BARCELONA — The first evidence-based recommendations issued by the European League Against Rheumatism for the management of systemic sclerosis address the current and future challenges in the treatment of this clinically heterogeneous condition.
The preliminary recommendations, which are based on research evidence, expert opinion, and clinical experience, have been formulated by a EULAR task force that included experts in systemic sclerosis from Europe, the United States, and Japan, according to Dr. Marco Matucci-Cerinic, professor of rheumatology and medicine at the University of Florence (Italy).
The recommendations include treatment considerations for digital vasculopathy and disease manifestations in the lung, skin, kidney, and gastrointestinal tract. They were summarized by Dr. Matucci-Cerinic at the annual European Congress of Rheumatology as follows:
▸ Vasculopathy. Among the first-line therapies recommended for reducing the frequency and severity of attacks of scleroderma-associated Raynaud's phenomenon are calcium channel blockers. Significant clinical benefits for these drugs were demonstrated in a meta-analysis that included six small trials (Arthritis Rheum. 2001;44:1841–7).
Prostacyclins, particularly iloprost, also are recommended for vasculopathy. Two randomized clinical trials have demonstrated benefits for these agents in the treatment of Raynaud's phenomenon and for healing digital ulcers.
A third recommendation for scleroderma-associated vasculopathy involves the use of endothelin receptor antagonists such as bosentan. Two large studies found that bosentan can prevent the development of new digital ulcers and improve hand function, although it did not affect healing of ulcers.
▸ Pulmonary arterial hypertension. Bosentan and another endothelin receptor antagonist, sitaxsentan, are strongly recommended for the treatment of pulmonary arterial hypertension, Dr. Matucci-Cerinic said. Also recommended is the phosphodiesterase inhibitor sildenafil, which improved exercise capacity and functional class in a high-quality clinical trial, he said. Epoprostenol is another agent that can be considered a feasible treatment for severe pulmonary arterial hypertension in systemic sclerosis.
▸ Interstitial lung disease. Two randomized controlled trials published in recent years form the basis of a recommendation favoring the use of cyclophosphamide in patients with scleroderma-associated interstitial lung disease despite the potential toxicity of this treatment.
▸ Renal crisis. “We all know that ACE inhibitors are helpful in renal crisis, but there are no randomized controlled trials,” Dr. Matucci-Cerinic said. Despite this lack of evidence, the expert recommendation is that angiotensin-converting enzyme inhibitors should be given.
With regard to corticosteroids, these drugs clearly are associated with a high risk of renal crisis in patients with systemic sclerosis. If they are used, patients should be very carefully monitored for blood pressure and kidney function, he said.
▸ Skin involvement. Two randomized clinical trials provided evidence for the use of methotrexate to alleviate the cutaneous manifestations of scleroderma, particularly in early diffuse disease.
▸ Gastrointestinal manifestations. Thus far there have been no randomized trials evaluating therapies for the various gastrointestinal disorders associated with systemic sclerosis. “Nonetheless, expert opinion tells us that we should be employing drugs such as proton-pump inhibitors, prokinetic agents, and antibiotics for bacterial overgrowth,” he said.
▸ Research agenda. Because many gaps and uncertainties remain in the understanding and treatment of systemic sclerosis, a research agenda was also established, Dr. Matucci-Cerinic said. Among the concerns that were identified as warranting further investigation and analysis were the safety and efficacy of long-term cyclophosphamide and mycophenolate mofetil and the use of sildenafil for Raynaud's phenomenon. Evidence for the safety and efficacy of ACE inhibitors in renal crisis also should be pursued, and clearer guidelines on their use should be developed.
Another member of the guidelines task force, Dr. Daniel E. Furst, said in an interview that these guidelines combine what is clear from the medical literature with experience from experts and patient representatives. “While these recommendations are preliminary and undoubtedly will change as more data become available, they are a good first step toward helping rheumatologists treat systemic sclerosis,” said Dr. Furst, who is Carl M. Pearson professor of medicine and director of the Rheumatology Clinical Research Center, University of California, Los Angeles.