A rare manifestation of STING-associated vasculopathy with onset in infancy: a case report.

BACKGROUND: STING-associated vasculopathy with onset in infancy (SAVI) is a rare type I interferonopathy caused by heterozygous variants in the STING gene. In SAVI, STING variants confer a gain-of-function which causes overactivation of type I interferon (IFN) signaling leading to autoinflammation and various degrees of immunodeficiency and autoimmunity. CASE PRESENTATION: We report the case of a 5 year old child and his mother, both of whom presented with systemic inflammatory symptoms yet widely varying organ involvement, disease course and therapeutic response. Genetic testing revealed a heterozygous STING variant, R281Q, in the child and his mother that had previously been associated with SAVI. However, in contrast to previously reported SAVI cases due to the R281Q variant, our patients showed an atypical course of disease with alopecia totalis in the child and a complete lack of lung involvement in the mother. CONCLUSIONS: Our findings demonstrate the phenotypic breadth of clinical SAVI manifestations. Given the therapeutic benefit of treatment with JAK inhibitors, early genetic testing for SAVI should be considered in patients with unclear systemic inflammation involving cutaneous, pulmonary, or musculoskeletal symptoms, and signs of immunodeficiency and autoimmunity.

Incidence, risk factors and outcome of acute kidney injury in critically ill COVID-19 patients in Tyrol, Austria: a prospective multicenter registry study.

INTRODUCTION: Acute kidney injury is a frequent complication in critically ill patients with and without COVID-19. The aim of this study was to evaluate the incidence of, and risk factors for, acute kidney injury and its effect on clinical outcomes of critically ill COVID-19 patients in Tyrol, Austria. METHODS: This multicenter prospective registry study included adult patients with a SARS-CoV-2 infection confirmed by polymerase chain reaction, who were treated in one of the 12 dedicated intensive care units during the COVID-19 pandemic from February 2020 until May 2022. RESULTS: In total, 1042 patients were included during the study period. The median age of the overall cohort was 66 years. Of the included patients, 267 (26%) developed acute kidney injury during their intensive care unit stay. In total, 12.3% (n = 126) required renal replacement therapy with a median duration of 9 (IQR 3-18) days. In patients with acute kidney injury the rate of invasive mechanical ventilation was significantly higher with 85% (n = 227) compared to 41% (n = 312) in the no acute kidney injury group (p < 0.001). The most important risk factors for acute kidney injury were invasive mechanical ventilation (OR = 4.19, p < 0.001), vasopressor use (OR = 3.17, p < 0.001) and chronic kidney disease (OR = 2.30, p < 0.001) in a multivariable logistic regression analysis. Hospital and intensive care unit mortality were significantly higher in patients with acute kidney injury compared to patients without acute kidney injury (Hospital mortality: 52.1% vs. 17.2%, p < 0.001, ICU-mortality: 47.2% vs. 14.7%, p < 0.001). CONCLUSION: As in non-COVID-19 patients, acute kidney injury is clearly associated with increased mortality in critically ill COVID-19 patients. Among known risk factors, invasive mechanical ventilation has been identified as an independent and strong predictor of acute kidney injury.

Treat-to-target strategies for the management of familial Mediterranean Fever in children.

BACKGROUND: The objective of this initiative was to develop a treat-to-target (T2T) approach for the management of patients with Familial Mediterranean Fever (FMF), including the definition of a complex treatment target, and establish strategies that improve patient care and long-term outcome. METHODS: An initial set of statements as well as a flow chart visualising the proposed concept was developed. To adapt the preliminary statements to the current state of knowledge, a systematic literature search was performed and the modified statements were subject to a Delphi approach. To ensure the applicability of the statements in daily practice, an online survey was conducted among paediatric rheumatologists in Germany. In addition, data from the national AID-NET registry were analysed with respect to therapeutic response. RESULTS: This T2T initiative yielded a total of 26 statements guiding FMF management with respect to diagnosis, treatment targets, treatment strategies and monitoring. The online survey identified cut-off values for inflammatory markers indicating treatment intensification and appropriate measures in case of colchicine intolerance or non-adherence. The analysis of data derived from the national AID-NET showed that colchicine therapy was successfully terminated in 61% of patients (27 out of 44) with heterozygous MEFV mutations. Multidimensional treatment targets incorporating objective and subjective reported outcome measures were developed. These provide the basis for stratifying patients into the following treatment paths: continue colchicine, persisting attacks / inflammation, colchicine intolerance, persisting arthritis, colchicine reduction and adjustment/reduction of biologics. CONCLUSIONS: The proposed consensus treatment plan for the management of FMF incorporates multidimensional targets allowing transparent treatment decisions, which will promote personalised disease management and increase adherence to therapy.

Application and performance of disease activity indices proposed for patients with systemic sclerosis in an international cohort of patients with juvenile systemic sclerosis.

Objectives: Juvenile systemic sclerosis is a rare childhood disease. Three disease activity indices have been published for adult patients with systemic sclerosis: the European Scleroderma Study Group Index, a modified version of the European Scleroderma Study Group Index and the revised European Scleroderma Trials and Research index. The objective of this study was to determine the feasibility and performance of the three disease activity indices in a prospectively followed cohort of patients with juvenile systemic sclerosis. Methods: The analysis cohort was selected from the prospective international inception cohort enrolling juvenile systemic sclerosis patients. The correlation of the disease activity indices with the physicians' and the patients' global assessment of disease activity was determined. The disease activity indices were compared between patients with active and inactive disease. Sensitivity to change between 6- and 12-month follow-up was investigated by mixed models. Results: Eighty percent of the 70 patients had a diffuse cutaneous subtype. The revised European Scleroderma Trials and Research index was highly correlated with the physician-reported global disease activity/parents-reported global disease activity (r = 0.74/0.64), followed by the European Scleroderma Study Group activity index (r = 0.61/0.55) and the modified version of the European Scleroderma Study Group activity index (r = 0.51/0.43). The disease activity indices significantly differed between active and inactive patients. The disease activity indices showed sensitivity to change between 6- and 12-month follow-up among patients who improved or worsened according to the physician-reported global disease activity and the parents-reported global disease activity. Conclusion: Overall, no disease activity score is superior to the other, and all three scores have limitations in the application in juvenile systemic sclerosis patients. Furthermore, research on the concept of disease activity and suitable scores to measure disease activity in patients with juvenile systemic sclerosis is necessary in future.

Gender differences in juvenile systemic sclerosis patients: Results from the international juvenile scleroderma inception cohort.

Objective: To compare organ involvement and disease severity between male and female patients with juvenile onset systemic sclerosis. Methods: Demographics, organ involvement, laboratory evaluation, patient-reported outcomes and physician assessment variables were compared between male and female juvenile onset systemic sclerosis patients enrolled in the prospective international juvenile systemic sclerosis cohort at their baseline visit and after 12 months. Results: One hundred and seventy-five juvenile onset systemic sclerosis patients were evaluated, 142 females and 33 males. Race, age of onset, disease duration, and disease subtypes (70% diffuse cutaneous) were similar between males and females. Active digital ulceration, very low body mass index, and tendon friction rubs were significantly more frequent in males. Physician global assessment of disease severity and digital ulcer activity was significantly higher in males. Composite pulmonary involvement was also more frequent in males, though not statistically significantly. After 12 months, they are the pattern of differences changed female patients had significantly more frequent pulmonary involvement. Conclusion: In this cohort, juvenile onset systemic sclerosis had a more severe course in males at baseline and but the pattern changed after 12 months. Some differences from adult findings persisted, there is no increased signal of pulmonary arterial hypertension or heart failure in male pediatric patients. While monitoring protocols of organ involvement in juvenile onset systemic sclerosis need to be identical for males and females.

Phosphomevalonate kinase deficiency expands the genetic spectrum of systemic autoinflammatory diseases.

BACKGROUND: In the isoprenoid biosynthesis pathway, mevalonate is phosphorylated in 2 subsequent enzyme steps by MVK and PMVK to generate mevalonate pyrophosphate that is further metabolized to produce sterol and nonsterol isoprenoids. Biallelic pathogenic variants in MVK result in the autoinflammatory metabolic disorder MVK deficiency. So far, however, no patients with proven PMVK deficiency due to biallelic pathogenic variants in PMVK have been reported. OBJECTIVES: This study reports the first patient with functionally confirmed PMVK deficiency, including the clinical, biochemical, and immunological consequences of a homozygous missense variant in PMVK. METHODS: The investigators performed whole-exome sequencing and functional studies in cells from a patient who, on clinical and immunological evaluation, was suspected of an autoinflammatory disease. RESULTS: The investigators identified a homozygous PMVK p.Val131Ala (NM_006556.4: c.392T>C) missense variant in the index patient. Pathogenicity was supported by genetic algorithms and modeling analysis and confirmed in patient cells that revealed markedly reduced PMVK enzyme activity due to a virtually complete absence of PMVK protein. Clinically, the patient showed various similarities as well as distinct features compared to patients with MVK deficiency and responded well to therapeutic IL-1 inhibition. CONCLUSIONS: This study reported the first patient with proven PMVK deficiency due to a homozygous missense variant in PMVK, leading to an autoinflammatory disease. PMVK deficiency expands the genetic spectrum of systemic autoinflammatory diseases, characterized by recurrent fevers, arthritis, and cytopenia and thus should be included in the differential diagnosis and genetic testing for systemic autoinflammatory diseases.

Testicular Rosai-Dorfman disease clonally related to CMML - Case report and literature review.

BACKGROUND: Rosai-Dorfman disease (RDD), a rare form of non-Langerhans cell histiocytosis with heterogenous clinical features, arises from precursor cells that give rise to cells of the histiocytic and monocytic lineages. An association with hematological neoplasms has been reported. Testicular RDD is rarely described, with only 9 reported cases in the literature. Genetic data to assess clonal relationships between RDD and other hematological neoplasms remain scarce. We describe an instance of testicular RDD against a background of chronic myelomonocytic leukemia (CMML), with genetic studies in both neoplasms. CASE PRESENTATION: A 72-year-old patient with a history of CMML sought evaluation of growing bilateral testicular nodules. Solitary testicular lymphoma was suspected; orchidectomy was performed. The diagnosis of testicular RDD was established morphologically and confirmed immunohistochemically. Molecular analysis of testicular lesions and of archived patient bone marrow revealed the KRAS variant c 0.35 G>A / p.G12D in both, suggesting a clonal relationship. CONCLUSION: These observations support classifying RDD as a neoplasm that can be clonally related to myeloid neoplasms.

Juvenile idiopathic arthritis patients with positive family history of autoimmune thyroid disease might benefit from serological screening: analysis of the international Pharmachild registry.

BACKGROUND: Little is known about the association between juvenile idiopathic arthritis (JIA) and autoimmune thyroid disease (AITD) and therefore there are no indications for AITD screening in this population, which is possible using standard blood tests. The objective of this study is to determine the prevalence and predictors of symptomatic AITD in JIA patients from the international Pharmachild registry. METHODS: Occurrence of AITD was determined from adverse event forms and comorbidity reports. Associated factors and independent predictors for AITD were determined using univariable and multivariable logistic regression analyses. RESULTS: The prevalence of AITD after a median observation period of 5.5 years was 1.1% (96/8965 patients). Patients who developed AITD were more often female (83.3% vs. 68.0%), RF positive (10.0% vs. 4.3%) and ANA positive (55.7% vs. 41.5%) than patients who did not. AITD patients were furthermore older at JIA onset (median 7.8 years vs. 5.3 years) and had more often polyarthritis (40.6% vs. 30.4%) and a family history of AITD (27.5% vs. 4.8%) compared to non-AITD patients. A family history of AITD (OR = 6.8, 95% CI: 4.1 - 11.1), female sex (OR = 2.2, 95% CI: 1.3 - 4.3), ANA positivity (OR = 2.0, 95% CI: 1.3 - 3.2) and older age at JIA onset (OR = 1.1, 95% CI: 1.1 - 1.2) were independent predictors of AITD on multivariable analysis. Based on our data, 16 female ANA positive JIA patients with a family history of AITD would have to be screened during ±5.5 years using standard blood tests to detect one case of AITD. CONCLUSIONS: This is the first study to report independent predictor variables for symptomatic AITD in JIA. Female ANA positive JIA patients with positive family history are at increased risk of developing AITD and thus might benefit from yearly serological screening.

Common variable immunodeficiency with granulomatous-lymphocytic interstitial lung disease treated with monoclonal antibodies against COVID-19: A case report.

Common variable immunodeficiency (CVID) is the most prevalent primary immunodeficiency. We present a 22-year-old Caucasian woman with CVID and granulomatous lymphocytic interstitial lung disease who contracted COVID-19 and was successfully treated with sotrovimab and molnupiravir. This treatment may have contributed to the relatively mild disease course of COVID-19 in our patient.

Working Towards a Treat-to-Target Protocol in Juvenile Proliferative Lupus Nephritis - A Survey of Pediatric Rheumatologists and Nephrologists in Germany and Austria.

Background: To describe treatment practices for juvenile proliferative lupus nephritis (LN) class III and IV of pediatric rheumatologists and nephrologists in Germany and Austria in preparation for a treat-to-target treatment protocol in LN. Methods: Survey study by members of the Society for Pediatric and Adolescent Rheumatology (GKJR) and the German Society for Pediatric Nephrology (GPN) on diagnostics and (concomitant) therapy of LN. Results: Fifty-eight physicians completed the survey. Overall, there was a considerable heterogeneity regarding the suggested diagnostics and management of juvenile proliferative LN. Increased urinary protein excretion, either assessed by 24 h urine collection or spot urine (protein-creatinine ratio), and reduced estimated glomerular filtration rate were specified as important parameters for indication of kidney biopsy to diagnose proliferative LN and monitoring of therapy. Corticosteroids were generally proposed for induction and maintenance therapy, most often in conjunction with either mycophenolate mofetil (MMF) or cyclophosphamide (CP) as steroid-sparing immunosuppressants. MMF was clearly preferred over CP for induction therapy of LN class III, whereas CP and MMF were equally proposed for LN class IV. MMF was most often recommended for maintenance therapy in conjunction with oral corticosteroids and continued for at least 3 years and 1 year, respectively, after remission. Hydroxychloroquine was widely accepted as a concomitant measure followed by renin-angiotensin system inhibitors in cases of arterial hypertension and/or proteinuria. Conclusion: The majority of pediatric rheumatologists and nephrologists in Germany and Austria propose the use of corticosteroids, most often in combination with either MMF or CP, for treatment of proliferative LN in children. The considerable heterogeneity of responses supports the need for a treat-to-target protocol for juvenile proliferative LN between pediatric rheumatologists and nephrologists.