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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 4  |  Issue : 1  |  Page : 36-41

A modified regimen of rituximab in pemphigus: A retrospective study


Department of Dermatology, Father Muller Medical College, Mangalore, Karnataka, India

Date of Submission06-Jun-2019
Date of Decision07-Oct-2019
Date of Acceptance18-Nov-2019
Date of Web Publication06-Jan-2020

Correspondence Address:
Tanvi Pradeep Vaidya
Department of Dermatology, Father Muller Medical College, Kankanady, Mangalore - 575 002, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CDR.CDR_22_19

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  Abstract 


Introduction: Rituximab is a chimeric monoclonal antibody targeted against CD20 T-cells. It acts by the destruction of autoreactive B-cells. It is a common biologic agent widely used for the treatment of B-cell lymphoma, lymphoproliferative disorders, and inflammatory conditions that are refractory to conventional treatment, such as rheumatoid arthritis. However, various recent studies have shown an increasing number of serious adverse events associated with the use of rituximab, such as serious, often fatal, infusion reactions, infections, rigors, fever, peripheral edema, hypertension, myelosuppression, elevated transaminases, and cardiac failure. Only a few such studies have been performed in Indian patients, where Rituximab is still a new molecule. Aims: The aim of this study is to assess the efficacy and adverse events profile in patients with pemphigus group of diseases treated with rituximab. Materials and Methods: In this retrospective study, we analyzed records of 20 cases of pemphigus who received a modified rheumatoid arthritis (RA) protocol from January 2016 to June 2018, for the efficacy of rituximab as well as for the immediate and late adverse effects encountered with the use of rituximab. Results: It was found that 50% of cases achieved complete remission for the entire duration of follow up. The mean duration of remission was 8.55 months. More than 75% of patients relapsed only after 6 months. Twelve patients (60%) had various infusion reactions such as fever, chills, giddiness, breathlessness, bradycardia, and cyanosis. About 30% of the patients developed late side effects such as onychomycosis and sepsis. One of the patients died due to sepsis. Conclusions: Hence, we conclude that rituximab is still very effective at half the dose in the conventional RA protocol, and although it is a highly efficacious drug, it must be used with great caution, keeping in mind, these catastrophic side effects.

Keywords: Rituximab, biologicals, infusion reactions, pemphigus


How to cite this article:
Vaidya TP, Martis J, Bhat RM, Dandekeri S. A modified regimen of rituximab in pemphigus: A retrospective study. Clin Dermatol Rev 2020;4:36-41

How to cite this URL:
Vaidya TP, Martis J, Bhat RM, Dandekeri S. A modified regimen of rituximab in pemphigus: A retrospective study. Clin Dermatol Rev [serial online] 2020 [cited 2020 May 30];4:36-41. Available from: http://www.cdriadvlkn.org/text.asp?2020/4/1/36/275240




  Introduction Top


Rituximab is a chimeric monoclonal antibody targeted against CD20 T-cells. It acts by the destruction of autoreactive B-cells, and its effect lasts from 6 to 9 months.[1]

It is a common biologic agent widely used for the treatment of B-cell lymphoma, lymphoproliferative disorders, and inflammatory conditions that are refractory to conventional treatment, such as rheumatoid arthritis (RA), Refractory idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, severe interstitial lung disease associated with connective tissue disease, and some vasculitides.

A very common dermatological indication for rituximab is in the treatment of pemphigus group of diseases, which used to be fatal until the advent of steroids. With the use of steroids, although mortality reduced dramatically, there was significant morbidity due to the side effects of high-dose steroids. Newer drugs targeted at the molecular level are said to have fewer side effects and improved effectiveness.[2]

Rituximab is one such drug, now being used as an adjuvant in patients with pemphigus refractory to conventional treatment and also as a first-line therapy.[3],[4]

However, through randomized controlled trials and postmarketing surveillance, an increasing number of serious adverse events are being associated with the use of rituximab, often leading to or complicating an intensive care unit admission.

Objectives of the study

  1. To assess the efficacy of rituximab in pemphigus
  2. To assess the various adverse reactions encountered during and after rituximab treatment.



  Materials And Methods Top


A hospital-based, retrospective study was carried out from January 2016 to June 2018, after obtaining the Institutional Ethics Committee clearance. All patients who received infusions of rituximab, for the treatment of any of the pemphigus groups of disorders in the Department of Dermatology were included in the study. Twenty cases were found: 17 of pemphigus vulgaris, 2 of pemphigus foliaceous, and 1 case of pemphigus vegetans. All the cases of pemphigus were proven cases by biopsy and direct immunofluorescence.

Patient records were obtained from the medical records section of our hospital. A detailed history was noted, including age, sex, indication for rituximab, disease duration before treatment, duration of treatment with rituximab, time to recovery posttreatment, duration of remission posttreatment with rituximab, and adverse reactions during or after treatment with rituximab. The patients were maintained on low-dose oral steroids during remission. Pemphigus Activity Scores [5] were noted from the records of the baseline visit, 1 month follow-up visit, and the 3 months follow-up visit.

All the patients received rituximab according to a modified RA protocol, as it has a higher response rate and lower mortality.[6] The protocol we used, gave half the total dose of rituximab, that is two infusions of rituximab were given 2 weeks apart, but each with only 500 mg per infusion (as against 1 g per infusion according to the Original RA Protocol). Rituximab used was the original molecule in most cases, although biosimilars were used in a few cases due to financial constraints.

After performing baseline tests (by complete blood counts, renal function and liver function tests, blood glucose Levels, Baseline ECG, Chest X-ray, and Mantoux test), patients were declared fit for rituximab administration. Premedication with injection hydrocortisone 100 mg, injection pheniramine 25 mg, and tablet paracetamol 500 mg was given half an hour before infusion. Five hundred milligram of rituximab was diluted in 250 ml of normal saline. The infusion was started at a rate of 10 ml/h and increased by 10 ml/h every 20 min, to a maximum of 80 ml/h. Half hourly monitoring of blood pressure, pulse, oxygen saturation, and temperature was done.

In case of signs of an infusion reaction, the infusion was stopped, and the patient was symptomatically treated, and 100 mg of hydrocortisone with 25 mg of pheniramine were injected intravenously. Half an hour later, rituximab infusion was restarted at a rate of 10 ml/h.

Collected data were analyzed by frequency, percentage, Friedman's test, Wilcoxon signed-rank test, and Fisher's exact test.


  Results Top


Of the twenty cases under study, 17 were cases of pemphigus vulgaris, 2 were cases of pemphigus foliaceous, and 1 was a case of pemphigus vegetans. Fifteen patients were males, and five were females. The mean age was 44.3 years. The mean disease duration before initiating rituximab was 10.5 months.

Ten patients (50%) went into remission. Ten patients relapsed, after a mean duration of 8.1 months postrituximab [Table 1]. The patients who relapsed were observed to have a longer disease duration (mean disease duration 11.8 months) as compared to the patients who stayed in remission (mean disease duration 8.22 months). The cases who did not relapse took a mean of only 4.22 weeks till recovery, as against 6.1 weeks taken by the cases who relapsed [Table 2]. The duration of remission was longer among those with longer disease duration (Pearson coefficient of −0.317 and P = 0.186). The mean Pemphigus Activity Score at baseline was 7.25, at 1 month was 1.47, and at 3 months was 0.47 [Table 3] and [Table 4]. The mean time till recovery after rituximab was 5.21 weeks. The clinical improvement can be appreciated in this 17-year-old boy with pemphigus vulgaris from baseline to just 3 months postrituximab in [Figure 1].
Table 1: Disease outcomes postrituximab

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Table 2: Time till recovery

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Table 3: Reduction in PAS

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Table 4: Reduction in PAS

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Figure 1: A 17-year-old boy with pemphigus vulgaris treated with rituximab at (a) baseline, (b) at 1 month of follow-up, (c) at 2 months of follow-up, (d) complete recovery at 3 months of follow-up

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Twelve patients were noted to have had immediate adverse reactions at the time of infusion of rituximab [Table 5]. Seven patients developed late adverse effects [Table 6].
Table 5: Immediate infusion reactions

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Table 6: Late adverse events

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  Discussion Top


Rituximab is a monoclonal antibody directed against CD 20 and is recently increasingly used in the treatment of refractory pemphigus. We have evaluated the efficacy as well as the various adverse effects encountered in the use of rituximab.

Of the twenty cases under study, 17 were cases of pemphigus vulgaris, 2 were cases of pemphigus foliaceous, and 1 was a case of pemphigus vegetans. The mean age of the patients in our study was 44.3 years, which is comparable to other studies.[7]

The average relapse rate was 50% with our modified protocol using only half the total dose. A review compiled by Zakka et al. of the case series showed a relapse rate of only 30.68% in various case series with the lymphoma protocol, and of 37.33% with the RA protocol.[6] Most of the patients who relapsed were found to relapse between 6 and 12 months, with the mean duration being 8.1 months post-Rituximab. This was much lower than other studies such as that by Joly et al., with a much longer mean duration before relapse of 18.9 months,[8] and Reguiai et al. with a mean duration of 18 months before relapse.[9]

Age, sex, and baseline PAS had no correlation with the relapse rate. It was found that the disease duration before starting rituximab had a direct correlation with disease-free remission. The relapse rate was higher among patients with longer disease duration. This was in concordance to the findings of various other studies.[10],[11]

The baseline PAS in our study was 7.25. The study by Londhe et al. had a baseline PAS of 5.58, which is much lower than that in our study.[7] The baseline PAS did not have an effect on the duration of remission (Pearson coefficient = −0.340, P = 0.154).

The average time till recovery after starting rituximab was 5.21 weeks in our study, which is much lower than studies by Ingen-Housz-Oro et al. (15 weeks), but a comparable duration of 6 weeks in a study by Ahmed and Shetty.[12],[13] The cases who eventually relapsed, took a long time to recover than those who did not relapse. This was similar to findings by Anandan et al.[2]

The PAS continued to decrease after the completion of 4 infusions of rituximab, as evidenced by the continued lowering of PAS at 1 and 3 months. This was in concordance to the study by Anandan et al.[2] This may be attributed to the effect of rituximab in causing prolonged B-cell depletion.[1]

One of the most common adverse reactions seen is serious, including fatal and infusion reactions. infusion related reactions (IRR) are adverse events occurring during or within 24 h of an infusion.[14] The mechanism by which rituximab elicits IRRs is not well understood; however, there is evidence that symptoms may be associated with the release of inflammatory cytokines as a result of rituximab binding to CD20 on B cells and cell lysis.[15],[16] The frequency of the reactions decreases with subsequent cycles, and life-threatening anaphylaxis is rare.[17],[18],[19]

There are also isolated case reports of severe or fatal systemic inflammatory response syndrome-like reactions developing within 24 h of infusing rituximab.[20],[21] These are likely a part of the spectrum of the “cytokine release syndrome” that has been described after rituximab infusions in patients with high tumor-cell burden.[22]

The reported clinical features include fevers, chills, rigors, nausea, dizziness, pruritus, urticaria/rash, angioedema, laryngeal edema, sneezing, throat irritation/tightness, cough, hoarseness, bronchospasm, pulmonary infiltrates, hypoxia, and acute respiratory insufficiency, with or without blood pressure changes or arrhythmias.[23] The frequency of infusion reactions, which form the bulk of major adverse reactions due to rituximab administration, decreases in patients who are premedicated with intravenous glucocorticoids [18] There also are reports of dermatological adverse effects such as itching, rash, and urticaria, which may be seen in high as 37% of patients.[24]

Twelve patients in our study (60%) developed infusion reactions such as giddiness, breathlessness, cyanosis, bradycardia, fever, and chills. All of them were observed during the first infusion. As reported by van Vollenhoven et al. in their study, the rate of infusion reactions was 23.0% during the first infusion of the first course and decreased with each subsequent infusion. Most IRRs were mild to moderate and rarely serious.[14] However, deaths within 24 h of Rituximab infusion have occurred. Approximately 80% of fatal infusion reactions in their study occurred in association with the first infusion.[25]

Other adverse effects reported include infections, skin abscess, deep-vein thrombosis, lung abscess, sepsis, pneumonia, cavernous sinus thrombosis, generalized arthralgia, and Stevens–Johnson syndrome, peripheral edema, hypertension, myelosuppression, and elevated transaminases, etc. However, only a few larger case series are available on this topic.[4]

Cytopenias, in particular, lymphopenias were observed in patients on rituximab, although more so when rituximab was combined with agents more frequently associated with myelosuppression.[26],[27],[28]

Another common complication occurring with rituximab is infections, which are seen more commonly with a greater number of doses or prolonged treatment, and in older individuals, although these infections are rarely fatal.[23],[26],[29] The most frequently experienced viral infections are HBV infection, cytomegalovirus infection, varicella-zoster virus, among others.[30]

Acute tumor lysis syndrome leading to acute kidney injury has been observed after rituximab monotherapy, especially in conditions with high tumor burden, like Non-Hodgkin lymphoma. This necessitates monitoring of urine output and serum creatinine in patients receiving rituximab.[31]

Cardiac monitoring is necessary during and after rituximab infusions in all patients with a history of arrhythmias or angina,[31] as there are reports of supraventricular arrhythmias,[32] tachycardia,[32] myocardial infarctions,[33] hypertension,[17] cardiac tamponade,[17] and some cases of fatal heart failure [34],[35],[36] and fatal myocarditis,[37] although these are very rare.

Seven of our patients (35%) developed late complications such as onychomycosis, herpes zoster of the eye, superficial skin infections, pneumonia, and sepsis.

In the study by Anandan et al., 35% of patients developed significant adverse effects, and 20% developed reactivation Herpes Simplex Virus.[2] We only had one case of herpes zoster in our study.

One patient died of sepsis, within 3 weeks of rituximab. He received only 2 weekly infusions out of 4. In a study by Joly et al., one patient died due to septicemia, although it was 18 months after treatment.[8]

Limitations

The main limitation of our study is the small sample size. The monitoring of counts was not carried out, and hence, we could not assess certain complications such as cytopenias. We also did not measure desmoglein levels, which would have allowed for better assessment and monitoring of disease activity.


  Conclusions Top


Hence, we conclude that rituximab, is highly efficacious even at half the dose as per the RA protocol, and this protocol may be used in patients with financial constraints. The efficacy though, must not blind us to its potentially catastrophic side effects, and it must be used with great caution.

Declaration of patient consent

The informed consent was obtained for participation in the study and publication of data and images for research and educational purposes.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Ahmed AR, Shetty S. A comprehensive analysis of treatment outcomes in patients with pemphigus vulgaris treated with rituximab. Autoimmun Rev 2015;14:323-31.  Back to cited text no. 13
    
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van Vollenhoven RF, Emery P, Bingham CO 3rd, Keystone EC, Fleischmann RM, Furst DE, et al. Long-term safety of rituximab in rheumatoid arthritis: 9.5-year follow-up of the global clinical trial programme with a focus on adverse events of interest in RA patients. Ann Rheum Dis 2013;72:1496-502.  Back to cited text no. 14
    
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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

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