Combination drug therapy boosts lung, skin health in SSc patients

Study: Biggest benefits seem when drugs started simultaneously, after short gap by Patricia Inácio, PhD | December 2, 2025

Combining rituximab and mycophenolate mofetil was significantly more effective than using either drug alone at reducing skin thickness and improving lung function after one year in people with systemic sclerosis (SSc), according to a large French study.

The safety profile of the combination therapy was similar to that of either drug alone. The greatest benefits were observed when both therapies were started simultaneously or after a short gap.

These findings support the need for additional studies assessing the combo therapy as a first-line treatment in SSc, researchers said.
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The study, “Evaluation of the mycophenolate mofetil–rituximab combination in systemic sclerosis: a French retrospective multicenter study (MycRiSSc),” was published in the Journal of Autoimmunity.

Evidence for combined use of two drugs in SSc limited
SSc, or scleroderma, is a chronic autoimmune disease that causes hardening and scarring (fibrosis) of the skin and internal organs. Many patients develop interstitial lung disease (ILD), a group of conditions that cause inflammation and scarring in the lungs.

Rituximab and mycophenolate mofetil are two immunosuppressants recommended for managing systemic sclerosis-associated interstitial lung disease (SSc-ILD). However, evidence for their combined use has been limited.
“Due to the challenges of conducting combination trials in SSc, high-quality real-world data comparing the [rituximab and mycophenolate mofetil] combination to [rituximab] or [mycophenolate mofetil] monotherapy are essential to inform clinical practice and strengthen the evidence base for this strategy,” the scientists wrote.

The team from France studied 127 adults with SSc, following them across 17 centers. Patients received either of the two drugs alone or a combination of both for at least 12 months.

A total of 47 patients, 61.7% of whom were women and whose median age at SSc diagnosis was 45, received the combo therapy. They were compared with 30 participants who were treated with rituximab and 50 who were given mycophenolate mofetil.

Within the combination group, most had diffuse cutaneous SSc (68.1%), and a vast majority had ILD (85.1%). Nearly 28% had overlapping autoimmune conditions, such as Sjögren’s disease.

Skin thickness decreased significantly with combo therapy
Patients in the mycophenolate mofetil-only group began treatment earlier after having been diagnosed. These patients also had better lung function than those in the combination group, as assessed by a higher forced vital capacity (FVC) — a key measure of lung function — at the start of treatment (baseline).

After one year, skin thickness, measured by the modified Rodnan skin score (mRSS), decreased significantly with the combination therapy, from 14 to 7 points. The mycophenolate mofetil group also showed a modest but significant improvement, while the rituximab group experienced no meaningful change.

Lung function, measured by FVC, also improved significantly in the combination group, from a median of 63.1% to 67%, while remaining stable with either rituximab or mycophenolate mofetil alone. The diffusing capacity for carbon monoxide — the ability of the lungs to transfer oxygen from the air to blood — did not change significantly in any group.

Compared with rituximab alone, combination therapy was more effective in reducing skin thickness and in improving skin and/or lung involvement.

Combination therapy eased ILD in almost two-thirds (63%) of patients, compared to 27.8% with rituximab or 28.6% with mycophenolate mofetil alone. Similarly, 70.4% of patients on combination therapy showed improvements in skin and/or lung complications, versus 27.8% of those given rituximab and 52.4% of those who received mycophenolate mofetil.

Upfront combination therapy linked to higher likelihood of ILD easing
Among the 47 patients on the combo approach, 20 (42.6%) received upfront combination therapy, while 27 (57.4%) received sequential combination therapy, when the second drug is added later.

In the upfront group, the median delay between the two medications was 3.5 months. In contrast, in the sequential group, mycophenolate mofetil was started first in nearly all cases (88.9%), and rituximab was added after a median of 31 months.

In the upfront treatment group, mRSS dropped from 18 to 7, and FVC increased from 67% to 80% after 12 months, while minimal changes occurred in the sequential group.

Overall, 73.7% of patients in the upfront group experienced improvement in ILD, compared with 25% in the sequential group. Likewise, 80% of upfront combination-treated patients improved in skin and/or lung measures, compared with 33.3% of those in the sequential therapy group.

Safety analyses showed that the higher frequency of adverse events in the combo therapy group was not statistically significant. Only one patient in the combination group had a severe drop in antibody levels, known as hypogammaglobulinemia.

A multivariate analysis — based on the relationship between several variables — confirmed that baseline mRSS was an independent predictor of skin improvement after 12 months, while upfront combination therapy was independently linked to a higher likelihood of ILD easing and skin and/or lung improvement.
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Overall, these findings show that the combination of rituximab and mycophenolate mofetil “reduces skin fibrosis [scarring], improves lung function, and is well tolerated in SSc, with no significant safety difference compared to monotherapy,” the researchers wrote.