Rituximab, a chimeric anti-CD20-antibody, attracts increasing attention as a treatment option for multiple sclerosis (MS). Apart from smaller controlled trials, an increasing number of studies in real-world populations indicate high efficacy based on clinical and neuroradiological outcomes for rituximab in relapsing-remitting MS patients. Additional evidence also demonstrates efficacy of rituximab with treatment of progressive MS phenotypes. In this topical review, we summarize and discuss current evidence on mechanisms of action, efficacy, safety, tolerance and other clinical aspects of rituximab in the treatment of MS. Finally, we will highlight current knowledge gaps and the need for comparative studies with other disease-modifying therapies in MS.

Rituximab treatment for multiple sclerosis.

B cell hyperactivity is a hallmark of the complex autoimmune disease systemic lupus erythematosus (SLE), which has justified drug development focusing on B cell altering agents during the last decades, as well as the off-label use of B cell targeting biologics. About a decade ago, the anti-B cell activating factor (BAFF) belimumab was the first biological agent to be licensed for the treatment of adult patients with active yet non-renal and non-neuropsychiatric SLE, to later be expanded to include treatment of pediatric SLE and, recently, lupus nephritis. B cell depletion is recommended as an off-label option in refractory cases, with the anti-CD20 rituximab having been the most used B cell depleting agent to date while agents with a slightly different binding specificity to CD20 such as obinutuzumab have also shown promise, forming a part of the current pipeline. In addition, terminally differentiated B cells have also been the targets of experimental therapies, with the proteasome inhibitor bortezomib being one example. Apart from being promising drug targets, B and plasma cells have also shown promise in the surveillance of patients with SLE, especially for monitoring B cell depleting or B cell altering therapies. Inadequate B cell depletion may signify poor expected clinical response to rituximab, for example, while prominent reductions in certain B cell subsets may signify a protection against flare development in patients treated with belimumab. Toward an era with a richer therapeutic armamentarium in SLE, including to a large extent B cell altering treatments, the challenge that emerges is to determine diagnostic means for evidence-based therapeutic decision-making, that uses clinical information, serological markers, and gene expression patterns to guide individualized precision strategies.

/pdf/b-cells-in-systemic-lupus-erythematosus-targets-of-new-2v9l55pf.pdf

B cells in systemic lupus erythematosus: Targets of new therapies and surveillance tools

It is now two decades since Rituximab was first used in the treatment of patients with systemic lupus erythematosus. There have been many challenges but in spite of failing to meet its primary endp...

/pdf/rituximab-the-first-twenty-years-37b7tt3uhk.pdf

Rituximab - The first twenty years.

Mechanisms for late-onset neutropenia (LON) after rituximab treatment are poorly defined both for non-Hodgkin lymphoma (NHL) and for autoimmune disorders. We performed a case–control analysis of a prospective cohort of 169 evaluable consecutive rituximab-treated NHL patients to assess cytokines involved in neutro- and lymphopoiesis (G-CSF, SDF1, BAFF, APRIL) and inflammation (CRP) as possible LON mechanisms. Fifteen patients (9%) developed LON (peripheral blood /PB/ absolute neutrophil counts /ANC/ < 0.5 G/L, all with marked depletion of CD20+ B-lymphocytes in bone marrows); they were compared with 20 matched NHL controls without LON. At start of LON, significantly higher PB G-CSF and BAFF levels (P = 0.0004 and 0.006, respectively), as well as CRP rises were noted compared to controls; these G-CSF and BAFF and most CRP values returned to levels of the controls in post-LON samples. G-CSF (but not BAFF) changes correlated to CRP rises (but not to ANC levels). BAFF levels correlated significantly to absolute monocyte counts and PB large granular lymphocyte counts (but not to ANC, C-CSF or CRP values). No changes of SDF1 or APRIL levels were noted. Neither LON cases nor controls displayed anti-neutrophil autoantibodies. Collectively, LON in NHL patients was timewise related to transient bursts of blood G-CSF and BAFF concentrations, suggesting that these neutro- and lymphopoiesis growth factors play a role in emergence of rituximab-induced LON, and that inflammation may be a trigger for G-CSF production during LON.

/pdf/the-role-of-baff-and-g-csf-for-rituximab-induced-late-onset-58lfq4ykez.pdf

The role of BAFF and G-CSF for rituximab-induced late-onset neutropenia (LON) in lymphomas.

Idiosyncratic drug-induced neutropenia (DIN) is a rare, potentially fatal adverse reaction. A literature search was performed on Pubmed and Embase, targeting articles indicating neutropenia as a complication during the treatment of non-neoplastic dermatological disorders. In 66 identified articles, the common incriminated drugs included conventional oral immunomodulators, topical cytotoxic agents, antibacterials, antifungals, biologics and targeted synthetic disease-modifying antirheumatic drugs, non-steroidal anti-inflammatory drugs, and retinoids, with dapsone being reported most often. The duration of drug exposure before the diagnosis of neutropenia varied, but mostly ranged from days to weeks. The majority of patients recovered after drug discontinuation and supportive management including antibiotics and granulocyte colony-stimulating factor, but fatal cases were reported. The proposed pathogenesis of DIN consists of direct drug toxicity and immune-mediated reaction. Certain genetic variants, individual variability in enzyme efficiency, and concomitant use of other drugs may increase the risk of DIN. Being familiar with the most commonly implicated agents and risk factors helps early identification and prompt management of this potentially fatal complication.

Drug-Induced Neutropenia During Treatment of Non-Neoplastic Dermatologic Diseases: A Review

Background Rituximab-mediated late-onset neutropenia (LON) has been described in various diseases. We investigated its prevalence and contributing factors, including B cell related cytokines and growth factors of the myeloid lineage, in patients with systemic lupus erythematosus (SLE). Methods Rituximab-treated patients from the Karolinska University Hospital (n=107) were enrolled. LON was defined as an absolute neutrophil count Results Thirty-two patients (29.9%) developed LON after a median time of 201.5 days (IQR: 66.8–322.0). Thirteen patients were admitted to the hospital; ten developed fever, and three developed critical conditions. BAFF levels increased from baseline (median: 0.62 ng/mL; IQR: 0.42–1.07) through the post-treatment measurement, both in patients who developed LON (median: 1.73 ng/mL; IQR: 1.03–2.56; p=0.005) and patients who did not (median: 1.03; IQR: 0.65–1.55; p=0.001), with significantly higher BAFF levels in the LON group (p=0.021). APRIL levels were higher in the LON group both at baseline (median: 1.54 versus 1.15 ng/mL; p=0.027) and post-treatment (median: 2.39 versus 1.11 ng/mL; p=0.011). IL-6 and GM-CSF levels decreased in the non-LON group (p Conclusion Post-rituximab LON is a common complication in SLE. Although the phenomenon was self-limiting in most cases, a few patients developed life-threatening conditions; this highlights the importance of regular surveillance for neutrophil counts, fever and infections. Distinct roles of BAFF and APRIL are implicated; BAFF might contribute to granulopoiesis disruptions, whereas APRIL might have a value in distinguishing predisposed patients.

https://lupus.bmj.com/content/lupusscimed/5/Suppl_1/A101.2.full.pdf

PS7:134 Rituximab-mediated late-onset neutropenia in systemic lupus erythematosus – distinct roles of baff and april

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PS7:134 Rituximab-mediated late-onset neutropenia in systemic lupus erythematosus – distinct roles of baff and april