A Novel Treatment of STING‐Associated Vasculopathy With Onset in Infancy

An 11-year-old girl was admitted to the hospital due to progressive exercise intolerance, dry cough, and recurrent fever. These symptoms began 1 year before the patient's admission, and their severity increased after a SARS-CoV-2 infection. She was born at term, and her perinatal period was uncomplicated. During infancy, the child presented with cutaneous lesions and was diagnosed with atopic dermatitis. At 3 years of age, recurrent wheezing led to a diagnosis of childhood asthma, which was well-controlled with inhaled corticosteroids. Her family history included a father with severe asthma and a paternal grandfather with hypersensitivity pneumonitis. On admission, she presented with tachypnea (30 breaths/minute), dyspnea, crackles on auscultation, and finger clubbing. There was no oxygen desaturation at rest. Her weight and height were within the normal range for her age. A chest X-ray revealed disseminated interstitial infiltrates indicative of interstitial lung disease (ILD). Further diagnostic evaluation with a computed tomography scan demonstrated diffuse ground-glass opacities, interlobular septal thickening, and cystic lesions (Figure 1). The echocardiogram and abdominal ultrasound were normal. Laboratory tests revealed a slightly elevated erythrocyte sedimentation rate and a normal C-reactive protein (CRP) level. The immune workup showed positivity for antineutrophil cytoplasmic antibodies, rheumatoid factor, and hyperglobulinemia. All other laboratory test results were within normal limits. Pulmonary function tests demonstrated a restrictive ventilatory pattern with evidence of air trapping. The patient discontinued the 6-min walk test after 4 min due to dizziness and a drop in oxygen saturation to 88%. A lung biopsy showed chronic lymphocytic inflammatory infiltration with lymphoid nodules containing proliferative centers, thickened interlobular septa, and evidence of honeycomb remodeling. The genetic test revealed a heterozygous pathogenic variant in the stimulator of interferon response cGAMP interactor 1 (STING1/TMEM173, variant c.463 G > A, p. Val155Met), confirming a diagnosis of STING-associated vasculopathy with onset in infancy (SAVI). She was started on systemic steroids (prednisone, 1 mg/kg) and a Janus kinase 1/2 (JAK 1/2) inhibitor (ruxolitinib), which began at 0.2 mg/kg/day and gradually increased to 0.8 mg/kg/day over 14 months. The patient achieved a good clinical response, including complete resolution of fever and improved exercise tolerance (Supp. Table 1). The frequency of dry cough episodes decreased. Pulmonary function tests showed minimal improvement (Supp. Figure 2). Besides myalgia, no side effects of treatment were reported. SAVI is a rare type I interferonopathy caused by gain-of-function gene variants in the transmembrane protein known as Stimulator of Interferon Genes (STING), which is vital in regulating immune response to pathogens through the type I interferon (INF-I) pathway. These pathogenic variants lead to chronic inflammation due to continuous activation of STING and overproduction of INF-I [1]. SAVI typically manifests within the first year of life. It presents as cutaneous vasculopathy and ILD, accompanied by impaired growth and systemic inflammatory symptoms. However, phenotype-genotype correlations remain poorly defined due to the limited number of reported cases. Patients with the same genetic variant may manifest with different symptoms. Some children mainly experience joint involvement and are often initially diagnosed with juvenile idiopathic arthritis. Cases without typical SAVI cutaneous or respiratory symptoms but with cardiac and renal involvement have also been reported [2, 3]. Progressive pulmonary fibrosis and end-stage respiratory failure are major contributors to morbidity and mortality. The presented patient carries the c.463 G > A (p. Val155Met) variant, which has been previously associated with diverse clinical manifestations, including ILD, polyarthritis, or renal disease. Severe skin lesions are typically not observed in such cases [2, 3]. At diagnosis, the patient presented with respiratory impairment without skin involvement. However, the skin lesions initially diagnosed as atopic dermatitis in infancy may have been misdiagnosed and could potentially represent a cutaneous manifestation of SAVI. The immunological test results were consistent with previously reported cases [2, 4]. Our patient had elevated inflammatory markers despite the absence of infection, hypergammaglobulinemia, and an elevated RF level. Treating SAVI presents a significant challenge. Recently, promising clinical responses have been observed for JAK inhibitors. Their use was first reported in 2016, with three cases demonstrating rapid resolution of fever, normalization of CRP levels, and significant improvement in cutaneous lesions and pulmonary function [5]. Since then, JAK inhibitors gained prominence as a therapeutic option and have been further evaluated in subsequent patients. Long-term follow-up has revealed more pronounced improvements in lung function in patients with less severe pulmonary disease, underscoring the need for early treatment initiation. A study by Frémond et al. indicated that initiating ruxolitinib therapy in patients with SAVI before they develop end-stage pulmonary fibrosis can notably improve clinical outcomes, particularly in lung function [2]. Furthermore, it was shown that the dosage and serum concentration of ruxolitinib may be of therapeutic significance. Given the rarity of the disease and the small number of patients, additional studies are required to determine the optimal dosage of JAK inhibitors [4]. After 14 months of treatment, our patient experienced resolution of clinical symptoms, minimal improvement in pulmonary function, and stabilization of the disease. The early initiation of treatment, before the progression to end-stage pulmonary fibrosis, may account for the patient's relatively favorable clinical response. SAVI poses a diagnostic and therapeutic challenge due to the considerable diversity of its clinical presentations and limited available therapeutic options. The presented case provides further insight into treatment options, highlighting JAK inhibitors as a promising therapeutic intervention. Katarzyna Solarska-Rydz: conceptualization, data curation, methodology, writing – original draft, writing – review and editing, investigation. Honorata Marczak: conceptualization, data curation, methodology, investigation, writing – review and editing. Marek Kulus: conceptualization, methodology, writing – review and editing. Katarzyna Krenke: conceptualization, investigation, methodology, writing – original draft, writing – review and editing. The authors have nothing to report. The Institutional Review Board of the Medical University of Warsaw approved the study (KB/118/2018), which was performed in accordance with the ethical standards of the Declaration of Helsinki. The Informed Consent of the caregiver was obtained. The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.