J Rheum Dis.  2024 Jul;31(3):182-187. 10.4078/jrd.2023.0075.

Unraveling the diagnostic odyssey: stimulator of interferon gene-associated vasculopathy with onset in infancy in a 30-year-old female

• Kim HR
• Lim SH
• Park JS
• Suh DI
• Lee S
• Kim SY
• Chae JH
• Kim SH

• KMID: 2557407
• DOI: http://doi.org/10.4078/jrd.2023.0075

Abstract

Stimulator of interferon gene (STING)-associated vasculopathy with onset in infancy (SAVI) is an extremely rare autoinflammatory disease. We present the case of a female Korean patient with early-onset interstitial lung disease who was initially suspected to have systemic lupus erythematosus (SLE) but was ultimately diagnosed with SAVI. The patient exhibited signs of interstitial lung disease and cutaneous manifestations before the age of 1 year and continued to have recurrent fever accompanied by pulmonary infiltrates. Based on positive findings for antibodies associated with SLE, such as antinuclear antibodies and anti-double-stranded DNA, the pulmonary involvement was considered a manifestation of SLE. Another significant symptom was recurrent skin ulceration, which led to partial spontaneous amputation of most of the toes due to inflammation. Given the early onset of interstitial lung disease, severe skin ulcers, and symptoms resembling SLE, autoinflammatory syndrome, especially SAVI was suspected. Following confirmation by genetic testing at age 29 years, the patient was started on tofacitinib, a Janus kinase inhibitor. Despite the prolonged use of multiple immunosuppressive therapies, the patient’s lung condition continued to worsen, ultimately requiring lung transplantation. This observational report highlights the importance of considering SAVI as a potential diagnosis when manifestations of interstitial lung disease are observed during infancy. Early proactive treatment is crucial for lung involvement, as this can have long-term effects on patient’s prognosis.

Keyword

Systemic lupus erythematosus; Interstitial lung disease; Janus kinase inhibitor; Diagnosis

Figure

• 

  Figure 1 Serum levels of anti-dsDNA antibodies of the patient. Anti-dsDNA: anti-double-stranded DNA.

• 

  Figure 2 The phenotypes associated with stimulator of interferon gene-associated vasculopathy with onset in infancy (SAVI). (A) Joint contracture of finger, (B) hand both x-ray, (C) partial amputation of toes, (D) ulcerative lesions of calf, (E,F) chest radiograph and computed tomographic scan taken at 15 years of age, and (G,H) chest radiograph and computed tomographic scan taken at 30 years of age.

• 

  Figure 3 Clinical timeline of the patient. Symptoms, clinical events, results of evaluations, fluctuation of C3 and anti-dsDNA levels, and treatments are listed. SNUCH: Seoul National University Children’s Hospital, FANA: fluorescent antinuclear antibody, NSAIDs: non-steroidal anti-inflammatory drugs, CT: computed tomography, PFT: pulmonary function test, PVC: passive vital capacity, FEV1: forced expiratory volume in one second, ILD: interstitial lung disease, FVC: forced vital capacity, WES: whole exome sequencing, C3: complement 3, anti-dsDNA: anti-double-stranded DNA, MTX: Methotrexate, HCQ: hydroxychloroquine, MMF: Mycophenolate mofetil, AZT: azathioprine, CPM: cyclophosphamide, TCZ: tocilizumab, CsA: cyclosporine A, RTX: rituximab, LFM: leflunomide.

Reference

1. Wang Y, Wang F, Zhang X. 2021; STING-associated vasculopathy with onset in infancy: a familial case series report and literature review. Ann Transl Med. 9:176. DOI: 10.21037/atm-20-6198. PMID: 33569478. PMCID: PMC7867893.

2. Seo J, Kang JA, Suh DI, Park EB, Lee CR, Choi SA, et al. 2017; Tofacitinib relieves symptoms of stimulator of interferon genes (STING)-associated vasculopathy with onset in infancy caused by 2 de novo variants in TMEM173. J Allergy Clin Immunol. 139:1396–9. DOI: 10.1016/j.jaci.2016.10.030. PMID: 28041677.

3. Kim D, Song KB, Choi EJ, Yu J. 2022; A 17-year-old girl diagnosed with STING-associated vasculopathy with onset in infancy (SAVI) after lung transplantation. Chest. 162:e249–52. DOI: 10.1016/j.chest.2022.05.025. PMID: 36344133.

4. David C, Frémond ML. 2022; Lung inflammation in STING-associated vasculopathy with onset in infancy (SAVI). Cells. 11:318. DOI: 10.3390/cells11030318. PMID: 35159128. PMCID: PMC8834229.

5. Liu Y, Jesus AA, Marrero B, Yang D, Ramsey SE, Sanchez GAM, et al. 2014; Activated STING in a vascular and pulmonary syndrome. N Engl J Med. 371:507–18. DOI: 10.1056/NEJMoa1312625. PMID: 25029335. PMCID: PMC4174543.

6. Jeremiah N, Neven B, Gentili M, Callebaut I, Maschalidi S, Stolzenberg MC, et al. 2014; Inherited STING-activating mutation underlies a familial inflammatory syndrome with lupus-like manifestations. J Clin Invest. 124:5516–20. DOI: 10.1172/JCI79100. PMID: 25401470. PMCID: PMC4348945.

7. Patel S, Jin L. 2019; TMEM173 variants and potential importance to human biology and disease. Genes Immun. 20:82–9. DOI: 10.1038/s41435-018-0029-9. PMID: 29728611. PMCID: PMC6212339.

8. Lin B, Berard R, Al Rasheed A, Aladba B, Kranzusch PJ, Henderlight M, et al. 2020; A novel STING1 variant causes a recessive form of STING-associated vasculopathy with onset in infancy (SAVI). J Allergy Clin Immunol. 146:1204–8.e6. DOI: 10.1016/j.jaci.2020.06.032. PMID: 32673614. PMCID: PMC8461559.

9. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. ACMG Laboratory Quality Assurance Committee. 2015; Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 17:405–24. DOI: 10.1038/gim.2015.30. PMID: 25741868. PMCID: PMC4544753.

10. Munoz J, Rodière M, Jeremiah N, Rieux-Laucat F, Oojageer A, Rice GI, et al. 2015; Stimulator of interferon genes-associated vasculopathy with onset in infancy: a mimic of childhood granulomatosis with polyangiitis. JAMA Dermatol. 151:872–7. DOI: 10.1001/jamadermatol.2015.0251. PMID: 25992765.

11. Charras A, Smith E, Hedrich CM. 2021; Systemic lupus erythematosus in children and young people. Curr Rheumatol Rep. 23:20. DOI: 10.1007/s11926-021-00985-0. PMID: 33569643. PMCID: PMC7875946.

12. Alperin JM, Ortiz-Fernández L, Sawalha AH. 2018; Monogenic lupus: a developing paradigm of disease. Front Immunol. 9:2496. DOI: 10.3389/fimmu.2018.02496. PMID: 30459768. PMCID: PMC6232876.