|Year : 2020 | Volume
| Issue : 1 | Page : 36-41
A modified regimen of rituximab in pemphigus: A retrospective study
Tanvi Pradeep Vaidya, Jacintha Martis, Ramesh M Bhat, Sukumar Dandekeri
Department of Dermatology, Father Muller Medical College, Mangalore, Karnataka, India
|Date of Submission||06-Jun-2019|
|Date of Decision||07-Oct-2019|
|Date of Acceptance||18-Nov-2019|
|Date of Web Publication||06-Jan-2020|
Tanvi Pradeep Vaidya
Department of Dermatology, Father Muller Medical College, Kankanady, Mangalore - 575 002, Karnataka
Source of Support: None, Conflict of Interest: None
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 2021 Jun 13];4:36-41. Available from: https://www.cdriadvlkn.org/text.asp?2020/4/1/36/275240
| Introduction|| |
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.
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.
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.,
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
- To assess the efficacy of rituximab in pemphigus
- To assess the various adverse reactions encountered during and after rituximab treatment.
| Materials And Methods|| |
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  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. 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|| |
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].
|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|
Click here to view
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].
| Discussion|| |
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.
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. 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, and Reguiai et al. with a mean duration of 18 months before relapse.
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.,
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. 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., 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.
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. This may be attributed to the effect of rituximab in causing prolonged B-cell depletion.
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. 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., The frequency of the reactions decreases with subsequent cycles, and life-threatening anaphylaxis is rare.,,
There are also isolated case reports of severe or fatal systemic inflammatory response syndrome-like reactions developing within 24 h of infusing rituximab., 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.
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. 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  There also are reports of dermatological adverse effects such as itching, rash, and urticaria, which may be seen in high as 37% of patients.
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. 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.
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.
Cytopenias, in particular, lymphopenias were observed in patients on rituximab, although more so when rituximab was combined with agents more frequently associated with myelosuppression.,,
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.,, The most frequently experienced viral infections are HBV infection, cytomegalovirus infection, varicella-zoster virus, among others.
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.
Cardiac monitoring is necessary during and after rituximab infusions in all patients with a history of arrhythmias or angina, as there are reports of supraventricular arrhythmias, tachycardia, myocardial infarctions, hypertension, cardiac tamponade, and some cases of fatal heart failure ,, and fatal myocarditis, 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. 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.
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|| |
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
Conflicts of interest
There are no conflicts of interest.
| References|| |
Zambruno G, Borradori L. Rituximab immunotherapy in pemphigus: Therapeutic effects beyond B-cell depletion. J Invest Dermatol 2008;128:2745-7.
Anandan V, Jameela WA, Sowmiya R, Kumar MM, Lavanya P. Rituximab: A magic bullet for pemphigus. J Clin Diagn Res 2017;11:WC01-6.
El Tal AK, Posner MR, Spigelman Z, Ahmed AR. Rituximab: A monoclonal antibody to CD20 used in the treatment of pemphigus vulgaris. J Am Acad Dermatol 2006;55:449-59.
Kasperkiewicz M, Shimanovich I, Ludwig RJ, Rose C, Zillikens D, Schmidt E. Rituximab for treatment-refractory pemphigus and pemphigoid: A case series of 17 patients. J Am Acad Dermatol 2011;65:552-8.
Herbst A, Bystryn JC. Patterns of remission in pemphigus vulgaris. J Am Acad Dermatol 2000;42:422-7.
Londhe PJ, Kalyanpad Y, Khopkar US. Intermediate doses of rituximab used as adjuvant therapy in refractory pemphigus. Indian J Dermatol Venereol Leprol 2014;80:300-5.
] [Full text]
Joly P, Mouquet H, Roujeau JC, D'Incan M, Gilbert D, Jacquot S, et al
. A single cycle of rituximab for the treatment of severe pemphigus. N Engl J Med 2007;357:545-52.
Reguiai Z, Tabary T, Maizières M, Bernard P. Rituximab treatment of severe pemphigus: Long-term results including immunologic follow-up. J Am Acad Dermatol 2012;67:623-9.
Cho HH, Jin SP, Chung JH. Clinical experiences of different dosing schedules of rituximab in pemphigus with various disease severities. J Eur Acad Dermatol Venereol 2014;28:186-91.
Lunardon L, Tsai KJ, Propert KJ, Fett N, Stanley JR, Werth VP, et al
. Adjuvant rituximab therapy of pemphigus: A single-center experience with 31 patients. Arch Dermatol 2012;148:1031-6.
Ingen-Housz-Oro S, Valeyrie-Allanore L, Cosnes A, Ortonne N, Hüe S, Paul M, et al
. First-line treatment of pemphigus vulgaris with a combination of rituximab and high-potency topical corticosteroids. JAMA Dermatol 2015;151:200-3.
Ahmed AR, Shetty S. A comprehensive analysis of treatment outcomes in patients with pemphigus vulgaris treated with rituximab. Autoimmun Rev 2015;14:323-31.
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.
Chung CH. Managing premedications and the risk for reactions to infusional monoclonal antibody therapy. Oncologist 2008;13:725-32.
Atmar J. Review of the safety and feasibility of rapid infusion of rituximab. J Oncol Pract 2010;6:91-3.
Cohen SB, Emery P, Greenwald MW, Dougados M, Furie RA, Genovese MC, et al
. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: Results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum 2006;54:2793-806.
Emery P, Fleischmann R, Filipowicz-Sosnowska A, Schechtman J, Szczepanski L, Kavanaugh A, et al
. The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: Results of a phase IIB randomized, double-blind, placebo-controlled, dose-ranging trial. Arthritis Rheum 2006;54:1390-400.
Coiffier B, Haioun C, Ketterer N, Engert A, Tilly H, Ma D, et al
. Rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with relapsing or refractory aggressive lymphoma: A multicenter phase II study. Blood 1998;92:1927-32.
Kulkarni HS, Aggarwal R. Successful treatment of acute respiratory failure using rituximab and cyclophosphamide as a combination immunosuppressive regimen in a ventilator-dependent patient having antisynthetase syndrome. Am J Respir Crit Care Med 2011;183:A5661.
Seifert G, Reindl T, Lobitz S, Seeger K, Henze G. Fatal course after administration of rituximab in a boy with relapsed all: a case report and review of literature. Haematologica 2006;91:ECR23.
Winkler U, Jensen M, Manzke O, Schulz H, Diehl V, Engert A. Cytokine-release syndrome in patients with B-cell chronic lymphocytic leukemia and high lymphocyte counts after treatment with an anti-CD20 monoclonal antibody (rituximab, IDEC-C2B8). Blood 1999;94:2217-24.
Ghielmini M, Rufibach K, Salles G, Leoncini-Franscini L, Léger-Falandry C, Cogliatti S, et al
. Single agent rituximab in patients with follicular or mantle cell lymphoma: Clinical and biological factors that are predictive of response and event-free survival as well as the effect of rituximab on the immune system: A study of the Swiss Group for Clinical Cancer Research (SAKK). Ann Oncol 2005;16:1675-82.
Gellrich S, Muche JM, Wilks A, Jasch KC, Voit C, Fischer T, et al
. Systemic eight-cycle anti-CD20 monoclonal antibody (rituximab) therapy in primary cutaneous B-cell lymphomas – An applicational observation. Br J Dermatol 2005;153:167-73.
Pritchard CH, Greenwald MW, Kremer JM, Gaylis NB, Rigby W, Zlotnick S, et al
. Safety of infusing rituximab at a more rapid rate in patients with rheumatoid arthritis: results from the RATE-RA study. BMC Musculoskelet Disord 2014;15:177.
Avilés A, Nambo MJ, Neri N, Cleto S, Castañeda C, Huerta-Guzmàn J, et al
. Dose dense (CEOP-14) vs. dose dense and rituximab (CEOP-14+R) in high-risk diffuse large cell lymphoma. Med Oncol 2007;24:85-9.
Buske C, Hoster E, Dreyling M, Eimermacher H, Wandt H, Metzner B, et al
. The addition of rituximab to front-line therapy with CHOP (R-CHOP) results in a higher response rate and longer time to treatment failure in patients with lymphoplasmacytic lymphoma: Results of a randomized trial of the German Low-Grade Lymphoma Study Group (GLSG). Leukemia 2009;23:153-61.
Copelan E, Pohlman B, Rybicki L, Kalaycio M, Sobecks R, Andresen S, et al
. A randomized trial of etoposide and G-CSF with or without rituximab for PBSC mobilization in B-cell non-Hodgkin's lymphoma. Bone Marrow Transplant 2009;43:101-5.
Herold M, Haas A, Srock S, Neser S, Al-Ali KH, Neubauer A, et al
. Rituximab added to first-line mitoxantrone, chlorambucil, and prednisolone chemotherapy followed by interferon maintenance prolongs survival in patients with advanced follicular lymphoma: An East German Study Group Hematology and Oncology Study. J Clin Oncol 2007;25:1986-92.
Aksoy S, Harputluoglu H, Kilickap S, Dede DS, Dizdar O, Altundag K, et al
. Rituximab-related viral infections in lymphoma patients. Leuk Lymphoma 2007;48:1307-12.
Kasi PM, Tawbi HA, Oddis CV, Kulkarni HS. Clinical review: Serious adverse events associated with the use of rituximab – A critical care perspective. Crit Care 2012;16:231.
Edwards JC, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A, Emery P, Close DR, et al
. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med 2004;350:2572-81.
Keystone E, Fleischmann R, Emery P, Furst DE, van Vollenhoven R, Bathon J, et al
. Safety and efficacy of additional courses of rituximab in patients with active rheumatoid arthritis: an open-label extension analysis. Arthritis Rheum 2007;56:3896-908.
Ghielmini M, Schmitz SF, Bürki K, Pichert G, Betticher DC, Stupp R, et al
. The effect of Rituximab on patients with follicular and mantle-cell lymphoma. Swiss Group for Clinical Cancer Research (SAKK). Ann Oncol 2000;11 Suppl 1:123-6.
Lenz G, Dreyling M, Hoster E, Wörmann B, Dührsen U, Metzner B, et al
. Immunochemotherapy with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone significantly improves response and time to treatment failure, but not long-term outcome in patients with previously untreated mantle cell lymphoma: Results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG). J Clin Oncol 2005;23:1984-92.
Ghielmini M, Schmitz SF, Cogliatti SB, Pichert G, Hummerjohann J, Waltzer U, et al
. Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly × 4 schedule. Blood 2004;103:4416-23.
Braendstrup P, Bjerrum OW, Nielsen OJ, Jensen BA, Clausen NT, Hansen PB, et al
. Rituximab chimeric anti-CD20 monoclonal antibody treatment for adult refractory idiopathic thrombocytopenic purpura. Am J Hematol 2005;78:275-80.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]