What are the causes of low Immunoglobulin M (IgM)?

From the Guidelines

Low IgM levels can be caused by various conditions, including primary immunodeficiency disorders, secondary causes such as medications and protein-losing conditions, and other factors like malnutrition, malignancies, and genetic disorders, as noted in the practice parameter for the diagnosis and management of primary immunodeficiency 1.

Primary Causes

• Primary immunodeficiency disorders like selective IgM deficiency, common variable immunodeficiency (CVID), and X-linked agammaglobulinemia can lead to low IgM levels.
• Transient hypogammaglobulinemia of infancy (THI) is a condition where IgM levels, along with IgG and sometimes IgA, are low during infancy and early childhood, but often correct by the age of 3 to 4 years, as seen in studies on THI 1.

Secondary Causes

• Medications such as rituximab, corticosteroids, and certain chemotherapy agents can suppress antibody production, leading to low IgM.
• Protein-losing conditions like nephrotic syndrome, protein-losing enteropathy, and severe burns can deplete IgM levels.

Other Factors

• Malnutrition, particularly protein deficiency, may impair antibody synthesis and lead to low IgM.
• Certain malignancies, especially lymphomas and leukemias, can disrupt normal B-cell function, resulting in low IgM.
• Genetic disorders like ataxia-telangiectasia and Wiskott-Aldrich syndrome may present with low IgM levels.
• Chronic infections can consume antibodies faster than they're produced, leading to low IgM.

Management

• Management of low IgM depends on the underlying cause, ranging from treating the primary condition to immunoglobulin replacement therapy in severe cases with recurrent infections, as recommended in the management of antibody deficiency 1.
• Regular monitoring of infection frequency and immunoglobulin levels is essential for patients with persistently low IgM, to assess the need for and response to treatment, such as IgG replacement therapy, which may be indicated in some cases 1.

From the FDA Drug Label

Hypogammaglobulinemia (IgG or IgM below the lower limit of normal), including prolonged hypogammaglobulinemia (defined as Ig levels below lower limit of normal for at least 4 months) was observed in GPA/MPA Study 4. During the overall study period, 18/25 patients (72%) had prolonged low IgG levels, including 15 patients who also had prolonged low IgM Hypogammaglobulinemia (IgG or IgM below the lower limit of normal), including prolonged hypogammaglobulinemia (defined as Ig levels below lower limit of normal for at least 4 months) was observed in PV Study 2. Based on levels less than LLN measured at Week 16, Week 24, Week 40, and Week 52,16. 4% (11/67) of patients with normal baseline immunoglobulins had prolonged hypogammaglobulinemia (10 patients – IgM, 1 patient – both IgG and IgM) after treatment with RITUXAN.

The causes of low IgM include hypogammaglobulinemia, which can be prolonged and is observed in patients treated with rituximab 2 2. Key points about low IgM include:

• Prolonged hypogammaglobulinemia was observed in 72% of patients in GPA/MPA Study 4, with 15 patients having both low IgG and IgM levels
• In PV Study 2,16.4% of patients with normal baseline immunoglobulins developed prolonged hypogammaglobulinemia after treatment with rituximab, with 10 patients having low IgM levels and 1 patient having both low IgG and IgM levels.

From the Research

Causes of Low IgM

• Low IgM levels can be caused by various factors, including genetic mutations and certain medical treatments 3, 4.
• Rituximab, a B cell depleting monoclonal antibody, has been shown to cause hypogammaglobulinemia, including low IgM levels, in patients with autoimmune diseases 4, 5, 6.
• The incidence and clinical significance of low IgM levels after rituximab therapy can vary depending on the underlying disease, cumulative dose, and other factors 4, 5, 6.
• Age, cumulative rituximab dosage, and daily steroid dosage have been found to be associated with IgM levels in patients with autoimmune diseases 6.
• Certain genetic conditions, such as primary hyper IgM syndromes, can also cause elevated IgM levels, while others may result in low IgM levels 3, 7.
• The pathophysiology of low IgM levels and their clinical significance are not yet fully understood and require further research 4, 6.