Hypogammaglobulinemia in patients affected by limited cutaneous systemic sclerosis: Case series and review of the literature

Abstract

Background: Hypogammaglobulinemia is a condition that can be related to both primary and secondary immunodeficiencies. While the role of primary immunodeficiency in immune-mediated diseases is well known, its occurrence in systemic sclerosis is not reported.

Objectives: This study aims to describe the clinical features associated with hypogammaglobulinemia in a cohort of limited cutaneous systemic sclerosis patients.

Methods: We retrospectively reviewed medical records of systemic sclerosis patients from two Italian referral centres (2010-2024). Included patients had limited cutaneous systemic sclerosis and presented reduced serum concentrations of one or more Ig isotypes (IgG < 700 mg/dL, IgA < 70 mg/dL or IgM < 50 mg/dL) in at least two separate measurements. Patients with secondary causes of hypogammaglobulinemia were excluded. Data collected included demographics, clinical features, Ig levels, infection history and comorbidities.

Results: We identified 30 systemic sclerosis patients (93% female, mean age 62 years) with limited cutaneous involvement and hypogammaglobulinemia. Most patients were positive for anti-centromere antibodies and received periodic intravenous infusions of prostaglandin analogues. No patient received immunosuppressive therapy. Median (interquartile range) serum IgG levels 519.5 (175) mg/dL, median IgA 65.5 (48) mg/dL and median IgM 71.5 (49) mg/dL. Four patients who met the European Society for Immunodeficiencies (ESID) criteria for common variable immunodeficiency experienced recurrent infections and had associated immune-mediated diseases. Five patients had selective IgA deficiency, with frequent immune-mediated comorbidities (thyroiditis, Sjögren's syndrome, arthritis, psoriasis). The other patients exhibited mild IgG deficiency without a significant infectious history.

Conclusions: This is the first study describing a cohort of patients with limited cutaneous systemic sclerosis and hypogammaglobulinemia. Our population presented a high prevalence of immune-mediated comorbidities but low infection rates. Further research is needed to explore the underlying mechanisms and clinical significance of hypogammaglobulinemia in these patients.

Keywords: Scleroderma; common variable immunodeficiency; hypogammaglobulinemia; selective IgA deficit; systemic sclerosis.