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E-IJD® - ORIGINAL ARTICLE
Year : 2022  |  Volume : 67  |  Issue : 4  |  Page : 477
Experience of rituximab therapy in pemphigus: A three-year retrospective study from a Sub-Himalayan State


From the Department of Dermatology, Indira Gandhi Medical College, Shimla, HP, India

Date of Web Publication2-Nov-2022

Correspondence Address:
Aditi Sharma
Department of Dermatology, Indira Gandhi Medical College, Shimla - 171 001, HP
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijd.ijd_169_22

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   Abstract 


Background: Pemphigus is a group of auto-immune blistering disorders, characterised clinically by mucocutaneous blisters and erosions and histopathologically by intra-epidermal acantholysis. It was traditionally associated with high morbidity and mortality. The use of rituximab has brought upon a new dawn in the treatment of pemphigus. Aim: A retrospective analysis to ascertain the efficacy, tolerance, adverse effect profile, remission, and relapse with the use of rituximab. Material and Methods: A retrospective analysis of all diagnosed pemphigus patients who received rituximab therapy over a period of 3 years was performed. The patient's baseline characteristics, disease duration, clinical presentations, mucosal involvement, disease-severity assessment, and adverse events with rituximab were noted. The outcomes were evaluated based on the definitions of the disease-outcome parameters as early and late endpoints. Results: Of the 17 pemphigus patients, there were 14 females (82.4%) and three males (17.6%) with a mean age of 35.9 ± 16.5 years (range: 9–65 years). Pemphigus vulgaris (PV) was the predominant type in 11 (64.7%) patients. After rituximab infusion, the 17 patients attained the end of consolidation phase (ECP) within 15 days to 3 months, and the mean duration was 1.24 months. The complete remission (CR on/off) ranged from 0.5 to 35 months, and the mean duration of remission was 21.7 months. Within a median time of 4.2 months, almost 80% patients achieved CR on therapy. Nine (53%) patients were in CR without any therapy till the end of the study period, and eight (47%) were in remission while on minimal therapy. Conclusion: Rituximab is an efficacious therapeutic agent for pemphigus and is better tolerated and safer to all the previous medications used in the treatment.


Keywords: Adjuvant, azathioprine (AZR), complete remission off/on therapy (CR on/off), cyclophosphamide (CP), desmoglein, ECP (end of consolidation phase), rituximab (RTX)


How to cite this article:
Verma G, Sharma A, Rattan R, Negi A, Gupta M, Sharma R. Experience of rituximab therapy in pemphigus: A three-year retrospective study from a Sub-Himalayan State. Indian J Dermatol 2022;67:477

How to cite this URL:
Verma G, Sharma A, Rattan R, Negi A, Gupta M, Sharma R. Experience of rituximab therapy in pemphigus: A three-year retrospective study from a Sub-Himalayan State. Indian J Dermatol [serial online] 2022 [cited 2022 Dec 4];67:477. Available from: https://www.e-ijd.org/text.asp?2022/67/4/477/360316





   Introduction Top


Pemphigus is a potentially life-threatening chronic immunobullous disease caused by auto-antibodies directed against the cell surface proteins, desmogleins (Dsg). Pemphigus was traditionally associated with high morbidity and mortality; however, with the advent of corticosteroids, the outlook of this fatal disease has dramatically changed and reduced the mortality rate to <10%.[1] The use of corticosteroids was associated with various metabolic complications, global immunosuppression, and an antecedent risk of serious infections. Thus, there was a continuous search for a safer and more target-oriented therapeutic option, especially in patients in whom corticosteroids were contraindicated. Rituximab (RTX), a chimeric monoclonal antibody, selectively acts on CD20-expressing B-cells, which are known to secrete auto-antibodies targeting the epidermal desmogleins. RTX primarily acts by direct induction of apoptosis, complement-dependent cytotoxicity (CMC), and antibody-dependent cellular cytotoxicity (ADCC).[2] Rituximab depletes CD20-expressing circulating B-cells but has no action on CD20 negative early pre-B-cells and terminally differentiated plasma cells. This selectivity allows for B-cell regeneration from unaffected haematopoietic precursors as well as the continued production of immunoglobulins from plasma cells. B-cell regeneration into peripheral circulation occurs at approximately 6–12 months following therapy.[3] In India, rituximab was first used by Kanwar et al. in 2010.[4] Since then, its use has increased exponentially over the recent years. In the recent guidelines, the current approval of rituximab has been extended to involve the pemphigus group of disorders, both as a first-line drug and as a therapeutic strategy for recalcitrant cases of pemphigus, unresponsive to conventional therapy.[5] A few authors have used azathioprine, cyclophosphamide, and mycophenolate mofetil as adjuvants in addition to rituximab. However, there is no consensus on the use of other immunosuppressants and immunomodulators along with rituximab.[5] In this era of evidence-based medicine, it is essential to provide customized treatment options; thus, we performed a retrospective analysis to ascertain the efficacy, tolerance, adverse effect profile, remission, and relapse of pemphigus with the use of rituximab.


   Material and Methods Top


Study population

The medical records of all pemphigus patients at the Dermatology, Venereology, and Leprosy department of a tertiary care centre in a sub-Himalayan state of India over a period of 3 years were retrospectively reviewed. Patients were diagnosed as pemphigus vulgaris (PV) or pemphigus foliaceus (PF) based on the typical clinical presentations, histopathology, and immunofluorescence. A total of 42 patients were diagnosed as pemphigus, and 17 among these patients were treated with rituximab. Rituximab was given to the refractory cases and as a first-line treatment to either young patients or those who could afford the drug (either through themselves or through government subsidies) and those who consented to the drug.

Exclusion criteria:

  • Hyper-sensitivity to the drug or murine protein,
  • Hepatitis B and C and any other active infection,
  • Coronavirus disease (COVID) infection and vaccination within the last 6 months,
  • Heart failure,
  • Human immunodeficiency virus infection,
  • Pregnancy and lactation.


Pre-medication

All the patients were pre-medicated 30 minutes prior to RTX infusion with Injection hydrocortisone 100 mg IV stat, Injection pheniramine maleate 22.75 mg IV stat, and Tablet paracetamol 500 mg PO.

Dosage and administration of rituximab

All the patients were given rituximab in accordance with the rheumatoid arthritis (RA) protocol[4],[6]: RTX 1 g was administered as an IV infusion. Two infusions, on day 1 and day 15, were given over a period of 5–6 hours with continuous monitoring.

After infusion as a protocol of our department, all the patients were started on steroids in tapering doses along with an immunosuppressant (azathioprine or cyclophosphamide in 50% of the maximum effective dose) for steroid sparing effects for 6 months after complete resolution.

Assessment of response to treatment

The outcomes were evaluated based on the definitions of the disease-outcome parameters defined in the recent international consensus[7] as early [end of consolidation phase (ECP)] and late endpoints [complete remission (CR) on/off therapy, immunological remission (IR), and relapse)].

ECP: ECP is when no new lesions have developed for a minimum of 2 weeks and approximately 80% of the lesions have healed;

CR on minimal therapy (CR on): when there is an absence of new and/or established lesions for at least 2 months while the patient is receiving prednisolone ≤10 mg/d and/or minimal adjuvant therapy;

CR off therapy (CR off): when there are no new and/or established lesions while being off all systemic therapy for at least 2 months;

Relapse: Relapse is the extension of established lesions or the appearance of more than three new lesions per month which do not heal spontaneously within a week after disease control.

Data collection

The patient's baseline characteristics, disease duration, clinical presentations, mucosal involvement, disease-severity assessment, adverse events, factors associated with remission, and relapses were then noted and statistically analysed.


   Results Top


A total of 17 pemphigus patients who received rituximab were retrospectively analysed in the study including 14 females (82.4%) and three males (17.6%). The mean age of the study group was 35.9 ± 16.5 years (range: 9–65 years), and a majority of ten (58.8%) patients were less than 40 years old and six (35.3%) patients each in the age groups of 20–40 and 41–60 years.

The duration of illness at the time of presentation ranged from 15 days to 20 years with the majority (53%) of the patients presenting within 1 year of onset of the disease. The patient with a long duration of illness of 20 years had received DAP (dexamethasone-azathioprine pulse) earlier and had relapsed after 15 years with acute exacerbation since the last 2 months.

PV was the predominant type in 11 (64.7%) patients, with exclusive oral involvement in one (5.9%) patient, followed by six (35.3%) patients diagnosed as PF. Clinically, 58.8% (n = 10) patients had both skin and mucosal lesions, compared to 35.3% (n = 6) who had only skin lesions and 5.9% (n = 1) who had only mucosal lesions. Of the 11 diagnosed PV patients, five (45.5%) had onset of the disease with oral lesions. The most common mucous membrane involved was oral mucosa in 11 (64.7%) patients, with buccal mucosa being the most common site of involvement, followed by genital and nasal mucosa in one (5.9%) patient each.

Among the associated diseases, type 2 diabetes mellitus, concentric left ventricular hypertrophy, hyperthyroidism, and eczema herpeticum were observed in one patient each.

Of the 17 pemphigus patients, 11 (64.7%) patients received rituximab as the first-line therapy, four (23.5%) patients were sifted to rituximab after receiving dexamethasone-cyclophosphamide pulses (DCP), and two (11.8%) patients received rituximab after being treated with dexamethasone-azathioprine pulses (DAP) because either they were not responding to the treatment and had treatment-related side effects or they were having difficulty in repeated hospital visits [Figure 1].
Figure 1: Segregation of patients as treatment naïve or previously treated

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After rituximab infusion, the 17 studied pemphigus patients attained ECP within 15 days to 3 months; the mean duration was 1.24 months [Table 1]. CR on/off ranged from 0.5 to 35 months; the mean duration of remission was 21.7 months. Within a median time of 4.2 months, almost 80% patients achieved CR on therapy. Nine (53%) patients were in CR without any therapy till the end of the study period, and eight (47%) were in remission while on minimal therapy.
Table 1: Baseline characteristics and follow-up

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All patients were maintained on an adjuvant immunosuppressant including azathioprine (AZR) in 70.6% (n ₌ 12) and cyclophosphamide (CP) in 29.4% (n ₌ 5) patients along with concomitant prednisolone post RTX infusion [Figure 2]. Corticosteroids were gradually tapered in accordance with the individual's clinical response. At a mean follow-up of 18 months, all (100%) patients responded to treatment, 11 (64.7%) patients achieved CR (off), six (35.3%) patients achieved CR (on), of which one patient just attained ECP and was under follow-up. Out of 11 patients, for two (18.1%) patients who were in CR (off), the treatment relapsed with 4–6 lesions after 18 months of follow-up. They were managed on minimal therapy (steroids in tapering doses with azathioprine or cyclophosphamide in 50% of the maximum effective dose) to attain CR (on).
Figure 2: Adjuvant immunosuppressant used after RTX

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In our study, four (23.5%) patients were aged <20 years (childhood/juvenile) with PF as the predominant type and a PF to PV ratio of 3:1. Two (50%) of these four patients relapsed over a mean follow-up of 18 months and were managed on minimal adjuvant therapy [Table 2].
Table 2: Baseline characteristics and follow-up of pemphigus in the age group <20 years

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The severity assessment was performed according to Mahajan's severity scoring, six (35.3%) patients were classified as mild, seven (41.2%) patients were classified as moderate, and four (23.5%) patients were classified as severe disease. Three (75%) of these four patients with severe disease were females and took a longer time to achieve ECP, with a mean duration of 2.38 months compared to patients with mild and moderate disease [Table 1].

No immediate adverse effects during the infusion were noted, except in one (5.9%) patient, who developed bradycardia, which was successfully managed by decreasing the infusion rate. In two (11.8%) patients, the interval between the two doses had to be increased and the second dose was delayed as one developed fever with upper respiratory tract infection and the other had pyuria diagnosed on routine pre-rituximab work-up. Both the patients were successfully managed with the course of antibiotics.


   Discussion Top


In 2001, a new era of targeted therapy dawned upon the treatment of pemphigus with the serendipitous discovery of improvement in mucocutaneous lesions of paraneoplastic pemphigus with the use of rituximab for the treatment of non-Hodgkin lymphoma by Heizmann et al.[8] Since then, rituximab has been widely used and recently has been approved as a first-line therapy for pemphigus in 2018.[5]

A total of 17 pemphigus patients were retrospectively analysed in the study including 14 females (82.4%) and three males (17.6%) with a mean age of 35.9 ± 16.5 years (range: 9–65 years), and a majority of ten (58.8%) patients were less than 40 years old. The small numbers of patients enrolled were in part contributed by low patient attendance in the COVID-19 pandemic, exclusion of patients with a history of COVID infection, and those who had or were to receive COVID vaccination. These patients were managed with alternative therapeutic modalities because of the apprehension regarding the safety of rituximab use during the pandemic. The female preponderance is just a patient selection bias caused by either the severity of the disease or affordability of the drug and does not determine the incidence among the females.

PV was the predominant type in 64.7% patients, with exclusive oral involvement in 5.9%, followed by 35.3% patients diagnosed as PF, as reported in earlier studies by Sehgal et al.[9] and Handa et al.[10] with PV predominance but is in contrast to our finding among young adults, where we found predominance of PF.

Post infusion, all patients were maintained on an adjuvant immunosuppressant including azathioprine in 70.6% (n ₌ 12) and cyclophosphamide in 29.4% (n ₌ 5) along with concomitant prednisolone in all patients in tapering doses according to the individual's clinical response. Because of the lack of specific guidelines, the choice of the drug is still a matter of debate and at our institute was based on the severity of the disease or on an adverse effect profile of a drug; for example, in patients of the reproductive age group, cyclophosphamide was avoided because of its dreaded complication of premature ovarian failure.

After rituximab infusion, the 17 studied pemphigus patients attained ECP within 15 days to 3 months; the mean duration was 1.24 months. Within a median time of 4.2 months, almost 80% of our patients achieved CR on therapy; our results were comparable to a recent retrospective study by Sharma et al.,[11] who report CR in 83.6% patients after rituximab, with a mean duration of 4.8 ± 2.52 months, and Kanokrungsee et al.,[12] where 79.3% patients achieved CR on therapy within 6.36 months. This outcome can be explained by assuming that rituximab depletes CD 20+cells, precursors of long-lived auto-antibody-forming plasma cells that are not immediately replaced.

Although all (100%) patients were successfully treated with rituximab, nine (53%) patients were in CR without any therapy and eight (47%) patients were in remission while on minimal therapy till the end of the study period. Of these eight patients, two juvenile pemphigus patients who earlier were in remission relapsed after 18 months of follow-up, suggesting that it is difficult to take young patients off all medication as in comparison to the adults, they have a recalcitrant and relapsing course. Similar findings have been reported in earlier studies, showing that pemphigus shows a relapsing course in paediatric patients and total remission is rare.[13],[14]

Among 11 patients who received rituximab as the first-line therapy, seven (63.6%) patients remained in CR off therapy throughout the study period, similar to the findings in the study by Vinay et al.,[15] who documented that the use of rituximab as the first-line therapy resulted in a statistically significant rate of achieving CR off therapy. Joly et al.[16] reported that in contrast to using prednisolone alone, short-term prednisolone as an adjuvant with other immunosuppresants resulted in a higher probability of achieving CR off therapy.

The majority (53%) of the patients treated with rituximab presented within 1 year of onset of the disease. As documented in earlier studies,[15],[17],[18] the probability of achieving CR (off) is more in pemphigus patients receiving rituximab within 6 months of disease onset, an observation similar to our study. We found strong evidence that the therapeutic outcomes were better when rituximab was given as a first-line treatment and also when given earlier in the course of the disease.

Kushner et al.[19] reported that the lymphoma regimen has superior efficacy in achieving deeper B-cell depletion in secondary lymphoid tissues compared to the rheumatoid regimen; however, we used the rheumatoid regimen with an advantage over the lymphoma protocol of less cost and fewer infusions with satisfactory results; thus, nothing can be said about the superiority of one over another and further studies can be planned to ascertain it.

Early treatment with rituximab has resulted in higher remission rates, long-term clinical response, lower incidence of serious adverse events, and rapid prednisolone tapering compared to previous immunosuppressive therapies.

Rituximab in the era of the COVID-19 pandemic!

Since the COVID-19 outbreak, several concerns have been raised amongst dermatologists as well as pemphigus patients on immunosuppressive drugs. These concerns include the need for proper disease control with minimal immune suppression to avoid possible fatal outcomes. It is also crucial to understand how the underlying mechanisms in COVID-19 (e.g., cytokine release storm)[20] could affect these auto-immune diseases such as pemphigus.

The safety of rituximab in the context of COVID-19 is unclear. B-cell depletion could compromise anti-viral immunity, including severe acute respiratory syndrome coronavirus 2 antibodies, increase the risk of reinfection, and impair vaccine efficacy. One case series during the COVID-19 pandemic reported that although the majority of COVID-19 cases experienced mild to moderate illness, the hospitalization rate (55.5%) and the proportion of patients with critical conditions (22.2%) who ended up in intensive care units were relatively high and thus implied unfavourable results of using rituximab during the pandemic. Also, rituximab was related to an increased rate of COVID-19 infection compared to other disease-modifying drugs.[21],[22] On the contrary, Uzuncakmak et al.[23] advocated the use of rituximab for the treatment of pemphigus if its use is deemed necessary. Furthermore, according to Fallet et al.,[24] rituximab may be protective against severe COVID-19 infection as anti-viral IgG has been shown to induce severe lung injury in COVID-19 illness and patients treated with rituximab may be less able to develop anti-viral IgG, but T-cell response to viral antigens can still occur after rituximab treatment. However, special attention must be paid to close monitoring of the patients and tapering concurrent corticosteroids to minimise susceptibility to life-threatening infections.

Rituximab and COVID-19 vaccination!

Anti-CD20 therapy may dramatically impair the humoral response to vaccination. Both T-cell-dependent and independent responses have been shown to be significantly impaired for at least 6 months after rituximab treatment. For these reasons, most guidelines recommend a timeframe of 6 months as necessary after the last infusion of anti-CD20 before effective vaccination.[25] The ideal timing of vaccination is unknown; however, individuals who have not initiated rituximab therapy are typically vaccinated at least 4 weeks before rituximab infusion. Individuals who are actively receiving rituximab are often vaccinated 12–20 weeks after completion of a treatment cycle.[26]

Limitations

A small sample size and a variable duration of follow-up were the main limitations of our study attributed to the COVID pandemic, which led to less number of patients who received rituximab. Also, being a retrospective study, findings were relied on the data available. Furthermore, immunological remission (IR) could not be determined because of unavailability of resources; thus, its correlation with the relapse could not be established.


   Conclusion Top


In our study, rituximab appears to be an efficacious, well-tolerated, and safer alternative to all the previous medications for pemphigus. Rituximab has now firmly established its role in treatment of pemphigus but with certain unanswered questions. What should be the criteria for adding additional immunosuppressants? How long should they be given? Should rituximab be given at an interval of 6 months to prevent relapse or maintain remission (because of B-cell regeneration) or an adjuvant therapy can be planned for longer remission? Further larger studies are needed to broaden our horizon.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

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4.
Kanwar AJ, Tsuruta D, Vinay K, Koga H, Ishii N, Dainichi T, et al. Efficacy and safety of rituximab treatment in Indian pemphigus patients. J Eur Acad Dermatol Venereol 2013;27:e17-23.  Back to cited text no. 4
    
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Murrell DF, Dick S, Ahmed AR, Amagai M, Barnadas MA, Borradori L, et al. Consensus statement on definitions of disease, end points, and therapeutic response for pemphigus. J Am Acad Dermatol 2008;58:1043–6.  Back to cited text no. 7
    
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Heizmann M, Itin P, Wernli M, Borradori L, Bargetzi MJ. Successful treatment of paraneoplastic pemphigus in follicular NHL with rituximab: Report of a case and review of treatment for paraneoplastic pemphigus in NHL and CLL. Am J Hematol 2001;66:142–4.  Back to cited text no. 8
    
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25.
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