IgM deficiency and rituximab
Question:
4/3/2020
Recently evaluated a 57 year-old female referred by rheumatology (Sjogren's syndrome) for a low serum IgM level. The patient has a history of recurrent lymphoma (three episodes) and has been treated with radiation therapy, chemotherapy and rituximab (patient has received rituximab twice annually for the past three years). The patient's infection history is significant for one bout of sinusitis a year on average and one or two episodes of bronchitis a year. History of pneumonia. No other history of severe or unusual infections. Patient mentioned she has a slow response to antibiotics at times.
Recent laboratory evaluation revealed a normal CBC and differential, serum IgA of 85, IgG of 863, and an IgM of 22. No antibody response post-immunization with Pneumovax. Baseline tetanus and diphtheria titers were within protective range. Serum protein electrophoresis was within normal limits. Lymphocyte enumeration reveals slightly depressed CD3 and 4, CD19 less than two, with the remainder of the values within normal limits. Assuming the rituximab has depressed the B cell numbers, but not sure how to explain the normal serum IgA and IgG but very low IgM. Could this be a selective IgM deficiency?
Answer:
Selective IgM deficiency is an isolated absence or profound deficiency of serum IgM associated with infections, atopic manifestations, autoimmunity, or malignant conditions. Serum IgM levels are less than 10–15 mg/dl in infants and children and less than 20–30 mg/dl in adults. Other immunoglobulin levels and T cell immunity are usually normal. Your patient meets these criteria, including both autoimmune disease and lymphoma. (1)
Management of Selective IgM patients same fashion as for other antibody deficiencies. Ig replacement would only be given if there were a significant associated antibody deficiency, which you have also demonstrated.
Another consideration is Dock 8 mutation: What is your patient’s IgE and is he atopic? IgM deficiency with elevated IgE and a h/o atopy may suggest a Dock 8 mutation.
Regarding Secondary Immunodeficiency, Rituximab does not significantly reduce levels of existing antibodies in the majority of patients because antigen-specific IgG is produced by plasma cells, which do not express surface CD20. It is estimated that 22.4% of rituximab-treated patients developed reduced IgM and 3.5% low IgG levels for ≥4 months after one or more course. Serious infection rates are typically similar before and during/after development of low immunoglobulin (Ig) levels; however, in patients with low IgG, rates were higher than in patients who never developed low IgG.
Makatsori et al. (2) describe a case series of 17 patients that had received Rituximab with persistent hypogammaglobulinemia and no preservation of pneumococcal antibody response. The IgG level in this cohort of patients was decreased with a mean of 3.42-0.4 g/l (normal range 5.8–16.3 g/l. The median IgG was 64.7% below the lower limit of normal. IgM was below the normal range in all but one patient with a markedly reduced mean of 0.29 0.05 g/l (normal range 0.7–3.50 g/l). The mean IgA level was within the lower end of the normal range. All serotype-specific pneumococcal responses were <01.3. Furthermore, patients who received Pneumococcal, tetanus or Hib vaccination failed to mount an immune response. Each of these patients were started on IVIG, responding with less frequency of infection. They remained on IVIG ranging from 7 months to 7 years, demonstrating that B-cell depletion and hypogammaglobulinemia may persist for a long time after discontinuation of rituximab treatment.
Furthermore, Makatsori et al. (2) recommended “that a trial of immunoglobulin replacement be considered on a case-by-case basis in patients with low IgG following rituximab treatment, who have ongoing infections despite the use of appropriate prophylactic antibiotics. In general, the need for this treatment would be reviewed on a regular basis, and withdrawn if no benefit was derived, or if there was evidence of recovery in natural immunoglobulin production”.
I also reached out to Dr Bonilla, an expert in this area. Please see Dr. Bonilla’s response below.
It is often challenging to distinguish primary vs secondary antibody deficiency or abnormal lymphocyte populations in patients who have received chemotherapy of various types. Due to its relative rarity, selective IgM deficiency continues to be somewhat ill-defined and is only recently regaining some currency as a diagnostic label. I found an abstract for a recent larger case series, the full text of which I do not have access to at the moment. (4)
It appears to be consistent with Dr. Demain's comments. In the context of the vignette summary of the patient's constellation of current problems and her history, I am in favor of IgG therapy.
1) Griffith LM, Cowan MJ, Notarangelo LD, et al. Primary Immune Deficiency Treatment Consortium (PIDTC) report. J Allergy Clin Immunol. 2014;133(2):335–347. doi:10.1016/j.jaci.2013.07.052
2) Makatsori M, Kiani-Alikhan S, Manson AL, et al. Hypogammaglobulinemia after rituximab treatment-incidence and outcomes. QJM. 2014;107(10):821–828. doi:10.1093/qjmed/hcu094
3) Bonilla FA. Update: Vaccines in primary immunodeficiency. J Allergy Clin Immunol. 2018;141(2):474–481. doi:10.1016/j.jaci.2017.12.980
4) (Lucuab-Fegurgur DL and Gupta S. Comprehensive clinical and immunological features of 62 adult patients with selective primary IgM deficiency. Am J Clin Exp Immunol. 2019 Dec 25;8(6):55-67).
I hope you find this response helpful. Very special thanks to Dr. Bonilla.
Respectfully submitted,
Jeffrey G Demain, MD, FAAAAI