Ultra-Low-Dose Rituximab in Pemphigus Vulgaris: How Low is the Lowest?

Rituximab (RTX) is rapidly becoming central to the management of pemphigus vulgaris (PV) as the first-line steroid-sparing agent. While there is little doubt regarding its excellent efficacy in PV, the most contentious issue remains its optimal dosing. A look at the evolution of RTX use in rheumatology as well as in PV shows that RTX was originally approved for non-Hodgkin’s lymphoma at a dose of 375 mg/m² weekly for 4 to 8 weeks. Eventually, the USFDA approved RTX for the management of rheumatoid arthritis (RA), granulomatosis with polyangiitis, and PV. The approved dose for initial induction of remission in PV is 1000 mg, given 2 weeks apart, along with tapering doses of glucocorticoids. No optimal dose-determining studies were performed by the original innovator for autoimmune conditions, probably due to the well-established safety and efficacy of higher doses and the cost involved in conducting large, multicentric clinical trials. Despite its good efficacy, this approach had an inherent flaw: It overlooked the fact that the quantity of CD20-positive B-cells, which are the target of RTX, differs in lymphoproliferative and autoimmune conditions. They are well within physiological limits in autoimmune conditions like RA and PV. It was only a matter of time before someone questioned the need to use the same dose to eliminate a few hundred versus millions of B-cells! The high cost and out-of-pocket expense owing to poor insurance coverage for PV in developing countries like India make trying lower doses even more compelling. The first step down the dosing ladder involved investigators testing a lower dose, with two infusions of 500 mg instead of 1000 mg in the management of PV, and they reported comparable efficacy.[1] Yet, the underlying question remained unanswered: What is the minimum effective dose of RTX for the management of PV? This brings ultra-low doses of RTX (ULD-RTX) into the picture. There is no universal criterion for determining at what dose RTX becomes “ultra-low.” Various investigators have tried 100 mg and 200 mg in various regimens, replacing 500 mg as ULD-RTX. The reason behind using doses in multiples of 100 mg could be that 100 mg is the lowest commercially available strength on the market. In a case series of 8 patients, Russo et al.[2] investigated a single infusion of 200 mg for the management of PV along with oral prednisolone. They observed that 5 out of 8 patients achieved a complete response at a mean duration of 7.5 weeks. Meanwhile, a randomized controlled noninferiority trial evaluating ULD-RTX for the continued treatment of RA (REDO study) fell short of establishing noninferiority of a single infusion of 200 mg against 1000 mg at 3- and 6-month time points due to a per-protocol hierarchical testing procedure.[3] In a recently published case series of 18 patients from our institute, we evaluated the efficacy and safety of two ULD-RTX (100 mg) 15 days apart as an adjuvant to corticosteroids and azathioprine in moderate to severe PV. We observed a complete response in 83.3% of patients at a mean interval of 12.75 weeks.[4] In a systematic review and meta-analysis on different regimens of RTX in PV, Wang et al.[5] reported no significant differences between the high-dose (>2000 mg) and low-dose (<1500 mg) regimens in terms of ‘complete remission (CR)’, ‘time for disease control’, and ‘time to complete response’ after the first cycle of RTX therapy. However, their analysis also showed that high-dose RTX treatment was associated with significantly longer duration of CR and a lower relapse rate compared with low-dose RTX. Neither of the case series on ULD-RTX investigated these endpoints.[2,4] In the case series published by us, we observed that B-cell depletion was achieved in 72.2% of patients, which is comparable to other published studies on the 1000 mg and 500 mg regimens.[1,6] Another important aspect regarding ULD-RTX, which remains to be investigated, is the timing of repeat infusion. Recent publications suggest the use of surrogate markers of disease activity, such as anti-desmoglein (dsg) antibody titer and B-cell repopulation or fixed duration repeat infusion to maintain remission. Whether ULD-RTX will require more frequent or similar repeat infusion to maintain remission is yet to be investigated.[7] Peripheral B-cell depletion is considered to be the primary mechanism of action of RTX in autoimmune diseases. An exploratory study in healthy volunteers by Schoergenhofer et al.[8] evaluating the effect of very-low-dose RTX demonstrated that a dose of ≤1 mg/m² is sufficient to achieve B-cell depletion. This was the first exploratory study in healthy volunteers on the pharmacokinetics, B-cell depletion, and immunogenicity of low-dose RTX, making it a compelling read for anyone using RTX in autoimmune diseases. Whether peripheral B-cell depletion achieved with ULD-RTX actually translates into clinical efficacy in disease conditions remains to be seen. Yet, if the findings of this study translate into real-world clinical efficacy, it could open up a whole new possibility of subcutaneous administration of RTX as the required volume may fall below 10 ml. The effect of ULD-RTX on other surrogate markers of disease activity, such as anti-dsg 1 and 3 antibody titers and B-cell repopulation time, remains to be seen. If established as equipotent and safe vis-à-vis the conventional regime in further studies, ultra-low-dose RTX will bring the benefits of low cost and shorter infusion time. Infusion reactions remain low when RTX is used in autoimmune conditions compared to hematological malignancies. One presumption made by some investigators of ULD-RTX is the possibility of fewer adverse events (AEs) due to the reduced dose. Our experience with the use of ULD-RTX in PV is contrary to this presumption, although adjuvant use of azathioprine in our case series could have contributed to more AEs. Theoretically, if B-cell depletion is effectively achieved, infection-related AEs could remain as much of a concern as with high-dose RTX. A few questions related to ULD-RTX, such as the durability of B-cell depletion and the duration of remission, can only be answered by high-quality randomized controlled trials (RCTs). In summary, data from the past few years regarding ULD-RTX, though not yet conclusive, are encouraging. Apart from scientific considerations, ULD-RTX brings significant excitement in terms of economic advantages. At a 100 mg dose, the reduction in cost to one-third to one-fourth of the existing 1000 mg dose will improve the accessibility of RTX for patients with PV who are bearing out-of-pocket expenses. At this time, high-quality RCTs evaluating the short-term and long-term efficacy and safety of ULD-RTX compared to the current high-dose RTX are urgently needed. The final word on ‘how low is the lowest’ may take some time to emerge, but in our opinion, Indian patients and dermatologists stand to be the biggest beneficiaries of dose reduction. The Indian Association of Dermatologists, Venereologists, and Leprologists (IADVL) can prioritize research in this area through grants, continued medical education programs, and conference coverage. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.