Digital ulcers are a frequent manifestation of systemic sclerosis, affecting approximately half of all patients with the multisystem connective tissue disorder. Often persistent and recurring, these ischemic wounds tend to be slow-healing and difficult to manage. In addition to pain and disability, severe complications such as tissue loss, infection, gangrene, autoamputation, and septicemia can exacerbate the clinical burden by an order of magnitude, according to Christopher Denton, Ph.D., director of the Center for Rheumatology at University College London.

In an effort to better understand the clinical and antibody characteristics, disease course, and outcomes associated with digital ulcers, Dr. Denton and his colleagues established the Digital Ulcers Outcome Registry, a European, multicenter, observational registry of systemic sclerosis (SSc) patients with ongoing digital ulcer disease. To date, the registry includes demographic, clinical, and treatment information for more than 2,500 patients, providing investigators with valuable insight into the nature and progression of digital ulcer disease in this at-risk population.

In this month’s column, Dr. Denton discusses the progress of the registry as well as the information that investigators have gleaned from it.

Question: What are the objectives for the Digital Ulcers Outcome (DUO) Registry?

Dr. Denton: The DUO registry is a prospective observational program for SSc patients with digital ulcers. In 2008, physicians at participating centers began enrolling consenting consecutive patients with ongoing digital ulcers associated with SSc. The objectives of the registry include tracking key information on the clinical course and outcome of digital ulcers, regardless of their treatment regimen, although an express goal is to collect safety information on the use of the dual endothelin receptor antagonist bosentan, which is approved in Europe for reducing the number of new digital ulcers in SSc.

The DUO registry is a noninterventional registry. Patients receive standard medical care and follow-up as determined by their physician. The data collected include patient demographics, SSc disease duration, classification of underlying disease, internal organ manifestations, autoantibodies, history of interventions and complications related to digital ulcers, ongoing complications related to digital ulcers, ongoing medications, and functional assessment based on a disease-specific questionnaire. Additionally, the presence of antinuclear antibodies, anti-scleroderma-70 antibodies, anticentromere antibodies, anti-RNA polymerase 3, anti-U1-ribonucleoprotein, and anti-U3-ribonucleoprotein is recorded, as well as all serology tests and other tests that have been performed.

Question: Based on the registry data collected to date, which SSc patients are most likely to develop digital ulcers?

Dr. Denton: Digital ulcers appear to develop earliest and most frequently in patients with diffuse cutaneous SSc, anti-scleroderma-70 antibodies, or both. In our recent review, we reported that among 2,439 patients enrolled through November 2010, most of whom had limited or diffuse cutaneous SSc, digital ulcers developed earlier in patients with the diffuse cutaneous subtype (Ann. Rheum. Dis. 2012;71:718-21). Patients who tested positive for anti-scleroderma-70 antibodies, in particular, developed first digital ulcers at a significantly younger mean age (44.7 years) than those who tested positive for anticentromere antibodies (ACAs) (50.1 years). Similarly, patients positive for anti-scleroderma-70 antibodies were younger than ACA-positive patients at the onset of the first symptoms of Raynaud’s phenomenon, and had less time between the onset of Raynaud’s and development of their first digital ulcer.

Question: What are some of the most common digital ulcer–associated complications that have been reported, and which patients are most vulnerable?

Dr. Denton: Infections requiring antibiotics, gangrene, and amputation were frequent complications across all of the major disease subsets. Patients positive for anti-scleroderma-70 were twice as likely to develop lung fibrosis compared with ACA-positive patients, and they were also more likely to have heart manifestations. Both lung fibrosis and heart disease are consistent with studies indicating more severe disease in patients positive for anti-scleroderma-70.

Question: Can the risk of the development of digital ulcers be minimized or prevented in SSc?

Dr. Denton: Treatment with the oral endothelin receptor antagonist bosentan appears to be effective in preventing new digital ulcers. Last year we reported results from the RAPIDS-2 randomized, double-blind, placebo-controlled trial (Ann. Rheum. Dis. 2011;70:32-8) showing that treatment with bosentan reduced the occurrence of new digital ulcers by 30% over 24 weeks compared with placebo in patients with at least one active digital ulcer at the time of enrollment. The effect was greater in patients who entered the trial with more digital ulcers.

Question: What is the optimal treatment of digital ulcers in this population?

Dr. Denton: There is still a great clinical need for a tolerable, effective therapeutic option for improving tissue integrity and viability and promoting ulcer healing, in addition to reducing the formation of new ulcers. Although bosentan has been approved [in Europe] for the prevention of new digital ulcers in patients with SSc and ongoing digital ulcer disease, our findings [from the RAPIDS-2 trial] suggest that the treatment has no effect on digital ulcer healing. Vasodilators may improve digital circulation, and small studies suggest that the prostanoids epoprostenol and iloprost may improve healing, but controlled data supporting their use is lacking. The DUO registry may provide data that informs clinical trials of targeted therapies.

Dr. Denton reported that he has financial relationships with
Actelion Pharmaceuticals, Aspreva, Biovitrum, Digna,
Encysive Pharmaceuticals, Genzyme, and Pfizer.

Digital Ulcer Disease in Systemic Sclerosis