To the best of our knowledge, this is the most extensive pediatric case series describing patients with STAT1 GOF mutations under JAKinib therapy to date. Our study provides a detailed description of the clinical experience with this treatment approach in children and highlights the heterogeneity in terms of indications, dosing schedules, and follow-up practices.
Treatment, Dosing, and Treatment Response
In the setting of IEI, the appropriate dosing and interval for JAKinibs remain to be established, as experience with these small molecule inhibitors in the pediatric age is very limited. Whilst the European Medicine Agency (EMA) has not yet approved ruxolitinib in children [
19], the Food and Drug Administration (FDA) indicates their use for steroid-refractory acute graft-versus-host disease (GVHD) in children older than 12 years of age in 2019 (recommended dose 5 mg every 12 h) [
20]. Of note, 50mg/m
2/day has been indicated to be the maximum well-tolerated dose in children [
21]. Based on serial drug level determination and functional assays, 8-h dose intervals have been recently suggested in a child with STAT3 GOF mutation associated with immune dysregulation (type 1 diabetes mellitus and interstitial lung disease). Interestingly, the dose needed and tolerated in this case report was high (2.2 mg/kg/day), being more than twice the dose compared to previous reports [
8,
22] and those used in our own cohort (see Table
S-1 and
S-2).
In our patients, ruxolitinib was used in 9/10 and barcitinib in 1/10 children, respectively. The attending physicians preferred ruxolitinib, given the larger literary experience in STAT1 GOF setting. We provide detailed dosing information (Table
1 and Table
S-1) for our patients, including the starting and maximum doses. Our starting (0.28 mg/kg/day vs 0.8 mg/kg/day) and maximum (0.6 mg/kg/day vs 1.05 mg/kg/day) doses were lower than previously reported [
3,
8‐
10,
17]. However, the absence of homogenous protocols (and dosing reported diversely as mg/kg/day, mg/day, and/or m
2/day) in the literature limits conclusive comparisons and should be unified in future studies. Dose adjustments in our cohort were performed mainly according to the clinical effect and absence of adverse events and in three cases supported by functional analysis using pSTAT1 stimulation assays (P3, P4, P9).
Collectively, CMC was the most prevalent disease manifestation (
n = 23) and JAKinib treatment was effective in almost all patients (overall response rate 20/22, Fig.
1) within 2–8 weeks of treatment. Contrastingly, Acker et al. recently described a patient with only transient responses to JAKinib, administered for CMC, enteropathy, and cytopenia [
18]. Importantly, in our cohort, the only patient receiving baricitinib did not show clinical improvement resulting in its discontinuation and switch to ruxolitinib.
In the absence of controlled prospective data, we suggest starting pediatric patients on 0.3–0.5 mg/kg/day of ruxolitinib twice per day and then progressively increasing the dose by 0.1–0.2 mg/kg/day every 2–4 weeks until achieving the expected clinical effect or occurrence of relevant side effects keeping in mind the suggested maximum dose of 50 mg/m
2/day by Loh et al. [
21].
For the clinician, the patients, and family, it is important to know how long it takes to achieve a JAKinib treatment response. In our cohort, the cytopenias and CMC responded rather promptly (1–8 weeks), whereas others, such as keratitis and autoimmune hepatitis, required prolonged treatment courses (4–8 months). No improvement or worsening of cerebral aneurysms was observed in two patients. Unfortunately, the information available in the literature regarding treatment responses is often unspecific and incomplete. Where such data were provided, the time to response was similar to what was observed in our cohort requiring several weeks of therapy to achieve improvement (Table S-1).
Despite the combined data presented here, the number of pediatric STAT1 GOF patients treated with JAKinibs is still small. Furthermore, it is likely that the time to response might vary depending on the organ involved, severity and duration of the disease, and JAKinib dosage. Therefore, larger, detailed, and prospective patient cohorts will need to address these aspects more consistently.
Baricitinib, a potent JAK1/JAK2 inhibitor, has shown good tolerability in rheumatologic diseases and other monogenic interferonopathies [
23,
24]. To date, one case report indicated efficacy in an adult patient with STAT1 GOF suffering from recurrent aphthae, as well as oral and esophageal CMC [
25]. Contrastingly, in our cohort, P2 failed to show any improvement after 2 months of treatment with 4mg/day. However, upon, upon switching to ruxolitinib, a fast, complete, and sustained remission of CMC and partial remission of aphthae after 3 months of treatment were observed. Whether baricitinib is inferior or not in the control of the disease manifestations in STAT1 GOF compared to ruxolitinib remains to be determined.
Adverse Events and Monitoring
Overall, the occurrence of adverse events potentially related to JAK inhibition was rare in our cohort. In fact, only one patient experienced an increased frequency of bacterial infections. Contrastingly, the reports in the literature for STAT1 GOF on JAKinib mention higher rates of urinary infections [
27,
28] and other less frequent infectious complications, such as herpes virus reactivation [
28], tuberculosis and/or other atypical mycobacterial infections [
27‐
29],
JC virus (four fatal cases) [
30‐
33],
Pneumocystis jirovecii [
34], hepatitis B [
35,
36], and toxoplasmosis [
37]. This discrepancy might be attributed to an earlier introduction of JAKinibs in our cohort compared to their predominant use as a rescue strategy following the failure of other immunosuppressive regimens in the previously reported cases [
3,
8,
10,
17,
18].
Although no published guidelines exist, we observed a surprisingly consistent approach chosen by the individual participating centers in terms of investigations performed prior to and during JAKinib therapy (Fig. S1, Table S1). These parameters most likely reflect concerns based on the published experience with JAKinibs in other scenarios, such as myelofibrosis, arthritis, and graft-versus-host disease (GVHD), as well as STAT1 GOF cases [
8,
27,
28], FDA and EMA recommendations [
19,
20]. They include screening for infectious complications and monitoring for organ toxicity. In the absence of an easy-to-perform assay to determine ruxolitinib serum levels and the lack of the well-defined correlation between drug levels and clinical response, other biomarkers have been explored to monitor the drug effect/clinical response, such as phosphorylated STAT1 levels (pSTAT1) and IL17 production in T lymphocytes. Whilst some studies suggest a correlation between normalization of these markers [
3,
11,
38], others reported a clear discrepancy [
5]. This might be due to differences in timing of sampling, sample preparation, and assay protocols. In future studies, harmonized treatment and monitoring protocols are needed to consistently evaluate the role of these and other biomarkers in patients with IEI under JAKinib therapy.
In our cohort, drug levels were not performed. All participating centers stated an overall interest to perform JAKinibs level testing but did not have test availability at their institutions.
Importantly, none of the patients described here experienced severe adverse events such as thromboembolism or pulmonary hypertension. Interestingly, one patient (P4), who was started on ruxolitinib despite suffering from pulmonary hypertension, showed a marked improvement allowing the reduction of chronic medication for pulmonary hypertension, as well as the suspension of long-term oxygen supplementation.
Our recommendation prior to starting the JAK inhibition in pediatric patients with STAT1 GOF is to obtain a complete medical history, aiming to identify previous, active, or chronic infections and potential underlying organ damage. We also suggest applying early and extensive diagnostic and therapeutic strategies when suspecting viral, bacterial, and/or fungal infections including blood, urine, stool, aspirate samples, and biopsies from affected tissues/organs, if indicated, to minimize the risk of severe and preventable infectious complications.
In the specific setting of JAK inhibition in (pediatric) STAT1 GOF patients, the role of primary or secondary antimicrobial, antiviral, and antifungal prophylaxis remains to be established. Most authors suggest antimicrobial prophylaxis in patients with recurrent (respiratory) infections [
39]. Systematic prevention of herpes virus infections is more controversial but should be considered in those patients with a history of systemic infection and severe lymphopenia as well as a history of long-term immunosuppression. In our cohort, immunoglobulin replacement therapy and antimicrobial and antiviral prophylaxis were prescribed according to the initial immunological workup and were not part of a specific strategy to prevent infections under JAKinib therapy.