木瓜直播

A drug already on the market for 20 years effectively reduced nodules associated with Dupuytren's disease in a mid-stage trial, researchers said.

Patients receiving intranodular injections of adalimumab (Humira) showed significant declines in nodule hardness and volume over 18 months, whereas these remained stable or increased in a saline-treated control group, reported Jagdeep Nanchahal, MBBS, PhD, of the University of Oxford in England, and colleagues.

Nodule hardness as measured with a standard durometer decreased from 63 to 55 AU in the 70-patient adalimumab group, versus almost no change among the 70 controls (61 AU at baseline and 60 at 18 months), according to the researchers' .

Adalimumab-treated nodules shrank in area from 28 to 18 mm³, while those injected with saline grew from 32 to 34 mm³. Nodule height also decreased with adalimumab by 0.9 mm; there was no change on average in controls.

Nanchahal and colleagues said there were no serious adverse events; "minor" injection-site reactions were spotted after 25 treatments (out of 560) and were about as common with saline as with the active drug.

Notably, the last doses were administered at month 9 and adalimumab's half-life averages 2 weeks, yet "the nodules continued to soften and regress on ultrasound at the 18-month timepoint," the researchers indicated. This "suggests that local administration has a profound local biological effect."

Dupuytren's disease is a condition in which fibrous cords develop in the palm of the hand, which pull patients' fingers in a claw-like position, at which point the word "contracture" is applied. Nodules in the palm are the condition's first clinical feature, comprising fibroblasts and myofibroblasts. Steroids may be used at this stage -- the American Academy of Orthopaedic Surgeons -- but they do not work in all patients and, Nanchahal and colleagues wrote, haven't been studied in well-designed trials. Other treatments are geared toward disrupting the cords, but these are not very effective long-term.

Why adalimumab? Previous studies had implicated tumor necrosis factor, adalimumab's target, as a mediator in the pathology underlying Dupuytren's disease. Adalimumab was first approved in the U.S. in 2002 and is now off patent, opening the way for anyone to come up with new applications. A pilot study by Nanchahal's group at Oxford found that adalimumab had encouraging effects on biomarkers of fibroblast activity, and they conceived the current trial to examine its potential clinical efficacy.

Patients were recruited from two centers in Great Britain (some patients were also enrolled in The Netherlands, but they were treated differently from those in the U.K. and Nanchahal's group decided not to include them in the current report). Adalimumab or saline were injected into each patient's largest nodule at 3-month intervals for a total of four injections. This dosing interval, the researchers explained, was set after surveying Dupuytren's patients about their tolerance for periodic injections, which can be very painful.

Mean patient age was 60 and about 35% were women. Mean duration of Dupuytren's features was 7 years. Many patients suffered other musculoskeletal fibrotic conditions including frozen shoulder, plantar disease, and Peyronie's disease.

The major unanswered question in the trial is whether adalimumab's effects on nodules will translate into lessened risk for contracture. Rates of progression in previous studies have ranged from 20% to 35% over periods of 7 to 18 years. That means, Nanchahal and colleagues wrote, "follow-up for 10 years or more would be required to ascertain whether intranodular injection of adalimumab and the observed significant reduction in nodule hardness and nodule size on ultrasound scan would affect the development of finger deformities and hand function." The same point was made in an by Ruud Selles, PhD, of Erasmus University Medical Center in Rotterdam, The Netherlands.

Thus, it may fall to individual clinicians, and patients willing to pay for adalimumab out of pocket (it may be off patent but it remains expensive, even in biosimilar form), to find out for themselves.

Comment