Rituximab in non-systemic vasculitic neuropathy: a single-center experience

Several new treatment options with improved side effect profiles compared to conventional chemotherapeutics for neurological autoimmune disorders, such as multiple sclerosis, but also for rare neuromuscular disorders, such as myasthenia gravis, were approved in recent years, leading to a shift of the therapeutic landscape. However, for immune-mediated neuropathies, these progresses are still lacking [1]. There are several reasons for this, e.g., the heterogeneity and the rarity of the diseases. Non-systemic vasculitic neuropathy (NSVN) is a rare immune neuropathy, with distally attenuated asymmetric motor and sensory deficits and mainly electrophysiological characteristics of axonal nerve damage [2]. NSVN responds to immunomodulatory treatment, but larger prospective randomized trials are missing and treatment regimens are based on retrospective cohort studies [3‐5]. According to guideline recommendations, corticosteroids alone or in combination with cyclophosphamide, azathioprine and methotrexate should be used. For severe cases, cyclophosphamide should be given to achieve clinical remission in the patients [3]. However, long-term treatment with cyclophosphamide has relevant dosage-related and treatment limiting myelotoxic side effects. Other escalating therapies option are currently not available. Extrapolation from randomized-controlled trials (RCTs) in small and medium vessel primary systemic vasculitides indicate that intravenous immunoglobulin, plasma exchange, and rituximab might be treatment options for NSVN patients [2]. Here, we report the clinical outcome and tolerability of rituximab treatment in four NVSN patients.

All patients were diagnosed with NSVN in the Department of Neurology at the University Hospital of Cologne between 2011 and 2018. Clinical and treatment data, including neurophysiological examinations and neuropathological results of nerve biopsies, were retrieved retrospectively from medical reports from first admission to December 2023 (approved by the local ethic committee, 21-1330). All four patients had been diagnosed with a pathologically confirmed definite (n = 1) or probable (n = 3) NSVN according to guideline [3]. An experienced neuropathologist analyzed all biopsy specimens. No patient had signs of a systemic vasculitis by clinical or laboratory measures, including ANCA-antibodies, serum electrophoresis, differential blood count, C-reactive protein, erythrocyte sedimentation rate, and cerebrospinal fluid analysis. Other causes of neuropathies had been excluded due to their individual history, presentation, and laboratory tests (e.g. immunofixation). As outcome variables, changes of sensorimotor symptoms evaluated by the Medical Research Council (MRC) sum score [6], Prineas Score [7], and Neurological Symptom Score (NSS) [8], from 12 months prior to rituximab induction, baseline (rituximab induction) and to follow-up (every 12 months) were included. All three scores have been used to quantify changes in motor symptoms [4] and in sensory symptoms [5] in NSVN.

Descriptive data are presented with GraphPad Prism, version 10.0.3 for Windows, GraphPad Software, Boston, Massachusetts USA.

Our case series displayed our single center experience for using the B-cell depleting agent rituximab in NSVN patients. NSVN is believed to be a mainly T-cell-mediated neuropathy, and guidelines recommend the use of the more T-cell directed immunosuppressants, such as corticosteroids and cyclophosphamide as first- and second-line treatments [3]. Accordingly, nerve biopsy specimen of NSVN patients in a larger cohort showed only few CD20 positive lymphocytes in only 50% of the biopsies [10]. However, B-cells regulate autoimmunity mostly not in a compartment specific pattern and localized pathological descriptions given by biopsies therefor offer only limited insights [11]. B-cell depletion impairs CD4+ T-cell activation and clonal expansion. It has been shown that CD4+ activation before tissue migration occurs in the regional lymph nodes [12, 13]. Further, complement activation in NSVN biopsies was detected in another study, for which (auto-)antibody-binding is critical for the classical pathway [14]. B-cell depletion is highly effective in preventing further relapses in other mainly T-cell-mediated disease, such as multiple sclerosis, highlighting the complex interplay and pivotal role of B-cells in sustaining autoinflammation. Monoclonal antibodies, in this case rituximab to target specifically B-cells, have several advantages compared to conventional chemotherapeutics, e.g. cyclophosphamide and azathioprine. Long-term dosage dependent cancerous effects are not observed and the drugs often show a favorable side effect profile, as shown by real-world data of on- and off-label use of anti-CD20 agents for autoimmune neurological diseases, such as multiple sclerosis [15]. For corticosteroids, long-term side effects of higher dosage are most-often therapy limiting. For many rheumatological and neurological autoimmune diseases, monoclonal antibodies replaced conventional chemotherapeutic drugs as first-line and escalation therapy. Side-effects were also a limiting factor for our patients. One patient suffering from short-term side effects of cyclophosphamide. The fourth patient was stable under cyclophosphamide, but long-term and dosage dependent side effects required a therapy switch. The observed side effect profile of rituximab was beneficial in our patients without reporting of any serious infections.

Regarding other cases of NSVN treated with rituximab, we identified two case reports with two patients each. In the first report, remission with a co-induction therapy of rituximab and oral corticosteroids was achieved [16]. In the second case report, clinical improvement with an escalation therapy of both, intravenous immunoglobulins and rituximab was successfully used in two patients with NSVN [17]. In both case reports, extensive clinical and histopathological characterization and long-term follow-up data are missing. We could not identify any further case reports or case series reporting the use of rituximab or another anti-CD20 agent for NSVN, however, extrapolation from RCTs of the small-to-medium vessel primary systemic vasculitides indicate a potential, but unproven benefit for rituximab [2, 3].

There are some uncertainties regarding the therapy scheme of rituximab. For multiple sclerosis, some centers prefer higher induction dosages of 2 × 1 g and a maintenance dose of 1 g every 6–12 months [18], while in Europe the effective use of much lower dosages was reported [19]. In hematological disorders the dosage is usually calculated based on body surface (375 mg/m² four times in the first months, followed by maintenance doses every six month) [20]. It is possible that suboptimal dosing was the reason for no observed clinical response to rituximab in patient 1. B-cell lysis could be another reason for the observed deterioration of the patient that could be addressed with corticosteroid bridging [21].

This study has clear limitations. First, the overall number of four patients is too small to draw relevant conclusions of the efficacy and safety profile of rituximab in NVSN. Second, even though all patients had pathological definite or probable diagnosis of NSVN, two patients also had diabetes mellitus type 2, possibly confounding disease progression data. Third, although hepatitis C infection as the main cause of cryoglobulinemic vasculitis was excluded in all patients and serum C3 levels used as surrogate marker were normal, no highly sensitive and specific diagnostic immunofixation or -electrophoresis was performed to definitively exclude cryoglobulinemic vasculitis [22].

Nevertheless, this case series offer valuable data to guide neurologist for escalation or therapy switch in NSVN and suggest that the use of rituximab might be treatment option for severe NSVN cases. Treatment alternatives in rare autoimmune neuropathies such as NSVN are urgently needed to either halt disease progression or minimize long-term and short-term side effects of other immunosuppressants. Drug repurposing might be a valuable tool as studies for these rare diseases due to their heterogeneity are hard to conduct [1].