Exploring Multidimensional Risk Factors Associated with Local Adverse Reactions to Subcutaneous Immunoglobulin Therapy: Insights from a Nationwide Multicenter Study

<b>Background/Objectives</b>: Subcutaneous immunoglobulin (SCIg) is a well-established alternative to intravenous immunoglobulin (IVIg) in patients with primary (PID) and secondary immunodeficiency (SID), with demonstrated benefits in safety and quality of life. However, its implementation remains limited in parts of Southern Europe, partly due to frequent local adverse reactions (LARs), which, despite being mild, can affect adherence and clinician confidence. This study aimed to identify clinical, anatomical, psychosocial, and geographical factors associated with LARs and to develop an exploratory model for individualized risk estimation. <b>Methods</b>: We conducted a retrospective, multicenter observational study in eight Spanish hospitals using data from the GEIE Registry. Patients aged ≥14 years with PID or SID receiving SCIg for ≥1 month were included. Demographic, clinical, anatomical, and psychosocial variables were collected. A multivariable logistic regression model was built to identify independent predictors of LARs and internally validated using bootstrap resampling (500 iterations). A nomogram was constructed for personalized risk prediction. <b>Results</b>: Among 223 included patients, 73.1% reported LARs, primarily swelling, pruritus, and rash. Independent predictors included smaller abdominal perimeter (OR 0.955, <i>p</i> < 0.001), history of skin disease (OR 2.75, <i>p</i> = 0.044), greater distance to hospital (OR 1.01, <i>p</i> = 0.050), and absence of anxiety (OR 0.089, <i>p</i> = 0.001). Model discrimination was good (AUC 0.801), with minimal optimism after internal validation (validated AUC 0.788). <b>Conclusions</b>: LARs are common among patients receiving SCIg and could be influenced by anatomical, dermatological, psychological, and geographical factors. This exploratory multicenter study underscores the clinical relevance of these factors and may guide more personalized and safer use of SCIg.