ROME – Updated expert recommendations from the European League Against Rheumatism for the treatment of systemic sclerosis will focus on several new treatment options, although the use of biologic agents is not included in detail because there are still too few data on these drugs to give firm guidance on their use.
The EULAR Scleroderma Trials and Research group (EUSTAR) recommendations for the treatment of scleroderma were first published 6 years ago (Ann. Rheum. Dis. 2009;68:620-8) and considered data through December 2006.
© Eveline Perroud
Dr. Otylia Kowal-Bielecka
“Since then, a number of new drugs have become available and new and important information has been published concerning treatments already known before,” said Dr. Otylia Kowal-Bielecka of the Medical University of Bialystok, Poland, who discussed some of the main highlights of the revised recommendations (Ann. Rheum. Dis. 2015;74:90-1) at the European Congress of Rheumatology.
Scleroderma experts from all EUSTAR centers were invited to participate in the update and submit questions that could form the basis of the updated recommendations. From a total of 170 questions suggested, 46 questions concerning 23 treatment categories were researched in more depth via a systematic review of the literature that considered papers published through September 2014. A task force of more than 30 experts from Europe and the United States, two patients with scleroderma, and a clinical epidemiologist then met in October 2014 to discuss and formulate the final 16 recommendations.
The guidance covers the same main organ categories as the 2009 iteration – Raynaud phenomenon (RP), digital ulcers, pulmonary arterial hypertension (PAH), skin and lung disease, scleroderma renal crisis, and systemic sclerosis (SSc)-related gastrointestinal (GI) disease – Dr. Kowal-Bielecka observed, but the main difference is that many of the treatment options have been updated or reworded.
For instance, phosphodiesterase (PDE)-5 inhibitors and fluoxetine (Prozac) have been added to the treatment options for SSc-RP, which previously only included dihydropyridine-type calcium antagonists and intravenous iloprost. The latter is recommended after oral therapy. Evidence for the use of fluoxetine is weaker than for the PDE-5 inhibitors, but it might be worth considering in a patient with SSc-RP attacks. PDE-5 inhibitors have also been added to the list of options for digital ulcers. For PAH, where sildenafil (Viagra) was already recommended, tadalafil (Cialis) had been specifically included.
Intravenous iloprost and the endothelin-receptor antagonist (ERA) bosentan (Tracleer) continue to be recommended for the management of digital ulcers. The recommendation on bosentan has been amended based on new data from two “high-quality,” randomized, clinical trials and now considers the whole patient population rather than just those with disseminated disease, Dr. Kowal-Bielecka noted. The new statement recommends considering bosentan to reduce the number of new digital ulcers, especially in patients with multiple ulcers that might not be responding to calcium-channel blockers, PDE-5 inhibitors, and iloprost.
The area with the most changes is the treatment of PAH, with many new drugs now recommended, including tadalafil, riociguat (Adempas), ambrisentan (Letairis), and macitentan (Opsumit), as well as more intravenous prostacyclin analogues such as epoprostenol (Flolan).
Hematopoietic stem cell transplantation (HSCT) has been added to the list of options for managing skin and lung disease, which includes methotrexate for skin manifestations of early diffuse SSc and cyclophosphamide for interstitial lung disease. HSCT is only for selected patients who have progressive scleroderma and were at risk of organ failure, Dr. Kowal-Bielecka qualified. “In view of the high risk of treatment-related side effects and of early treatment-related mortality, careful selection of SSc patients for this kind of treatment and experience of medical team are of key importance,” part of the draft recommendation reads.
Evidence from several descriptive cohort studies support the use of angiotensin-converting enzyme inhibitors for scleroderma renal crisis, and the expert opinion is that they should be used immediately. *The recommendations continue to advise against using glucocorticoids in this patient population, based on retrospective study data. It is important to monitor patients’ blood pressure and renal function while on treatment with steroids.
Recommendations have not changed for the management of SSc-related GI disease, but have been reworded slightly to recommend prokinetic drugs and the intermittent or rotating use of antibiotics.
“Several biologics were considered as potentially interesting, we had tocilizumab [Actemra], rituximab [Rituxan], and TNF-alpha blockers on our list, and they also underwent the systematic literature research and review process,” Dr. Kowal-Bielecka said in an interview. “However, the evidence available at the moment was considered by the expert panel to be insufficient to provide any recommendations,” she said.
Dr. Kowal-Bielecka also noted that the expert panel had developed a research agenda for a list of drugs that are considered promising and which should be more carefully looked at in future trials.