Lung involvement in juvenile idiopathic inflammatory myopathy: A systematic review.

OBJECTIVE: Juvenile idiopathic inflammatory myopathies (JIIM) are a group of connective tissue disorders characterized by muscle inflammation and variable systemic involvement, including interstitial lung disease (ILD). Available data on JIIM-associated ILD are very limited. We performed a systematic review of the available clinical, laboratory, and radiological features of JIIM-associated ILD. METHODS: A systematic literature review was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. RESULTS: A total of 90 patients were identified, of whom 77.8% had JDM, 10% amyopathic JDM, 7.8% anti-synthetase syndrome, 3.3% overlap syndrome, and 1.1% juvenile polymyositis. Anti-melanoma differentiation-associated gene 5 (MDA-5/CADM-140) was the most frequently reported myositis-specific antibody (32.2%). At diagnosis of ILD, 55.5% of patients had respiratory symptoms. Ground glass opacity was the most reported radiological feature (52.9%). Thirty-three % of patients developed rapidly progressive (RP) lung disease; 26.7% were admitted to the intensive care unit (ICU); 28.9% died; all deaths were due to ILD, with a median interval of 2 months (IQR 1.5-4.7) between the onset of respiratory symptoms and death. Patients admitted to the ICU and who died of ILD were more likely to be male, to have a rapidly progressive pattern, progression of radiological features, and a higher level of KL-6. CONCLUSIONS: MDA-5/CADM-14 is associated with RP-ILD. ILD is a rare but severe manifestation among the spectrum of systemic involvement associated with JIIM, with a high rate of ICU admission and mortality. Early recognition and aggressive treatment are needed to prevent a severe outcome.

A wide spectrum of phenotype of deficiency of deaminase 2 (DADA2): a systematic literature review.

INTRODUCTION: Deficiency of adenosine deaminase 2 (DADA2) is a rare monogenic autoinflammatory disease, whose clinical phenotype was expanded since the first cases, originally described as mimicker of polyarteritis nodosa, with immunodeficiency and early-onset stroke. METHODS: A systematic review according to PRISMA approach, including all articles published before the 31st of August 2021 in Pubmed and EMBASE database was performed. RESULTS: The search identified 90 publications describing 378 unique patients (55.8% male). To date 95unique mutations have been reported. The mean age at disease onset was 92.15 months (range 0-720 months), 32 (8.5%) showed an onset of the first signs/symptoms after 18 years old and 96 (25.4%) after 10 years old. The most frequent clinical characteristics described were cutaneous (67.9%), haematological manifestations (56.3%), recurrent fever (51.3%), neurological as stroke and polyneuropathy (51%), immunological abnormalities (42.3%), arthralgia/arthritis (35.4%), splenomegaly (30.6%), abdominal involvement (29.8%), hepatomegaly (23.5%), recurrent infections (18.5%), myalgia (17.9%), kidney involvement (17.7%) etc. Patients with skin manifestations were older than the others (101.1 months SD ± 116.5, vs. 75.3 SD ± 88.2, p 0.041), while those with a haematological involvement (64.1 months SD ± 75.6 vs. 133.1 SD ± 133.1, p < 0.001) and immunological involvement (73.03 months SD ± 96.9 vs. 103.2 SD ± 112.9, p 0.05) are younger than the others. We observed different correlations among the different clinical manifestations. The use of anti-TNFα and hematopoietic cell stems transplantation (HCST) has improved the current history of the disease. CONCLUSION: Due to this highly variable phenotype and age of presentation, patients with DADA2 may present to several type of specialists. Given the important morbidity and mortality, early diagnosis and treatment are mandatory.

Concomitant Use of Elexacaftor/Tezacaftor/Ivacaftor and Etanercept in a Cystic Fibrosis Patient with Juvenile Idiopathic Arthritis.

Patients with cystic fibrosis often complain of joint manifestations. However, only a few studies have reported the association between cystic fibrosis and juvenile idiopathic arthritis and addressed the therapeutic challenges of these patients. We describe the first paediatric case of a patient affected by cystic fibrosis, Basedow's disease and juvenile idiopathic arthritis who was contemporarily treated with elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) and anti-tumor necrosis factor α (anti-TNFα). This report seems to reassure regarding the potential side effects of these associations. Moreover, our experience suggests that anti-TNFα is an effective option in CF patients affected by juvenile idiopathic arthritis, and is even safe for children receiving a triple CFTR modulator.

CD38high/HLA-DR+ CD8+ T cells as potential biomarker of hemophagocytic lymphohistiocytosis secondary to visceral Leishmania infection.

Leishmaniasis is a cause of infection associated with hemophagocytic lymphohistiocytosis (HLH). The measurement of the CD8+ CD38high/HLA-DR+ T cells in children presenting with acute onset of shock and multisystem organ failure represents an important parameter to distinguish HLH from sepsis or healthy control. CONCLUSION: We report a case series of 4 Italian children suffering from HLH secondary to visceral Leishmaniasis in which the lymphocyte subset assay suggests a potential role of CD38high/HLA-DR+ CD8+ T cells as HLH diagnostic biomarkers. WHAT IS KNOWN: • Visceral Leishmaniasis is a well-known cause of infection associated with hemophagocytic lymphohistiocytosis (HLH). • The measurement of the CD8+ CD38high/HLA-DR+ T cells in children presenting with acute onset of shock and multisystem organ failure represents an important diagnostically useful parameter to readily distinguish HLH from sepsis or healthy controls. WHAT IS NEW: • We report a case series of 4 Italian children suffering from HLH secondary to visceral Leishmaniasis in which the lymphocyte subset assay suggests a potential role of CD38high/HLA-DR+ CD8+ T cells as HLH diagnostic biomarker. • The flow cytometry assay, performed at the disease onset before starting treatment, revealed a mean percentage value of CD38 cells of 36.95% among CD8+ T cells.

Clinical and Therapeutic Aspects of Sideroblastic Anaemia with B-Cell Immunodeficiency, Periodic Fever and Developmental Delay (SIFD) Syndrome: a Systematic Review.

BACKGROUND AND PURPOSE: Sideroblastic anaemia with B-cell immunodeficiency, periodic fever and developmental delay (SIFD) syndrome is a novel rare autoinflammatory multisystem disorder. We performed a systematic review of the available clinical and therapeutics aspects of the SIFD syndrome. METHODS: A systematic review according to PRISMA approach, including all articles published before the 30th of July 2021 in Pubmed and EMBASE database, was performed. RESULTS: The search identified 29 publications describing 58 unique patients. To date, 41 unique mutations have been reported. Onset of disease is very early with a median age of 4 months (range 0-252 months). The most frequent manifestations are haematologic such as microcytic anaemia or sideroblastic anaemia (55/58), recurrent fever (52/58), neurologic abnormalities (48/58), immunologic abnormalities in particular a humoral immunodeficiency (48/58), gastrointestinal signs and symptoms (38/58), eye diseases as cataract and retinitis pigmentosa (27/58), failure to thrive (26/58), mucocutaneous involvement (29/58), sensorineural deafness (19/58) and others. To date, 19 patients (35.85%) died because of disease course (16) and complications of hematopoietic cell stems transplantation (3). The use of anti-TNFα and hematopoietic cell stems transplantation (HCST) is dramatically changing the natural history of this disease. CONCLUSIONS: SIFD syndrome is a novel entity to consider in a child presenting with recurrent fever, anaemia, B-cell immunodeficiency and neurodevelopmental delay. To date, therapeutic guidelines are lacking but anti-TNFα treatment and/or HCST are attractive and might modify the clinical course of this syndrome.

Pseudo-rheumatic manifestations of limping: Camptodactyly-arthropathy-coxa vara-pericarditis syndrome: Single case report and review of the literature.

Camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome is a rare genetic disease characterized by tetrad camptodactyly, noninflammatory arthropathy, coxa vara deformity, and pericardial effusion. Arthropathy typically affects large joints and presents with joint swelling in the absence of other signs of inflammation. We described the case of a girl affected by CACP syndrome caused by a novel compound heterozygous variant in proteoglycan 4 gene (c.2831_2832insT; c.3892C > T) and associated with temporomandibular involvement. The patient received treatment with intra-articular hyaluronic acid injections, which presented rapid but transient improvements of pain and range of motion. A literature review of previously reported CACP patients has been performed. Of the patients. 69.2% (101 out of 146) were Middle Eastern, and 65.7% (96) were consanguineous. The median age of onset was 24 months (interquartile range of 12-36 months), and median age of diagnosis was 96 months (interquartile range of 48-156 months). Arthropathy was always present, mainly involving hips (95.2%), knees (92.4%), wrists (87.7%), elbows (79.5%), and ankles (57.5%). Camptodactyly and pericardial effusion were described, respectively, in 97.3% (142) and 15.1% (22) of patients. The main radiological findings were coxa vara (95.2%), femoral changes (64.4%), intraosseus cysts (14.4%), and bone erosion (5%). Of the patients, 32.9% (48) had received a previous juvenile idiopathic arthritis diagnosis. CACP syndrome can be easily misdiagnosed with juvenile idiopathic arthritis. A prolonged lack of response to immunosuppressive therapy associated with typical clinical and radiological features should prompt consideration of this rare syndrome.

Adjunctive treatment with infliximab in pediatric immunoglobulin A (IgA) vasculitis: A case report.

Immunoglobulin A vasculitis (IgAV) is the most common childhood vasculitis affecting small vessels. No clear recommendations are available for severe pediatric cases, and until now, anti-TNF agents have had a limited role in IgAV management. In this report, we describe a pediatric case of severe IgAV, successfully treated with combined therapy including the anti-TNF, infliximab.

Tocilizumab and Abatacept for the Treatment of Childhood Chronic Uveitis: A Monocentric Comparison Experience.

Background: Our study aimed to evaluate the efficacy of Tocilizumab and Abatacept for treating Childhood Chronic non-infectious Uveitis (CCU), resistant to anti-tumor necrosis factor (anti-TNF) treatment. Methods: This is a monocentric retrospective charts review study (January 2010-April 2021) recruiting CCU, refractory to anti-TNF. To be included, children should have active uveitis at the time of Tocilizumab (8 mg/kg, every 4 weeks) or Abatacept (10 mg/kg, every 4 weeks). The main outcome was the achievement of ocular remission on treatment defined as the absence of flares for ≥ 6 months. Results: In this study, 18 patients with CCU (14 F), previously treated with Methotrexate and Adalimumab, were enrolled: 15 had juvenile idiopathic arthritis (JIA) (83.3%), 2 idiopathic (11.1%), and 1 Behçet (5.6%). Furthermore, ten patients received Abatacept and 8 patients received Tocilizumab. The mean duration of treatment on Abatacept was 31.6 months (SD ± 30.8), on Tocilizumab 25.25 months (SD ± 17.8). In total, 13 children (72.2%) achieved remission, with a better remission rate for the Tocilizumab group (8/8) compared to the Abatacept group (5/10) (χ2 5.53, p = 0.019). No difference was evaluated between the two groups in the proportion of patients who showed flares during the treatment (2/6 Abatacept vs. 1/8 Tocilizumab). A significant difference was evaluated in the proportion of patients who flared after treatment discontinuation: 3/3 Abatacept vs. 0/3 Tocilizumab (χ2 3.8, p = 0.025). Conclusion: Even though this is a monocentric retrospective study, in a relatively small group, our study suggests a superior efficacy of Tocilizumab over Abatacept for treating anti-TNF refractory CCU.

A case of unilateral acute hypertensive uveitis in a child.

A 6-year-old boy was referred to our hospital for sudden blurring vision in the left eye. An ophthalmological evaluation showed white endothelial keratic precipitates and increased intra-ocular pressure. To our knowledge, this is the first reported case of hypertensive uveitis in children under 10 years of age and we also discuss the role of Epstein-Barr virus as a possible infectious trigger.

A systematic review on biological therapies in juvenile idiopathic inflammatory myopathies: an evidence gap in precision medicine.

OBJECTIVES: Juvenile idiopathic inflammatory myopathies (JIIMs) are a heterogeneous group of systemic autoimmune diseases. Juvenile dermatomyositis (JDM) is the predominant form of JIIMs, and is a rare, chronic autoimmune illness characterised by symmetric, proximal muscle damages and involvement of the skin. In the last two decades, the use of monoclonal antibodies has also been expanded to JIIMs; however, there is limited evidence on use of these treatments. We assessed the efficacy/effectiveness and safety of biologic agents in JIIMs. METHODS: A systematic literature review was conducted using Embase®, MEDLINE®, MEDLINE®-In Process and Cochrane library to identify studies on biologics agents in JIIMs published in English language as full-text articles (1975 to December 2020) or conference abstracts (2000 to December 2020). Databases were searched with the key words regarding chronic myositis crossed with "biologic agents OR tocilizumab OR rituximab OR adalimumab OR infliximab OR anti-TNF OR etanercept". Of note, we did not include children, age, or age limits in the search as medical subject headings terms because we may have been able to extract a sub cohort of children from studies including both children and adults. RESULTS: Of the 1633 retrieved publications, 18 articles were identified for a total of 165 patients. In real-world studies, definition of complete (CR) or partial response (PR) varied. JIIMs patients were most often treated with anti-TNF (88 pts); patients received etanercept (ETA), 48 patients infliximab (IFX), 4 patients received adalimumab (ADA). In other 15 patients IFX was followed by ADA. Rituximab (RTX) was used in 73 children. A single case series reported the use of abatacept (ABA) in 4 patients. Despite the reduced number of treated patients, complete response on myositis was reported in 29.6% (8/26) patients treated with at least one anti-TNF and in 38% (10/26) treated by RTX. Complete response of skin vasculitis has been reached in 33% (4/12) children on anti-TNF and in 36% on RTX (21/58). Anti-TNF agents might be efficient in treating calcinosis lesions. CONCLUSIONS: Currently, the available evidence regarding the use of biologic treatment in JIIMs results quite limited but suggest a promising the use of anti-TNF agents and RTX in treating active JIIMs. Anti-TNF treatment might have a role in treating calcinosis. However, an overall very low quality of the available studies and multiple confounding factors hamper to suggest a treatment over another. Thus, randomised clinical trials are urgently required to attempt the optimal treatment in real-world setting.

Ocular involvement in monogenic autoinflammatory disease.

OBJECTIVE: Monogenic Autoinflammatory diseases (AIDs) are a broad spectrum of rare hereditary diseases whose ocular involvement has not been well characterized yet. This systematic review aims to provide an overview of the current knowledge about ocular findings in AIDs. METHODS: A systematic literature review was conducted using 2 electronic databases, according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. A combination of AIDs and ophthalmology-related search terms were used. All articles were screened by 2 independent reviewers for title, abstract and full text level. We included solely studies that investigated ocular findings in AIDs. RESULTS: 198 papers of 4268 records were retained. Data about 1353 patients with a diagnosis of autoinflammatory disease and ocular involvement were collected (680 CAPS, 211 FMF, 138 TRAPS, 238 Blau, 32 MKD, 21 SIFD, 7 Aicardi Goutières, 3 CANDLE, 8 DADA2, 9 HA20, 6 APLAID). Conjunctivitis was significantly more frequent in CAPS (p < 0.00001), uveitis in Blau, MKD, HA20 and CANDLE (p < 0.00001), papillitis/papilledema in CAPS (p < 0.00001), optic neuritis in Aicardi and DADA2 (p < 0.008), retinal vasculitis in FMF (p < 0.00001), progressive reduction in choroidal thickness in FMF and DADA2 (p < 0.00001), periorbital oedema in TRAPS (p < 0.00001) and retinitis in SIFD (p < 0.00001). Among AIDs with uveitis, granulomatous inflammation was more common in Blau syndrome (p < 0.00001). CONCLUSION: This systematic literature review characterized the ocular involvement of several AIDs, and the present data may encourage to consider a timely ophthalmological screening program for these rare diseases.

A peptide-based anti-Adalimumab antibody assay to monitor immune response to biologics treatment in juvenile idiopathic arthritis and childhood chronic non-infectious uveitis.

Immune response to biologics treatment, while widely reported, yet fails to correlate with clinical outcomes and assay to assay comparison is often not possible. Hence, we developed a new peptide based-detection assay to stratify pediatric patients with juvenile idiopathic arthritis (JIA) or chronic non-infectious uveitis (CNU) and monitor anti-drug antibodies (ADAbs) formed as part of an immune response to treatment with the fully human monoclonal therapeutic antibody Adalimumab. Adalimumab derived synthetic peptides were optimized for maximum immunogenicity and were tested by SP-ELISA on a development cohort of 18 JIA and CNU treated patients. The two best performing peptides able to differentiate patient groups were selected for evaluation with a larger scale ELISA testing on a total of 29 sera from pediatric patients with JIA or CNU. The results of this peptide-based assay were compared to an in-house developed SPR biosensor ADAbs assay and a commercially available bridging ELISA. The first peptide, termed HC3, was able to positively detect ADAbs in 7 out of the 29 sera, while the second peptide, called LC3, was able to detect ADAbs in 11 out of 29 sera in the evaluation group. Following statistical data evaluation, it has been found that the detection of ADAbs using the peptide-based ELISA assay positively correlates with disease progression and remission. Two synthetic peptides derived from Adalimumab may provide a beneficial tool to clinicians for monitoring patient response to such treatment and taking informed decisions for treatment alternatives.

Menetrier disease and Cytomegalovirus infection in paediatric age: report of three cases and a review of the literature.

Paediatric Menetrier disease (PMD) is a protein-losing gastropathy, presenting with generalized oedema and abdominal symptoms. PMD commonly has an acute course and may be associated with Cytomegalovirus (CMV) infection. The aim of this retrospective study is to assess the epidemiological and clinical data, diagnostic procedures, treatment and outcome of CMV-associated PMD. The medical charts of the patients with PMD and CMV infection diagnosed at our hospital have been reviewed. Then, a systematic literature's review of all the cases of PMD and a selection of those associated with CMV infection have been performed. Three previously healthy boys were admitted for vomiting and oedema. Endoscopy showed hypertrophic gastric folds and CMV infection was diagnosed. Albumin was administered in all cases, with clinical resolution within few weeks. In literature, PMD has been described in 150 children and the association between CMV and PMD was found in 89 cases. Clinical and laboratory data, radiological and histological exams, therapy and outcome were reviewed.Conclusions: Basing on the present experience and on the current knowledge, PMD has a benign course without long-term sequelae. Although PMD is rare in children, we recommend paediatricians to consider CMV-related PMD when facing children with vomiting and diffuse oedema. What is Known: • Paediatricians should consider Menetrier disease (MD) when facing oedematous child complaining of abdominal symptoms with hypoalbuminemia, without proteinuria and liver dysfunction. • Typical ultrasound features (hypertrophic gastric folds) suggest such condition which requires endoscopy and biopsy for definitive diagnosis. What is New: • A familial susceptibility to CMV gastric infection has been recently suggested; thus when suspecting MD, the family history of gastric diseases should be investigated. • Menetrier disease has been found associated with other unusual conditions either benign (such as gastric bezoar) or malign as neoplasms (acute lymphatic leukaemia and adenocarcinoma) even in children.

Changing evidence over time: updated meta-analysis regarding anti-TNF efficacy in childhood chronic uveitis.

OBJECTIVE: To summarize evidence regarding efficacy of anti-TNFα in childhood chronic uveitis, refractory to common DMARDs. METHODS: An updated systematic search was conducted between November 2012 and January 2020. Studies investigating the efficacy of anti-TNFα therapy, in children of ages <16 years, as the first biologic treatment for childhood chronic uveitis, refractory to topical and/or systemic steroid and at least one DMARD were eligible for inclusion. The primary outcome measure was the improvement of intraocular inflammation according to Standardization of Uveitis Nomenclature Working Group criteria. A combined estimate of the proportion of children responding to etanercept (ETA), infliximab (INF), and adalimumab (ADA) was determined. RESULTS: We identified 1677 articles of which 37 articles were eligible. Three were randomized controlled trials, one on ETA and two on ADA, and were excluded from pooled analysis. From the observational studies, a total of 487 children were identified: 226 received ADA, 213 INF and 48 ETA. The proportion of responding children was 86% (95% CI: 76%, 95%) for ADA, 68% (95% CI: 50%, 85%) for INF and 36% (95% CI: 9%, 67%) for ETA. Pooled analysis showed clear differences (χ2 = 32.2, P < 0.0001): ADA and INF were both significantly superior to ETA (χ2 = 26.8, P < 0.0001, and χ2 = 7.41, P < 0.006, respectively), ADA significantly superior to INF (χ2 = 13.4, P < 0.0002). CONCLUSION: This meta-analysis, consistent with recent randomized controlled trial data, suggests the efficacy of ADA and INF in childhood chronic uveitis treatment. However, ADA results were superior to those of INF in this clinical setting.

Development and initial validation of a composite disease activity score for systemic juvenile idiopathic arthritis.

OBJECTIVE: To develop a composite disease activity score for systemic JIA (sJIA) and to provide preliminary evidence of its validity. METHODS: The systemic Juvenile Arthritis Disease Activity Score (sJADAS) was constructed by adding to the four items of the original JADAS a fifth item that aimed to quantify the activity of systemic features. Validation analyses were conducted on patients with definite or probable/possible sJIA enrolled at first visit or at the time of a flare, who had active systemic manifestations, which should include fever. Patients were reassessed 2 weeks to 3 months after baseline. Three versions were examined, including ESR, CRP or no acute-phase reactant. RESULTS: A total of 163 patients were included at 30 centres in 10 countries. The sJADAS was found to be feasible and to possess face and content validity, good construct validity, satisfactory internal consistency (Cronbach's alpha 0.64-0.65), fair ability to discriminate between patients with different disease activity states and between those whose parents were satisfied or not satisfied with illness outcome (P < 0.0001 for both), and strong responsiveness to change over time (standardized response mean 2.04-2.58). Overall, these properties were found to be better than those of the original JADAS and of DAS for RA and of Puchot score for adult-onset Still's disease. CONCLUSION: The sJADAS showed good measurement properties and is therefore a valid instrument for the assessment of disease activity in children with sJIA. The performance of the new tool should be further examined in other patient cohorts that are evaluated prospectively.

The conundrum of juvenile spondyloarthritis classification: Many names for a single disease? Lesson learned from an instructive clinical case.

Pediatric rheumatic diseases are often characterized by an evolving phenotype, resulting in diagnostic dilemma for physicians involved in their management. Although several classification criteria are used in childhood to uniform patients' diagnoses, several conditions share similar clinical features and therefore their classifications may overlap or be ambiguous. This is particularly paradigmatic for the classification of juvenile spondyloarthritis (JSpA), as the currently available criteria do not encompass their complexity. The differential diagnosis of sacroiliitis is often challenging for clinicians and requires considering several conditions, which include infective, neoplastic and rheumatic diseases. We report the case of a 13-year-old boy with an evolving clinical phenotype; its progression shows the wide differential diagnosis required in pediatric rheumatic diseases and emphasizes the issues of the actual classification system.

Common variable immunodeficiency presenting as sarcoidosis in a 9-year-old child.

BACKGROUND: Granulomatous diseases are a heterogeneous group of conditions characterized by an inflammatory infiltrate with a core of macrophages, epithelioid, giant cells and a corona of fibroblasts and lymphocytes. They are associated with a wide range of disorders such as mycobacterial and fungal infections, neoplasms, immunodeficiencies and systemic inflammatory disorders as sarcoidosis. CASE REPORT: We report the case of a previously healthy 9-year-old male child who presented with persistent cough, diffuse lymphadenopathy, enlargement of liver and spleen and protracted fever. Anemia, lymphopenia and reduced platelet count was reported, with an increase of inflammatory markers. High levels of Angiotensin-converting enzyme and chitotriosidases were noted. A PET-CT scan showed increased uptake of 18 F-FDG glucose in multiple lymph nodes in thorax and abdomen and in the spleen. Biopsy of inguinal and bronchial nodes showed nodal granulomatous inflammation. The child was diagnosed with sarcoidosis and treated with corticosteroids with only transient efficacy. Further tests reported panhypogammaglobulinaemia and a reduced pool of B-memory lymphocytes. Thus, the diagnosis was revised to common variable immunodeficiency (CVID). CONCLUSION: Common variable immunodeficiency is a heterogeneous condition with a highly variable clinical phenotype and a strong association with autoimmune disorders. The presence of noncaseating granuloma and pulmonary lesions, along with extrapulmonary features required a step by step approach to differentiate between CVID and sarcoidosis. This enables early introduction of immunoglobulin replacement therapy and decreases the morbidity and mortality of CVID.