A Novel Low-Dose Rituximab and IVIg Protocol for Treating Moderate to Severe Pemphigus: A Prospective Study

A Novel Low-Dose Rituximab and IVIg Protocol for Treating Moderate to Severe Pemphigus: A Prospective Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article A Novel Low-Dose Rituximab and IVIg Protocol for Treating Moderate to Severe Pemphigus: A Prospective Study Kamran Balighi, Pedram Molhem-azar, Vahide Lajevardi, Narges Ghandi, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7509683/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 19 You are reading this latest preprint version Abstract Background Pemphigus is a chronic autoimmune disease of skin and mucous membranes which presents with painful blisters. Conventional treatment with high doses of corticosteroids may lead to remission, but this often causes significant side effects. Therefore, steroid-sparing treatments like rituximab (a monoclonal antibody) and intravenous immunoglobulin (IVIg) have been tried and appear to be safe and effective alternatives. This study looked at how well a low-dose combination of rituximab and IVIg works for moderate to severe pemphigus cases. Methods The study involved 25 patients, most of whom (92%) had pemphigus vulgaris, while the rest (8%) had pemphigus foliaceus. All patients had a Pemphigus Disease Area Index (PDAI) score greater than 15. The treatment was initiated with IVIg (2 g/kg), followed by a 500 mg dose of rituximab two weeks later. Patients received prednisolone as premedication. Clinical responses were evaluated at 3 months using PDAI scores and changes in anti-desmoglein (anti-Dsg1 and anti-Dsg3) antibody levels. Results By the end of the study, 48% of patients had complete remission, 44% achieved partial remission, and 8% experienced a relapse, with no significant difference in regard to treatment response between old and new cases. PDAI scores significantly dropped from an average of 21.56 ± 13.46 to 7.12 ± 1.05 (P < 0.001). Antibody levels also fell sharply (P = 0.010 for anti-Dsg1; P = 0.00043 for anti-Dsg3). Side effects were minimal, with 12% of patients reporting mild upper respiratory infections. Conclusion This combination of low-dose rituximab and IVIg seems to be a safe and effective way to manage pemphigus. It helped reduce symptoms and antibody levels while avoiding serious side effects. Even though the results are promising, more research with larger groups and longer follow-up periods is necessary to confirm these findings and improve the treatment. Introduction Pemphigus is a group of uncommon autoimmune disorders affecting the mucocutaneous membranes, characterized by acantholysis (the breakdown of cell-to-cell adhesion) and the development of blisters within the epithelial layer. These blisters manifest as fragile, flaccid lesions on the skin and/or mucous membranes, causing painful erosions. The core of pemphigus pathogenesis is the production of immunoglobulin (Ig) antibodies against desmosomes. The two most common forms of pemphigus are pemphigus vulgaris (PV) and pemphigus foliaceus (PF). In PV, IgG autoantibodies target desmoglein 3, and sometimes desmoglein 1. In PF, the autoantibodies primarily attack desmoglein 1. ( 1 , 2 ) Systemic corticosteroids, either alone or combined with immunosuppressive agents like azathioprine or mycophenolate mofetil, have long been used to treat pemphigus with generally favorable outcomes. However, prolonged high-dose use carries significant risks, including infections, osteoporosis, hypertension, diabetes, and even death. ( 3 ) While pursuing better treatment alternatives, rituximab has emerged as a promising option. It has also received approval from the US FDA for the treatment of adult patients with moderate to severe PV. ( 4 ) Rituximab is a monoclonal antibody that targets CD20, a protein found on B cells, depleting these cells and reducing the autoantibodies production. ( 5 ) Despite its effectiveness, rituximab is costly and comes with the risk of serious side effects, such as pneumocystis carinii pneumonia and septicemia, particularly with higher doses. ( 4 ) Administering lower doses of rituximab, which have been shown to be successful in treating PV, may help reduce these concerns. ( 6 ) Intravenous immunoglobulin (IVIg) is another corticosteroid-sparing treatment that is also non-immunosuppressive and has a favorable safety profile. IVIg has shown promising results in treating autoimmune bullous dermatoses, including PV and PF. ( 7 , 8 ) It works through different mechanisms, such as modulating apoptosis, regulating immune cell growth and function, neutralizing autoantibodies through anti-idiotypes, suppressing antibody production, inhibiting complement activity, increasing antibody breakdown, and activating or inhibiting Fc receptors. ( 9 , 10 ) Several researchers have explored a multidrug strategy that involves combining rituximab with IVIg across various treatment protocols, demonstrating encouraging outcomes. ( 11 , 12 ) In this study, we propose a new treatment protocol combining low-dose rituximab with IVIg infusion. The use of a lower dose of rituximab helps reduce both the overall treatment cost and the risk of adverse effects. The study was performed during the outbreak of COVID-19 to evaluate whether treatment could lead to increase in infection. Methods In this study, 25 patients with pemphigus were chosen from those referred to the Autoimmune Bullous Diseases Clinic at Razi Hospital, affiliated with Tehran University of Medical Sciences (TUMS). Each patient was informed about the study’s purpose and procedures, and all gave written consent to participate. Pemphigus was diagnosed through a combination of physical exams, histopathological analysis (observing intraepidermal clefts and acantholysis), and direct immunofluorescence (DIF) tests to detect deposits of IgG and/or complement component C3. To evaluate the severity of pemphigus, the Pemphigus Disease Area Index (PDAI) was used. ( 13 ) Only patients with a PDAI score exceeding 15 were included in this study. Patients with infectious complications were excluded. The patients initially received a cycle of IVIg at a dose of 2 g per kg. Two weeks later, a low-dose infusion of 500 mg of rituximab was administered. To minimize the risk of hypersensitivity reactions, a single dose of 100mg hydrocortisone and 10mg chlorpheniramine was given as premedication before the rituximab infusion. Patients were followed every month for six months. The patient’s response to treatment was evaluated three months later. Serum concentrations of anti-Dsg1 and anti-Dsg3 antibodies were measured at the end of 6 months. Demographic and clinical information, along with treatment responses and recovery outcomes, were documented in the patients' medical records. The treatment response was assessed based on the criteria outlined in the 2008 Consensus Statement on pemphigus. ( 14 , 15 ) Complete remission was defined as having no new or existing lesions for at least two months. Partial remission meant that any new lesions were temporary and healed within a week. If new lesions continued to appear, existing ones worsened, or old lesions didn’t heal, this was interpreted as no remission. A relapse was identified when a patient who had previously controlled their disease developed three or more new lesions in a month that didn’t heal within a week or saw a worsening of existing lesions. Serum concentrations of anti-Dsg1 and anti-Dsg3 antibodies were quantified using an enzyme-linked immunosorbent assay (ELISA) with a commercial kit (Euroimmun, Lübeck, Germany), conducted both before and 6 months after treatment. The protocol for this study received approval from the ethical committee of TUMS. Statistical analyses were performed using SPSS software version 26. Comparisons of data were conducted using Pearson’s chi-square test for nominal data and the Mann-Whitney U test or Wilcoxon signed-rank test for scale data. Data were presented as frequencies or means ± standard deviations (SD), with a p-value of less than 0.05 considered statistically significant. Results This study evaluated the efficacy and safety of IVIG combined with a low dose of rituximab in 25 patients with moderate to severe pemphigus. The mean age of the participants was 52.44 (± 10.89) years. They consisted of 16 males (64%) and 9 females (36%). Regarding the type of pemphigus, 23 patients (92%) had PV, while 2 patients (8%) were diagnosed with PF. Among the participants, 18 (72%) were newly diagnosed cases, while 7 (28%) were in the recurrence phase. The mean disease duration was 5.21 (± 1.84) years. [Table 1 ] In the recurrence group, 5 patients had received previous rituximab treatment: 4 had undergone one cycle of rituximab consisting of 4 doses, while 1 patient had completed two cycles of rituximab with 4 doses each. Additionally, 1 patient had been treated with mycophenolate mofetil, and 1 patient had been treated with methotrexate. Table 1 Baseline data of patients Age of patients, y, mean (± SD) 52.44 (± 10.89) Disease duration, y, mean (± SD) 5.21 (± 1.84) Gender of patient, N (%) male 16 (64%) female 9 (36%) Type of pemphigus, N (%) pemphigus vulgaris 23 (92%) pemphigus foliaceus 2 (8%) Disease onset New case 7 (28%) Recurrent 18 (72%) Regarding the final outcomes of the patients, complete remission was observed in 12 patients (48%), partial remission in 11 patients (44%), and relapse in 2 patients (8%) by the end of the study. Among the 12 patients who achieved a complete response, 9 (75%) were new cases, whereas 3 (25%) were old cases. Out of the 11 patients with a partial response, 7 (63.6%) were new cases. On top of that, there were two relapsed patients who belonged to the new case group. Generally, there was no difference in the treatment response and relapse rates between the new and old cases (p = 0.545). The PDAI score was 21.56 ± 13.46 before treatment, which dropped to 7.12 ± 1.05 after three months (P < 0.001). The initial anti-desmoglein 1 (IU/mL) level was 123.96 ± 82.5, and the final anti-desmoglein 1 (IU/mL) level was 67.56 ± 79.14. The initial anti-desmoglein 3 (IU/mL) level was 188.12 ± 38.43, while the final anti-desmoglein 3 (IU/mL) level was 107.04 ± 84.08. Treatment led to a significant reduction in both anti-desmoglein 1 (P = 0.011) and anti-desmoglein 3 levels (P < 0.001). The only adverse effect noted was that 3 patients (12%) developed an upper respiratory system infection. [Table 2 ] Table 2 Clinical characteristics of study subjects before and after treatment Initial PDAI score, mean ± SD 21.56 ± 13.46 Final PDAI score, cm, mean ± SD 7.12 ± 1.05 P- value < 0.001 Initial anti-Dsg 1 (IU/mL), mean ± SD 123.96 ± 82.5 Final anti-Dsg 1 (IU/mL), mean ± SD 67.56 ± 79.14 P- value 0.011 Initial anti-Dsg 3 (IU/mL), mean ± SD 188.12 ± 38.43 Final anti-Dsg 3 (IU/mL), mean ± SD 107.04 ± 84.08 P- value < 0.001 Final outcomes of the patients Complete remission 12 patients (48%) Partial remission 11 patient (44%) Disease relapse 2 patients (8%) Adverse effect 3 patients (12%) PDAI, Pemphigus Disease Area Index; Dsg, desmoglein. Discussions Rituximab plus IVIG is an efficacious treatment for pemphigus because it addresses both immediate symptoms and underlying causes of the disease. IVIg reduces pathogenic autoantibodies in circulation almost immediately, providing symptom relief without immunosuppression or raising the risk of infection. Furthermore, rituximab eliminates B cells, meaning that new autoantibodies will not be produced. Therefore, the combination permits quick remission of the disease and a low risk of relapse. ( 7 ) Clinical studies show supporting evidence of the efficacy of this combination therapy. In 2006, Ahmed AR et al. published a paper about a combination therapy of rituximab and IVIG, administered to 11 patients with severe, treatment-resistant PV. Rituximab was administered weekly for three weeks at a dose of 375 mg/m² for each infusion, and then IVIg was administered at the dose of 2 g/kg in the fourth week. This cycle was repeated, and rituximab and IVIg were given monthly from months 3 to 6. A total of 10 rituximab and 6 IVIG infusions were administered over six months to the patients. Those who achieved clinical remission then went on to receive additional maintenance therapy with IVIG. Rapid improvement and sustained remission for an average of 31.1 months with only two relapses were seen in nine patients. The treatment was quite effective and had minimal side effects. ( 11 ) In another study by Ahmed AR et al. 10 PV patients were evaluated, for whom systemic corticosteroids and immunosuppressant’s were contraindicated. The protocol combined rituximab and IVIg therapy. Rituximab was administered weekly for 8 weeks (375 mg/m² per dose), followed by monthly infusions for 4 months, targeting pathogenic B cell depletion. IVIg (2 g/kg/cycle) was administered in three phases: one for immune prophylaxis prior to rituximab, then once a month until patients' CD20 + B cells reached ≥ 15%, and the third at extended times to restore immune regulation. These were successful enhancements with durable remission and no need for additional systemic therapy. But 12 infusions of rituximab and almost 20 IVIg cycles caused significant cost burden. ( 12 ) Another study looked at 19 individuals diagnosed with PV who were administered rituximab and IVIg. Among these individuals, 58% achieved sustained long-term remission, while 42% experienced relapses. The patients received a total of 12 doses of rituximab over a 6-month period. This was combined with IVIg to modulate immune responses and reduce the pathogenic autoantibodies generation. In this study, when patients experienced a relapse, they were retreated using the same rituximab/IVIg combination, and most of them achieved remission again. Rituximab completely eliminated B-cells without delaying repopulation. Rising anti-Dsg levels and B-cell repopulation were associated with relapses, indicating that these are relapse biomarkers. For refractory PV, this combination therapy outperforms conventional immunosuppressive therapies. ( 16 ) There is a new approach based on the Ahmed Protocol; it consists of B cell depletion therapy (BDT) with rituximab and IVIg. There are 12 rituximab infusions for 6–14 months, and then there are monthly IVIg infusions until B cell repopulation. Once repopulation occurs, 6 more cycles are done. IVIg continues during clinical recovery and beyond, helping with the reduction and disappearance of pathogenic autoantibodies. It seemed a valuable modality to treat patients, particularly for refractory autoimmune diseases unresponsive to conventional therapies or BDT alone. ( 17 ) Finally, a comparative study evaluated three different protocols for pemphigus treatment: protocol 1 (lymphoma protocol) with four weekly doses of 375 mg/m², protocol 2 (rheumatoid arthritis protocol) with two doses of 1 g given two weeks apart, and protocol 3 (rituximab plus IVIG) over six to eight months with monthly infusions. The highest early endpoint rate was observed with Protocol 3 (100%), but it had the longest time to disease control (9.6 weeks) and the highest relapse rate of 75%. With faster disease control (4.6 weeks) and fewer relapses, Protocol 2 did better in the long term. Protocol 1 was slower in reaching disease control and had lower complete remission rates compared to the other two protocols. Protocol 3 was most effective for severe cases. ( 18 ) There is no consensus on the ideal rituximab dose for pemphigus; lower doses, such as two infusions of 500 mg ( 19 ), a single infusion of 200 mg ( 14 ), or even 20 mg ( 20 ), have shown acceptable results. A large meta-analysis also found no superiority of higher doses over lower ones, except for a longer duration of complete remission ( 21 ). However, higher doses are associated with significantly increased costs and a dose-dependent increase in infection risk ( 22 ). Based on these findings, we chose to treat our patients with a cycle of IVIg at 2 g/kg, followed by a low-dose infusion of 500 mg rituximab. Within three months of therapy, 48% of patients had achieved CR; this was promising, especially because a low dose of rituximab was used. Clinical symptoms also improved significantly; The PDAI score decreased from an average of 21.56 to just 7.12 (P < 0.001). This result not only establishes the efficacy of the treatment but also suggests that the treatment could possibly have the potential to improve the patients' quality of life. The reduction in anti-Dsg antibody levels also shows the effectiveness of this approach. Almost 50% reduction in Anti-Dsg1 (123.96 IU/mL to 67.56 IU/mL; P = 0.010) and Anti-Dsg3 levels (188.12 IU/mL to 107.04 IU/mL; P = 0.00043) were seen. These changes are in concordance with disease control and remission. 12% of patients had mild upper respiratory infections, including covid infection, and there were no reports of severe or life-threatening complications. This is significant as it indicates this treatment protocol is a safe option in viral outbreaks. Although the results are encouraging, the 44% rate of partial remission and 8% relapse rate suggests that there is room for improvement. Previous studies have indicated that retreatment with rituximab and IVIg or additional courses of low-dose rituximab can lead to the recovery of disease control and induce remission. ( 16 , 23 ) Limitations: Some of the limitations of this study include the small number of participants, the absence of a control group, the short duration of the follow-up, and the insufficient information on the patients who did not respond to the treatment or had a relapse. Future work should also concentrate on larger, more detailed investigations to enhance the findings and develop specific treatment plans. Conclusions This paper aims at exploring the efficacy and safety of a combined low-dose rituximab and IVIg regimen for the management of moderate to severe pemphigus, showing this effective, safe, and budget-friendly treatment protocol could be a better choice for elderly or comorbid patients where conventional immunosuppressive drugs are associated with high risk. Declarations Author Contribution K.B. and P.M. contributed equally to the study.K.B. and P.M. and contributed to the concept and design.V.L and N.GH and R.A and M.D and H.M and A.A collected the data.H.B and A.A analyzed the data.K.B and A.A and P.M. and H.B. wrote the main manuscript text.All authors reviewed the manuscript. Data Availability Data are available upon request. References Kridin K (2018) Pemphigus group: overview, epidemiology, mortality, and comorbidities. Immunol Res 66(2):255–270 Malik AM, Tupchong S, Huang S, Are A, Hsu S, Motaparthi K (2021) An Updated Review of Pemphigus Diseases. Med (Kaunas). ;57(10) Kridin K (2018) Emerging treatment options for the management of pemphigus vulgaris. Ther Clin Risk Manag 14:757–778 Abulikemu K, Hu F, Liang J, Kang X (2023) Targeting therapy in pemphigus: Where are we now and where are we going? Heliyon 9(6):e16679 Khandelwal K, Jajoo V, Bajpai K, Madke B, Prasad R, Wanjari MB et al (2023) Rituximab in Pemphigus Vulgaris: A Review of Monoclonal Antibody Therapy in Dermatology. Cureus 15(6):e40734 Durães SMB, Santos NR, Batzner CN, Cerqueira FGM (2024) Use of low-dose rituximab to treat pemphigus. An Bras Dermatol 99(5):791–792 Czernik A, Toosi S, Bystryn JC, Grando SA (2012) Intravenous immunoglobulin in the treatment of autoimmune bullous dermatoses: an update. Autoimmunity 45(1):111–118 Frew JW, Martin LK, Murrell DF (2011) Evidence-based treatments in pemphigus vulgaris and pemphigus foliaceus. Dermatol Clin 29(4):599–606 Grando SA, Rigas M, Chernyavsky A (2020) Rationale for including intravenous immunoglobulin in the multidrug protocol of curative treatment of pemphigus vulgaris and development of an assay predicting disease relapse. Int Immunopharmacol 82:106385 Lolis M, Toosi S, Czernik A, Bystryn J-C (2011) Effect of intravenous immunoglobulin with or without cytotoxic drugs on pemphigus intercellular antibodies. J Am Acad Dermatol 64(3):484–489 Ahmed AR, Spigelman Z, Cavacini LA, Posner MR (2006) Treatment of pemphigus vulgaris with rituximab and intravenous immune globulin. N Engl J Med 355(17):1772–1779 Ahmed AR, Nguyen T, Kaveri S, Spigelman ZS (2016) First line treatment of pemphigus vulgaris with a novel protocol in patients with contraindications to systemic corticosteroids and immunosuppressive agents: Preliminary retrospective study with a seven year follow-up. Int Immunopharmacol 34:25–31 Boulard C, Duvert Lehembre S, Picard-Dahan C, Kern JS, Zambruno G, Feliciani C et al (2016) Calculation of cut-off values based on the Autoimmune Bullous Skin Disorder Intensity Score (ABSIS) and Pemphigus Disease Area Index (PDAI) pemphigus scoring systems for defining moderate, significant and extensive types of pemphigus. Br J Dermatol 175(1):142–149 Russo I, Miotto S, Saponeri A, Alaibac M (2020) Ultra-low dose rituximab for refractory pemghigus vulgaris: a pilot study. Expert Opin Biol Ther 20(6):673–678 Murrell DF, Dick S, Ahmed AR, Amagai M, Barnadas MA, Borradori L et al (2008) Consensus statement on definitions of disease, end points, and therapeutic response for pemphigus. J Am Acad Dermatol 58(6):1043–1046 Feldman RJ, Christen WG, Ahmed AR (2012) Comparison of immunological parameters in patients with pemphigus vulgaris following rituximab and IVIG therapy. Br J Dermatol 166(3):511–517 Ahmed AR, Kaveri S (2018) Reversing Autoimmunity Combination of Rituximab and Intravenous Immunoglobulin. Front Immunol 9:1189 Hamadah I, Chisti MA, Haider M, Binamer Y, Alajlan S, Aleyouni Y, Alfadley A (2019) Rituximab/IVIG in pemphigus - a 10-year study with a long follow-up. J Dermatolog Treat 30(2):170–175 Horváth B, Huizinga J, Pas HH, Mulder AB, Jonkman MF (2012) Low-dose rituximab is effective in pemphigus. Br J Dermatol 166(2):405–412 Ciolfi C, Tartaglia J, Alaibac M (2024) Is It Time to Reconsider Rituximab Dosing Regimens for Pemphigus Vulgaris? Antibodies (Basel). ;13(1) Wang HH, Liu CW, Li YC, Huang YC (2015) Efficacy of rituximab for pemphigus: a systematic review and meta-analysis of different regimens. Acta Derm Venereol 95(8):928–932 Kasi PM, Tawbi HA, Oddis CV, Kulkarni HS (2012) Clinical review: Serious adverse events associated with the use of rituximab - a critical care perspective. Crit Care 16(4):231 Robinson AJ, Vu M, Unglik GA, Varigos GA, Scardamaglia L (2018) Low-dose rituximab and concurrent adjuvant therapy for pemphigus: Protocol and single-centre long-term review of nine patients. Australas J Dermatol 59(1):e47–e52 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 05 Jan, 2026 Reviews received at journal 30 Dec, 2025 Reviews received at journal 28 Dec, 2025 Reviews received at journal 27 Dec, 2025 Reviewers agreed at journal 20 Dec, 2025 Reviewers agreed at journal 20 Dec, 2025 Reviewers agreed at journal 19 Dec, 2025 Reviewers agreed at journal 14 Dec, 2025 Reviews received at journal 10 Dec, 2025 Reviewers agreed at journal 08 Dec, 2025 Reviewers agreed at journal 08 Dec, 2025 Reviews received at journal 25 Nov, 2025 Reviews received at journal 20 Nov, 2025 Reviewers agreed at journal 20 Nov, 2025 Reviewers agreed at journal 17 Nov, 2025 Reviewers invited by journal 10 Nov, 2025 Editor assigned by journal 06 Sep, 2025 Submission checks completed at journal 06 Sep, 2025 First submitted to journal 01 Sep, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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10:21:19","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":415551,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7509683/v1/43ed4449-7fef-426a-ba71-e3e31b99dfab.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"A Novel Low-Dose Rituximab and IVIg Protocol for Treating Moderate to Severe Pemphigus: A Prospective Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePemphigus is a group of uncommon autoimmune disorders affecting the mucocutaneous membranes, characterized by acantholysis (the breakdown of cell-to-cell adhesion) and the development of blisters within the epithelial layer. These blisters manifest as fragile, flaccid lesions on the skin and/or mucous membranes, causing painful erosions. The core of pemphigus pathogenesis is the production of immunoglobulin (Ig) antibodies against desmosomes. The two most common forms of pemphigus are pemphigus vulgaris (PV) and pemphigus foliaceus (PF). In PV, IgG autoantibodies target desmoglein 3, and sometimes desmoglein 1. In PF, the autoantibodies primarily attack desmoglein 1. (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e\u003cp\u003eSystemic corticosteroids, either alone or combined with immunosuppressive agents like azathioprine or mycophenolate mofetil, have long been used to treat pemphigus with generally favorable outcomes. However, prolonged high-dose use carries significant risks, including infections, osteoporosis, hypertension, diabetes, and even death. (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) While pursuing better treatment alternatives, rituximab has emerged as a promising option. It has also received approval from the US FDA for the treatment of adult patients with moderate to severe PV. (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) Rituximab is a monoclonal antibody that targets CD20, a protein found on B cells, depleting these cells and reducing the autoantibodies production. (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) Despite its effectiveness, rituximab is costly and comes with the risk of serious side effects, such as pneumocystis carinii pneumonia and septicemia, particularly with higher doses. (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) Administering lower doses of rituximab, which have been shown to be successful in treating PV, may help reduce these concerns. (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e)\u003c/p\u003e\u003cp\u003eIntravenous immunoglobulin (IVIg) is another corticosteroid-sparing treatment that is also non-immunosuppressive and has a favorable safety profile. IVIg has shown promising results in treating autoimmune bullous dermatoses, including PV and PF. (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e) It works through different mechanisms, such as modulating apoptosis, regulating immune cell growth and function, neutralizing autoantibodies through anti-idiotypes, suppressing antibody production, inhibiting complement activity, increasing antibody breakdown, and activating or inhibiting Fc receptors. (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e) Several researchers have explored a multidrug strategy that involves combining rituximab with IVIg across various treatment protocols, demonstrating encouraging outcomes. (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e)\u003c/p\u003e\u003cp\u003eIn this study, we propose a new treatment protocol combining low-dose rituximab with IVIg infusion. The use of a lower dose of rituximab helps reduce both the overall treatment cost and the risk of adverse effects. The study was performed during the outbreak of COVID-19 to evaluate whether treatment could lead to increase in infection.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eIn this study, 25 patients with pemphigus were chosen from those referred to the Autoimmune Bullous Diseases Clinic at Razi Hospital, affiliated with Tehran University of Medical Sciences (TUMS). Each patient was informed about the study\u0026rsquo;s purpose and procedures, and all gave written consent to participate. Pemphigus was diagnosed through a combination of physical exams, histopathological analysis (observing intraepidermal clefts and acantholysis), and direct immunofluorescence (DIF) tests to detect deposits of IgG and/or complement component C3. To evaluate the severity of pemphigus, the Pemphigus Disease Area Index (PDAI) was used. (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e) Only patients with a PDAI score exceeding 15 were included in this study. Patients with infectious complications were excluded.\u003c/p\u003e\u003cp\u003eThe patients initially received a cycle of IVIg at a dose of 2 g per kg. Two weeks later, a low-dose infusion of 500 mg of rituximab was administered. To minimize the risk of hypersensitivity reactions, a single dose of 100mg hydrocortisone and 10mg chlorpheniramine was given as premedication before the rituximab infusion. Patients were followed every month for six months. The patient\u0026rsquo;s response to treatment was evaluated three months later. Serum concentrations of anti-Dsg1 and anti-Dsg3 antibodies were measured at the end of 6 months.\u003c/p\u003e\u003cp\u003eDemographic and clinical information, along with treatment responses and recovery outcomes, were documented in the patients' medical records. The treatment response was assessed based on the criteria outlined in the 2008 Consensus Statement on pemphigus. (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e) Complete remission was defined as having no new or existing lesions for at least two months. Partial remission meant that any new lesions were temporary and healed within a week. If new lesions continued to appear, existing ones worsened, or old lesions didn\u0026rsquo;t heal, this was interpreted as no remission. A relapse was identified when a patient who had previously controlled their disease developed three or more new lesions in a month that didn\u0026rsquo;t heal within a week or saw a worsening of existing lesions. Serum concentrations of anti-Dsg1 and anti-Dsg3 antibodies were quantified using an enzyme-linked immunosorbent assay (ELISA) with a commercial kit (Euroimmun, L\u0026uuml;beck, Germany), conducted both before and 6 months after treatment.\u003c/p\u003e\u003cp\u003e The protocol for this study received approval from the ethical committee of TUMS.\u003c/p\u003e\u003cp\u003eStatistical analyses were performed using SPSS software version 26. Comparisons of data were conducted using Pearson\u0026rsquo;s chi-square test for nominal data and the Mann-Whitney U test or Wilcoxon signed-rank test for scale data. Data were presented as frequencies or means\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviations (SD), with a p-value of less than 0.05 considered statistically significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThis study evaluated the efficacy and safety of IVIG combined with a low dose of rituximab in 25 patients with moderate to severe pemphigus. The mean age of the participants was 52.44 (\u0026plusmn;\u0026thinsp;10.89) years. They consisted of 16 males (64%) and 9 females (36%). Regarding the type of pemphigus, 23 patients (92%) had PV, while 2 patients (8%) were diagnosed with PF. Among the participants, 18 (72%) were newly diagnosed cases, while 7 (28%) were in the recurrence phase. The mean disease duration was 5.21 (\u0026plusmn;\u0026thinsp;1.84) years. [Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e] In the recurrence group, 5 patients had received previous rituximab treatment: 4 had undergone one cycle of rituximab consisting of 4 doses, while 1 patient had completed two cycles of rituximab with 4 doses each. Additionally, 1 patient had been treated with mycophenolate mofetil, and 1 patient had been treated with methotrexate.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eBaseline data of patients\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eAge of patients, y, mean (\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e52.44 (\u0026plusmn;\u0026thinsp;10.89)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eDisease duration, y, mean (\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5.21 (\u0026plusmn;\u0026thinsp;1.84)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eGender of patient, N (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003emale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e16 (64%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003efemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e9 (36%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eType of pemphigus, N (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003epemphigus vulgaris\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e23 (92%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003epemphigus foliaceus\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (8%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eDisease onset\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNew case\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7 (28%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRecurrent\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e18 (72%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eRegarding the final outcomes of the patients, complete remission was observed in 12 patients (48%), partial remission in 11 patients (44%), and relapse in 2 patients (8%) by the end of the study. Among the 12 patients who achieved a complete response, 9 (75%) were new cases, whereas 3 (25%) were old cases. Out of the 11 patients with a partial response, 7 (63.6%) were new cases. On top of that, there were two relapsed patients who belonged to the new case group. Generally, there was no difference in the treatment response and relapse rates between the new and old cases (p\u0026thinsp;=\u0026thinsp;0.545). The PDAI score was 21.56\u0026thinsp;\u0026plusmn;\u0026thinsp;13.46 before treatment, which dropped to 7.12\u0026thinsp;\u0026plusmn;\u0026thinsp;1.05 after three months (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The initial anti-desmoglein 1 (IU/mL) level was 123.96\u0026thinsp;\u0026plusmn;\u0026thinsp;82.5, and the final anti-desmoglein 1 (IU/mL) level was 67.56\u0026thinsp;\u0026plusmn;\u0026thinsp;79.14. The initial anti-desmoglein 3 (IU/mL) level was 188.12\u0026thinsp;\u0026plusmn;\u0026thinsp;38.43, while the final anti-desmoglein 3 (IU/mL) level was 107.04\u0026thinsp;\u0026plusmn;\u0026thinsp;84.08. Treatment led to a significant reduction in both anti-desmoglein 1 (P\u0026thinsp;=\u0026thinsp;0.011) and anti-desmoglein 3 levels (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e\u003cp\u003eThe only adverse effect noted was that 3 patients (12%) developed an upper respiratory system infection. [Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e]\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eClinical characteristics of study subjects before and after treatment\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eInitial PDAI score, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e21.56\u0026thinsp;\u0026plusmn;\u0026thinsp;13.46\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eFinal PDAI score, cm, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7.12\u0026thinsp;\u0026plusmn;\u0026thinsp;1.05\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eP- value\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eInitial anti-Dsg 1 (IU/mL), mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e123.96\u0026thinsp;\u0026plusmn;\u0026thinsp;82.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eFinal anti-Dsg 1 (IU/mL), mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e67.56\u0026thinsp;\u0026plusmn;\u0026thinsp;79.14\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eP- value\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.011\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eInitial anti-Dsg 3 (IU/mL), mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e188.12\u0026thinsp;\u0026plusmn;\u0026thinsp;38.43\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eFinal anti-Dsg 3 (IU/mL), mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e107.04\u0026thinsp;\u0026plusmn;\u0026thinsp;84.08\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eP- value\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eFinal outcomes of the patients\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eComplete remission\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12 patients (48%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePartial remission\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e11 patient (44%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eDisease relapse\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 patients (8%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eAdverse effect\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3 patients (12%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"3\"\u003ePDAI, Pemphigus Disease Area Index; Dsg, desmoglein.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"Discussions","content":"\u003cp\u003eRituximab plus IVIG is an efficacious treatment for pemphigus because it addresses both immediate symptoms and underlying causes of the disease. IVIg reduces pathogenic autoantibodies in circulation almost immediately, providing symptom relief without immunosuppression or raising the risk of infection. Furthermore, rituximab eliminates B cells, meaning that new autoantibodies will not be produced. Therefore, the combination permits quick remission of the disease and a low risk of relapse. (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) Clinical studies show supporting evidence of the efficacy of this combination therapy.\u003c/p\u003e\u003cp\u003eIn 2006, Ahmed AR et al. published a paper about a combination therapy of rituximab and IVIG, administered to 11 patients with severe, treatment-resistant PV. Rituximab was administered weekly for three weeks at a dose of 375 mg/m\u0026sup2; for each infusion, and then IVIg was administered at the dose of 2 g/kg in the fourth week. This cycle was repeated, and rituximab and IVIg were given monthly from months 3 to 6. A total of 10 rituximab and 6 IVIG infusions were administered over six months to the patients. Those who achieved clinical remission then went on to receive additional maintenance therapy with IVIG. Rapid improvement and sustained remission for an average of 31.1 months with only two relapses were seen in nine patients. The treatment was quite effective and had minimal side effects. (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e)\u003c/p\u003e\u003cp\u003eIn another study by Ahmed AR et al. 10 PV patients were evaluated, for whom systemic corticosteroids and immunosuppressant\u0026rsquo;s were contraindicated. The protocol combined rituximab and IVIg therapy. Rituximab was administered weekly for 8 weeks (375 mg/m\u0026sup2; per dose), followed by monthly infusions for 4 months, targeting pathogenic B cell depletion. IVIg (2 g/kg/cycle) was administered in three phases: one for immune prophylaxis prior to rituximab, then once a month until patients' CD20\u0026thinsp;+\u0026thinsp;B cells reached\u0026thinsp;\u0026ge;\u0026thinsp;15%, and the third at extended times to restore immune regulation. These were successful enhancements with durable remission and no need for additional systemic therapy. But 12 infusions of rituximab and almost 20 IVIg cycles caused significant cost burden. (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e)\u003c/p\u003e\u003cp\u003eAnother study looked at 19 individuals diagnosed with PV who were administered rituximab and IVIg. Among these individuals, 58% achieved sustained long-term remission, while 42% experienced relapses. The patients received a total of 12 doses of rituximab over a 6-month period. This was combined with IVIg to modulate immune responses and reduce the pathogenic autoantibodies generation. In this study, when patients experienced a relapse, they were retreated using the same rituximab/IVIg combination, and most of them achieved remission again. Rituximab completely eliminated B-cells without delaying repopulation. Rising anti-Dsg levels and B-cell repopulation were associated with relapses, indicating that these are relapse biomarkers. For refractory PV, this combination therapy outperforms conventional immunosuppressive therapies. (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e)\u003c/p\u003e\u003cp\u003eThere is a new approach based on the Ahmed Protocol; it consists of B cell depletion therapy (BDT) with rituximab and IVIg. There are 12 rituximab infusions for 6\u0026ndash;14 months, and then there are monthly IVIg infusions until B cell repopulation. Once repopulation occurs, 6 more cycles are done. IVIg continues during clinical recovery and beyond, helping with the reduction and disappearance of pathogenic autoantibodies. It seemed a valuable modality to treat patients, particularly for refractory autoimmune diseases unresponsive to conventional therapies or BDT alone. (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e)\u003c/p\u003e\u003cp\u003eFinally, a comparative study evaluated three different protocols for pemphigus treatment: protocol 1 (lymphoma protocol) with four weekly doses of 375 mg/m\u0026sup2;, protocol 2 (rheumatoid arthritis protocol) with two doses of 1 g given two weeks apart, and protocol 3 (rituximab plus IVIG) over six to eight months with monthly infusions. The highest early endpoint rate was observed with Protocol 3 (100%), but it had the longest time to disease control (9.6 weeks) and the highest relapse rate of 75%. With faster disease control (4.6 weeks) and fewer relapses, Protocol 2 did better in the long term. Protocol 1 was slower in reaching disease control and had lower complete remission rates compared to the other two protocols. Protocol 3 was most effective for severe cases. (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e)\u003c/p\u003e\u003cp\u003eThere is no consensus on the ideal rituximab dose for pemphigus; lower doses, such as two infusions of 500 mg (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e), a single infusion of 200 mg (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e), or even 20 mg (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e), have shown acceptable results. A large meta-analysis also found no superiority of higher doses over lower ones, except for a longer duration of complete remission (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). However, higher doses are associated with significantly increased costs and a dose-dependent increase in infection risk (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Based on these findings, we chose to treat our patients with a cycle of IVIg at 2 g/kg, followed by a low-dose infusion of 500 mg rituximab.\u003c/p\u003e\u003cp\u003eWithin three months of therapy, 48% of patients had achieved CR; this was promising, especially because a low dose of rituximab was used. Clinical symptoms also improved significantly; The PDAI score decreased from an average of 21.56 to just 7.12 (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). This result not only establishes the efficacy of the treatment but also suggests that the treatment could possibly have the potential to improve the patients' quality of life. The reduction in anti-Dsg antibody levels also shows the effectiveness of this approach. Almost 50% reduction in Anti-Dsg1 (123.96 IU/mL to 67.56 IU/mL; P\u0026thinsp;=\u0026thinsp;0.010) and Anti-Dsg3 levels (188.12 IU/mL to 107.04 IU/mL; P\u0026thinsp;=\u0026thinsp;0.00043) were seen. These changes are in concordance with disease control and remission.\u003c/p\u003e\u003cp\u003e12% of patients had mild upper respiratory infections, including covid infection, and there were no reports of severe or life-threatening complications. This is significant as it indicates this treatment protocol is a safe option in viral outbreaks.\u003c/p\u003e\u003cp\u003eAlthough the results are encouraging, the 44% rate of partial remission and 8% relapse rate suggests that there is room for improvement. Previous studies have indicated that retreatment with rituximab and IVIg or additional courses of low-dose rituximab can lead to the recovery of disease control and induce remission. (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e)\u003c/p\u003e\u003cp\u003eLimitations: Some of the limitations of this study include the small number of participants, the absence of a control group, the short duration of the follow-up, and the insufficient information on the patients who did not respond to the treatment or had a relapse. Future work should also concentrate on larger, more detailed investigations to enhance the findings and develop specific treatment plans.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThis paper aims at exploring the efficacy and safety of a combined low-dose rituximab and IVIg regimen for the management of moderate to severe pemphigus, showing this effective, safe, and budget-friendly treatment protocol could be a better choice for elderly or comorbid patients where conventional immunosuppressive drugs are associated with high risk.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eK.B. and P.M. contributed equally to the study.K.B. and P.M. and contributed to the concept and design.V.L and N.GH and R.A and M.D and H.M and A.A collected the data.H.B and A.A analyzed the data.K.B and A.A and P.M. and H.B. wrote the main manuscript text.All authors reviewed the manuscript.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eData are available upon request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eKridin K (2018) Pemphigus group: overview, epidemiology, mortality, and comorbidities. Immunol Res 66(2):255\u0026ndash;270\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMalik AM, Tupchong S, Huang S, Are A, Hsu S, Motaparthi K (2021) An Updated Review of Pemphigus Diseases. Med (Kaunas). ;57(10)\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKridin K (2018) Emerging treatment options for the management of pemphigus vulgaris. Ther Clin Risk Manag 14:757\u0026ndash;778\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAbulikemu K, Hu F, Liang J, Kang X (2023) Targeting therapy in pemphigus: Where are we now and where are we going? Heliyon 9(6):e16679\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKhandelwal K, Jajoo V, Bajpai K, Madke B, Prasad R, Wanjari MB et al (2023) Rituximab in Pemphigus Vulgaris: A Review of Monoclonal Antibody Therapy in Dermatology. Cureus 15(6):e40734\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDur\u0026atilde;es SMB, Santos NR, Batzner CN, Cerqueira FGM (2024) Use of low-dose rituximab to treat pemphigus. An Bras Dermatol 99(5):791\u0026ndash;792\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCzernik A, Toosi S, Bystryn JC, Grando SA (2012) Intravenous immunoglobulin in the treatment of autoimmune bullous dermatoses: an update. Autoimmunity 45(1):111\u0026ndash;118\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFrew JW, Martin LK, Murrell DF (2011) Evidence-based treatments in pemphigus vulgaris and pemphigus foliaceus. Dermatol Clin 29(4):599\u0026ndash;606\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGrando SA, Rigas M, Chernyavsky A (2020) Rationale for including intravenous immunoglobulin in the multidrug protocol of curative treatment of pemphigus vulgaris and development of an assay predicting disease relapse. Int Immunopharmacol 82:106385\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLolis M, Toosi S, Czernik A, Bystryn J-C (2011) Effect of intravenous immunoglobulin with or without cytotoxic drugs on pemphigus intercellular antibodies. J Am Acad Dermatol 64(3):484\u0026ndash;489\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAhmed AR, Spigelman Z, Cavacini LA, Posner MR (2006) Treatment of pemphigus vulgaris with rituximab and intravenous immune globulin. N Engl J Med 355(17):1772\u0026ndash;1779\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAhmed AR, Nguyen T, Kaveri S, Spigelman ZS (2016) First line treatment of pemphigus vulgaris with a novel protocol in patients with contraindications to systemic corticosteroids and immunosuppressive agents: Preliminary retrospective study with a seven year follow-up. Int Immunopharmacol 34:25\u0026ndash;31\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBoulard C, Duvert Lehembre S, Picard-Dahan C, Kern JS, Zambruno G, Feliciani C et al (2016) Calculation of cut-off values based on the Autoimmune Bullous Skin Disorder Intensity Score (ABSIS) and Pemphigus Disease Area Index (PDAI) pemphigus scoring systems for defining moderate, significant and extensive types of pemphigus. Br J Dermatol 175(1):142\u0026ndash;149\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRusso I, Miotto S, Saponeri A, Alaibac M (2020) Ultra-low dose rituximab for refractory pemghigus vulgaris: a pilot study. Expert Opin Biol Ther 20(6):673\u0026ndash;678\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMurrell DF, Dick S, Ahmed AR, Amagai M, Barnadas MA, Borradori L et al (2008) Consensus statement on definitions of disease, end points, and therapeutic response for pemphigus. J Am Acad Dermatol 58(6):1043\u0026ndash;1046\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFeldman RJ, Christen WG, Ahmed AR (2012) Comparison of immunological parameters in patients with pemphigus vulgaris following rituximab and IVIG therapy. Br J Dermatol 166(3):511\u0026ndash;517\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAhmed AR, Kaveri S (2018) Reversing Autoimmunity Combination of Rituximab and Intravenous Immunoglobulin. Front Immunol 9:1189\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHamadah I, Chisti MA, Haider M, Binamer Y, Alajlan S, Aleyouni Y, Alfadley A (2019) Rituximab/IVIG in pemphigus - a 10-year study with a long follow-up. J Dermatolog Treat 30(2):170\u0026ndash;175\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHorv\u0026aacute;th B, Huizinga J, Pas HH, Mulder AB, Jonkman MF (2012) Low-dose rituximab is effective in pemphigus. Br J Dermatol 166(2):405\u0026ndash;412\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCiolfi C, Tartaglia J, Alaibac M (2024) Is It Time to Reconsider Rituximab Dosing Regimens for Pemphigus Vulgaris? Antibodies (Basel). ;13(1)\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWang HH, Liu CW, Li YC, Huang YC (2015) Efficacy of rituximab for pemphigus: a systematic review and meta-analysis of different regimens. Acta Derm Venereol 95(8):928\u0026ndash;932\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKasi PM, Tawbi HA, Oddis CV, Kulkarni HS (2012) Clinical review: Serious adverse events associated with the use of rituximab - a critical care perspective. Crit Care 16(4):231\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRobinson AJ, Vu M, Unglik GA, Varigos GA, Scardamaglia L (2018) Low-dose rituximab and concurrent adjuvant therapy for pemphigus: Protocol and single-centre long-term review of nine patients. Australas J Dermatol 59(1):e47\u0026ndash;e52\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"archives-of-dermatological-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [Archives of Dermatological Research](https://www.springer.com/journal/403)","snPcode":"403","submissionUrl":"https://submission.nature.com/new-submission/403/3","title":"Archives of Dermatological Research","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7509683/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7509683/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003ePemphigus is a chronic autoimmune disease of skin and mucous membranes which presents with painful blisters. Conventional treatment with high doses of corticosteroids may lead to remission, but this often causes significant side effects. Therefore, steroid-sparing treatments like rituximab (a monoclonal antibody) and intravenous immunoglobulin (IVIg) have been tried and appear to be safe and effective alternatives. This study looked at how well a low-dose combination of rituximab and IVIg works for moderate to severe pemphigus cases.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eThe study involved 25 patients, most of whom (92%) had pemphigus vulgaris, while the rest (8%) had pemphigus foliaceus. All patients had a Pemphigus Disease Area Index (PDAI) score greater than 15. The treatment was initiated with IVIg (2 g/kg), followed by a 500 mg dose of rituximab two weeks later. Patients received prednisolone as premedication. Clinical responses were evaluated at 3 months using PDAI scores and changes in anti-desmoglein (anti-Dsg1 and anti-Dsg3) antibody levels.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eBy the end of the study, 48% of patients had complete remission, 44% achieved partial remission, and 8% experienced a relapse, with no significant difference in regard to treatment response between old and new cases. PDAI scores significantly dropped from an average of 21.56\u0026thinsp;\u0026plusmn;\u0026thinsp;13.46 to 7.12\u0026thinsp;\u0026plusmn;\u0026thinsp;1.05 (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Antibody levels also fell sharply (P\u0026thinsp;=\u0026thinsp;0.010 for anti-Dsg1; P\u0026thinsp;=\u0026thinsp;0.00043 for anti-Dsg3). Side effects were minimal, with 12% of patients reporting mild upper respiratory infections.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eThis combination of low-dose rituximab and IVIg seems to be a safe and effective way to manage pemphigus. It helped reduce symptoms and antibody levels while avoiding serious side effects. Even though the results are promising, more research with larger groups and longer follow-up periods is necessary to confirm these findings and improve the treatment.\u003c/p\u003e","manuscriptTitle":"A Novel Low-Dose Rituximab and IVIg Protocol for Treating Moderate to Severe Pemphigus: A Prospective Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-20 02:19:20","doi":"10.21203/rs.3.rs-7509683/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-01-05T20:25:24+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-30T12:21:17+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-28T08:40:07+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-27T18:43:13+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"97538258056220535618649183472299575388","date":"2025-12-20T14:08:36+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"75641249053916601759401553403765250374","date":"2025-12-20T10:52:49+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"146040734167550074524687058806848819663","date":"2025-12-19T13:43:55+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"59106239007577794865837988750394004535","date":"2025-12-14T10:17:44+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-10T19:36:17+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"18438505890961697744782191896139070259","date":"2025-12-08T18:56:30+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"179710272516808028514060434211880893989","date":"2025-12-08T09:20:57+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-25T13:56:15+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-20T15:31:02+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"229575805920644148568652657719622701990","date":"2025-11-20T14:45:23+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"34607757630529159204481120032903181342","date":"2025-11-17T09:01:43+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-11-10T16:56:42+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-06T15:57:09+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-09-06T15:56:50+00:00","index":"","fulltext":""},{"type":"submitted","content":"Archives of Dermatological Research","date":"2025-09-01T14:40:30+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"archives-of-dermatological-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [Archives of Dermatological Research](https://www.springer.com/journal/403)","snPcode":"403","submissionUrl":"https://submission.nature.com/new-submission/403/3","title":"Archives of Dermatological Research","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"08671037-e1d8-4435-b39b-b4e38850fa31","owner":[],"postedDate":"November 20th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-21T15:38:55+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-20 02:19:20","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7509683","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7509683","identity":"rs-7509683","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}