Autoimmune Cytopenias and Inborn Errors of Immunity: When Immune Thrombocytopenia Isn’t Just ITP Free

You are referred a 21-year-old female patient for management of immune thrombocytopenia (ITP). She has a history of steroid-dependent ITP, hypothyroidism, and pneumococcal septic arthritis, as well as a family history of ITP and a mother with inflammatory bowel disease. She is followed in the immunology clinic for common variable immunodeficiency (CVID) on intravenous immunoglobulin (IVIg) replacement therapy. She was previously suspected of having an autoimmune lymphoproliferative syndrome (ALPS)-like syndrome given the presence of hepatosplenomegaly, and genetic testing is currently pending. You are asked to provide advice on next steps in the diagnosis and management of this patient.

How do you evaluate and treat autoimmune cytopenias in patients with primary immune deficiencies?

The International Union of Immunological Societies Expert Committee’s recently published 2024 update on the classification of human inborn errors of immunity (IEI) subdivides these conditions into 10 tables by disease phenotype.¹  The table describing diseases of immune dysregulation such as ALPS and cytotoxic T-lymphocyte antigen 4 (CTLA4) haploinsufficiency includes 19 novel IEI gene defects — the largest number described in the update.¹ 

CTLA4 is an immune checkpoint protein constitutively expressed on FoxP3+ T regulatory cells and upregulated on activated T cells to prevent overactivation of autoreactive T cells.²  Pathogenic variants in the CTLA4 gene can result in impaired function of T regulatory cells, as well as decreased circulating T cells and B cells, through a mechanism of autosomal dominant CTLA4 haploinsufficiency.²  Clinical manifestations can include autoimmune cytopenias, lymphoproliferation, lymphocytic infiltration of the gastrointestinal tract and lungs, and recurrent infections.¹  Similar to ALPS and CVID, CTLA4 haploinsufficiency also carries an increased risk of lymphoma.³ 

There is increasing awareness among hematologists that diseases of immune dysregulation are an important cause of autoimmune cytopenias. Evaluation for IEI is particularly recommended for patients with refractory ITP or autoimmune cytopenias with compatible clinical manifestations or family history.⁴  It is also important to consider other mechanisms by which IEI can produce cytopenias, including antibody-mediated autoimmunity, splenomegaly, bone marrow failure, and secondary myelosuppression in the context of infection.⁵ 

Investigations should be pursued in these patients in collaboration with immunologists and geneticists to guide test selection and facilitate diagnostic evaluation. In particular, the use of targeted next-generation sequencing panels is important for rapid molecular diagnosis of patients with suspected IEI. Testing options span a spectrum from targeted single gene tests or panels to whole exome or even whole genome sequencing.⁶ 

Select immunologic investigations are recommended prior to immunosuppression or use of immunoglobulin (Ig) replacement therapy, as they can be directly affected by either therapy. These include quantitative Igs; T cell, B cell, and natural killer cell quantification through flow cytometry; and vaccine titres (e.g., tetanus and diphtheria). Other investigations can be considered based on the patient’s phenotype, including CD27+IgD+ and CD27+IgD− memory B cells, in vitro lymphocyte proliferation assays, double-negative T cells, cytokine markers such as interleukin 10, and vitamin B12.⁵  Further functional analysis can be pursued in collaboration with immunology to clarify the clinical relevance of a variant of unknown significance.

In this case, a molecular diagnosis of CTLA4 haploinsufficiency was confirmed given the history of recurrent infections, autoimmunity, and lymphoproliferation, with a commercially available IEI gene panel confirming a known pathogenic variant in the CTLA4 gene.

When possible, patients with confirmed primary immunodeficiency should have their treatment tailored to the underlying IEI. The ideal situation is for the immune cytopenia and other aspects of immune dysregulation to be concurrently treated with a targeted therapy. If investigations are pending or there is no available targeted therapy, evaluation of the clinical phenotype (e.g., lymphoproliferation, lymphocytic infiltration, recurrent infections, etc.) may help guide initial choice of therapy.^5,7 

David Egg and colleagues reported the initial management of 77 patients of a cohort of 173 with CTLA4 haploinsufficiency who developed autoimmune cytopenias, 43 of whom had Evans syndrome.⁸  In the acute setting, 50 patients were treated with doses of prednisolone ranging from 0.25 to 1 mg/kg daily, with 43 (86%) demonstrating at least a transient response.⁸  Thirty patients went on to receive rituximab, with 25 (83%) demonstrating response.⁸  The authors recommend initial therapy with a combination of steroids and IVIg in the setting of autoimmune hemolytic anemia, ITP, or Evans syndrome, with the addition of rituximab in the event of relapse. The management of ALPS somewhat differs, as current guidance recommends avoiding rituximab due to the risk of opportunistic and frequently fatal infections.⁹  Splenectomy was only effective in four of 16 patients with CTLA4 haploinsufficiency (25%). Splenectomy is also avoided in the setting of ALPS, again due to significant infectious risk.^8,9  Sirolimus has also been used as a steroid-sparing agent in the context of autoimmune cytopenias related to CTLA4 haploinsufficiency and ALPS, with the added benefit of usefulness in addressing lymphoproliferation.^9,10 

Targeted therapy for CTLA4 haploinsufficiency is available in the form of the CTLA4 Ig fusion protein abatacept to directly replace insufficient or dysfunctional CTLA4. This treatment has been shown to improve numerous immune manifestations, including autoimmune cytopenia, lymphoproliferation, and enteropathy.¹¹ 

Given rapid advances in the recognition of novel IEI and the increasing access of rapid genomic testing modalities, it is important to consider repeat testing periodically for patients with a suspicious clinical picture but no specific abnormality initially identified. A thorough and up-to-date evaluation is necessary to tailor therapy for IEI-associated autoimmune cytopenias, particularly with the emerging role of targeted therapies. Close collaboration between immunology and hematology is essential for the optimal management of these patients.

Drs. Ravindran and Wong-Pack contributed equally to this article.

Drs. Ravindran and Wong-Pack indicated no relevant conflicts of interest. Dr. Scott has received honoraria from Amgen, Pfizer, and Sobi.