Assessment of disease activity and management of patients with NFkB1 insufficiency

NFkB1-haploinsufficiency is being identified as the cause for CVID and various other immune dysregulation disorders in an increasing number of patients. To date, there are no universal guidelines on how to clinically manage patients with pathogenic genetic variants in NFkB1. We set out to measure and compare the success of different therapeutic approaches. While doing so, we aim to validate and continually improve our novel scoring system for NFkB1 disease activity. In a worldwide collaborative effort, we collected clinical data on 70 patients, as well as detailed information on various different therapeutic strategies that are currently being deployed. Therefore, treating physicians were asked to complete our novel NFkB1-specific questionnaire. To take patients subjective well-being into account, we included three quality-of-life-surveys (the FACIT fatigue scale, the CVID-specific quality-of-life questionnaire developed by Quinti et. al., and the SF-12/SF-10 questionnaire). Patients will be prospectively evaluated at six-months intervals for at least one year. To treat autoinflammatory or autoimmune complications in our cohort of 70 NFkB1-patients, immunomodulatory drugs were used in 40 patients: 19 patients received monoclonal antibodies, including rituximab (13), adalimumab (3), infliximab (2), vedolizumab (2), guselkumab (1), natalizumab (1), and ustekinumab (1) or the Fc-fusion protein abatacept (5); 39 patients received DMARDs, including azathioprin (7), sirolimus (7), mycophenolate (6), cyclophosphamid (2), or steroids (24). Outcome will be presented at the meeting. Fourty-five patients had immunoglobulin replacement due to symptomatic hypogammaglobulinemia. Eight patients received prophylactic antibiotics and four patients each needed antifungal or antiviral prophylaxis. Two patients have recently been transplanted with hematopoietic stem cells, the final outcome remains to be determined in both cases. We furthermore propose an online-version of our newly developed NFkB1-specific questionnaire, which is well suited for clinical use. We present an overview of the therapeutic strategies currently being applied worldwide to treat individuals with NFkB1 insufficiency, including IgG-substitution, biologicals, and immunosuppressants. We will further monitor the effects on disease activity and patients’ well-being in our longitudinal observation. The heterogeneous clinical phenotype of NFkB1 insufficiency calls for pathway-targeted therapeutic strategies including anti-TNF, anti-IL1, anti-IL18, and JAK-inhibition.