Benefit of adjunctive tacrolimus in connective tissue disease-interstitial lung disease

Abstract

We evaluated the safety and effectiveness of adjunctive tacrolimus therapy with conventional immunosuppression in patients with severe connective tissue disease-related interstitial lung disease (CTD-ILD). We included patients from our interstitial lung disease (ILD) registry with CTD-ILD, in whom tacrolimus was added to corticosteroids and an additional immunosuppressive agent. Demographic data, clinical features, lung function, radiographic images, and pathologic findings were reviewed. Effectiveness was assessed by comparing pulmonary function tests (PFTs) closest to tacrolimus initiation to PFTs approximately 6–12 months later. Corticosteroid dose at these time points was also evaluated. We report adverse events attributed to tacrolimus. Seventeen patients with CTD-ILD were included in adverse event analysis; twelve were included in efficacy analysis. Length of tacrolimus therapy ranged from 6 to 110 months (mean 38.8 months ± 31.4). The mean improvement in percent predicted total lung capacity was 7.5% ± 11.7 (p=0.02). Forced vital capacity mean improvement was 7.4% ± 12.5 (p=0.06). The average decrease in corticosteroid dose at follow-up was 20.3mg ± 25.2 (p=0.02) with complete discontinuation in six patients. No patients experienced a life-threatening adverse event attributed to tacrolimus. Tacrolimus can be effective and is well tolerated as an adjunctive therapy and allows tapering of corticosteroids.

The Diagnosis and Treatment of Antisynthetase Syndrome

“…No study has demonstrated the superiority of a particular agent, so the choice of therapy is guided by practitioner comfort and a careful assessment of potential risks of therapy in an individual patient. Our practice is to initiate prednisone and azathioprine or mycophenolate mofetil in patients with anti-synthetase syndrome related ILD, with the addition of tacrolimus for rapid disease control in more severe ILD (50). In the setting of anti-synthetase syndrome, we use rituximab for patients with severe progressive and/or refractory ILD and have used cyclophosphamide in ARDS.…”

“…Six of these patients had anti-Jo-1 and two had anti-SRP autoantibodies. Since that time, numerous case reports and studies have suggested the efficacy of tacrolimus in patients with CTD and IIM related ILD (49), even as add-on therapy in combination with corticosteroids and an additional immunosuppressive agent (50). A 2005 case series specifically studied tacrolimus efficacy in 15 patients with anti-synthetase syndrome-ILD.…”

“…It is our practice to initiate tacrolimus at 1mg twice daily, and increase by 1–2 mg weekly until 12 hour target trough levels reach 5–8 ng/mL (50). Final doses are typically 1 mg to 5 mg, twice daily.…”

Interstitial Pneumonia With Autoimmune Features: Overview of Proposed Criteria and Recent Cohort Characterization

“…44 Mejia and colleagues recently demonstrated that all patients with ILD and a circulating tRNA synthetase antibody who failed to meet criteria for dermatomyositis subsequently met IPAF criteria and that survival was similar between the two groups. 45 Over one third of patients included in the IPAF cohort characterized by Chartrand and colleagues had a positive tRNA synthetase antibody, which given the proclivity of this group to respond to immunosuppression 46–48 , may explain the low mortality in this group compared to other IPAF cohorts.…”

Pharmacogenetics and interstitial lung disease

“…48-50 Polymorphisms within cytochrome p450 genes CYP3A5 and CYP3A5 have been shown to influence the bioavailability of tacrolimus. 51 Absorption of tacrolimus may also be influenced by the presence of polymorphisms within the MDR1 gene, which encodes a cellular efflux pump protein.…”