A pediatric cystic fibrosis arthropathy case who responded to Elexacaftor/Tezacaftor/Ivacaftor therapy.

Cystic fibrosis arthropathy (CFA) is a transient, intermittent form of arthritis that cannot be associated with any other disease other than CF thus making CFA a diagnosis of exclusion. NSAIDs, short-term intermittent splinting, glucocorticoids, and disease-modifying anti-rheumatic drugs are treatment options for CFA. Currently, there is no consensus on how to best treat CFA. Diagnosis and treatment of CFA remain a challenge for physicians and people with CF. The newest CFTR modulator therapy, elexacaftor/tezacaftor/ivacaftor (ETI), was approved by the FDA recently for children over the age of 6 with at least one Phe508del allele in the CFTR gene. Multiple clinical benefits of ETI in pulmonary functions and overall disease burden have been reported since its approval, however, the data on the musculoskeletal therapeutic benefits of ETI has been limited. In this report, we present a 7-year-old female with CF whose CFA symptoms resolved after starting ETI therapy.

Implementation of genomic medicine for rare disease in a tertiary healthcare system: Mayo Clinic Program for Rare and Undiagnosed Diseases (PRaUD).

BACKGROUND: In the United States, rare disease (RD) is defined as a condition that affects fewer than 200,000 individuals. Collectively, RD affects an estimated 30 million Americans. A significant portion of RD has an underlying genetic cause; however, this may go undiagnosed. To better serve these patients, the Mayo Clinic Program for Rare and Undiagnosed Diseases (PRaUD) was created under the auspices of the Center for Individualized Medicine (CIM) aiming to integrate genomics into subspecialty practice including targeted genetic testing, research, and education. METHODS: Patients were identified by subspecialty healthcare providers from 11 clinical divisions/departments. Targeted multi-gene panels or custom exome/genome-based panels were utilized. To support the goals of PRaUD, a new clinical service model, the Genetic Testing and Counseling (GTAC) unit, was established to improve access and increase efficiency for genetic test facilitation. The GTAC unit includes genetic counselors, genetic counseling assistants, genetic nurses, and a medical geneticist. Patients receive abbreviated point-of-care genetic counseling and testing through a partnership with subspecialty providers. RESULTS: Implementation of PRaUD began in 2018 and GTAC unit launched in 2020 to support program expansion. Currently, 29 RD clinical indications are included in 11 specialty divisions/departments with over 142 referring providers. To date, 1152 patients have been evaluated with an overall solved or likely solved rate of 17.5% and as high as 66.7% depending on the phenotype. Noteworthy, 42.7% of the solved or likely solved patients underwent changes in medical management and outcome based on genetic test results. CONCLUSION: Implementation of PRaUD and GTAC have enabled subspecialty practices advance expertise in RD where genetic counselors have not historically been embedded in practice. Democratizing access to genetic testing and counseling can broaden the reach of patients with RD and increase the diagnostic yield of such indications leading to better medical management as well as expanding research opportunities.

Postdischarge Glucocorticoid Use and Clinical Outcomes of Multisystem Inflammatory Syndrome in Children.

Importance: Minimal data are available regarding the postdischarge treatment of multisystem inflammatory syndrome in children (MIS-C). Objectives: To evaluate clinical characteristics associated with duration of postdischarge glucocorticoid use and assess postdischarge clinical course, laboratory test result trajectories, and adverse events in a multicenter cohort with MIS-C. Design, Setting, and Participants: This retrospective cohort study included patients with MIS-C hospitalized with severe illness and followed up for 3 months in an ambulatory setting. Patients younger than 21 years who were admitted between May 15, 2020, and May 31, 2021, at 13 US hospitals were included. Inclusion criteria were inpatient treatment comprising intravenous immunoglobulin, diagnosis of cardiovascular dysfunction (vasopressor requirement or left ventricular ejection fraction ≤55%), and availability of complete outpatient data for 3 months. Exposures: Glucocorticoid treatment. Main Outcomes and Measures: Main outcomes were patient characteristics associated with postdischarge glucocorticoid treatment, laboratory test result trajectories, and adverse events. Multivariable regression was used to evaluate factors associated with postdischarge weight gain (≥2 kg in 3 months) and hyperglycemia during illness. Results: Among 186 patients, the median age was 10.4 years (IQR, 6.7-14.2 years); most were male (107 [57.5%]), Black non-Hispanic (60 [32.3%]), and Hispanic or Latino (59 [31.7%]). Most children were critically ill (intensive care unit admission, 163 [87.6%]; vasopressor receipt, 134 [72.0%]) and received inpatient glucocorticoid treatment (178 [95.7%]). Most were discharged with continued glucocorticoid treatment (173 [93.0%]); median discharge dose was 42 mg/d (IQR, 30-60 mg/d) or 1.1 mg/kg/d (IQR, 0.7-1.7 mg/kg/d). Inpatient severity of illness was not associated with duration of postdischarge glucocorticoid treatment. Outpatient treatment duration varied (median, 23 days; IQR, 15-32 days). Time to normalization of C-reactive protein and ferritin levels was similar for glucocorticoid duration of less than 3 weeks vs 3 or more weeks. Readmission occurred in 7 patients (3.8%); none was for cardiovascular dysfunction. Hyperglycemia developed in 14 patients (8.1%). Seventy-five patients (43%) gained 2 kg or more after discharge (median 4.1 kg; IQR, 3.0-6.0 kg). Inpatient high-dose intravenous and oral glucocorticoid therapy was associated with postdischarge weight gain (adjusted odds ratio, 6.91; 95% CI, 1.92-24.91). Conclusions and Relevance: In this multicenter cohort of patients with MIS-C and cardiovascular dysfunction, postdischarge glucocorticoid treatment was often prolonged, but clinical outcomes were similar in patients prescribed shorter courses. Outpatient weight gain was common. Readmission was infrequent, with none for cardiovascular dysfunction. These findings suggest that strategies are needed to optimize postdischarge glucocorticoid courses for patients with MIS-C.

Pediatric rheumatologists' perspectives on diagnosis, treatment, and outcomes of Sjögren disease in children and adolescents.

BACKGROUND: Sjögren disease in children and adolescents (pedSD) presents differently than adult disease. Diagnosis and classification are controversial, optimal treatment is unknown and outcomes are poorly understood. Here, we describe the current perspectives of pediatric rheumatologists on diagnosis, treatment, and outcomes of pedSD. METHODS: A voluntary, 17-question survey was distributed to providers in the Childhood Arthritis and Rheumatology Research Alliance and/or the American College of Rheumatology Childhood Sjögren's Study Group at the 2020 Convergence Virtual Conference. Findings are reported using descriptive statistics and chi-square testing. RESULTS: Of 465 eligible providers, 157 (34%) responded with 135 (29%) completing the survey. The majority (85%) saw five or fewer patients with pedSD in the past year. Parotitis, dry eye and/or dry mouth, and constitutional symptoms were among the most specific and common clinical features. Most providers (77%) used clinical judgment guided by adult criteria for diagnosis. The vast majority (86-99%) of survey participants indicated routine use of serologic testing, while salivary gland ultrasound, minor salivary gland biopsy and other diagnostic tests were less often used. The most commonly prescribed systemic immunomodulators were hydroxychloroquine, corticosteroids, methotrexate, rituximab, and mycophenolate. Seven providers reported malignancy in a patient with pedSD, including one death. CONCLUSIONS: Pediatric rheumatologists diagnose and treat pedSD; however, most only see a few patients per year and rely on clinical judgment and laboratory testing for diagnosis. Treatment frequently includes systemic immunomodulators and malignancies are reported. More studies are needed to better understand natural history, risk factors, and the impact of interventions on outcomes.

SOCS1 Haploinsufficiency Presenting as Severe Enthesitis, Bone Marrow Hypocellularity, and Refractory Thrombocytopenia in a Pediatric Patient with Subsequent Response to JAK Inhibition.

Haploinsufficiency of suppressor of cytokine signaling 1 (SOCS1) is a recently discovered autoinflammatory disorder with significant rheumatologic, immunologic, and hematologic manifestations. Here we report a case of SOCS1 haploinsufficiency in a 5-year-old child with profound arthralgias and immune-mediated thrombocytopenia unmasked by SARS-CoV-2 infection. Her clinical manifestations were accompanied by excessive B cell activity, eosinophilia, and elevated IgE levels. Uniquely, this is the first report of SOCS1 haploinsufficiency in the setting of a chromosomal deletion resulting in complete loss of a single SOCS1 gene with additional clinical findings of bone marrow hypocellularity and radiologic evidence of severe enthesitis. Immunologic profiling showed a prominent interferon signature in the patient's peripheral blood mononuclear cells, which were also hypersensitive to stimulation by type I and type II interferons. The patient showed excellent clinical and functional laboratory response to tofacitinib, a Janus kinase inhibitor that disrupts interferon signaling. Our case highlights the need to utilize a multidisciplinary diagnostic approach and consider a comprehensive genetic evaluation for inborn errors of immunity in patients with an atypical immune-mediated thrombocytopenia phenotype.

Simultaneous presentation of idiopathic uveitis in monozygotic 4-year-old twin boys.

Purpose: To report monozygotic twin 4-year-old boys with chronic bilateral anterior uveitis with simultaneous onset. Observations: Here we report monozygotic twin 4-year-old boys with chronic bilateral anterior uveitis. The boys had simultaneous onset of uveitis and identical features. Evaluation, including whole exome sequencing (WES), failed to reveal a specific causative etiology. Each patient responded well to immune modulation and achieved uveitis remission on methotrexate monotherapy off topical glucocorticoids. Conclusions and Importance: From this case of monozygotic twin boys presenting with chronic uveitis, we conclude that monozygotic twins may warrant evaluation in the setting of idiopathic uveitis, especially in young patients unable to express an adequate history.

Epidemiology of Childhood-Onset Systemic Lupus Erythematosus: A Population-Based Study.

OBJECTIVE: To characterize the incidence and prevalence of childhood-onset systemic lupus erythematosus (SLE), and to estimate the proportion of patients who are diagnosed with SLE during childhood. METHODS: A cohort of patients with incident childhood-onset SLE from 1976 to 2018 from an 8-county region in the US were identified based on comprehensive medical record review. All patients met the European Alliance of Associations for Rheumatology (EULAR)/American College of Rheumatology (ACR) classification criteria for SLE or the ACR SLE classification criteria from 1997 at or before age 18 years. Incidence rates were estimated using Poisson methods. We estimated the childhood-onset SLE point prevalence for January 1, 2015. Results were sex and age adjusted to the US 2000 population. Among all the SLE patients living in the 8-county region on January 1, 2015, the proportion of patients diagnosed at ≤18 years was estimated. RESULTS: A total of 13 children were diagnosed with childhood-onset SLE during the study period (using the EULAR/ACR definition; mean age at diagnosis 15.1 years, 85% female, 69% White). Childhood-onset SLE overall adjusted incidence rate was 0.7 (95% confidence interval [95% CI] 0.2-1.1) per 100,000 children. The incidence rate in girls was 1.2 (95% CI 0.5-1.9) per 100,000 children, while in boys it was 0.2 (95% CI 0.0-0.5) per 100,000. The adjusted prevalence of childhood-onset SLE was 1.1 (95% CI 0.0-3.1) per 100,000 children. The proportion of patients with SLE diagnosed as children was 9% (95% CI 6-13%). CONCLUSION: In this population-based study, both the incidence and prevalence rates of childhood-onset SLE were ~1 per 100,000 children. One in 10 adults with SLE was diagnosed in childhood. More studies are needed to further characterize the epidemiology of childhood-onset SLE in minorities.

Childhood Sjögren syndrome: features of an international cohort and application of the 2016 ACR/EULAR classification criteria.

OBJECTIVE: Sjögren syndrome in children is a poorly understood autoimmune disease. We aimed to describe the clinical and diagnostic features of children diagnosed with Sjögren syndrome and explore how the 2016 ACR/EULAR classification criteria apply to this population. METHODS: An international workgroup retrospectively collected cases of Sjögren syndrome diagnosed under 18 years of age from 23 centres across eight nations. We analysed patterns of symptoms, diagnostic workup, and applied the 2016 ACR/EULAR classification criteria. RESULTS: We identified 300 children with Sjögren syndrome. The majority of patients n = 232 (77%) did not meet 2016 ACR/EULAR classification criteria, but n = 110 (37%) did not have sufficient testing done to even possibly achieve the score necessary to meet criteria. Even among those children with all criteria items tested, only 36% met criteria. The most common non-sicca symptoms were arthralgia [n = 161 (54%)] and parotitis [n = 140 (47%)] with parotitis inversely correlating with age. CONCLUSION: Sjögren syndrome in children can present at any age. Recurrent or persistent parotitis and arthralgias are common symptoms that should prompt clinicians to consider the possibility of Sjögren syndrome. The majority of children diagnosed with Sjögren syndromes did not meet 2016 ACR/EULAR classification criteria. Comprehensive diagnostic testing from the 2016 ACR/EULAR criteria are not universally performed. This may lead to under-recognition and emphasizes a need for further research including creation of paediatric-specific classification criteria.

Bacterial infections in a pediatric cohort of primary and acquired complement deficiencies.

BACKGROUND: Acquired complement deficiency can occur in the setting of autoimmune syndromes, such as systemic lupus erythematosus (SLE), with very low or, occasionally, undetectable C3 levels. Based on inherited complement defects, patients with transiently low complement may be at similar risk for serious bacterial infection, but the degree of risk related to C3 level and temporal association is unknown. METHODS: We performed a retrospective study including pediatric patients with undetectable total complement activity or absent individual complement components measured at our institution from 2002 to 2018. We assessed annual rate of serious bacterial infection (SBI) defined as requiring hospitalization and/or parenteral antibiotics by manual chart review. Among included SLE patients, we assessed the 30-day probability of SBI for given C3 measurements using a logistic regression model to determine risk. Primary complement deficiency was analyzed for SBI rate as comparison. Covariates included age, level of immune suppression and history of lupus nephritis. RESULTS: Acquired complement deficiency secondary to SLE-related disease [n = 44] was the most common underlying diagnosis associated with depressed complement levels and were compared to a cohort of primary complement deficient patients [n = 18]. SBI per 100 person-years and cohort demographics were described in parallel. Our logistic regression analysis of pediatric patients with SLE showed low C3 level was temporally associated with having an SBI event. Given equivalent immunosuppression, patients with an SBI had lower C3 levels at the beginning of the observation period relative to patients without SBI. CONCLUSION: Pediatric patients with the diagnosis of SLE can develop very low C3 levels that associate with risk of serious bacterial infection comparable to that of patients with primary complement deficiency. Patients prone to severe complement consumption may particularly be at risk.

Pediatric chronic nonbacterial osteomyelitis of the mandible: Seattle Children's hospital 22-patient experience.

BACKGROUND: Studies evaluating treatment responses for chronic nonbacterial osteomyelitis (CNO) are lacking. We aimed to measure and compare response rates of medical treatments, time to response of medical treatments among patients with CNO of the mandible, and describe bacterial contamination rates from biopsy. METHODS: We conducted a retrospective chart review of all patients diagnosed with CNO of mandible between 2003 and 2017 and extracted demographic, clinical, laboratory, imaging and surgical data. Detailed medication use and response to medications were recorded. The primary outcome was response to medical treatments defined as improvement of presenting symptoms, inflammatory markers, and imaging if available. Medical treatments included nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, disease modifying anti rheumatic drugs (DMARDs), anti-tumor necrosis factor (TNF) therapy, and pamidronate. Descriptive analysis was performed when appropriate. Multivariable logistic regression and Kaplan-Meier curves were applied to compare the responses to medical treatments and time to full response. RESULTS: We identified 22 patients with a median age of 11 and 36% were female. Four patients (18%) had multifocal bone lesions. CT findings (n = 21) showed lytic lesions (62%) and sclerosis (90%). MRI (n = 14) revealed hyperintensity within bone marrow (100%), soft tissue (71%) and bony expansion (71%). Non-antibiotic treatments including NSAIDs (n = 18), glucocorticoids (n = 10), DMARDs (n = 9), anti-TNF therapy (n = 5) and pamidronate (n = 6) were applied. Rates of full responses to anti-TNF therapy (60%) and pamidronate (67%) were higher than that to NSAIDs (11%) (p < 0.05). Patients receiving pamidronate responded more rapidly than those receiving anti-TNF therapy (median two vs 17 months, p = 0.01) when there was a full response. All had bone biopsies. Intraoral biopsy was performed in 12 of 13 operated in our center and the most common contaminants were Neisseria spp and Streptococcus viridians. CONCLUSION: Both anti-TNF and pamidronate appeared superior to NSAIDs alone in treating mandibular CNO. Patients receiving pamidronate responded faster than those receiving anti-TNF therapy.

Incidence of Pneumocystis jirovecii and Adverse Events Associated With Pneumocystis Prophylaxis in Children Receiving Glucocorticoids.

BACKGROUND: Antimicrobial prophylaxis is indicated to prevent Pneumocystis jirovecii pneumonia (PJP) in profoundly immunosuppressed children. The incidence of PJP infection in children with chronic glucocorticoid exposure is unknown, and PJP prophylaxis has been associated with adverse events. We hypothesized that PJP infection is rare in children without human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), cancer, or a transplant history who are using chronic glucocorticoids and that those exposed to PJP prophylaxis are more likely to experience a cutaneous hypersensitivity reaction or myelosuppression than unexposed patients. METHODS: This study involved a retrospective cohort from the Clinformatics Data Mart Database (OptumInsight, Eden Prairie, MN). We identified patients ≤18 years of age who received at least 2 prescriptions for a systemic glucocorticoid within a 60-day period and excluded patients with a history of PJP infection, an oncologic diagnosis, transplant, or HIV/AIDS. PJP prophylaxis exposure was identified by using national drug codes. Cutaneous hypersensitivity reaction or myelosuppression was identified by using International Classification of Diseases, 9th Revision (ICD-9), codes. We used a discrete time-failure model to examine the association between exposure and outcome. RESULTS: We identified 119399 children on glucocorticoids, 10% of whom received PJP prophylaxis. The incidences of PJP were 0.61 and 0.53 per 10000 patient-years in children exposed and those unexposed to PJP prophylaxis, respectively. In a multivariable model, trimethoprim-sulfamethoxazole was associated with cutaneous hypersensitivity reaction (odds ratio, 3.20; 95% confidence interval, 2.62-3.92) and myelosuppression (odds ratio, 1.85; 95% confidence interval, 1.56-2.20). CONCLUSIONS: PJP infection was rare in children using glucocorticoids chronically, and PJP prophylaxis-associated cutaneous hypersensitivity reactions and myelosuppression are more common. The use of PJP chemoprophylaxis in children without HIV/AIDS, cancer, or a transplant history who are taking glucocorticoids chronically should be considered carefully.

Consensus Treatment Plans for Chronic Nonbacterial Osteomyelitis Refractory to Nonsteroidal Antiinflammatory Drugs and/or With Active Spinal Lesions.

OBJECTIVE: To develop standardized treatment regimens for chronic nonbacterial osteomyelitis (CNO), also known as chronic recurrent multifocal osteomyelitis (CRMO), to enable comparative effectiveness treatment studies. METHODS: Virtual and face-to-face discussions and meetings were held within the CNO/CRMO subgroup of the Childhood Arthritis and Rheumatology Research Alliance (CARRA). A literature search was conducted, and CARRA membership was surveyed to evaluate available treatment data and identify current treatment practices. Nominal group technique was used to achieve consensus on treatment plans for CNO refractory to nonsteroidal antiinflammatory drug (NSAID) monotherapy and/or with active spinal lesions. RESULTS: Three consensus treatment plans (CTPs) were developed for the first 12 months of therapy for CNO patients refractory to NSAID monotherapy and/or with active spinal lesions. The 3 CTPs are methotrexate or sulfasalazine, tumor necrosis factor inhibitors with optional methotrexate, and bisphosphonates. Short courses of glucocorticoids and continuation of NSAIDs are permitted for all regimens. Consensus was achieved on these CTPs among CARRA members. Consensus was also reached on subject eligibility criteria, initial evaluations that should be conducted prior to the initiation of CTPs, and data items to collect to assess treatment response. CONCLUSION: Three consensus treatment plans were developed for pediatric patients with CNO refractory to NSAIDs and/or with active spinal lesions. Use of these CTPs will provide additional information on efficacy and will generate meaningful data for comparative effectiveness research in CNO.

Variation in Preventive Care in Children Receiving Chronic Glucocorticoid Therapy.

OBJECTIVE: To assess preventive care measure prescribing in children exposed to glucocorticoids and identify prescribing variation according to subspecialty and patient characteristics. STUDY DESIGN: Retrospective cohort study of children initiating chronic glucocorticoids in the gastroenterology, nephrology, and rheumatology divisions at a pediatric tertiary care center. Outcomes included 25-hydroxyvitamin D (25OHD) and lipid testing, pneumococcal polysaccharide (PPV) and influenza vaccination, and stress dose hydrocortisone prescriptions. RESULTS: A total of 701 children were followed for a median of 589 days. 25OHD testing was performed in 73%, lipid screening in 29%, and PPV and influenza vaccination in 16% and 78%, respectively. Hydrocortisone was prescribed in 2%. Across specialties, 25OHD, lipid screening, and PPV prescribing varied significantly (all P < .001). Using logistic regression adjusting for specialty, 25OHD testing was associated with older age, female sex, non-Hispanic ethnicity, and lower baseline height and body mass index z-scores (all P < .03). Lipid screening was associated with older age, higher baseline body mass index z-score, and lower baseline height z-score (all P < .01). Vaccinations were associated with lower age (P < .02), and PPV completion was associated with non-White race (P = .04). CONCLUSIONS: Among children chronically exposed to glucocorticoids, 25OHD testing and influenza vaccination were common, but lipid screening, pneumococcal vaccination, and stress dose hydrocortisone prescribing were infrequent. Except for influenza vaccination, preventive care measure use varied significantly across specialties. Quality improvement efforts are needed to optimize preventive care in this high-risk population.

BIRC4 Mutation: An Important Rare Cause of Uveitis.

We report a 6-year-old man with chronic severe recalcitrant bilateral anterior uveitis and a remote history of hemophagocytic lymphocytic histiocytosis secondary to Epstein-Barr virus infection. The patient was treated for idiopathic uveitis after an initial extensive evaluation failed to reveal a specific diagnosis. The patient failed to achieve sustained inactive disease with multiple monotherapies including topical glucocorticoid, methotrexate, infliximab, mycophenolate mofeti, and cyclosporine. Disease control was finally attained with a combination of cyclosporine and adalimumab. After more recent testing, he was found to have a novel deletion on the BIRC4 (baclovirus inhibitor of apoptosis repeat containing protein 4) gene, the causative gene for X-linked lymphoproliferative syndrome type 2. We conclude that male patients with chronic idiopathic uveitis should be questioned about a history of hemophagocytic lymphocytic histiocytosis during their workup and screened for BIRC4 mutation if appropriate.