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The rationale of targeting the CD20 antigen relies on depletion of both healthy and autoreactive\/malignant CD20\u2010espressing cells, but normal B\u2010cell reconstitution is expected within months after treatment. Nevertheless, a number of recent studies have documented prolonged B\u2010cell deficiency associated with new\u2010onset hypogammaglobulinemia in patients receiving RTX. Awareness of post\u2010RTX hypogammaglobulinemia has become wider among clinicians, with a growing number of reports about the increased incidence, especially in children. Although these patients were previously regarded as affected by secondary\/iatrogenic immunodeficiency, atypical clinical and immunological manifestations (e.g., severe or opportunistic infections; prolonged B\u2010cell aplasia) raise concerns of delayed manifestations of genetic immunological disorders that have been unveiled by B\u2010cell perturbation. As more patients with undiagnosed primary immune deficiency receiving RTX have been identified, it remains the challenge in discerning those that might display a higher risk of persistent RTX\u2010associated hypogammaglobulinemia and need a tailored immunology follow\u2010up. In this review, we summarize the principal evidence regarding post\u2010RTX hypogammaglobulinemia and provide a guideline for identifying patients at higher risk of RTX\u2010associated hypogammaglobulinemia that could harbor an inborn error of immunity.<\/jats:p>","DOI":"10.1002\/eji.202149667","type":"journal-article","created":{"date-parts":[[2022,7,27]],"date-time":"2022-07-27T03:58:13Z","timestamp":1658894293000},"page":"1572-1580","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Secondary rituximab\u2010associated versus primary immunodeficiencies: The enigmatic border"],"prefix":"10.1002","volume":"52","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3777-0394","authenticated-orcid":false,"given":"Giorgio","family":"Ottaviano","sequence":"first","affiliation":[{"name":"Molecular and Cellular Immunology Unit UCL Institute of Child Health  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7493-5226","authenticated-orcid":false,"given":"Mayla","family":"Sgrulletti","sequence":"additional","affiliation":[{"name":"Pediatric Immunopathology and Allergology Unit Policlinico Tor Vergata University of Rome Tor Vergata  Rome Italy"},{"name":"PhD. 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