Bridging the Gap in Secondary Antibody Deficiencies: Current Evidence and Unmet Needs in Diagnosis and Management with Immunoglobulin Replacement.

Secondary antibody deficiency (SAD) represents a substantial yet under-recognised global healthcare burden. It is more prevalent than primary antibody deficiency, but frequently under-diagnosed and variably managed worldwide. Prompt diagnosis is often hindered by insufficient awareness among clinicians, lack of global consensus on screening/monitoring for SAD among at-risk patients, inadequate clinical immunology services and lack of standardised referral pathways/protocols. Management practices vary widely, with little international agreement, particularly regarding threshold to initiate immunoglobulin replacement, as well as regimen, dosage and frequency of immunoglobulin administration. Subcutaneous immunoglobulin (SCIg) replacement emerged as a promising alternative to traditional intravenous immunoglobulin (IVIg) replacement. IVIg requires monthly infusions in inpatient/day-hospital settings leading to high peak serum IgG and subsequent variations with end-of-cycle 'wear-off effect', causing more systemic side effects and increased risk of breakthrough infections, and disruption of daily life and employment. While previous evidence was largely derived from primary antibody deficiency, recent comparative studies on SAD patients indicate that SCIg replacement, through weekly self-administered infusions, can achieve more stable and higher trough serum IgG, lower infection rates, fewer systemic adverse reactions and enhanced health-related quality-of-life compared to IVIg. There is also potential cost-savings from the use of SCIg replacement. This review emphasises the urgent need for standardised guidelines on screening/diagnosis and treatment of SAD, and large-scale multi-centre trials and real-world studies on IVIg vs SCIg replacement among SAD patients, which will facilitate better identification, management, and health-outcomes for SAD patients, ultimately alleviating a significant global health challenge through coordinated clinical, research, and policy efforts.