P34 Early-onset neutropenia in rituximab treated rheumatoid arthritis patients: a case series
Authors: Lin Chung Mun Alice , Lorenzi Alice R , Cooles Faye A. H 
Published: April 2020

Abstract

Background
Rituximab is a chimeric monoclonal anti-CD20 antibody, used in the management of autoimmunity. It is known to have a favourable safety profile, however, a rare complication includes early-onset neutropenia (EON), defined as neutropenia having occurred within four weeks of rituximab treatment. Only eight case reports have been published so far, the majority of which relate to its use in SLE and none in rheumatoid arthritis (RA). We report here the first dedicated case series of post-rituximab EON in RA.

Methods
We identified 4 RA patients with EON. All were anti-citrullinated protein antibody (ACPA) and rheumatoid factor (RF) positive. Demographics were female:male ratio 3:1, with mean age 58 (range 33-69). Our first patient (65F) had a past medical history (PMH) of asymptomatic primary biliary cirrhosis (ANA+ve, AMA+ve, M2+ve), the second (65F) had Sjogren’s syndrome (ANA+ve, dsDNA+ve, IgG+ve) and the third (69F) had diverticulosis, Raynaud’s phenomenon and subacute cutaneous lupus with no systemic manifestations (ANA+ve, Ro and La +ve). The fourth patient (33M) had no PMH. Three had previously reported intermittent neutropenia on prior disease modifying anti-rheumatic drug (DMARD) therapy, but none were on DMARDs/doses known to cause this at the time of Rituximab. Standard Rituximab regimens were administered (1g with 100mg IV methylprednisolone, two weeks apart) with two patients (33M, 69F) on concurrent methotrexate (15mg) and hydroxychloroquine (200mg) respectively.

Results
EON occurred at 4, 11 and 14 days (n = 2) (mean 10 days) post-infusion with mean nadir 0.57x109/L (range 0.05 - 1.17x109/L). It was the first treatment cycle for two patients (65F and 33M), whilst the others (65F and 69F) had received 2-3 previous cycles uneventfully. Patient 2, 65F and ANA+ve, subsequently developed neutropenic sepsis and was treated with standard protocol and G-CSF (granulocyte-colony stimulating factor). Cultures were negative and other investigations did not identify any infective source. The other three patients’ (33M, 69F) neutropenia resolved spontaneously without required intervention.

Conclusion
EON is a rare but serious complication of rituximab but to date no clear mechanism has been identified. It has been suggested that EON may be due to a bystander effect of lysozyme and granzyme release, secondary to B cell killing and that individuals with a high-affinity FcγRIIIa 158 V allele are more susceptible to this mechanism and therefore prone to a greater depth of neutropenia. Because of its relative acute onset, we may actually be under-recognising uncomplicated episodes of EON due to variability in routine blood monitoring post-treatment. We therefore want to highlight the need for vigilance in this patient cohort, particularly in those who are already susceptible to drug-induced neutropenia or are ANA+ve, in addition to vigilance irrespective of cycle number. Future monitoring of early neutrophil counts in Rituximab-treated RA patients may provide additional insight into this rare complication.

Disclosures
C. Lin None. A.R. Lorenzi None. F.A.H. Cooles None.