Biological and Clinical Changes in a Pediatric Series Treated with Off-Label JAK Inhibitors

Abstract

Off-label use of medications is still a common practice in pediatric rheumatology. JAK inhibitors are authorized in adults in the treatment of rheumatoid arthritis, psoriatic arthritis and ulcerative colitis. Although their use is not authorized yet in children, JAK inhibitors, based on their mechanism of action and on clinical experiences in small series, have been suggested to be useful in the treatment of pediatric interferon-mediated inflammation. Accordingly, an increased interferon score may help to identify those patients who might benefit of JAK inhibitors. We describe the clinical experience with JAK inhibitors in seven children affected with severe inflammatory conditions and we discuss the correlation between clinical features and transcriptomic data. Clinical improvements were recorded in all cases. A reduction of interferon signaling was recorded in three out of seven subjects at last follow-up, irrespectively from clinical improvements. Other signal pathways with significant differences between patients and controls included upregulation of DNA repair pathway and downregulation of extracellular collagen homeostasis. Two patients developed drug-related adverse events, which were considered serious in one case. In conclusion, JAK inhibitors may offer a valuable option for children with severe interferon-mediated inflammatory disorders reducing the interferon score as well as influencing other signal pathways that deserve future studies.

An Update on the Management of Childhood-Onset Systemic Lupus Erythematosus

“…A recent case report of three cSLE patients allergic to rituximab demonstrated that ofatumumab, a fully humanized anti-CD20 monoclonal antibody, was a safe, well tolerated, and effective alternative for B-cell depletion [ 156 ]. Another report suggested Janus kinase (JAK) inhibitors as an alternative treatment for pediatric patients with severe IFN-mediated inflammatory disorders, including cSLE patients, reducing progressively inflammatory markers, IFN score, and inducing upregulation of the DNA repair pathway [ 157 ].…”

Emerging Place of JAK Inhibitors in the Treatment of Inborn Errors of Immunity

“…Of note, one PRAAS patient discontinued the treatment due to acute renal injury related to BK virus infection and subsequently died after a relapse of his disease and a respiratory tract infection. Nevertheless, these very encouraging results in PRAAS were further confirmed by two single patient cases treated with another JAKinib (tofacitinib) (91,92).…”

“…Studies from four different teams demonstrated that mutations in COPA led to STING-mediated IFN signaling and defined a role for wild-type COPA in STING retrieval from the Golgi back to the ER to prevent chronic immune activation (85)(86)(87)(88). Considering these data, a few COPA patients (five in total) have been treated with JAKinib (85,(89)(90)(91) and follow-up on treatment has been reported for 3 (89)(90)(91). Complete or partial remission has been achieved for arthritis in two patients (89,91) while a major improvement was observed in a COPA patient with a severe diffuse alveolar hemorrhage (90).…”

“…Considering these data, a few COPA patients (five in total) have been treated with JAKinib (85,(89)(90)(91) and follow-up on treatment has been reported for 3 (89)(90)(91). Complete or partial remission has been achieved for arthritis in two patients (89,91) while a major improvement was observed in a COPA patient with a severe diffuse alveolar hemorrhage (90). However, she has subsequently experienced recurrences of diffuse alveolar hemorrhage associated with progression toward lung fibrosis on chest CT scan (authors' personal observation).…”

Vasculitis, Autoimmunity, and Cytokines: How the Immune System Can Harm the Brain

“…Nowadays, four molecules received market authorization in humans: tofacitinib (acting on JAK1, JAK2, and JAK3), baricitinib, upadacitinib, and ruxolitinib (JAK1 and JAK2). These drugs have been widely used for clinical trials or as off-label prescriptions, due to their wide spectrum of actions: the effect on JAK1 and JAK2 provides the inhibition of type I and II IFNs and IL-6 signalings, and the blockade of JAK3 (particularly exerted by tofacitinib) significantly reduces the activity of other cytokines and the lymphocyte activation (IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21) [ 45 ].…”