An appropriate molecular diagnosis of inborn errors of immunity, including cold agglutinin disease (CAD), directly impacts the prognosis while also allowing the use of novel target therapies, according to a new study published in Frontiers in Immunology. These potential therapies can correct abnormal functioning of the typical immune responses in these diseases.

The team of researchers led by Cortesi described how the currently accepted pathogenic mechanisms underlying autoimmune cytopenias (AIC) in inborn errors of immunity include cellular or humoral autoimmunity, and immune dysregulation in cases of hemophagocytosis or lymphoproliferation with or without splenic sequestration, bone marrow failure, myelodysplasia, or secondary myelosuppression.

In terms of diagnostic tools, early genetic characterization of AIC is of fundamental importance since it improves the outcome and allows a better-targeted therapy, such as cytotoxic T-lymphocyte-associated protein 4, immunoglobulin G fusion protein, and small molecule inhibitors like Janus kinase inhibitors, or gene therapy. 

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The authors explained how modern-day gene therapy represents one of the most attractive approaches to treating selected inborn errors of immunity, such as CAD. Nonetheless, in the absence of specific targeted therapies, whole-exome genetic testing for children with chronic multilineage cytopenias should be considered an early diagnostic tool for genetic counseling.

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Regarding treatment options according to international guidelines, for CAD, which is classified as cold autoimmune hemolytic anemia (AIHA), monotherapy with rituximab is considered the first-line approach while avoiding glucocorticoids given their poor therapeutic response. In contrast, with primary warm AIHA, prednisolone or prednisone is the standard treatment. 

“These therapies are particularly effective in patients with hyper inflammation and immune dysregulation, but access to this new family of drugs requires precise identification of the genetic basis of the disease,” the authors said. “Additional studies are needed to evaluate whether the use of precision therapies can optimize disease management in children with AIC.”

Moreover, if a patient does not respond to first-line therapy, the authors recommend a diagnostic reevaluation, focusing on any previously overlooked cause of secondary AIC. In brief, CAD and other AIHAs are very rare in infancy and childhood (0.2 per 10/year). There is a link between these diseases and immune disorders in about 50% of patients, who often have a more severe, chronic, and relapsing course.

Autoimmune disorders are usually associated with environmental triggers and genetic predisposition. However, few of these have a monogenic cause, most of them occurring in children. These diseases may be the expression, isolated or associated with other symptoms, of underlying inborn errors of immunity such as CAD.


Cortesi M, Soresina A, Dotta L, et al. Pathogenesis of autoimmune cytopenias in inborn errors of immunity revealing novel therapeutic targets. Front Immunol. Published April 6, 2022. doi:10.3389/fimmu.2022.846660