Fatores preditores de resposta a Azatioprina e Micofenolato de Mofetila em pacientes com a Doença do Espectro da Neuromielite Óptica: um estudo de coorte multicêntrico

Abstract

Introduction: Neuromyelitis Optica Spectrum Disorder (NMOSD) is an autoimmune inflammatory disease of the central nervous system, clinically characterized by relapses and remissions, causing functional disability. Relapse rates of 44-53% have been reported in patients with NMOSD receiving azathioprine (AZA) and 27-50% with mycophenolate mofetil (MMF). Predicting unsatisfactory response could assist to determine which patients are most likely to benefit from monoclonal antibody treatments from the outset. Objective: to define predictors of unsatisfactory response to azathioprine and mycophenolate mofetil in patients with NMOSD. Methodology: ambispective cohort study, patients treated at the neuroimmunology outpatient clinic in Salvador, Brazil and the Walton Centre, Liverpool, UK. AZA and MMF were used for at least six months in patients diagnosed with NMOSD. The main outcome is unsatisfactory response to therapy. Unsatisfactory responders were those that, despite using the medication for at least 4 months, presented one severe attack (characterized by EDSS ≥ 6 or an increase ≥ 0,5 if the patient already had EDSS ≥ 6 or if a severe visual impairment < 20/200 affects one eye or bilateral visual involvement) or two non-severe attacks in one year. Cox regression was used to identify predictors of unsatisfactory response to AZA and MMF. Results: 103 patients with NMOSD were included, median age 38 years, 83% female, 65% black ethnicity with 2.5 years (IQR 1.0–8.8) of follow-up. Unsatisfactory response to azathioprine or mycophenolate mofetil was observed in 42% of patients. A preceding severe attack was more common in unsatisfactory response (31.1% vs. 76.7%, p ≤ 0.001). In multivariable analysis, severe attack (RR 3.13; 95% CI 1.37-7.18, p = 0.007) or annualized relapse rate ≥ 1 (RR 4.84; 95% CI 2.01-11.65, p ≤ 0.001) were unsatisfactory response predictors to AZA and MMF. Interestingly, black patients with NMOSD had a lower risk of this outcome (RR 0.39, 95% CI 0.17-0.85, p = 0.019). Conclusion: Severe attack and a higher annualized relapse rate before commencing AZA or MMF were associated with unsatisfactory response to AZA and MMF. These findings may guide the prescription of higher efficacy drugs since outset in patients with elevated risk of worse outcomes.