MAUI, HAWAII – Belimumab shows promise as a novel biologic treatment for skin involvement in early diffuse cutaneous systemic sclerosis, Janet E. Pope, MD, said at the 2020 Rheumatology Winter Clinical Symposium.
Bruce Jancin/MDedge News
Dr. Janet Pope
She highlighted a single-center, double-blind, placebo-controlled, New York pilot study including 20 patients with early diffuse cutaneous systemic sclerosis and moderate skin involvement. Participants had recently started on background mycophenolate mofetil (MMF) at 1,000 mg twice daily and were then randomized to add-on belimumab (Benlysta) at the dosing approved for systemic lupus erythematosus or to infusions of normal saline.
At 52 weeks, the modified Rodnan skin thickness score (mRSS) decreased by a median of 10 points from a baseline of 27 in the belimumab group, compared with just a 3-point reduction in controls on MMF plus placebo.
This small study raises several key points. It definitely warrants confirmation in a large phase 3 trial, according to Dr. Pope, professor of medicine at the University of Western Ontario and head of the division of rheumatology at St. Joseph’s Health Care, both in London.
For one thing, the pilot study makes a good case for multidrug therapy in scleroderma. “In rheumatoid arthritis, if in general one drug is not as good as two, why would we ever think, in our most difficult-to-treat disease, one drug would be okay?” the rheumatologist observed.
The belimumab study also highlights the role of abnormalities in B-cell function in the pathogenesis of skin involvement in early diffuse cutaneous systemic sclerosis. Belimumab is a fully human monoclonal antibody which binds to soluble B-lymphocyte stimulator and inhibits autoantibody production.
Belimumab’s mechanism of benefit was as expected: The improvement in skin scores in the belimumab group was accompanied by decreased expression of profibrotic genes and B-cell signaling, changes that didn’t occur in the controls on MMF alone.
The belimumab study makes another important point: MMF, despite its growing popularity for treatment of skin manifestations of scleroderma, is actually a wimpy drug for that purpose, achieving a mere 3-point reduction in mRSS.
“To be quite honest, mycophenolate mofetil is not all that great on skin,” Dr. Pope said.
Nonetheless, when she and her coworkers recently polled 170 scleroderma experts as to their favored treatments directed at various target organs impaired by the disease, as she had previously done in 2012, a clear trend was evident. “There’s a shift in that mycophenolate mofetil is moving to first-line treatment across the board for skin,” Dr. Pope observed.
Indeed, in the more recent survey, 71% of the experts agreed upon a scleroderma skin involvement treatment algorithm in which the first-line treatment for severe skin disease as defined by an mRSS of 32 was MMF, with methotrexate as second line, intravenous cyclophosphamide third, and autologous stem cell transplantation as fourth line for the small number of patients who qualify for it.
For moderate skin involvement, with an mRSS of 24, methotrexate was endorsed as first line, although by the narrowest of margins, over MMF, with intravenous cyclophosphamide as third line. For mild disease, with an mRSS of 10, methotrexate again narrowly beat out MMF by expert consensus as the preferred first-line therapy.
When asked about concomitant use of corticosteroids for treatment of skin involvement, 35% of experts said they never prescribe them for that indication, 33% do so occasionally, 19% sometimes, and 13% routinely. There was an even split on dosing among those who prescribe steroids: 49% suggested using prednisone at less than 7.5 mg/day, and 51% recommended 7.5-20 mg/day.
The purpose in polling the experts, who were drawn from the Scleroderma Clinical Trials Consortium and the Canadian Scleroderma Research Group, was to provide treatment guidance to general rheumatologists and dermatologists who may not see many patients with scleroderma. In contrast, the great majority of the polled experts see more than 50 scleroderma patients per year. And they had a high level of total agreement for treatment algorithms addressing not only skin disease, but also pulmonary arterial hypertension, interstitial lung disease, Raynaud’s phenomenon, renal crisis, digital ulcers, inflammatory arthritis, cardiac involvement, and gastrointestinal disease, Dr. Pope noted.
She attributed the experts’ rising enthusiasm for MMF for scleroderma skin involvement to the results of the Scleroderma Lung Study II, the first randomized, controlled trial to compare MMF and cyclophosphamide for the treatment of symptomatic scleroderma interstitial lung disease. Two years of MMF improved forced vital capacity as much as 1 year of oral cyclophosphamide. At 2 years of follow-up, the mRSS dropped modestly from baseline by an average of 6.1 points in the cyclophosphamide group and 2.9 points with MMF, a nonsignificant difference. But the incidence of serious adverse events was roughly three times higher and deaths were twice as frequent in the cyclophosphamide group.
“I think mycophenolate mofetil is surging for treatment of skin because of the lung protection and it was safer, but it’s hard for me to know if the deaths were more common in the cyclophosphamide group because of the cyclophosphamide or because of no treatment in year 2,” Dr. Pope commented.
She reported receiving research grants from Bristol-Myers Squibb, Merck, Roche, Seattle Genetics, and UCB, and serving as a consultant to more than a dozen pharmaceutical companies.