What Works When Treating Granulomatous Disease in Genetically Undefined CVID? A Systematic Review

Abstract

BackgroundGranulomatous disease is reported in at least 8–20% of patients with common variable immunodeficiency (CVID). Granulomatous disease mainly affects the lungs, and is associated with significantly higher morbidity and mortality. In half of patients with granulomatous disease, extrapulmonary manifestations are found, affecting e.g. skin, liver, and lymph nodes. In literature various therapies have been reported, with varying effects on remission of granulomas and related clinical symptoms. However, consensus recommendations for optimal management of extrapulmonary granulomatous disease are lacking.ObjectiveTo present a literature overview of the efficacy of currently described therapies for extrapulmonary granulomatous disease in CVID (CVID+EGD), compared to known treatment regimens for pulmonary granulomatous disease in CVID (CVID+PGD).MethodsThe following databases were searched: Embase, Medline (Ovid), Web-of-Science Core Collection, Cochrane Central, and Google Scholar. Inclusion criteria were 1) CVID patients with granulomatous disease, 2) treatment for granulomatous disease reported, and 3) outcome of treatment reported. Patient characteristics, localization of granuloma, treatment, and association with remission of granulomatous disease were extracted from articles.ResultsWe identified 64 articles presenting 95 CVID patients with granulomatous disease, wherein 117 different treatment courses were described. Steroid monotherapy was most frequently described in CVID+EGD (21 out of 53 treatment courses) and resulted in remission in 85.7% of cases. In CVID+PGD steroid monotherapy was described in 15 out of 64 treatment courses, and was associated with remission in 66.7% of cases. Infliximab was reported in CVID+EGD in six out of 53 treatment courses and was mostly used in granulomatous disease affecting the skin (four out of six cases). All patients (n = 9) treated with anti-TNF-α therapies (infliximab and etanercept) showed remission of extrapulmonary granulomatous disease. Rituximab with or without azathioprine was rarely used for CVID+EGD, but frequently used in CVID+PGD where it was associated with remission of granulomatous disease in 94.4% (17 of 18 treatment courses).ConclusionAlthough the number of CVID+EGD patients was limited, data indicate that steroid monotherapy often results in remission, and that anti-TNF-α treatment is effective for granulomatous disease affecting the skin. Also, rituximab with or without azathioprine was mainly described in CVID+PGD, and only in few cases of CVID+EGD.

Clinical and experimental treatment of primary humoral immunodeficiencies

“…In comparison to rituximab, it has a lower ability to deplete B cells. Perhaps it can be also used in CVID complications instead of rituximab [ 102 ]. Emapalumab is a fully human immunoglobulin G1 monoclonal antibody directed against interferon-gamma (IFN-gamma).…”

The pediatric common variable immunodeficiency — from genetics to therapy: a review

“…The proposed first-line therapy for CVID-related GLILD is systemic corticosteroids (GCS), followed by azathioprine, mycophenolate mofetil either combined with GCS or as monotherapy, and rituximab (a monoclonal antibody against CD20) as the second-line therapy. In single cases only, infliximab (a monoclonal antibody against TNF-α), cyclophosphamide, cyclosporine, methotrexate, and hydroxychloroquine alone or in combination with Ig-RT have also been reported with different degree of remission [ 62 , 76 , 79 ].…”

Granulomatous inflammation in inborn errors of immunity

“…Granulomas in lungs, liver, spleen, lymph nodes and skin were identified in 46 CVID patients within a cohort of 473 subjects (9.7%) ( 6 ). A systematic review by van Stigt et al ( 16 ) showed that 50% of CVID patients with granulomatous disease displays extrapulmonary granulomatous manifestation. Granulomatous and lymphocytic interstitial lung disease (GLILD) instead occurs in around 20%–30% of CVID patients ( 17 ).…”

“…Glucocorticoid-sparing agents such as weekly Rituximab 375 mg/m 2 for 4 weeks repeated every 4 months for 3–4 courses ( 25 ), azathioprine 1–2 mg/kg/day or mycophenolate mofetil 250–1000 mg twice daily can be also considered ( 25 ). With such treatment, remission of extrapulmonary granulomas affecting the skin, liver and lymph nodes has been reported in 86% of patients ( 16 ). Anti-TNF-α therapy has been successful to treat extrapulmonary granulomas in CVID ( 16 , 26 ).…”

“…With such treatment, remission of extrapulmonary granulomas affecting the skin, liver and lymph nodes has been reported in 86% of patients ( 16 ). Anti-TNF-α therapy has been successful to treat extrapulmonary granulomas in CVID ( 16 , 26 ).…”