Pulmonary arterial hypertension in interferonophaties: a case report and a review of the literature

Abstract

Background Pulmonary arterial hypertension consists in an increase of mean pulmonary arterial pressure (PAPm ≥ 25 mmHg), and may lead to right ventricular failure. Pulmonary arterial hypertension can arise in several disorders, encompassing inflammatory conditions and connective tissue diseases. The occurrence of pulmonary arterial hypertension has recently been reported in monogenic interferonopathies and in systemic lupus erythematosus, highlighting the pathogenic role of type I interferons and paving the way to therapies aimed at inhibiting interferon signaling. Case We describe a 17-year-old boy with DNase II deficiency, presenting a clinical picture with significant overlap with systemic lupus erythematosus. During treatment with the Janus kinase inhibitor ruxolitinib, he developed pulmonary arterial hypertension, raising the question whether it could represent a sign of insufficient disease control or a drug-related adverse event. The disease even worsened after drug withdrawal, but rapidly improved after starting the drug again at higher dosage. Summary and conclusion Pulmonary arterial hypertension can complicate type I interferonopathies. We propose that ruxolitinib was beneficial in this case, but the wider role of Janus kinase inhibitors for the treatment of pulmonary arterial hypertension is not clear. For this reason, a strict cardiologic evaluation must be part of the standard care of subjects with interferonopathies, especially when Janus kinase inhibitors are prescribed.

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

“…However, patient #1 experienced adverse events that led to brief transitory reduction of the drug dosage. After six months of treatment, he developed pulmonary arterial hypertension, with questionable relationship with the treatment, as he improved afterwards by increasing the dose of ruxolitinib together with starting vasodilators [ 10 ]. One year later, he developed shingles at the root of the left thigh, which did not require hospitalization and recovered in two weeks with antiviral treatment.…”

New Applications of JAK/STAT Inhibitors in Pediatrics: Current Use of Ruxolitinib

“…The use of JAK inhibitors, including ruxolitinib, in pediatric settings remained canonically limited to rare therapeutic indications that consisted, essentially, in its anecdotal use in interferonopathies, such as a deficit of DNAse2 or SAVI syndrome, or for relapsed or refractory hemophagocytic lymphocytosis (HLH). In this setting, ruxolitinib was used as a long-life therapy or as bridging to hematopoietic stem cell transplantation (HSCT) with good response (73.5% OR) and acceptable toxicity [ 36 , 37 ]. In the last few years, there has been growing interest in ruxolitinib in the setting of HSCT.…”

The Third Man: DNA sensing as espionage in pulmonary vascular health and disease

“…A second method of nucleic acid sequestration, preventing cytosolic sensing and activation, involves a large family of DNA-targeting enzymes (DNAse) that function in large part to digest double-stranded DNA (dsDNA) prior to propagation of the danger signal. Vital to vascular health, deficiency in one of these proteins, DNAse II -functioning within the phagolysosomal compartment -has recently been linked to development of pulmonary hypertension in a patient with systemic lupus erythematosus (SLE)-like symptoms 50 . Similarly, mutations in TREX1 (or DNAse III) have been strongly linked with autoimmunity and SLE 51 .…”

“…Vital to vascular health, deficiency in one of these proteins, DNAse II—functioning within the phagolysosomal compartment—has recently been linked to development of PH in a patient with SLE-like symptoms. 50 Similarly, mutations in TREX1 (or DNAse III) have been strongly linked with autoimmunity and SLE. 51 Functioning primarily within the cell cytosol, TREX1 loss-of-function mutations result in a rare disease entity, Aicardi-Goutieres syndrome (AGS).…”