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.

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.

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.

STAT3-confusion-of-function: Beyond the loss and gain dualism.

BACKGROUND: Germline mutations of signal transducer and activator of transcription 3 (STAT3) are responsible for 2 distinct human diseases: autosomal-dominant hyper-IgE syndrome (AD-HIES) caused by STAT3 loss-of-function mutations and STAT3 gain-of-function disease. So far, these entities have been regarded as antithetic, with AD-HIES mainly associated with characteristic infections and a connective tissue phenotype and STAT3 gain-of-function characterized by lymphoproliferation and poly-autoimmunity. The R335W substitution in the DNA-binding domain of STAT3 was initially described in 2 patients with typical AD-HIES, but paradoxically, recent functional analysis demonstrated a gain-of-function effect of this variant. OBJECTIVES: A patient with Sjögren syndrome and features of AD-HIES with this mutation is described and the molecular consequences are further characterized. METHODS: This study provides a clinical and immunological description of the patient. STAT phosphorylation in primary patient cells was studied and A4 cells transfected with the patient allele were used to study phosphorylation kinetics, transcriptional activity, and target-gene induction. RESULTS: The hybrid clinical features of the patient were associated with normal TH17 cells. Enhanced and prolonged STAT3 phosphorylation, an increased STAT3 driven luciferase reporter activity upon IL-6 stimulation, but reduced IL-6-induced SOCS3 production were all observed. CONCLUSIONS: The germline R335W-STAT3 variant displays a mixed behavior in vitro that mainly shows gain-of-function, but also loss-of-function features. This is matched by an ambiguous clinical and immunological phenotype that dismantles the classical antithetic dualism of gain- versus loss-of-function. Germline STAT3 mutation-related disease represents a pathological spectrum with the p.R335W associated phenotype locating between the 2 recognized clinical disease patterns.

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 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.

Comparative Effectiveness of Tumor Necrosis Factor Agents and Disease-modifying Antirheumatic Therapy in Children with Enthesitis-related Arthritis: The First Year after Diagnosis.

OBJECTIVE: To characterize the effect of anti-tumor necrosis factor (TNF) therapy compared to conventional synthetic disease-modifying antirheumatic drugs (csDMARD) in children with enthesitis-related arthritis (ERA) over the first year after diagnosis. METHODS: We conducted a multicenter retrospective comparative effectiveness study of children diagnosed with ERA. We estimated the effect of anti-TNF therapy on clinical variables (active joint count, tender entheses count) and patient-reported pain and global assessment of disease activity over the first year after diagnosis using state-of-the-art comparative effectiveness analytic methods. RESULTS: During the study period, 217 patients newly diagnosed with ERA had a total of 965 clinic visits the first year after disease diagnosis. Children [median age 11.6 yrs, interquartile range 10-14] were treated with anti-TNF monotherapy (n = 33, 15.2%), csDMARD monotherapy (n = 73, 33.6%), or both (n = 52, 23.9%) in the first year after disease diagnosis. There was a statistically significant improvement in the primary outcome, active joint count, over time in children who received an anti-TNF drug versus those who did not (p = 0.03). Additionally, use of anti-TNF therapy versus no anti-TNF therapy was associated with less patient-reported pain (p < 0.01) and improved disease activity over time as assessed by the clinical Juvenile Arthritis Disease Activity Score (p < 0.01). The magnitude of estimated effect on clinical outcomes was uniformly greater, with the exception of tender entheses count, in children treated with an anti-TNF drug versus a csDMARD. CONCLUSION: During the first year after diagnosis, anti-TNF exposure was associated with benefits for several clinically meaningful outcomes in children with enthesitis-related arthritis.

Idiopathic Inflammatory Myopathies: an Update on Classification and Treatment with Special Focus on Juvenile Forms.

Juvenile inflammatory myopathies represent a heterogeneous group of rare and potentially fatal disorders of unknown aetiology, characterised by inflammation and proximal and symmetric muscle weakness. Beyond many similarities, specific clinical, laboratoristic and histopathologic features underlie different subsets with distinguishing demographic, prognostic and therapeutic peculiarities. Over time, several forms of inflammatory idiopathic myopathies have been described, including macrophagic myofascitis, immune-mediated necrozing myopathy and the spectrum of amyopathic dermatomyositis that include hypomyopathic dermatomyositis, inclusion body myositis and cancer-associated myositis occurring almost exclusively in adults. However, juvenile dermatomyositis is the most frequent in childhood, whereas polymyositis is relatively more frequent in adults. The aetiology is nowadays widely unclear; however, current theories contemplate a combination of environmental triggers, immune dysfunction and specific tissue responses involving muscle, skin and small vessels endothelium in genetically susceptible individuals. Myositis-specific autoantibodies, found almost exclusively in patients with myositis and myositis-associated autoantibodies, detectable both among patients with myositis and in subjects suffering from other autoimmune diseases, have an important clinical role because of their relation to specific clinical features, response to therapy and prognosis. The gold standard treatment for juvenile dermatomyositis is represented by corticosteroids, along with adjunctive steroid-sparing immunosuppressive therapies, which are used to counteract disease activity, prevent mortality, and reduce long-term disability. Further treatment approach such as biologic agents and autologous stem cell transplantation are emerging during the last years, in particular in patients difficult to treat and with poor prognosis. Therefore, a highly medical specialised approach is required for diagnosis and management of these conditions. This review comprehensively examines juvenile inflammatory myopathies focusing on clinical and laboratory classifications as well as on the current treatment approaches, referring in particular on biologic agents and latest therapeutic opportunities.

Difficult-To-Treat Juvenile Idiopathic Arthritis: Current and Future Options.

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in childhood and is usually treated with non-steroidal anti-inflammatory drugs or disease-modifying anti-rheumatic drugs (DMARDs) such as methotrexate or sulfasalazine. However, not all patients respond to these treatments, and toxicities may limit long-term use or diminish compliance. With advances in pharmacotherapy and the development of new therapeutic agents, there have been improvements in treatment of both systemic and non-systemic JIA, particularly with biologic agents such as anti-tumor necrosis factor (TNF)-α, anti-interleukin (IL)-1, and anti-IL6. Anti-cell therapies, such as co-stimulator blockers or anti-CD20, small molecules, and biosimilars represent new areas of interest, and, while many are not yet currently commercially available for use in children, preliminary studies appear to be promising. In the present article, the authors review therapeutic strategies for the different JIA subtypes, mainly according to guidelines and recommendations. Newer and possible future treatments for arthritis, already approved in adults but currently under study in children, are also discussed. Drugs currently in development plans for rheumatoid arthritis, which hopefully will also be useful for JIA patients in the future, are also mentioned in this paper.

Sequential MR angiography in childhood primary angiitis of the CNS.

Central nervous system (CNS) vasculitis is rare in childhood. Diagnosis is sometimes difficult, and imaging methods range from MRI to MRA to conventional angiography. In doubtful cases a brain biopsy is necessary for diagnostic purposes. We describe a 6-year old child affected with primary angiitis of the CNS who was treated successfully with corticosteroids and mycophenolate mofetil and who was followed with MRI and MRA, which guided treatment decisions throughout the disease course. Sequential images are shown.

Glucocorticoids in the management of systemic juvenile idiopathic arthritis.

Glucocorticoids have been the mainstay of treatment for many years in systemic-onset juvenile idiopathic arthritis (sJIA), causing important side effects and some difficulties in the management of this disease. Until the introduction of biologic agents, oral glucocorticoids were used to control fever and other systemic features for several months or even years if systemic manifestations persisted. Nowadays, clinicians have valid alternatives that have revolutionized the natural history of sJIA. Biologic agents, such as the interleukin-1 inhibitors anakinra and the more recent canakinumab, or the interleukin-6 inhibitor tocilizumab, have improved the prognosis of this debilitating disease. Glucocorticoids still have to be considered at the onset of disease when a non-steroidal anti-inflammatory drug therapy fails or when there are life-threatening complications such as severe anemia or pericarditis, or macrophage activation syndrome. Local (intra-articular) triamcinolone hexacetonide is the treatment of choice for arthritis limited to one joint or a few joints in patients without systemic activity. To date, there is still great heterogeneity in the management of sJIA patients, but in recent years there have been attempts to design algorithms and treatment protocols for glucocorticoids, disease-modifying anti-rheumatic drugs, and biologic agents. This review provides an overview of the current knowledge of glucocorticoid therapy in sJIA, comments on recently published recommendations, and gives practical support to the clinician for management of this disease.

Clinical and transcriptional response to the long-acting interleukin-1 blocker canakinumab in Blau syndrome-related uveitis.

OBJECTIVE: To report on the clinical response to canakinumab in a patient with sporadic nucleotide-binding oligomerization domain-containing protein 2 (NOD-2)-associated pediatric granulomatous arthritis (Blau syndrome) and severe resistant panuveitis, and to describe gene expression profile changes throughout such treatment. METHODS: A 4-year-old boy was diagnosed as having Blau syndrome on the basis of typical clinical features, histologic evidence of noncaseating granulomas, and a NOD2 mutation. Ocular involvement was initially controlled by topical and oral corticosteroids, but over the years visual impairment and complications, such as macular edema and retinal detachment, progressed. Ocular disease remained persistently active despite treatment with multiple different immunosuppressants; therefore, canakinumab treatment was started. Before and during the first 6 months of treatment, the gene expression profile was determined each month. RESULTS: Canakinumab treatment was well tolerated and led to rapid quiescence of uveitis, which had been continuously active before this treatment. Gene expression profiling analysis of the patient's blood prior to initiation of interleukin-1 (IL-1) blockade revealed differential expression of 1,993 transcripts when compared to healthy controls, and among the up-regulated transcripts, pathway analysis showed that the predominant network consisted of innate immunity-related transcripts. The transcriptional signature of the patient overlapped with the transcriptional signature of patients with systemic-onset juvenile idiopathic arthritis, and canakinumab treatment led to the normalization of most of these transcriptional changes. CONCLUSION: The pathogenesis of Blau syndrome may be mediated by IL-1, and canakinumab may be useful when this disorder is unresponsive to more conventional treatments.