Trial Will Test New Treatment for Diffuse Cutaneous Systemic Sclerosis
Hospital for Special Surgery is evaluating a novel therapeutic approach for diffuse cutaneous systemic sclerosis (dcSSc), one of the most serious, potentially disabling and life-threatening rheumatic diseases. The double-blind, randomized, placebo-controlled phase II trial is only available at HSS and will test the combination of rituximab (Rituxan, Genentech) and belimumab (Benlysta, GSK) plus standard therapy with mycophenolate.
"Better therapies for scleroderma are a major unmet medical need," said Robert F. Spiera, MD, Director of the Vasculitis and Scleroderma Program at HSS. "Our current treatments depend on the symptoms and organ systems involved, and there are no therapies that are specifically approved by the FDA to treat systemic sclerosis."
DcSSc is a subtype of systemic scleroderma characterized by widespread skin thickening and problems in many organs that can occur at any age, but often begins in people between ages 30 through 50. Symptoms vary and include Raynaud’s syndrome; skin hardening and thickening beginning on fingers and face that can rapidly generalize; severe heartburn; dry mouth and dental involvement; joint pain; muscular pain; heart problems, and severe problems involving the lungs and kidneys. The exact cause of dcSSC is unknown.
Different arms of the immune system are overactive in patients with scleroderma, and in the past ten years, several lines of evidence suggest that B cells are important. "We know there is evidence of B cell activation in the skin and lungs of patients with scleroderma, and there have been a few studies looking at strategies to inhibit B cells that have shown promise," said Dr. Spiera. "The first were some studies looking at rituximab, which is a drug that targets B Cells and is relatively well-tolerated in scleroderma patients. Belimumab is a drug known to work in lupus, and there was rationale to think that the target of belimumab would be promising in systemic sclerosis patients. A protein that belimumab blocks is overexpressed in patients with scleroderma and higher levels of that protein correlate with people with scleroderma doing worse observationally."
The HSS team previously evaluated belimumab, which is approved for the treatment of adult patients with systemic lupus erythematosus, in a double-blinded trial in patients with dcSSc and found acceptable safety and tolerability, as well as a trend suggesting possible efficacy, although the differences between patients treated with active belimumab vs placebo did not reach statistical significance in that small pilot study.
The 52-week trial now being launched will evaluate whether rituximab and belimumab plus standard therapy with the immunosuppressive agent mycophenolate mofetil (MMF, CellCept,) is safe and tolerable in the treatment of patients with early dcSSc. "Everyone will be getting background active therapy with mycophenalate which we think is a good drug for skin involvement," said Dr. Spiera. The trial will enroll 30 patients, and 20 will receive the experimental treatment consisting of 2 rituximab infusions (1000mg separated by 2 weeks), followed by weekly self-injected belimumab (as is used in lupus) or placebo infusions followed by placebo injections. Neither the patients nor the treating physicians will know whether they are receiving the active treatment. The researchers are hoping to see improvements in a few different domains.
"The most common thing we look at in a trial outcome in scleroderma is the amount of skin involvement as measured by the Modified Rodnan Skin Score. That is an important outcome, but we are also looking at a more holistic outcome measure called the combined response index in systemic sclerosis or CRISS," said Dr. Spiera. "CRISS is an outcome measure provisionally endorsed by the American College of Rheumatology for scleroderma clinical trials, which looks not only at skin, but also incorporates the patient’s general sense of how well they are doing, the patient’s lung function measured by the forced vital capacity of the lung function test, and how the physician globally feels the patients are doing, and an index that measures how patients are functioning."
CRISS incorporates change in the modified Rodnan Skin Score, forced vital capacity percent predicted, physician and patient global assessments, and the Health Assessment Questionnaire Disability Index. Patients will also be evaluated using hemoglobin corrected diffusion capacity, the Medsger Disease Severity Scale and with other physician and patient-derived outcome measures. The biological activity of the two treatments will be determined by evaluating skin histology; gene expression in skin and blood; B-Cell profiles including assessment of B regulatory cells; and serological and cutaneous biomarkers of disease activity. "We want to see if what we are finding signals that the biology is changing in a favorable way that suggests improvements or lack thereof," said Dr. Spiera.
This investigator-initiated trial is sponsored by HSS and supported by funding and belimumab supply from GSK.