What is the relationship between leukopenia and autoimmune disease?

From the Guidelines

Leukopenia in patients with autoimmune diseases, particularly systemic lupus erythematosus (SLE), should be managed by addressing the underlying disease activity and monitoring for infections, with treatment guided by the severity of the leukopenia and the presence of symptoms, as recommended by the 2019 update of the EULAR recommendations for the management of SLE 1.

Management of Leukopenia

• For mild leukopenia (white blood cell count >2,000/μL) without symptoms, close monitoring may be sufficient without specific treatment.
• For moderate to severe leukopenia, immunosuppressive medications like hydroxychloroquine, prednisone, or mycophenolate mofetil may be used to address the underlying autoimmune disease.
• In cases of severe neutropenia (absolute neutrophil count <500/μL), granulocyte colony-stimulating factor (G-CSF) may be used temporarily.

Infection Prevention and Monitoring

• Patients with SLE should be screened for HIV, HBV, and HCV infections before administering immunosuppressive therapy, as recommended by the European League Against Rheumatism 1.
• Routine TB testing is not recommended in non-endemic areas, but TB testing before glucocorticoids and immunosuppressive drugs is recommended according to the US Centers for Disease Control and Prevention (CDC) recommendations.
• Patients should be educated about infection prevention strategies and when to seek medical attention for fever or signs of infection, as leukopenia increases infection risk.

Vaccination and Immunosuppression

• Inactivated live vaccines are contraindicated in patients taking immunosuppressive drugs and/or glucocorticoids at a dose >20 mg/day.
• Vaccination against flu, Pneumococcus, and hepatitis B appears safe and does not lead to SLE flares, with the majority of patients developing protective antibodies.

From the FDA Drug Label

1. 3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of RITUXAN. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure Hematologic: prolonged pancytopenia, marrow hypoplasia, Grade 3-4 prolonged or late-onset neutropenia, hyperviscosity syndrome in Waldenstrom's macroglobulinemia, prolonged hypogammaglobulinemia [see Warnings and Precautions (5. 6)]. Immune/Autoimmune Events: uveitis, optic neuritis, systemic vasculitis, pleuritis, lupus-like syndrome, serum sickness, polyarticular arthritis, and vasculitis with rash

The rituximab drug label mentions hematologic adverse reactions, including prolonged pancytopenia, marrow hypoplasia, and Grade 3-4 prolonged or late-onset neutropenia, which can be associated with leukopenia. Additionally, it mentions immune/autoimmune events, including systemic vasculitis, lupus-like syndrome, and vasculitis with rash, which can be related to autoimmune disease. However, the label does not directly address the relationship between rituximab and leukopenia in patients with autoimmune disease. 2

From the Research

Leukopenia with Autoimmune Disease

• Leukopenia, often used interchangeably with neutropenia, is an abnormal reduction of circulating white blood cells, especially granulocytes, and can result from reduced production or increased utilization and destruction of white blood cells 3.
• Autoimmune diseases, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), can be associated with leukopenia, particularly neutropenia, due to the production of autoantibodies against neutrophils 4.
• The mechanism of neutropenia in autoimmune diseases involves the production of antineutrophil antibodies, increased neutrophil apoptosis, and the role of immune complexes in affecting neutrophil traffic and function 4.
• Treatment options for neutropenia associated with autoimmune diseases include methotrexate, cyclosporine A, granulocyte colony-stimulating factor (G-CSF), and granulocyte-macrophage colony-stimulating factor (GM-CSF) 4, 5.
• G-CSF has been shown to be effective in reversing neutropenia and decreasing the risk of infections in patients with Felty's syndrome and SLE, but should be administered at the lowest dose effective at elevating the neutrophil count above 1,000/microL 4.
• Autoimmune neutropenia (AIN) is a rare disorder that may cause life-threatening infections, and treatment options include G-CSF, prednisolone, and other immunosuppressive therapies 6, 7.
• Diagnostic procedures and optimal treatments for AIN need to be established, and management requires identification of the cause and effective antimicrobial therapy, especially when serious systemic infection is present 7, 3.