Surgical remission of Cushing’s disease associated with higher rates of autoimmune disorders

1. In this retrospective cohort study, patients achieving surgical remission of Cushing’s disease (CD) had a higher incidence of autoimmune disorders than those with non-functioning pituitary adenomas (NFPA).

2. Patients with CD had higher rates of postoperative adrenal insufficiency and lower post-operative nadir serum cortisol levels than those with NFPAs.

Evidence Rating Level: 2 (Good)

Study Rundown: CD is characterized by an excess production of cortisol arising from increased adrenocorticotropic hormone (ACTH) secreted by a pituitary adenoma. It can result in a range of comorbidities and metabolic complications, including diabetes and hypertension, and exhibit clinical features such as facial plethora, rounded face, decreased libido, and violaceous striae. Transsphenoidal surgery (TSS) to resect the ACTH-producing tumor is the first-line treatment, and complete resection of the tumor results in temporary adrenal insufficiency (AI). In cases where AI is prolonged, glucocorticoid replacement is required. Previous studies have shown an increased incidence of autoimmune disorders following surgical remission of CD with several proposed mechanisms, but further controlled studies are required. This retrospective matched cohort analysis aimed to determine the incidence of autoimmune disorders in patients with CD following surgical remission versus those treated with surgery for NFPAs and to investigate the clinical presentation and risk factors for the development of autoimmune disorders in surgically treated patients with CD. Overall, patients achieving surgical remission of CD had a higher incidence of autoimmune disease than those with NFPAs after three years. Patients with CD also had higher rates of post-operative AI and lower post-operative nadir serum cortisol levels than those with NFPAs. Moreover, among patients with CD, those who developed autoimmune disease following surgical remission had a higher prevalence of family history of autoimmune disorders. Due to the small sample size, the study could not identify independent risk factors for the development of autoimmune disease.

Click to read the study in AIM

In-Depth [retrospective cohort]: This matched retrospective cohort study investigated the incidence of autoimmune disease in patients with surgically treated CD versus those with surgically treated NFPAs, as well as the clinical presentation and risk factors for new-onset autoimmune disorders in CD after remission. A retrospective chart review of patients 17.5 years or older who had undergone TSS for CD or NFPA at Massachusetts General Hospital between 2005 to 2019, with at least one follow-up visit after TSS, was performed. All patients included in the CD group were 17.5 years or older and had both biochemical and clinical evidence of the disease. Patients included for surgically confirmed NFPA were age- and sex-matched to the patients with CD. The primary outcome was the cumulative incidence of autoimmune diseases, such as rheumatoid arthritis, Sjogren syndrome, autoimmune thyroiditis, and systemic lupus erythematous, at three years following surgery. 194 patients who received TSS for CD and 92 patients who received TSS for NFPA were included in the analysis. Overall, the incidence of autoimmune disease at three years was 10.4% in the CD group (95% Confidence Interval [CI], 5.7% to 15.1%) versus 1.6% in the NFPA group (95% CI, 0 to 4.6%); Hazard Ratio, 7.80; 95% CI, 2.88 to 21.10). The most common autoimmune disease that developed in the CD group was autoimmune thyroiditis, and 41.2% of the patients in this group developed autoimmune disease while having AI. The CD group also exhibited a higher prevalence of postoperative AI (93.8% vs. 16.5%) and lower post-operative nadir serum cortisol levels (63.8 vs. 282.3 nmol/L) than the NFPA group. Moreover, among patients with CD, those who developed the new-onset autoimmune disease had a higher prevalence of family history of autoimmune disease (41.2% vs. 20.9%) and a lower pre-operative 24-hour urine free cortisol ratio (2.7 vs. 6.3). In summary, patients who had surgical remission of CD had a higher incidence of autoimmune disease than age- and sex-matched patients who received surgery for NFPA.

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