Case Report: ISG15 deficiency caused by novel variants in two families and effective treatment with Janus kinase inhibition.

ISG15 deficiency is a rare disease caused by autosomal recessive variants in the ISG15 gene, which encodes the ISG15 protein. The ISG15 protein plays a dual role in both the type I and II interferon (IFN) immune pathways. Extracellularly, the ISG15 protein is essential for IFN-γ-dependent anti-mycobacterial immunity, while intracellularly, ISG15 is necessary for USP18-mediated downregulation of IFN-α/ß signalling. Due to this dual role, ISG15 deficiency can present with various clinical phenotypes, ranging from susceptibility to mycobacterial infection to autoinflammation characterised by necrotising skin lesions, intracerebral calcification, and pulmonary involvement. In this report, we describe novel variants found in two different families that result in complete ISG15 deficiency and severe skin ulceration. Whole exome sequencing identified a heterozygous missense p.Q16X ISG15 variant and a heterozygous multigene 1p36.33 deletion in the proband from the first family. In the second family, a homozygous total ISG15 gene deletion was detected in two siblings. We also conducted further analysis, including characterisation of cytokine dysregulation, interferon-stimulated gene expression, and p-STAT1 activation in lymphocytes and lesional tissue. Finally, we demonstrate the complete and rapid resolution of clinical symptoms associated with ISG15 deficiency in one sibling from the second family following treatment with the Janus kinase (JAK) inhibitor baricitinib.

Evaluating the performance of ACR, SLICC and EULAR/ACR classification criteria in childhood onset systemic lupus erythematosus.

BACKGROUND: The ACR 1997, SLICC 2012 and EULAR/ACR 2019 classification criteria were validated based on adult patients. To date, there are no classification criteria specific for children with SLE. The aim of the study is to compare the performance characteristics among the three SLE classification criteria (ACR-1997, SLICC-2012 and EULAR/ACR-2019) in childhood onset SLE (cSLE) cohort of Arab ethnicity from Oman. METHODS: We conducted a retrospective multicenter study in Oman of cSLE patients as cases and patients with other rheumatic disease with a positive ANA titer as controls. The cSLE cases recruited were children diagnosed with SLE before 13 years of age. Data was retrospectively collected to establish the ACR-1997, SLICC-2012 and EULAR/ACR-2019 criteria fulfilled at first visit, first year follow up and last follow up. RESULTS: Study population included 113 cSLE cases (mean age at diagnosis of 7.3 ± 3.4 years with disease duration of 6.1 ± 4.6 years) and 51 controls (mean age at diagnosis 5.0 ± 3.4 with disease duration 5.7 ± 3.9). The cSLE cases had higher frequency of familial SLE than controls (38% vs 7.8%; p < 0.001). The performance measures demonstrated that EULAR/ACR-2019 criteria had the highest sensitivity (81, 88, 89%) compared to ACR 1997 (49, 57, 66%) and SLICC 2012 (76, 84,86%); while the ACR 1997 had the highest specificity (96%) compared to SLICC 2012 (94%) and EULAR/ACR 2019 (90%) at first visit, first year and last assessment. When we increased the threshold score to ≥13 rather than the traditional score ≥ 10 for ACR/EULAR 2019, there was increased specificity (96%) at the expense of lower sensitivity (76, 83, and 84%) at first visit, first year and last assessment. CONCLUSION: In this cSLE population, EULAR/ACR 2019 scored better at initial presentation, first year and last assessment follow up. Further multinational studies are needed to validate the appropriate cut off score for the newly proposed ACR/EULAR 2019 classification criteria in cSLE to increase early sensitivity and specificity for cSLE classification.