Gamma globulin replacement with decreased IgM and autoimmune disease
Question:
6/2/2021
I have a 58-year-old female followed for intermittent asthma and selective IgM deficiency. Several years ago, immunologic evaluation showed evidence of selective antibody deficiency and she received subcutaneous immunoglobulin replacement. This was discontinued when insurance company refused to cover. Since then, the patient has shown evidence of good functional antibody (11 of 14 protective pneumococcal serotypes) but continued absence of IgM. She has had frequent health problems in the last few years with evidence of autoimmune pancreatitis with chronic diarrhea and significant weight loss, polyarthritis, gangrenous appendicitis, severe GE reflux with esophageal strictures, and gallbladder infection. She would like to resume immunoglobulin replacement however I indicated that she currently is not categorized as specific antibody deficiency. She did note significant improvement in multiple symptoms with immunoglobulin replacement. I know selective IgM deficiency is not ordinarily a candidate for immunoglobulin replacement however I have read that individuals with this condition and continued recalcitrant infections benefited from immunoglobulin replacement. Do you feel that this patient's autoimmune and infection conditions might benefit from immunoglobulin replacement?
Answer:
The decrease in IgM does not likely reflect immunodeficiency in light of the preserved IgG and IgG response to immunization. However, the other problems you mention might indicate a problem with immune dysregulation. The recognition of the association of autoimmunity and immunodeficiency is increasing with genetic testing of immunologic dysregulation, and genetic testing may suggest specific therapies if a pathway of immune dysfunction is identified. Isolated decrease in IgM is not characteristic of a specific immunodeficiency to my knowledge (1) but has been reported in autoimmune syndromes associated with select immunodeficiencies (2). Isolated decrease in IgM rarely occurs following rituximab or other B lymphocyte depleting therapy, but this does not seem relevant in this case (3). You might consider measuring an IgM antibody such as isohemagglutinins.
A consideration would be to measure IgG subclasses as IgG4 disease could explain the autoimmune pancreatitis (4,5). This would be in the spectrum of systemic disease termed “IgG4-Related Disease” and is generally associated with peripheral eosinophilia and high normal or increased serum IgG4. In addition, there are numerous case reports of IgG4-related disease and hypo-IgM (5,6). Inflammatory bowel disease is also be a consideration, and this is associated with granulocytic autoimmune pancreatitis (7). Inflammatory bowel disease is also associated with immune dysregulation, but I could not find reports of hypogammaglobulinemia IgM associated with inflammatory bowel disease.
I suggest you obtain isohemagglutinins (assuming the patient is not AB blood type), perform an immunoelectrophoresis of serum and urine to exclude a monoclonal gammopathy which can be associated with abnormal IgM, obtain IgG subclasses and ask for a review of the pathology related to the autoimmune pancreatitis. The latter is divided into Type I (IgG4-related disease with storiform fibrosis, tissue eosinophilia, CD4 + T cells, obliterative phlebitis and IgG4+ plasma cells) and Type II (neutrophilic with inflammation focused on pancreatic ducts) (4). Keep in mind a normal serum IgG4 does not exclude the diagnosis, but generally the level is high normal or increased. I would not favor initiating immunoglobulin replacement without stronger evidence of a humoral immunodeficiency. Lymphocyte subsets and measurement of switched memory B cells (CD19+ CD27+ IgM- IgD-) might also be helpful. If there are abnormalities in the lymphocyte subpopulations this may warrant additional assessment for an immunodeficiency.
1. Chovancova, Zita, et al. "Selective IgM deficiency: clinical and laboratory features of 17 patients and a review of the literature." Journal of clinical immunology 37.6 (2017): 559-574.
2. Gennery, A. R., et al. "Antibody deficiency and autoimmunity in 22q11. 2 deletion syndrome." Archives of disease in childhood 86.6 (2002): 422-425.
3. Chovancova, Zita, et al. "Selective IgM deficiency: clinical and laboratory features of 17 patients and a review of the literature." Journal of clinical immunology 37.6 (2017): 559-574.
4. Okazaki, Kazuichi, et al. "Recent advances in the concept and diagnosis of autoimmune pancreatitis and IgG4-related disease." Journal of gastroenterology 46.3 (2011): 277-288.
5. Chuang, Tzyy-Ling, et al. "Gallium SPECT/CT in evaluation of IgG4-related disease: a case report and literature review." Medicine 95.37 (2016).
6. Carlson, G., and C. Coop. "M228 EARLY PRESENTATION OF SECONDARY SELECTIVE IGM DEFICIENCY-LIKE THE SPREADING CRACK ON A DAM." Annals of Allergy, Asthma & Immunology 123.5 (2019): S102-S103.
7. Klöppel G, Detlefsen S, Chari ST, Longnecker DS, Zamboni G. Autoimmune pancreatitis: the clinicopathological characteristics of the subtype with granulocytic epithelial lesions. J Gastroenterol. 2010;45:787–93.
I hope this information is of help to you and your practice.
All my best.
Dennis K. Ledford, MD, FAAAAI