Agranulocytosis under biotherapy in rheumatoid arthritis: three cases hypothesis of parvovirus B19 involvement in agranulocytosis observed under tocilizumab and rituximab for the treatment of rheumatoid arthritis

Abstract

Leukopenia is a considerably common complication of tocilizumab [TCZ] and rituximab [RTX] therapy. RTX-induced leukopenia typically exhibits delayed onset. While agranulocytosis has been reported linked to RTX treatment of lymphoma, this complication rarely occurs in rheumatoid arthritis (RA) treatment and, to our knowledge, has never been reported in association with TCZ therapy. We herein report four agranulocytosis cases in three patients, with the first two cases suspected to be secondary to human parvovirus B19 (PVB19) infection. Agranulocytosis manifested in the first patient 2 months following a third RTX course. Bone marrow (BM) polymerase chain reaction (PCR) was positive for PVB19. The patient relapsed after three TCZ courses, with her PCR again positive for PVB19. Both episodes resolved under granulocyte-macrophage colony-stimulating factor (GM-CSF). In the second patient, agranulocytosis manifested after the 74th TCZ course. Bone marrow PCR was positive for PVB19, and the evolution was favorable under intravenous immunoglobulin administration. The third case was a 53-year-old female patient with seropositive RA who presented agranulocytosis after the first infusion of her fourth RTX course. Unfortunately, no PCR PVB19 was made on myelogram. Evolution was favorable after 5 days of GM-CSF. PVB19 infection should be investigated in patients suffering from agranulocytosis manifesting during biotherapy. In cases manifesting from the 15th day of RTX treatment onwards, hemogram must be conducted before readministering the infusion.

State of Art of Idiosyncratic Drug-Induced Neutropenia or Agranulocytosis, with a Focus on Biotherapies

“…Outside the context of oncology, biotherapies have been reported as being the cause of early and transient Grade 1–2 neutropenia in 10–15% of the treated patients, often with TNF-α inhibitors [16,19,20,21,22,23,24], tocilizumab [25,26,27], rituximab [14,27,28,29,30,31,32,33,34,35,36], and alemtuzumab [15,37,38,39,40,41,42]. In a retrospective cohort study involving 499 patients with rheumatic diseases (rheumatoid arthritis in 72% of the diseases) treated by intravenous abatacept, infliximab, or tocilizumab, Espinoza et al report at least one neutropenic episode in 52 patients (10.4%) [26].…”

“…Among 2624 rituximab-treated patients for refractory autoimmune and auto-inflammatory disorders and at least one follow-up visit, late onset neutropenia was observed in 40 patients (1.53%; 25 with rheumatoid arthritis (1.3% of these patients, 0.6/100 patient-years), and 15 with other rheumatologic disorders (2.3% of patients with these disorders, 1.5/100 patient-years)) [14]. Only a few case reports of Grade 3–4 neutropenia have been reported to date with anti-TNF-α therapy, tocilizumab therapy, and IL1 inhibitors [16,27,43]. To our knowledge, no severe neutropenia case has yet been reported with belimumab.…”

“…In autoimmune or auto-inflammatory disorders, several chemical drugs have been identified as the cause of neutropenia, including most of the nonsteroidal anti-inflammatory drugs and more rarely glucocorticoids; several DMARDs, particularly hydroxychloroquine, penicillamine, and sulfasalazine; and other drugs as colchicine and dapsone (Table 1) [1,2,3]. In this context, all biotherapies on the market in the USA and Europe have also been associated with neutropenia (especially well-documented for TNF-α inhibitors, tocilizumab, rituximab, and alemtuzumab) as described above (Table 1) [14,15,16,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43]. For most of these biotherapies, the overall neutropenia risk is estimated to be around 10%, but this risk appears minimal (<1%) for Grade 3–4 neutropenia and agranulocytosis [2,14,15,16,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43].…”

The Efficacy and Safety of Rituximab in Rheumatoid Arthritis: New Evidence

“…C. Giraud и соавт. [40] представили описание двух случаев РТМ-индуцированно-го агранулоцитоза на фоне В19-инфекции, подтвержден-ной выявлением парвовируса В19 в костном мозге. При этом получен быстрый и стойкий эффект на фоне ле-чения ГМ-КСФ.…”

Parvovirus B19 infection presenting with neutropenia and thrombocytopenia

“…In immunocompromised individuals, chronic anemia could be developed, and in patients with hereditary spherocytosis and sickle-cell disease, an anemic crisis could develop. [2] Neutropenia has been infrequently reported in various clinical situations as well as in healthy individuals, [3–7] and there is limited data for PV-associated neutropenia and thrombocytopenia. Here, we describe the clinical and laboratory characteristics of 3 patients with PV infection presenting with neutropenia and thrombocytopenia.…”