Case report: JAK inhibitor treatment of immune dysregulation symptoms in a patient with PTPN2 deficiency

Abstract

A heterozygous mutation in the PTPN2 gene has recently been described in several patients exhibiting symptoms of immune dysregulation. The gene encodes a ubiquitous non-receptor T-cell protein tyrosine phosphatase that exerts a negative feedback on the JAK-STAT pathway. Limited clinical data are available advocating the use of JAK inhibitors as an effective treatment for autoimmune complications of PTPN2 deficiency. However, the mechanism of pathogenesis for these complications suggests this possibility. We report on a 32-year-old male patient with interstitial lung disease, cytopenia, and lymphadenopathy accompanied by de-novo deletion in PTPN2. The patient has been receiving systemic steroid treatment for decades, which has resulted in hormone dependence as well as therapy-related adverse side effects. After the diagnosis of PTPN2 deficiency, treatment with the JAK inhibitor ruxolitinib was initiated at a dose of 15 mg per day, which was escalated to 30 mg daily after 1 month. The steroid treatment was discontinued within 3 months. At the 9- and 16-month checkpoint, after 6 and 13 months correspondingly of monotherapy with ruxolitinib at a dosage of 30 mg per day, the patient had stable blood counts, lymphadenopathy decreased, and the lung interstitial disease improved. Thus, according to our experience, JAK inhibitors are able to alleviate the PTPN2 deficiency symptoms, including hematological changes and interstitial lung damage.

Keywords: JAK-inhibitor; PTPN2; case report; immune dysregulation; inborn errors of immunity.

Figure 1

(A) CT scan before the thoracoscopic lung biopsy and steroid initiation, showing massive bilateral areas of airless lung tissue, more prominent in the lower lobes, located in both central and peripheral areas. (B) CT scan after 2 weeks of treatment with high doses of steroids.

Figure 2

Assessment of phosphorylation of intracellular protein STAT1 after stimulation by IFNγ in monocytes of the patient and healthy donor. The histogram displays the analysis of the STAT1 protein phosphorylation, with the stimulation time in minutes (15, 60, and 120 min) on the left and the mean fluorescence intensity on the right. The non-stimulated sample is noted as NON STIM, the red color shows the phosphorylation points of the patient before the therapy (A1), the blue color shows after 1 year of the JAK inhibitor therapy course (A2), and the gray color shows a control sample from a conditionally healthy person (B). To determine the kinetics of phosphorylation, we compared the fluorescence intensity of the samples stimulated during different time intervals with an unstimulated sample. The in-house references showed the enhanced phosphorylation of the STAT1 protein in the patient before therapy with a maximum value of 60 min. After the course of therapy, the result complied with the reference values and was comparable with the protein phosphorylation in a conditionally healthy person.

Figure 3

CT scans: (A) at the beginning of ruxolitinib treatment (started from the dose of 15 mg/day then escalated to 30 mg/day) and steroid tapering (from the dose of 12 mg/day of methylprednisolone to complete withdrawal); (B) after 3 months of ruxolitinib treatment and straight after complete steroid discontinuation; (C, D) 9 and 16 months since ruxolitinib initiation (which is 6 and 13 months of monotherapy with ruxolitinib correspondingly, 30 mg per day). (A, B) Reduced pneumatization of the lung tissue in the basal sections, with no dynamics in the areas of hypostatic changes between (C, D) improved pneumatization in the basal sections, with less prominent reticular changes. Shown below are the lung function tests in time correlation with CT scan performance. FVC, forced vital capacity; FEV1, forced expiratory volume in 1 s; VC, vital capacity; PEF, peak expiratory flow.