This prospective, phase 2, open-label study compared tacrolimus monotherapy with tacrolimus and prednisone for the maintenance of disease remission in subjects with noninfectious posterior segment intraocular inflammation (PSII). It showed corticosteroids can be withdrawn in tacrolimus-treated patients who are able to achieve control of PSII with 10 mg prednisone daily, and any advantage of dual therapy in preventing disease reactivation was offset by a greater intolerance.
The study demonstrated that two-thirds of patients who achieved disease control with tacrolimus and prednisone could discontinue prednisone rather rapidly (in two weeks as opposed to the standard of several months) without recurrence. It also showed that changes in logMAR visual acuities are less useful outcome measures in an open-label study since exit criteria for the trial allowed patients to be withdrawn for increased inflammation without a reaching a specific logMAR change threshold of 10 letters.
Subjects were 58 patients with PSII treated with oral tacrolimus and at least 10 mg prednisone daily. The tacrolimus dose was titrated to achieve a trough serum level of 8 to 12 ng/ml, while the prednisone was reduced to 10 mg daily. Subjects who subsequently were able to taper their prednisone dose without disease reactivation were assigned randomly either to stop prednisone or to continue 7.5 to 10 mg prednisone daily for nine months.
Thirty-five patients successfully tapered their prednisone to 10 mg daily. The difference in the mean visual acuity change between those randomized to monotherapy and those randomized to dual therapy group was less than 1 logMAR letter. The proportion of patients who tolerated treatment and maintained disease remission for nine months after randomization also was similar in both groups (monotherapy, 62.5 percent; dual therapy, 68.4 percent; P = 0.694). All monotherapy treatment failures were the result of disease reactivation, whereas 50 percent of dual-therapy failures were the result of drug intolerance.
My main criticism of this study is that the definition of PSII is a little vague and does not follow Standardization of Uveitis Nomenclature (SUN) criteria. Although the parameters describing disease activity included vitreous haze and choroidal thickening, they also included CME and anterior segment inflammation. I am not sure if these patients had intermediate uveitis or true posterior uveitis or panuveitis using SUN criteria. PSII was an odd term to use since the rest of study seemed to rely heavily on previous SUN criteria (prednisone maintenance dosing, for example).
I do not use calcineurin inhibitors as frequently now as I did 20 years ago since the advent of mycophenolate. I have used cyclosporine or tacrolimus as a first- or second-line immunomodulatory agent in retinal vasculitis patients. Based on this study, I may consider using tacrolimus in the future since the side effect and adverse event profile for it is better than cyclosporine. I still feel uneasy, however, about rapidly tapering corticosteroids in patients with good disease control on a combination of immunomodulator and prednisone since I cannot predict who will recur or relapse. I would much rather taper prednisone (doses less than 10mg/day) slowly over months. The authors write that this trial should challenge us to consider steroid-free maintenance therapy in patients who empirically demonstrate the ability to reach 10 mg prednisone daily in conjunction with therapeutic tacrolimus serum levels. This would enable us to stratify patients into the majority who are able to continue tacrolimus monotherapy, with the minority requiring dual therapy with prednisone.