Value
Prevalence of COVID-19 symptoms in pemphigus patients receiving rituximab in terms of different variable.
TA B L E 2 COVID-19 outcomes in pemphigus patients.COVID symptoms