Abstract
BackgroundDupuytren's disease is a common fibrotic condition of the hand that causes irreversible flexion contractures of the fingers, with no approved therapy for early stage disease. Our previous analysis of surgically-excised tissue defined tumour necrosis factor (TNF) as a potential therapeutic target. Here we assessed the efficacy of injecting nodules of Dupuytren's disease with a TNF inhibitor. MethodsPatients were randomised to receive adalimumab on one occasion in dose cohorts of 15 mg in 0.3 ml, 35 mg in 0.7 ml, or 40 mg in 0.4 ml, or an equivalent volume of placebo in a 3:1 ratio. Two weeks later the injected tissue was surgically excised and analysed. The primary outcome measure was levels of mRNA expression for α-smooth muscle actin (ACTA2). Secondary outcomes included levels of α-SMA and collagen proteins. The trial was registered with ClinicalTrial.gov (NCT03180957) and the EudraCT (2015-001780-40). FindingsWe recruited 28 patients, 8 assigned to the 15 mg, 12 to the 35 mg and 8 to the 40 mg adalimumab cohorts. There was no change in mRNA levels for ACTA2, COL1A1, COL3A1 and CDH11. Levels of α-SMA protein expression in patients treated with 40 mg adalimumab (1.09 ± 0.09 ng per μg of total protein) were significantly lower (p = 0.006) compared to placebo treated patients (1.51 ± 0.09 ng/μg). The levels of procollagen type I protein expression were also significantly lower (p < 0.019) in the sub group treated with 40 mg adalimumab (474 ± 84 pg/μg total protein) compared with placebo (817 ± 78 pg/μg). There were two serious adverse events, both considered unrelated to the study drug. InterpretationIn this dose-ranging study, injection of 40 mg of adalimumab in 0.4 ml resulted in down regulation of the myofibroblast phenotype as evidenced by reduction in expression of α-SMA and type I procollagen proteins at 2 weeks. These data form the basis of an ongoing phase 2b clinical trial assessing the efficacy of intranodular injection of 40 mg adalimumab in 0.4 ml compared to an equivalent volume of placebo in patients with early stage Dupuytren's disease. FundingHealth Innovation Challenge Fund (Wellcome Trust and Department of Health) and 180 Therapeutics LP.
Highlights
Dupuytren's disease (DD) is a common fibrotic disease confined to the hand that affects approximately 4% of the general UK and US populations [1]
Levels of α-SMA protein expression in patients treated with 40 mg adalimumab (1.09 ± 0.09 ng per μg of total protein) were statistically significantly lower (p = 0.006) compared to placebo treated patients (1.51 ± 0.09 ng per μg of total protein) and compared to those treated with 15 mg (1.60 ± 0.09 ng per μg of total protein; p b 0.001) or 35 mg (1.44 ± 0.08 ng per μg of total protein; p = 0.024) adalimumab, whilst 35 mg and 15 mg adalimumab cohorts showed no difference compared to placebo (Fig. 3)
Our results show that two weeks following administration of 40 mg of adalimumab in 0.4 ml into Dupuytren's nodules there was down regulation of the myofibroblast phenotype as evidenced by lower expression of α-SMA and pro-collagen type I proteins
Summary
Dupuytren's disease (DD) is a common fibrotic disease confined to the hand that affects approximately 4% of the general UK and US populations [1]. Interpretation: In this dose-ranging study, injection of 40 mg of adalimumab in 0.4 ml resulted in down regulation of the myofibroblast phenotype as evidenced by reduction in expression of α-SMA and type I procollagen proteins at 2 weeks. These data form the basis of an ongoing phase 2b clinical trial assessing the efficacy of intranodular injection of 40 mg adalimumab in 0.4 ml compared to an equivalent volume of placebo in patients with early stage Dupuytren's disease.
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