Janus Kinase Inhibitors in the Treatment of Type I Interferonopathies: A Case Series From a Single Center in China

Abstract

Objective: This study aimed to assess the efficacy and safety of 2 Janus kinase (JAK) inhibitors (jakinibs) tofacitinib and ruxolitinib in the treatment of type I interferonopathies patients including STING-associated vasculopathy with onset in infancy (SAVI), Aicardi-Goutières syndrome (AGS), and spondyloenchondrodysplasia with immune dysregulation (SPENCD).

Methods: A total of 6 patients were considered in this study: 2 patients with SAVI, 1 patient with AGS1, 1 patient with AGS7, and 2 patients with SPENCD. Clinical manifestations, laboratory investigations, radiology examinations, treatment, and outcomes were collected between November 2017 and November 2021 in Peking Union Medical College Hospital. The disease score for patients with SAVI and AGS scale for patients with AGS were documented. The expression of 6 interferon-stimulated genes (ISGs) was assessed by real-time PCR.

Results: Three patients (1 patient with SAVI, 2 patients with AGS) were treated with ruxolitinib and 3 patients (1 patient with SAVI, 2 patients with SPENCD) were treated with tofacitinib. The mean duration of the treatment was 2.5 years (1.25-4 years). Upon treatment, cutaneous lesions and febrile attacks subsided in all affected patients. Two patients discontinued the corticoid treatment. Two patients with SAVI showed an improvement in the disease scores (p < 0.05). The erythrocyte sedimentation rate normalized in 2 patients with AGS. The interferon score (IS) was remarkably decreased in 2 patients with SPENCD (p < 0.01). Catch-ups with growth and weight gain were observed in 3 and 2 patients, respectively. Lung lesions improved in 1 patient with SAVI and remained stable in 3 patients. Lymphopenia was found in 3 patients during the treatment without severe infections.

Conclusion: The JAK inhibitors baricitinib and tofacitinib are promising therapeutic agents for patients with SAVI, AGS, and SPENCD, especially for the improvement of cutaneous lesions and febrile attacks. However, further cohort studies are needed to assess the efficacy and safety.

Keywords: Janus kinase inhibitors; autoinflammatory disorders; ruxolitinib; tofacitinib; type I interferonopathies.

Figure 1

Cutaneous manifestations, chest CT, and brain MRI of patients with IFNopathies before and after the treatment with jakinibs. Chilblain-like lesions and ulcerations on the cheek of patient 1 (A1) disappeared after the treatment with ruxolitinib (A4). Chest CT scan of patient 1 demonstrating diffuse cords, patchy consolidation, and ground-glass opacities (A2) before the treatment, which improved after the treatment (A5). Chest CT scan showing no significant improvement of reticular opacities, ground-glass opacities, and cysts in patient 2 before (A3) and after (A6) the treatment with tofacitinib. Erythematous rashes on the left leg of patient 3 (B1) resolved after the treatment with ruxolitinib (B5). Susceptibility weighted imaging showing symmetric hypointense signal in the basal ganglia region in patient 3 (B2), patient 4 (C3), patient 5 (D1), and patient 6 (D3) corresponding to calcification areas in brain CT scan and no improvement observed after the treatment (B6, C7, D5, D7). Diffusion weighted imaging showing hyperintensity in the right head of the caudate nucleus and right anterior limb of the internal capsule (B3) in patient 3. Repeated MRI showing hypointense signal in diffusion weighted imaging (B7) indicating encephalomalacia after the treatment. Brain magnetic resonance angiography indicating stenosis and occlusion of the posterior cerebral artery (B4) in patient 3 and recanalization after the treatment (B8). Erythematous rashes, chilblain-like lesions, ulcerations on the cheeks, and the arm of patient 4 (C1, C2) disappeared after the treatment with ruxolitinib, left with subcutaneous lipoatrophy (C5, C6). T2 FLAIR MRI showing hyperintensity in the bilateral frontal lobe in patient 4 (C4) and no improvement after the treatment with ruxolitinib (C8). Brain magnetic resonance angiography reveling occlusion of the left middle cerebral artery with the formation of peripheral collateral circulation with no changes before (D2) and after the treatment (D6) in patient 5. T2-weighted MRI of patient 6 demonstrating hyperintensity in the left corona radiata (D8) the after treatment with tofacitinib which was not observed before the treatment (D4). Abdominal CT scan showing multiple calcifications in the liver in patient 6 (E). P, patient.

Figure 2

Treatment and prognosis of patients with IFNopathies. (A) The treatment of patients with IFNopathies. Each row represents a patient, and each column represents a drug. A grey box indicates the presence of this treatment. (B) The change of clinical manifestations before and after jakinib treatment. Each row represents a manifestation, and each column represents a patient. The shade of color indicates the severity of the symptoms. The light blue box represents the absence of this symptom. P, patient; R, ruxolitinib; Tof, tofacitinib; Pre, prednisone; Tha, thalidomide; Amb, ambrisentan; L-th, levothyroxine sodium; Tad, tadalafil; The, theophylline; SMZ, sulfamethoxazole; H, hydroxychloroquine; Asp, aspirin; M0, the time before jakinibs treatment; Mmax, the time at the last follow-up visit.

Figure 3

Response to jakinib treatment. Height in standard deviation (SD) (A) showing catch-up growth in 3 patients and further failure to thrive in 1 patient (ns). Weight (B) in SD showing weight gain in 2 patients and further growth failure in 2 patients (ns). Disease score of 2 patients with SAVI improved after the treatment (p < 0.05) (C). AGS scale elevated and stayed stable during the treatment in patient 3 and patient 4 (D). Measures of CRP (E) and ESR (F) showing no improvement after the treatment (ns). Six gene-based IFN score (G) decreased after the treatment (p < 0.01). The dotted line indicates the cutoff value (2.56). HC, healthy control; M0, the time before jakinib treatment; Mmax, the time at the last follow-up visit; P, patient; ^* p < 0.05; ^** p < 0.01; ^**** p < 0.0001; ns, nonsignificant.