OR WAIT null SECS
Proof of Concept: Targeting Mitochondrial Dysfunction in SLE With NAC, with Rosalind Ramsey-Goldman, MD
Ramsey-Goldman discussed the potential of NAC for treating systemic lupus erythematosus.
N-acetylcysteine (NAC) shows promise as a novel therapeutic strategy for systemic lupus erythematosus (SLE), although these findings remain to be confirmed by the double-blind phase of the ongoing multicenter trial.
Data from the first phase of the trial were presented by Rosalind Ramsey-Goldman, MD, Gallagher Research Professor of Rheumatology, Feinberg School of Medicine, Northwestern University, at the American College of Rheumatology (ACR) Convergence 2025, held October 24–29 in Chicago, Illinois.
Unlike immunosuppressants, NAC aims to correct core metabolic defects driving lupus pathogenesis rather than broadly suppressing the immune system. The therapy is designed to restore intracellular cysteine and glutathione (GSH) levels, thereby reducing mitochondrial oxidative stress, mTOR activation, inflammatory lineage skewing, and antinuclear autoantibody production. The trial uses an enriched-enrollment randomized-withdrawal design, with all eligible patients completing a 3-month open-label titration phase of NAC (2.4–4.8 g/day) prior to randomization into the blinded phase.
In the first 3 months of the study, NAC produced statistically significant reductions in global SLE disease activity among 68 patients. Mean SLEDAI scores decreased from 8.73 (SD, 3.093) at baseline to 4.91 (SD, 2.92) at month 3 (P = 1.1×10⁻¹²), with a mean difference of 3.671 (SD, 3.201). BILAG total scores demonstrated an even larger shift, falling from 23.808 (SD 5.099) to 8.750 (SD 6.027; P = 1.9×10⁻²²), with a mean difference of 15.058 (SD, 8.424).
Importantly, NAC also improved patient-reported cognitive and fatigue symptoms in 54 participants. ADHD-Inattention scores improved from 19.259 (SD, 2.960) to 16.407 (SD, 7.449), a mean difference of 2.851 (SD 6.645; P = 1.5×10⁻²), and ADHD-Hyperactivity improved from 14.962 (SD, 7.530) to 13.185 (SD, 7.809), a mean difference of 1.777 (SD, 4.063; P = 1.3×10⁻²). Physical fatigue decreased from 19.259 (SD, 2.960) to 16.092 (SD, 3.972), a mean difference of 3.166 (SD, 3.318; P = 2.5×10⁻⁸), while mental fatigue improved from 14.425 (SD, 4.574) to 12.092 (SD, 4.814), a mean difference of 2.333 (SD, 3.518; P = 6.2×10⁻⁵).
Adverse events included headache, nausea, gastrointestinal symptoms, constipation, and diarrhea and were transient and reversible. Eighteen participants withdrew during this phase, though only 1 withdrawal was attributed to adverse events.
In an interview with HCPLive, Ramsey-Goldman emphasized that while these early, open-label results are encouraging, the ongoing double-blind phase will be essential to confirm NAC’s disease-modifying potential and determine whether this mitochondria-directed approach could offer a safer alternative to traditional immunosuppression in SLE.
"What NAC does is it replaces the chemicals that were missing so that the mitochondria function properly, so that the cell doesn't push itself toward overdrive or an inflammatory state, and it diminishes the antibodies that are causing the lupus [with] less side effects," Ramsey-Goldman said.
Ramsey-Goldman's reported disclosures include Ampel Solutions, AstraZeneca, Biogen, Cabaletta, Duke, Exagen Diagnostics, Merck, and SUNY Syracuse.
