Primary adrenal insufficiency in autoimmune rheumatic diseases: a systematic review of reported cases and mechanisms

Background: Primary adrenal insufficiency (PAI) is an uncommon but potentially life-threatening endocrine disorder. Although Addison’s disease is classically recognized within autoimmune polyendocrine syndromes, its occurrence in association with autoimmune rheumatic diseases (ARDs) remains poorly characterized and is largely described in case-based literature. Objective: To systematically synthesize reported cases of confirmed PAI occurring in patients with ARDs and describe clinical patterns, chronology, proposed mechanisms, and outcomes. Methods: A systematic search of PubMed/MEDLINE, Embase, Web of Science, Scopus, and Google Scholar was conducted from inception to August 2025, without language restrictions. We included case reports, case series, and observational studies with extractable individual-level data reporting confirmed ARD and confirmed PAI. Data were extracted on demographics, ARD type, temporal sequence of diagnoses, clinical presentation, endocrine and imaging findings, immunologic markers (including anti–21-hydroxylase antibodies when available), treatment, and outcomes. Due to heterogeneity and the predominance of descriptive evidence, findings were synthesized narratively. Results: Thirty-one publications were included, reporting 78 patients with ARD and confirmed PAI. Most cases occurred in women. Systemic lupus erythematosus and antiphospholipid syndrome were the most commonly reported underlying conditions. Two main mechanistic patterns emerged: autoimmune adrenalitis and vascular adrenal injury (hemorrhage/infarction), the latter particularly associated with antiphospholipid syndrome and often presenting with acute adrenal crisis. Across reports, adrenal insufficiency could occur before, after, or concurrently with the rheumatic disease diagnosis, and frequently presented with nonspecific systemic and gastrointestinal symptoms, hypotension, and electrolyte disturbances. Conclusions: PAI in the context of ARDs is rare but clinically significant and may be under-recognized due to symptom overlap with flares, infections, and treatment-related complications. Early endocrine evaluation and appropriate imaging should be considered in ARD patients presenting with unexplained hypotension, fatigue, gastrointestinal symptoms, or electrolyte abnormalities, particularly when antiphospholipid syndrome is suspected.