TOPLINE

Advanced combination therapy (ACT) — using two or more biologics or JAK inhibitors simultaneously — led to complete response in more than 50% of patients with difficult-to-treat systemic autoinflammatory diseases (SAIDs), with significant reductions in glucocorticoid use and C-reactive protein (CRP) levels.

METHODOLOGY

• Researchers conducted an observational retrospective longitudinal cohort study, including patients with genetically confirmed SAIDs or undifferentiated SAIDs who received two or more advanced treatments simultaneously between 2002 and 2024.
• A total of 38 patients who received ACT were included, with a median age at enrollment of 30 years and a median disease duration of 19 years; 13 patients were in the pediatric age group at ACT initiation. All patients were refractory to multiple conventional drugs.
• The most common diagnoses requiring ACT were pyogenic arthritis, pyoderma gangrenosum and acne, mevalonate kinase deficiency, and undifferentiated SAIDs. The primary indications included active systemic disease with frequent flares, pyoderma gangrenosum, nodulocystic acne, inflammatory bowel disease, and others.
• In total, 65 ACT regimens were administered, with 57 involving regular use of two or more advanced treatments and eight administered on a flare-directed basis; the most common combinations included interleukin (IL)-1 inhibitors with TNF inhibitors or IL-1 inhibitors with JAK inhibitors.
• Treatment response was assessed using a composite score incorporating a reduction in glucocorticoid dose to ≤ 7.5 mg/d prednisone or its equivalent, suppression of CRP levels to < 10 mg/L, and Clinical Global Impression Improvement scale scores for changes in clinical symptoms and organ damage, with responses categorized as nonresponse, partial response, or complete response.

TAKEAWAY

• Complete response was achieved in 55.3% of patients, partial response in 31.6%, and no response in 13.1% after multiple ACT trials.
• Among the 26 patients who had sustained success with an ACT combination, median CRP levels decreased from 9.9 mg/L to 1.5 mg/L (P < .001) and the median daily prednisone dose decreased from 20 mg to 0 mg (P < .001).
• Secondary loss of efficacy occurred after a median duration of 32 months and was most common with the combination of anti-IL-1 and anti-TNF agents; however, switching to a drug within the same class appeared effective. During the final assessment, discontinuation was noted for 39 of the ACT regimens used, with primary nonresponse and loss of effectiveness over time being common reasons.
• Infections that required hospitalization were the only serious adverse events. Twenty patients experienced 37 infectious episodes, 16 of which resulted in hospitalization. No deaths occurred during follow-up.

IN PRACTICE

"Combination regimens appeared to be relatively safe, with infections being the leading cause of treatment discontinuation; however, there were no cases of unexpected or opportunistic infections," the authors wrote.

SOURCE

The study was led by Abdurrahman Tufan, National Human Genome Research Institute, National Institutes of Health in Bethesda, Maryland. It was published online on August 24 in Seminars in Arthritis and Rheumatism.

LIMITATIONS

The retrospective uncontrolled design, small sample size, heterogeneity of SAID phenotypes, and different follow-up durations made it hard to draw robust conclusions. Quality-of-life measures were not used, and the median follow-up duration of 60 months may not have been long enough for lifelong diseases.

DISCLOSURES

This study was supported by the Intramural Research Program of the National Institutes of Health. The authors reported no relevant conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.