Rituximab Plus CellCept Durably Improves Lung Function in Refractory SSc-ILD, Study Suggests

Rituximab, in combination with CellCept (mycophenolate mofetil), reverses the decline in lung function in people with interstitial lung disease (ILD) associated with scleroderma (SSc) who did not respond to immunosuppressant therapies, a study suggested.

The study, “Rituximab as a rescue treatment added on mycophenolate mofetil background therapy in progressive systemic sclerosis associated interstitial lung disease unresponsive to conventional immunosuppression,” was published in the journal Seminars in Arthritis and Rheumatism.

ILD, characterized by scarring of the lungs, is a common feature of scleroderma — an autoimmune disease in which the immune system mistakenly attacks healthy connective tissue. 

CellCept, an oral medication developed by Genentech, a Roche subsidiary, is a first-line immunosuppressant therapy that has been shown to improve and stabilize lung function in people with scleroderma.

However, a small portion of patients do not adequately respond to conventional immunosuppressants such as CellCept and require a second-line (rescue) therapy.

Rituximab has been developed by Roche and is approved to treat blood cancers, including non-Hodgkin’s lymphoma, as well as rheumatoid arthritis. The antibody-based medicine binds to the CD20 protein on the surface of immune B-cells to suppress overactive immune responses.

A recent study, including patients with scleroderma from the European Scleroderma Trials and Research (EUSTAR) network, found that while rituximab eased scarring of the skin, it did not demonstrate clear benefits in ILD. 

Still, an analysis of the EUSTAR data showed that patients with SSc-ILD treated with both CellCept and rituximab responded well, and as such, this combination therapy requires further assessment. 

To that end, researchers based at the Hospital Universitario de Bellvitge in Spain analyzed the medical records of 24 patients with progressive SSc-ILD, who were treated with off-label rituximab after failing to respond to conventional therapies (refractory). All patients had undergone lung function tests over at the previous year.

The patients’ mean age at rituximab start was 58 years. Most (21) were women. Median time since scleroderma diagnosis was five years, and median ILD duration was 4.7 years. A total of 15 patients had diffuse systemic scleroderma and nine had limited scleroderma. As for ILD pattern, seven had usual interstitial pneumonia and 14 patients had non-specific interstitial pneumonia.

Before rituximab treatment, all patients had been treated with low to medium doses of the corticosteroid prednisone, and one or more immunosuppressant therapies, including CellCept (100%), cyclophosphamide (58%), azathioprine (33%), and methotrexate (21%). 

Along with rituximab, all patients mantained treatment with CellCept, and 23 received prednisone. 

The average decline in lung function during the two years preceding rituximab treatment, measured by percent predicted forced vital capacity (%FVC) and diffusing capacity of the lungs for carbon monoxide (%DLCO), was about 13%. FVC measures the total amount of air a patient can exhale after taking a deep breath and DLCO measures how much oxygen travels from the lungs to the bloodstream. 

After one year of rituximab treatment, improvements were seen in %FVC (8.8%), and %DLCO (4.6%). The distance walked in six minutes, a test of exercise capacity, also increased by 58 meters (about 63 yards). 

The levels of the inflammatory marker C-reactive protein decreased from 10.2 to 6.8 mg/L, and the mean modified Rodnan skin score (mRSS), a measure of skin scarring, decreased from 19 to 11 in patients with diffuse skin involvement. 

In addition, the patient’s median dose of prednisone was reduced, with six patients being able to suspend the therapy. 

Regarding ILD pattern, the combination treatment improved lung function only in those without usual interstitial pneumonia.

After two years of rituximab treatment, nine patients had discontinued the therapy, while the remaining 15 maintained the significant improvements in %FVC (11.1%), %DLCO (8.7%), and the distance walked in six minutes (53 meters, or 58 yards). 

An analysis of ILD using scores based on CT scans, conducted in 21 patients, showed stable lung disease in 18 participants. One patient had an almost complete disappearance of inflammation, while two patients worsened. 

By the end of the follow-up period, 14 patients were still receiving rituximab. Three patients stopped the therapy due to adverse effects (side effects), six with severe lung disease before rituximab treatment did not respond to the therapy, and one died due to a ruptured brain aneurysm deemed unrelated to rituximab.

Seven of the patients who continued treatment and had a follow-up greater than three years (median 44 months) demonstrated durable improvement in lung function as measured by %FVC (16.6%) and %DLCO (12.8%).

The most common side effects of rituximab were respiratory or urinary infections (33%), low antibody count (25%), and a temporary low number of immune cells called neutrophils (8%). Three patients withdrew due to recurrent infections. 

“According with our our experience, [rituximab] rescue therapy used as an add-on treatment to [CellCept] was able to reverse the decline of lung function parameters in a not negligible proportion of these patients,” the scientists concluded.  “Our data needs to be replicated in additional studies in order to confirm these encouraging results.”