Off-label JAK inhibitors may stabilize lung function in systemic sclerosis
Study: Their use needs further confirmation in larger controlled studies
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Off-label treatment with JAK inhibitors appeared to keep lung function stable and reduce skin thickening, joint pain, and swelling in a small real-world study of systemic sclerosis (SSc).
They also caused some side effects and their use needs further confirmation in larger controlled studies, researchers wrote.
The study, “Longitudinal clinical response to Janus kinase inhibitors in systemic sclerosis: a real-life multicentric study across multiple clinical domains,” was published in Clinical Rheumatology by an international team of researchers from the U.K., France, Spain, Bulgaria, and Italy.
Some JAK inhibitors showed effectiveness in SSc mouse models
JAK inhibitors are medications that inhibit Janus kinase enzymes, which are part of the JAK/STAT pathway involved in immune signaling. These medications are usually effective in diseases marked by inflammation alone, but have generally been less effective in those marked by both inflammation and scarring, such as scleroderma.
SSc occurs when the immune system becomes overactive and mistakenly attacks the connective tissues, causing excessive inflammation and scarring. Symptoms include thickened, hardened skin and numbness in the fingers and toes. The lungs and other internal organs may also be affected.
In this study, the researchers looked at whether JAK inhibitors could help adults with SSc in real-world clinical practice based on medical records from 32 patients. They were treated with different JAK inhibitors, including baricitinib, filgotinib, tofacitinib, and upadacitinib. Both baricitinib and tofacitinib have been effective in mouse models of scleroderma.
Most patients (91%) were women, with a median age of 60 years. Half of the patients had interstitial lung disease (scarring of the lungs) and eight (25%) had pulmonary arterial hypertension (high blood pressure in the blood vessels of the lungs). About two-thirds (69%) had a history of finger ulcers (open sores), and seven (22%) had an active ulcer.
After 12 months (one year) of treatment, lung function remained stable based on no significant worsening or improvement in forced vital capacity, which is how much air a patient can forcefully exhale, and diffusing capacity of the lungs for carbon monoxide, which measures how well oxygen passes from the lungs into the blood.
Our findings suggest a potential role for JAK/STAT pathway inhibition across multiple disease domains in selected SSc patients.
On average, the modified Rodnan skin score (mRSS), which measures skin thickness, improved by 0.29 points after 12 months of treatment with JAK inhibitors. Having thicker skin before treatment predicted a greater mRSS reduction (improvement) at follow-up. The number of tender and swollen joints also decreased significantly. By 24 months (two years), improvements in skin and joints were still present but no longer statistically significant.
Of the 11 patients who had calcinosis (abnormal deposits of calcium in tissues), five (46%) showed improvements, while others remained stable or worsened (27% each). Ten patients developed new digital ulcers during follow-up. According to the investigators, the rate of new digital ulcers “remained relatively low.”
Fifteen patients were also taking corticosteroids, which are medications that reduce inflammation but can have serious long-term side effects. There was a trend suggesting that patients on JAK inhibitors could reduce their dose of corticosteroids, although this was not statistically significant. However, 13 of the 15 patients did reduce their dose during follow-up.
During follow-up, 17 patients stopped taking JAK inhibitors. The most common reason, reported in seven patients, was ineffectiveness.
“Our findings suggest a potential role for JAK/STAT pathway inhibition across multiple disease domains in selected SSc patients. Prospective controlled trials with adequate follow-up and mechanistic exploratory endpoints are warranted to confirm the efficacy, safety, and ideal patient profiles,” the researchers concluded.
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