Markers of progressive lung damage in SSc eased by Actemra, study finds

Blood levels of proteins tied to inflammation, fibroblast activation analyzed

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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Elevated levels of certain blood proteins are associated with poorer long function and skin involvement in systemic sclerosis (SSc) patients, according to a recent study.

In an analysis of data from the focuSSced Phase 3 trial that supported the approval of Actemra (tocilizumab) in the U.S., researchers also found that the therapy’s use lowered several of these markers.

“These biomarkers are potentially useful in future studies to help classify patient subsets, elucidate drug mechanisms of action, and help identify patients whose disease is most likely to progress,” they wrote.

The study, “Biomarkers of fibrosis, inflammation, and extracellular matrix in the phase 3 trial of tocilizumab in systemic sclerosis,” was published in the journal Clinical Immunology. The work was funded by Genentech, which markets Actemra, and by Roche, which owns Genentech.

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Scleroderma’s course is variable, raising a need for predictive biomarkers

SSc, also known as scleroderma, is characterized by inflammation and fibrosis (scarring) of the skin and, potentially, of internal organs such as the lungs. The disease course is highly variable, which is a hurdle for predicting disease progression and developing new therapies. Reliable biomarkers that help to predict outcomes and reflect how well patients respond to a certain treatment are needed.

Actemra works by blocking the action of a protein called interleukin-6, preventing immune attacks against healthy cells. It was approved by the U.S. Food and Drug Administration  in March 2021 to slow lung function decline in adults with SSc-associated interstitial lung disease (SSc-ILD).

The approval was based in part on the Roche-sponsored focuSSced trial (NCT02453256), which enrolled 212 adults with SSc. Among them, 136 patients had ILD detected on CT scans before treatment began.

Participants were randomly assigned to weekly subcutaneous (under-the-skin) injections of Actemra at 162 mg or to a placebo for 48 weeks — almost one year — followed by all being treated weekly with Actemra for another 48 weeks.

While no easing was seen in skin fibrosis — the trial’s primary goal — after 48 weeks, those randomized to be treated with Actemra showed preserved lung function.

To better understand how Actemra works and to identify useful biomarkers, scientists working at Genentech, in collaboration with a researcher with the University of Michigan Scleroderma Program, analyzed a panel of blood proteins in diffuse cutaneous SSc patients enrolled in the focuSSced study.

Blood samples from healthy people obtained from three sources — Genentech Samples for Science program, Discovery Life Sciences, and BioIVT — were used as controls. SSc patients were younger than the controls and predominantly female.

Researchers assessed the levels of six proteins — CCL18, YKL-40, CXCL13, COMP, periostin, and SP-D — in blood samples collected at the start of the study (baseline). These proteins have been associated with lung disease progression as well as skin scarring.

The levels of all six proteins were higher in SSc patients relative to controls, indicating activated pathways in immune response (CCL18, YKL-40, and CXCL13), damage to cells lining the lungs (SP-D), and fibroblast activation (COMP and periostin).

In SSc, fibroblasts become overactive and produce excess collagen, a major component of the extracellular matrix that supports and gives structure to cells.

Levels of CRPM, a biomarker of inflammation, as well as several markers of collagen formation and degradation (C3M, C4M, Pro-C3, and Pro-C4) also were elevated in SSc blood samples.

Levels of SP-D correlated with the percentage of ILD, lung fibrosis, and ground glass opacification — hazy findings on CT scans associated with respiratory conditions.

At baseline, COMP and periostin levels correlated with the modified Rodnan Skin Scores (mRSS), a measure of skin thickness.

Actemra lowered levels of several proteins linked to lung disease progression

After 48 weeks of treatment with Actemra, levels of CCL18, YKL-40, CRP, CRPM, C3M, C4M, and Pro-C4 were lower.

“In fibrotic lung, where function is preserved with anti-IL-6 treatment, [Actemra] does not change ongoing epithelial damage (no change in SP-D), but instead reduces inflammation induced by activated macrophages (reduction of CRP, CRPM, CCL18, and YKL-40), which in turn, reduces fibroblast activation (reduction of C3M, C4M, and Pro-C4),” the team wrote.

Researchers then assessed how well the different biomarkers predicted disease progression, by analyzing how their levels changed throughout the 48 weeks in patients given a placebo or Actemra.

CRP, periostin, and SP-D showed a weak correlation with worsening lung function, as measured the forced vital capacity, which measures how much air is exhaled after a deep breath. CRP was deemed the strongest predictor.

In addition, baseline levels of IL-6, COMP, periostin, and Pro-C3 showed a weak correlation with worse skin involvement, as measured by the mRSS.

Study findings suggest that “patients with higher inflammatory, fibrosis, and lung epithelial injury burdens have faster lung function decline,” the team wrote, with inflammation and fibrosis also being linked with skin thickening.

“While these findings are promising, they require further confirmation in additional studies before any implementation in future studies for prognostic use,” the researchers concluded.