Off-the-Shelf Drugs May Treat This New Autoimmune Disease

Janus kinase (JAK) inhibitors look to be a good treatment option for the newly recognized, rare autoimmune disease known as SOCS1 insufficiency, researchers found.

Which was not exactly a surprise. SOCS1 stands for “suppressor of cytokine signalling 1,” an endogenous factor that keeps cytokine activity mediated through the so-called JAK-STAT pathway under control. When genetic mutations render it ineffectual, hyperactive JAK signalling results, as explained in the new study led by Stephan Ehl, MD, of the University of Freiburg in Germany.

But SOCS1 insufficiency was only recognized 5 years ago and its natural history and optimal management are still being worked out. The study, appearing in The Lancet Rheumatology and examining what its authors hoped was most patients now known to have the condition, has fleshed out many of its details, including effects of JAK inhibitor treatment.

SOCS1 insufficiency is part of a family of so-called monogenetic immune dysregulatory disorders — in other words, conditions caused by mutations in a single gene that let certain immune components run wild. Besides SOCS1, genes that may be affected include those encoding CTLA4, NF-κB, and PI3K-δ. The most common manifestation is immune cell proliferation, which may become overt hematologic malignancies; but clinical symptoms of allergy and inflammation also appear to be frequent.

How frequent, and what management strategies have been employed, for SOCS1 insufficiency was the new study’s focus.

Ehl and colleagues analyzed data from two cohorts: 67 patients followed in the multinational European Society for Immunodeficiencies (ESID) registry, which also has data from China, Taiwan, and the U.S.; and 52 from the massive U.K. Biobank registry. SOCS1 insufficiency patients in ESID were added to the registry by their treating clinicians after diagnosis, which included genetic testing to identify the particular mutations responsible as well as information on clinical symptoms and other testing, treatments provided, and (in some cases) outcomes.

The U.K. Biobank is an ongoing longitudinal registry in which more than a half-million adult Britons were enrolled from 2006 to 2010. Diagnoses of SOCS1 insufficiency were not made clinically or recorded in the data, but the Biobank’s ambitious program included whole-exome sequencing for all participants. Ehl and colleagues scanned those data for mutations first identified in the ESID registry, yielding 52 individuals with SOCS1 genetic defects.

Patients in the two cohorts were similar in some respects and different in others — as might be expected, insofar as ESID patients were diagnosed clinically in the main, whereas those in the Biobank were genetic carriers who might never have been diagnosed with anything. The ESID records suggested that clinical disease comes early, with initial symptoms first appearing at a median age of 10 (interquartile range 5-15). (Biobank participants were enrolled at ages 40-69 and there was no data on symptom onset.)

Similarities in the cohorts included sex distribution (just over half female) and that more than three-quarters in both groups had mutations previously validated as causing SOCS1 insufficiency. However, many more Biobank participants had no records of symptoms (42% vs 7%), indicating that “penetrance” — the frequency with which mutations cause symptoms — is incomplete in this condition.

And among those with symptoms, the spectrum varied considerably. Allergies and classic rheumatologic symptoms (i.e., those resembling conditions such as lupus, Sjögren’s syndrome, and rheumatoid arthritis) affected 54% of Biobank participants, whereas those in ESID showed a wider distribution — only 31% had allergic or rheumatologic symptoms — and also a wider variety of symptoms in a given participant. Only three in the Biobank had more than three manifestations, while more than half of those in ESID had four or more. Symptoms that were more common in ESID versus Biobank members included lymphoproliferation, autoimmune cytopenia, and liver and gastrointestinal involvement.

Symptoms ran the gamut of autoimmune possibilities. Some patients qualified for diagnoses of lupus, with positive tests for antinuclear antibodies and other lupus-related markers. Others had enough gastrointestinal symptoms to be diagnosed with inflammatory bowel disease. Other conditions present in SOCS1 insufficiency included atopic dermatitis, eosinophilic esophagitis, and granulomatous interstitial lung disease, to name a few.

Reflective of this variability, treatments also spanned the rheumatologic arsenal. Some 60% of symptomatic ESID patients had received systemic corticosteroids; smaller proportions were given conventional disease-modifying antirheumatic drugs (DMARDs) such as azathioprine, mycophenolate mofetil, methotrexate, and/or hydroxychloroquine. Many also had tried biologic DMARDs including tumor necrosis factor inhibitors and the anti-B-cell agent rituximab.

Thirteen ESID members, 10 of whom were pediatric patients, were treated with JAK inhibitors, primarily ruxolitinib (Jakafi, Opzelura) and baricitinib (Olumiant), with two receiving tofacitinib (Xeljanz). Clinicians in ESID were asked to rate treatment responses on a 10-point scale. In nine patients, the rating was “very good” (8 or higher), and “good” responses (4-7 points) were seen in three; just one patient’s response was rated “poor” (3 or less).

“Notably, initiation of a JAK inhibitor enabled a reduction of steroids and other immunosuppressants in 10 (77%) of 13 participants,” Ehl and colleagues pointed out. Because so few patients got any kind of JAK inhibitor, the researchers couldn’t tell if one product was better than others.

Clinical implications, the group asserted, include the following:

• Genetic testing for SOCS1 insufficiency or other “inborn errors of immunity” could be considered in all patients with early-onset, multifarious autoimmune disease
• Management ideally involves a team approach, comprising rheumatologists, hematologists, allergists, and immunologists
• Persons carrying SOCS1 defects may not develop symptoms (as seen in the Biobank data), therefore requiring “personalized approaches to diagnosis and management”

Limitations included potential “referral bias” in the ESID registry, such that patients not seen in rheumatology clinics could easily be missed, and lack of early-life data on U.K. Biobank participants. Registry data are always subject to error as well. Also, the European-centric nature of both cohorts means the findings may not be generalizable to other regions.

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