Understanding which molecules, genes and proteins are active or inactive in sarcoidosis patients may help explain differences in the disease’s severity from patient to patient, a study reported.
The variations in these actions and inactions — which scientists call molecular differences — may also explain which organs sarcoidosis will impact. And, importantly, they may explain why a therapy affects individuals differently, according to research from Janssen.
The findings underscore the notion that to achieve meaningful results, clinical trials need to stratify patients according to molecular changes, the researchers said.
The study, “Sarcoidosis Extent Relates to Molecular Variability,” explored molecular variability among sarcoidosis patients who participated in a Phase 2 clinical study (NCT00955279) assessing Stelara (ustekinumab) and Simponi (golimumab). The report was published in the journal Clinical & Experimental Immunology.
Patients in the study were categorized according to whether they had skin or lung problems, or both, and randomized to receive Stelara, Simponi, or a placebo.
Researchers analyzed samples of participants’ blood and serum, a blood component. They found that, although all patients had gene-activity signatures that differed from controls, there were also differences between the groups.
In particular, there were differences in gene and protein expression between patients with both lung and skin disease, compared with those having either skin or lung symptoms alone.
The team then looked at the molecular pathways that were most commonly altered among the three disease types. They observed that while all patients had abnormally low activity in genes related to immune T-cell signaling, pathways related to interferon signaling differed between the three groups.
The biggest changes in interferon signaling were in patients with both lung and skin disease. Those with only skin sarcoidosis also had abnormally elevated interferon signaling, while patients with lung disease did not show any changes.
Analyses of proteins in serum showed similar differences, with the proteins IL12p40 and RANTES elevated in patients with skin problems, or both lung and skin symptoms. Those with sarcoidosis that affected only the lungs showed no such changes. Patients with skin symptoms only also had higher levels of angiotensin-converting enzyme and TNF-alpha in their serum. The two factors are associated with skin disease.
Further analyses showed that Stelara and Simponi could normalize gene expression abnormalities in patients with lung disease or a combination of lung and skin symptoms, but did not benefit patients with skin sarcoidosis.
“These results suggest that multiple factors may contribute to molecular heterogeneity [differences] across sarcoidosis cohorts in a manner that may affect the clinical efficacy of targeted therapeutics.” the team concluded. “Future studies involving direct sampling of disease tissue will be necessary to assess our findings of pronounced molecular heterogeneity in sarcoidosis.”
The authors further suggested that “our data invite speculation that therapeutic interventions in sarcoidosis will be optimized through clinical patient stratification that reflects the molecular heterogeneity of the disease.”
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