US Study Shows Urgent Unmet Need in Diffuse Cutaneous Scleroderma

Despite immunosuppressive therapy, skin and lung involvement still progresses in about 20% of people with early or at-risk diffuse cutaneous systemic sclerosis (dcSSc) within the first three years, according to a study in the U.S.

In addition, most people in the at-risk group went on to develop dcSSc during that period, and 6% of all patients died, with heart and gastrointestinal involvement as the main causes of death.

Together, these findings highlight the urgent need for disease-modifying therapies for dcSSc and for appropriately controlled clinical trials dedicated to this patient population, the researchers noted.

The study, “Clinical characteristics, visceral involvement, and mortality in at-risk or early diffuse systemic sclerosis: a longitudinal analysis of an observational prospective multicenter US cohort,” was published in the journal Arthritis Research & Therapy.

Accounting for nearly one-third of all patients with SSc, or scleroderma, dcSSc is considered the most severe scleroderma type due to “lower survival rate, higher overall progression, and severity of skin and visceral involvement,” the researchers wrote.

At the beginning of the disease, dcSSc patients may have limited skin involvement — considered an important window of opportunity for disease management.

However, there is limited information about the characteristics, current treatment regimens, and disease progression of people with early dcSSc or at risk of the disease, which can limit the evidence-based design of clinical trials and subsequent development of disease-targeted treatments.

To fill this knowledge gap, researchers in the U.S. analyzed the demographic, clinical, and treatment data of 301 adults with early or at-risk dcSSc who were participating in the observational, national Prospective Registry of Early Systemic Sclerosis (PRESS).

A total of 263 (87.3%) had early dcSSc, defined as less than two years since the first non-Raynaud’s phenomenon symptom. Raynaud’s phenomenon is an early symptom of SSc in which the fingers and toes feel numb, prickly, and frigid in response to cold temperatures or stress,

The remaining 38 patients with limited skin involvement were defined as at risk of dcSSc due to the presence of swollen hands or thickened skin on the fingers or toes linked to disease-associated autoantibodies, and/or grating or rubbing sensation when tendons were palpated (tendon friction rubs).

Participants, recruited from 12 U.S. centers starting in April 2012, had a mean age of 50.7 years and a median disease duration of 1.2 years since their first Raynaud’s phenomenon symptom. The analysis ran until July 2020.

Nearly half of all participants had puffy hands or fingers as the first non-Raynaud’s phenomenon symptom, suggesting this symptom could be used “as a criterion for the very early diagnosis of systemic sclerosis,” the researchers wrote. Also, more than half (53.6%) had evidence of interstitial lung disease, one of the major causes of death in SSc.

Participants were followed up for a median of 24.5 months (about two years). Follow-ups ranged from less than one year to more than three years.

Results showed that immunosuppressive therapy was being given to 63.1% participants at study start (baseline), to 85.7% during the first year, and to 86.4% at any time during the study. Roche’s CellCept (mycophenolate mofetil) was the most commonly used immunosuppressive therapy at baseline (40.2%) and during follow-up (68.8%).

Despite the high proportion of patients on immunosuppressive therapy, 21.1% showed clinically significant worsening of skin scarring during the study, mainly in the first year of follow-up, while 23.3% had significant lung function decline.

“The use of immunomodulatory treatments at baseline had no statistically significant impact on the onset of skin progression or [lung function] decline during follow-up,” the researchers wrote.

These findings highlight the importance of including early dcSSc patients in clinical trials based on skin involvement progression, the team noted.

Moreover, most (71%) of the at-risk group developed dcSSc during the study. These patients had higher functional disability and significantly greater skin involvement at baseline, compared with those whose disease remained limited during follow-up.

Also, all participants with tendon friction rubs at study start progressed to dcSSc, suggesting that this symptom is also a risk factor for future dcSSc.

A total of 20 (6.6%) participants died during the study, with 18 deaths occurring in the first three years of follow-up. A three-year mortality rate of 6% “is still high,” the team wrote.

The main causes of death included heart involvement (33.3%), gastrointestinal dysmotility (22.2%), followed by progressive interstitial lung disease (16.7%; including one patient in the at-risk group).

A lower proportion of patients on immunomodulatory treatment at study start had died, compared with those not on such therapies (5.3% vs. 9%), but this difference did not reach statistical significance.

“A disease-modifying [therapy] that could simultaneously target multiple visceral damages to provide an overall improvement of the disease and limit mortality is thus needed,” the team wrote.

This study of early and at-risk dcSSc patients in the U.S. “highlights the management of early SSc in the current era, demonstrating progression of skin and lung involvement despite immunosuppressive therapy and high mortality due to cardiac involvement,” the researchers wrote.

Since PRESS is ongoing, data from longer follow-up may help to better characterize the progression of people with early or at-risk dcSSc and inform future clinical trials, the team noted.