Secukinumab for children and adolescents with enthesitis-related arthritis and psoriatic arthritis: lessons from treatment in adults and the way forward.

INTRODUCTION: Targeting IL-17A using Secukinumab, a humanized monoclonal immunoglobulin G1 (IgG1)/κ against IL-17A is a therapeutic option for immune-mediated disorders such as psoriasis and ankylosing spondylitis. The US Food and Drug Administration and the European Medicines Agency have approved it for the treatment of moderate to severe plaque psoriasis, active psoriatic arthritis, ankylosing spondylitis, and non-radiographic axial spondylarthritis. Recently it has also been approved for use in children with severe plaque psoriasis, active psoriatic arthritis, and enthesitis-related arthritis. AREAS COVERED: This review focuses on the role of Secukinumab in the management of children and adolescents with enthesitis-related arthritis and psoriatic arthritis. We discuss the salient findings of pivotal RCTs and other studies supporting the use of Secukinumab in adults and children, in particular, focusing on its safety and efficacy. EXPERT OPINION: Secukinumab is a therapeutic target for psoriasis, psoriatic arthritis, and spondyloarthropathies in both adults and children. No major safety signals are observed with its use in short-term follow-up. Thus far, Secukinumab has not been found to significantly increase the risk of tuberculosis (TB).

Infliximab in chronic non-infectious paediatric uveitis refractory to previous biologic therapy.

OBJECTIVES: To examine the outcome of infliximab treatment in patients with non-infectious paediatric uveitis who have previously failed biologic treatment. METHODS: A retrospective cohort study was performed at Bristol Eye Hospital, UK. Paediatric patients with chronic non-infectious uveitis who had been switched to infliximab due to inadequate uveitis control were identified. Two separate groups were evaluated: group 1 consisted of 20 children (36 eyes) who had been switched to infliximab following treatment failure with adalimumab (=in-class switching), while group 2 (5 patients; 9 eyes) included those who had been switched to infliximab from a non-TNF antagonist after failing several biologics (=across-class switching). The change in anterior chamber (AC) activity between baseline and 6- and 24-months follow-up was the primary outcome measure. RESULTS: A statistically significant reduction in AC activity was found between baseline and 6-months follow-up (RE: p = 0.002; LE: p < 0.001) and between baseline and 24-months follow-up (RE: p = 0.016; LE: p = 0.011) in group 1. No statistically significant difference was found for either eye in the number of steroid eye drops needed between time points or the difference in visual acuity in time. In group 2, analysis of change of AC activity, number of steroid eye drops and visual acuity failed to reach statistical significance. Treatment failure occurred in four patients (20% of group 1) and adverse events developed in six patients including three patients with acute infusion reactions. CONCLUSIONS: This study supports the efficacy and safety of infliximab in adalimumab-refractory patients with paediatric non-infectious uveitis.

Uveitis Associated with Monogenic Autoinflammatory Syndromes in Children.

Monogenic autoinflammatory syndromes (MAISs), are caused by pathogenic genetic variants in the innate immune system, leading to dysregulation and aberrant inflammasome activation spontaneously or with minimal triggering. The diagnosis and treatment of MAISs can be intricate, relying on an increased recognition of potential differential diagnoses. This review examines the clinical features of MAIS, with a special focus on uveitis. It also evaluates treatment options and assesses the effects of activating molecular and cytokine pathways.

Scope of JAK Inhibitors in Children: Recent Evidence and Way Forward.

Over the last decade, there has been an increase in the use of targeted therapy using small molecules such as Janus kinase (JAK) inhibitors. Since the introduction of ruxolitinib, the first non-selective JAK inhibitor approved for use in myelofibrosis, many other JAK inhibitors have been tried in a wide spectrum of immune-mediated disorders. Although various trials have shown the promising efficacy of JAK inhibitors in immune-mediated inflammatory disorders (IMIDs), there is a growing concern over the major cardiovascular events and malignancies associated with the use of these molecules in older adults, particularly those over 65 years of age. In this review, we aim to discuss the immunology of the JAK-STAT pathway, the scope of use of JAK inhibitors, and their safety in paediatric practice. Here, we discuss high-quality evidence favouring the use of JAK inhibitors in children with juvenile idiopathic arthritis (JIA) who are refractory to one or more conventional/biological disease-modifying drugs, demonstrated in two randomised controlled trials (RCTs). In addition to JIA, there are reports favouring the role of JAK inhibitors in other IMIDs such as systemic-onset JIA and interferonopathies. Thus far, the existing literature suggests an acceptable safety profile for JAK inhibitors in children. With the expanding scope of JAK inhibitors in a wide range of IMIDs in children, there is a significant need for long-term close vigilance for any potential harm.

Gathering expert consensus to inform a proposed trial in chronic nonbacterial osteomyelitis (CNO).

Chronic nonbacterial osteomyelitis (CNO) is an autoinflammatory bone disease that primarily affects children and adolescents. CNO is associated with pain, bone swelling, deformity, and fractures. Its pathophysiology is characterized by increased inflammasome assembly and imbalanced expression of cytokines. Treatment is currently based on personal experience, case series and resulting expert recommendations. Randomized controlled trials (RCTs) have not been initiated because of the rarity of CNO, expired patent protection of some medications, and the absence of agreed outcome measures. An international group of fourteen CNO experts and two patient/parent representatives was assembled to generate consensus to inform and conduct future RCTs. The exercise delivered consensus inclusion and exclusion criteria, patent protected (excludes TNF inhibitors) treatments of immediate interest (biological DMARDs targeting IL-1 and IL-17), primary (improvement of pain; physician global assessment) and secondary endpoints (improved MRI; improved PedCNO score which includes physician and patient global scores) for future RCTs in CNO.

Outcome of adalimumab monotherapy in paediatric non-infectious uveitis.

BACKGROUND: Adalimumab in combination with other disease-modifying antirheumatic drugs (DMARD) such as methotrexate has a proven efficacy in the management of paediatric non-infectious uveitis. However, many children experience significant intolerance to methotrexate while on this combination, leaving a dilemma for clinicians for choosing the subsequent therapeutic roadmap. Continuation of adalimumab monotherapy might be an alternative feasible option under such settings. This study aims to investigate the efficacy of adalimumab monotherapy in paediatric non-infectious uveitis. METHODS: Children with non-infectious uveitis on adalimumab monotherapy (from August 2015 to June 2022) following intolerance to accompanying methotrexate or mycophenolate mofetil were included in this retrospective study. Data were collected at the initiation of adalimumab monotherapy and at three monthly intervals until the last visit. The primary outcome was to evaluate disease control on adalimumab monotherapy as determined by the proportion of patients who had less than a 2-step worsening in uveitis (as per SUN score) and no additional systemic immunosuppression during follow-up. Secondary outcome measures were visual outcome, complications and side-effect profile of adalimumab monotherapy. RESULTS: Data was collected for 28 patients (56 eyes). The most common uveitis type and course were anterior and chronic uveitis respectively. Juvenile idiopathic arthritis-associated uveitis was the most common underlying diagnosis. During the study period, 23 (82.14%) of the study subjects met the primary outcome. On Kaplan-Meier survival analysis 81.25% (95% CI; 60.6-91.7%) children maintained remission at 12 months on adalimumab monotherapy. CONCLUSION: Continuation of adalimumab monotherapy is an effective therapeutic option for the treatment of non-infectious uveitis in children who are intolerant to the combination of adalimumab and methotrexate or mycophenolate mofetil.

Differentiating Multisystem Inflammatory Syndrome in Children (MIS-C) and Its Mimics - A Single-Center Experience From a Tropical Setting.

OBJECTIVE: Identifying clinical and laboratory indicators that differentiate multisystem inflam-matory syndrome in children (MIS-C) apart from other febrile diseases in a tropical hospital setting. METHODS: Review of hospital records done in a tertiary care exclusive children's hospital for children admitted from April, 2020 till June, 2021. Laboratory values, severe acute respiratory syndrome coronavirus (SARS-CoV-2) serological status, and clinical signs and symptoms of patients with MIS-C, and those with similar presentations were analyzed. RESULTS: 114 children fulfilled the inclusion criteria (age group of 1 mo-18 y) for whom a diagnosis of MIS-C was considered in the emergency room based on the clinical features. Among them, 64 children had the final diagnosis of MIS-C, and the remaining 50 children had confirmatory evidence of infections mimicking MIS-C such as enteric fever, scrub typhus, dengue and appendicitis. CONCLUSION: Older age group, presence of muco-cutaneous symptoms, very high C-reactive protein, neutrophilic leukocytosis, abdominal pain and absence of hepatosplenomegaly favor a diagnosis of MIS-C.

2021 update of the EULAR points to consider on the use of immunomodulatory therapies in COVID-19.

OBJECTIVES: To update the EULAR points to consider (PtCs) on the use of immunomodulatory therapies in COVID-19. METHODS: According to the EULAR standardised operating procedures, a systematic literature review up to 14 July 2021 was conducted and followed by a consensus meeting of an international multidisciplinary task force. The new statements were consolidated by formal voting. RESULTS: We updated 2 overarching principles and 12 PtC. Evidence was only available in moderate to severe and critical patients. Glucocorticoids alone or in combination with tocilizumab are beneficial in COVID-19 cases requiring oxygen therapy and in critical COVID-19. Use of Janus kinase inhibitors (baricitinib and tofacitinib) is promising in the same populations of severe and critical COVID-19. Anti-SARS-CoV-2 monoclonal antibodies and convalescent plasma may find application in early phases of the disease and in selected subgroups of immunosuppressed patients. There was insufficient robust evidence for the efficacy of other immunomodulators with further work being needed in relation to biomarker-based stratification for IL-1 therapy CONCLUSIONS: Growing evidence supports incremental efficacy of glucocorticoids alone or combined with tocilizumab/Janus kinase inhibitors in moderate to severe and critical COVID-19. Ongoing studies may unmask the potential application of other therapeutic approaches. Involvement of rheumatologists, as systemic inflammatory diseases experts, should be encouraged in clinical trials of immunomodulatory therapy in COVID-19.

Macrophage Activation Syndrome in Children: Diagnosis and Management.

Macrophage activation syndrome is a severe yet under-recognized complication encountered in pediatric rheumatology. It manifests as secondary hemophagocytic lymphohistiocytosis leading to a hyper-inflammatory state resulting from an underlying cytokine storm. If unchecked, it may lead to multiorgan failure and mortality. Early diagnosis and timely initiation of specific therapy is pivotal for a successful outcome. This review outlines the key clinical and laboratory features and management of macrophage activation syndrome.

Correlation of SARS-CoV-2 Serology and Clinical Phenotype Amongst Hospitalised Children in a Tertiary Children's Hospital in India.

INTRODUCTION: Children usually present with minimal or no symptoms of COVID-19 infection. Antibody responses to SARS-CoV-2 in children from low- and middle-income countries (LMIC) have not been well described. We describe the prevalence of anti-SARS-CoV-2 antibodies and clinical phenotype of seropositive children admitted to a tertiary children's hospital in South India. METHODS: To determine the seropositivity and describe the clinical characteristics of COVID-19 infection amongst hospitalised children, we performed a prospective clinical data collection and blood sampling of children admitted to Kanchi Kamakoti CHILDS Trust Hospital, Chennai, India over 4 months of the COVID-19 pandemic. In seropositive children, we compared antibody titres between children with and without PIMS-TS. RESULTS: Of 463 children, 91 (19.6%) were seropositive. The median (range) age of seropositive children was 5 years (1 month-17 years). Clinical presentation was consistent with Paediatric inflammatory multisystem syndrome associated or related with SARS-CoV-2 infection (PIMS-TS) in 48% (44/91) of seropositive children. The median (range) antibody titre was 54.8 (11.1-170.9) AU/ml among all seropositive children. The median antibody titre among the children with PIMS-TS (60.3 AU/mL) was significantly (p = 0.01) higher when compared to the children without PIMS-TS (54.8 AU/mL). CONCLUSION: We describe the antibody responses to SARS-CoV-2 amongst hospitalised children in a LMIC tertiary children's hospital. Almost half of the seropositive children had PIMS-TS. Antibody levels may be helpful in the diagnosis and disease stratification of PIMS-TS. LAY SUMMARY: Children usually present with minimal or no symptoms of COVID-19 infection. However, Multisystem Inflammatory Syndrome in Children (MIS-C) or Paediatric inflammatory multisystem syndrome associated or related with SARS-CoV-2 infection (PIMS-TS) has emerged as a distinctive paediatric illness related to SARS-CoV-2. Recently, antibody testing for SARS-CoV-2 is being used increasingly as a diagnostic test for PIMS-TS. However, data on the antibody responses to SARS-CoV-2 in children are sparse. We, therefore, attempted to identify the seropositivity and describe the clinical spectrum of COVID-19 infection amongst infants and children getting hospitalised in a children's hospital in south India. Nearly one-fifth of the hospitalised children tested serology positive over 4 months. Antibody levels in children with PIMS-TS were significantly higher in comparison to the other two groups (acute COVID-19 infection and children without PIMS-TS). Results from our study suggest that all children are at risk of COVID-19 infection though they may present with mild illness or no symptoms. We also observed that antibody testing may have a possible role in diagnosis of PIMS-TS.

Tuberculosis in Children with Rheumatic Diseases Treated with Biologic Disease-Modifying Anti-Rheumatic Drugs.

Chronic rheumatic diseases entail the use of biologics in children. Immunosuppressive effects of drug therapy put children at risk of various infections including tuberculosis (TB). Even though TB is a major concern among individuals on biological DMARDs, the incidence and distribution among children on these drugs is not known. Hence, we performed a literature search to ascertain the prevalence of tuberculosis amongst children with rheumatic disorders treated with biological agents. Articles available on MEDLINE and SCOPUS published on or after January 1, 2010 to 1 October 2019 were reviewed and collated. We found that published data on TB infections in children with rheumatic disorders on biologics is scant even from regions with highest TB burden. Tuberculosis was reported on occasion (0-5 cases per country) in the developed world with most reports being from Turkey. While most of the retrospective studies suggest that TB risk is minimal in the paediatric rheumatology patients, prospective studies suffer from a short observation period. Most registries focus on response to therapy rather than complications. In this review we have then discussed about the variation in screening strategies for latent TB and the role of bacille Calmette-Guerin (BCG) vaccination. Based on the dearth of data and inconsistency in data collection, we propose a way forward in the form of establishing well-designed long-term prospective national registries from countries with high background prevalence of TB with focus not only on treatment efficacy but also on adverse events and infections.

Epidemiological and Clinical Profile of Pediatric Inflammatory Multisystem Syndrome - Temporally Associated with SARS-CoV-2 (PIMS-TS) in Indian Children.

Background: We describe the demographic, clinical and labo-ratory findings along with the treatment and outcomes among children meeting the case definition of Pediatric Inflammatory Multisystem Syndrome - Temporally associated with SARS-CoV-2 (PIMS-TS). METHODS: We analyzed the clinical and laboratory findings of children who presented with PIMS-TS during an 8-week period from May 4, 2020 to July 8, 2020. RESULTS: We report 19 children with a median age of 6 year (IQR: 13 months-16 years), who met the case definition of PIMS-TS. All of them presented with fever. Multi organ involvement (79%), mucocutaneous involvement (74%), cardiovascular symptoms (63%) and gastrointestinal symptoms (42%) were the other features. Elevated levels of C-reactive protein was found in all of them and the majority of them had evidence of coagulopathy; intensive care admissions were needed in 12 (63%) and vasoactive medications were given to 6 (31.5%) children. There were no deaths. CONCLUSION: Children with PIMS-TS present with a wide range of signs and symptoms. Fewer children in this series had coronary artery abnormalities, and there was a low incidence of RT-PCR positivity with high presence of SARS-CoV-2 antibodies.

Type 1 interferonopathy presenting as juvenile idiopathic arthritis with interstitial lung disease: report of a new phenotype.

BACKGROUND: STING-associated vasculopathy with onset in infancy (SAVI) is a type 1 interferonopathy manifesting as a pulmonary and vascular syndrome resulting from gain-of-function mutations in TMEM173, the gene encoding STING. Familial reports in the literature are sparse. CASE PRESENTATION: We report a case series of SAVI in a three generation kindred, with a phenotype of interstitial lung disease (ILD) and rheumatoid factor positive polyarticular juvenile idiopathic arthritis (JIA). Current and historical medical records were reviewed for clinical and laboratory information. Whole blood from cases 1 and 2, plus stored appendicectomy tissue from case 3, underwent DNA sequencing of the TMEM173 gene. Peripheral blood RNA was obtained from cases 1 and 2 for functional assessment of the TMEM173 mutation. DNA sequencing identified the same heterozygous TMEM173 mutation (c.463G > A; p.Val155Met) in all three cases, consistent with a diagnosis of the autosomal dominant condition SAVI. Functional assessment of this mutation identified a prominent interferon signature which was confirmed on repeat testing. CONCLUSIONS: SAVI presented in this family as ILD with early onset juvenile rheumatoid arthritis. This condition should be considered in all rheumatoid arthritis patients with early-onset ILD and in all JIA patients with ILD.