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Objective: To evaluate the long-term efficacy of methotrexate (MTX) monotherapy in patients with juvenile idiopathic arthritis-associated uveitis (JIA-U). Methods: We analyzed a cohort of patients with JIA-U treated with MTX monotherapy, divided into two groups depending on whether MTX was started before (on-MTX group) or after uveitis diagnosis (MTX-naive group). The primary endpoint was the time between uveitis inactivity and first relapse. Results: 84 patients entered the study. The median duration of remission on MTX monotherapy resulted 8.2 months. The on-MTX group showed a significant longer time interval between arthritis and uveitis onset and higher need for biologic agents (bDMARD). During follow-up, 40 patients (47.6%) needed bDMARD due to poor control of uveitis. Clinical remission off medication was achieved in 11.9% of patients, all belonging to the MTX-naive group. Conclusions: MTX monotherapy, although effective in early stages of JIA-U, showed poor disease control in the long term.

Objective Juvenile systemic sclerosis (JSSc) is a rare condition in childhood and its variety with no skin involvement, sine scleroderma (ssJSSc), is anecdotal. We report the first case series of patients with ssJSSc. Methods Demographic, clinical and laboratory data of patients with JSSc followed at our centre were retrospectively collected. Patients with no skin involvement but with all of the features RP, positive ANA, intestinal dysmotility and/or interstitial lung disease (ILD) or pulmonary arterial hypertension (PAH) and/or cardiac or renal involvement typical of scleroderma were defined as having ssJSSc and compared with those with classic JSSc (cJSSc). Results Among 52 JSSc patients seen in 20 years, five (9.6%) presented with ssJSSc. Their clinical features and those of the only two patients reported in the literature so far were compared with classic JSSc with available complete data. Six patients had cardiac involvement as presenting feature, three primary cardiomyopathy, three secondary to PAH. Two patients died after a brief disease course and one rapidly underwent heart transplantation. In comparison with cJSSc, ssJSSc showed a significantly longer diagnostic delay (20.1 vs 8.3 months, P = 0.017), higher frequency of cardiac involvement (85.7 vs 15.6%, P = 0.001) and worse outcome, intended as mortality or end-stage organ failure rates (42.9% vs 6.2%, P Conclusion Cardiac involvement represents the most important characteristic of ssJSSc and carries a high morbidity and mortality rate. The longer delay in diagnosis underlines the need for a comprehensive rheumatological work-up in patients with isolated cardiomyopathy or PAH/ILD.

Tubulointerstitial nephritis and uveitis (TINU) syndrome combines acute inflammatory nephritis (AIN) and uveitis. Uveitis in TINU often requires systemic immunomodulatory therapy (IMT), including steroid-sparing agents. Although common for other noninfectious uveitides, the use of tumor necrosis factor-α inhibitors (TNFi) in TINU has seldom been described.This retrospective case series included patients18 years of age with TINU followed at our tertiary care pediatric hospital. Disease characteristics at time of diagnosis and subsequent ophthalmological and rheumatologic evaluations were extracted from the record. AIN was defined as the presence of abnormal renal function and urinalysis or renal biopsy findings consistent with TINU. Uveitis grading, site of inflammation, inactivity, and flare were defined according to Standardization of Uveitis Nomenclature.A total of 10 patients (median age, 12.3 years; 6 females) were included. AIN preceded uveitis onset in 6 patients. Uveitis was bilateral at onset in 7 patients. Uveitis inactivity was achieved with systemic corticosteroids (CS) in 2 and with mycophenolate mofetil (MMF) in 3 patients. Because of persistent ocular inflammation, despite CS and IMT, 4 patients were treated with TNFi. All rapidly achieved uveitis quiescence and maintained prolonged inactivity under combined treatment with TNFi and MMF.Most patients in our study cohort required a steroid-sparing immunomodulator to achieve and maintain uveitis control. In the 50% of the cohort in whom conventional IMTs were inadequate, TNFi were able to maintain quiescence. TNF inhibition might be a useful treatment in IMT-refractory uveitis in TINU patients.

Objectives SARS-CoV-2 infection has now a global resonance. Data on how COVID-19 is affecting immunocompromised patients are however few. With our study we aimed to systematically review the current knowledge on SARS-CoV-2 cases in children and adults with immunosuppression, to evaluate outcomes in this special population. Methods A systematic review of literature was carried out to identify relevant articles, searching the EMBASE, Medline, and Google Scholar databases. Studies reporting data on pre-defined outcomes and related to immunosuppressed adults and children with SARS-CoV-2 were included. Results Sixteen relevant articles were identified with 110 immunosuppressed patients, mostly presenting cancer, along with transplantation and immunodeficiency. Cancer was more often associated with a more severe course, but not necessarily with a bad prognosis. Our data show that both children and adults with immunosuppression seem to have a favorable disease course, as compared to the general population. Conclusion Immunosuppressed patients with COVID-19 seem to be few in relation to the overall figures, and to present a favorable outcome as compared to other comorbidities. This might be explained by a hypothetical protective role of a weaker immune response, determining a milder disease presentation and thus underdiagnosis. Nevertheless, surveillance on this special population should be encouraged.

Treatment of scleroderma in children is challenging since little is known about its pathogenesis. Herein, we review the most recent evidence regarding the treatment of juvenile scleroderma. According to the recent recommendations for Pediatric Rheumatology in Europe (SHARE), systemic treatment in localized scleroderma is needed when there is a risk for disability, such as in generalized or pansclerotic morphea and progressive linear scleroderma. In juvenile systemic sclerosis, the introduction of the severity score, J4S, has standardized the assessment of the patients in the daily practice and allowed a more tailored therapeutic approach. Since, to date, no clinical trial is available in JSSc, due to its rarity, the treatment is based on adults’ experience. The recent recommendations for juvenile scleroderma represent an important instrument to standardize the treatment approach, confirm the role of methotrexate, and open new windows for effective experimental treatments, such as mycophenolate mofetil and biological agents, for severe or refractory cases.

Long-term home isolation due to lockdown measures to prevent the spread of the COVID-19 outbreak bears the potential for increased risk of domestic accidents in children, as an additional collateral damage of this pandemic.1–3 Hence, we aimed to assess the frequency and severity of presentations for domestic accidents between 8 March, when lockdown measures were enforced in our region, and 20 April 2020 compared with the corresponding period during the previous year. We searched the paediatric emergency department (PED) electronic database for injury presentations related to trauma, poisoning, burns and foreign bodies (in the respiratory/gastrointestinal tract, or in the ear/nose/throat), as well as any presentations flagged as domestic injury at triage. We reviewed the identified records to accurately select injuries sustained in the household. We excluded children

Background We aimed to test if standardized point-of-care outcome monitoring and clinical decision support (CDS), as compared to standard care, improves disease activity and patient-reported pain in children with enthesitis-related arthritis (ERA). Methods This was a retrospective cohort study of outcomes of children with ERA after phased implementation of I) standardized outcome monitoring with CDS for polyarticular JIA, and II) CDS for ERA, compared to a pre-intervention group of historical controls. We used multivariable mixed-effects models for repeated measures to test whether implementation phase or other disease characteristics were associated with change over time in disease activity, as measured by the clinical juvenile arthritis disease activity score (cJADAS), and pain. Results One hundred fifty-two ERA patients (41% incident cases) were included with a median age of 14.9 years. Implementation of standardized outcome monitoring or ERA-specific CDS did not result in significant differences in cJADAS or pain over time compared to the pre-intervention cohort. Higher cJADAS at the index visit, pain and more tender entheses were significantly associated with higher cJADAS scores over time (all p p = 0.02). Regardless of intervention period, incident ERA cases had a greater rate of cJADAS improvement over time compared to prevalent cases (p Conclusions There was no significant effect of point-of-care outcome monitoring or CDS interventions on disease activity or pain over time in children with ERA in this single center study. Future efforts to improve disease outcomes using standardized outcome monitoring and CDS will need to consider the importance of addressing pain as a target in addition to spondyloarthritis-specific disease activity metrics.

Kawasaki disease is a childhood vasculitis of unknown origin, whose major complication is the development of coronary artery aneurysms (CAA). The purpose of this review is to provide an overview on the most recent evidence on the pathogenesis, diagnosis and treatment options of Kawasaki disease summarizing the most relevant studies published in the last year.Several genetic polymorphisms leading to Kawasaki disease susceptibility have been identified, mostly related to immune system regulation; potential external triggers are being investigated by environmental epidemiology studies. A new diagnostic test based on trascriptomics has been tested with promising preliminary results. With regards to first-line treatments, the real effectiveness of high-dose aspirin remains a matter of debate. For refractory cases, the ones at the highest risk for developing CAA, promising results come from the use of biologic agents, especially TNF and IL-1 blockers.Recent literature has provided interesting insights on the various factors involved in the complex scenario behind the pathogenesis of Kawasaki disease, especially genetic ones. Novel diagnostic tests and new evidence on the use of biologic agents in Kawasaki disease are emerging, but further evidence is needed to permit early diagnosis and effective treatment of this condition.

Background Tinea amiantacea is a papulo-squamous condition of the scalp that can lead to scalp fibrosis and subsequent permanent hair loss. It is thought to represent a reaction pattern to inflammatory skin disease as psoriasis or seborrheic dermatitis (1). Objectives To highlight an adverse reaction which involved the skin in the disease course of a young JIA (juvenile idiopathic arthritis) patient, during treatment with adalimumab. Methods A 16-month-old female patient presented to our clinic with a 4-week history of knee swelling, associated with functional limitation and morning stiffness. Family history was unremarkable, while past medical history revealed atopic dermatitis in the first year of life. The baby was initially treated with NSAIDs, but one month later, due the persistence of arthritis and the appearance of uveitis, subcutaneous methotrexate was started (15 mg/m2/weekly). However 5 months later, given the persistence of uveitis and the onset of a severe hypertransaminasemia, methotrexate was interrupted and adalimumab (24 mg/m2 every 2 weeks) was introduced with a prompt and stable control of ocular and articular disease and a gradual normalization of transaminases. One year later the patient developed dry, itchy, red and cracked skin behind her ears, with fissuringin the lower attachment of the ear lobe, and presented right parietal yellowish scalp lesions which were pruriginous, thick, and scaly, attached both to the scalp and to the proximal hair shafts. A first diagnosis of pityriasis amiantacea secondary to atopic dermatitis was made. A paradoxical cutaneous reaction to the anti-TNF therapy was later hypothesized (2), and 7 months later adalimumab was interrupted with quick resolution of the dermatologic lesions. However, both arthritis and uveitis rapidly recurred, showing an inadequate response to a six month cycle of abatacept treatment (10 mg/kg/month). Adalimumab was than reintroduced with a rapid improvement. Results Currently, after 16 months of adalimumab treatment, the patient still shows complete disease control, without any new dermatologic lesions up to now. Conclusion TNF antagonist-induced tinea amiantacea is a rare adverse reaction that may require the drug discontinuation. Although the exact pathogenetic mechanism is unclear, an imbalance in the cytokine milieu with a selective overexpression of type I interferon has been hypothesized. References [1] F. Osorio, F. Magro, C. Lisboa, S. Lopes, G. Macedo, H. Bettencourt, F. Azevedo, S. Magina, Anti-TNF-Alpha induced psoriasiform eruptions with severe scalp involvement and alopecia: report of five cases and review of the literature. Dermatology. 2012;225(2):163-7. doi: 10.1159/000342503 [2] J. Ettler, D.A. Wetter, M.R. Pittelkow. Pityriasis amiantacea: a distinctive presentation of psoriasis associated with tumour necrosis factor-α inhibitor therapy. Clin Exp Dermatol. 2012Aug;37(6):639-41. doi: 10.1111/j.1365-2230.2011.04286.x. Disclosure of Interests Maria Costanza Caparello: None declared, Francesca Tirelli: None declared, Gabriele Simonini Grant/research support from: Abbvie, Speakers bureau: Abbvie, Rolando Cimaz: None declared, Teresa Giani: None declared

Microbial diversity plays a key role in the maintenance of intestinal homeostasis and in the development of the immune system in the gut mucosa. Maybe one of the most important function of our gut microbiota is the immune system education, in particular the discrimination of friends from foes that occurs during childhood. In addition to bacterial antigens, several metabolites of microbial origin have a crucial role in training of the immune system, such as Short Chain Fatty Acids (SCFAs). There are many evidences on the role of the gut microbiota in rheumatic diseases, in particular modifications of microbiota composition causing dysbiosis that, in turn, can induce gut permeability, and thus immunological imbalance and trigger inflammation. In particular, immune cells can reach extra-intestinal sites, such as joints and trigger local inflammation. Childhood is a crucial period of life for development and evolution of the gut microbiota, especially for the acquisition of fundamental functions such as immunotolerance of commensal microorganisms. For this reason, gut dysbiosis is gaining interest as a potential pathogenetic factor for Juvenile Idiopathic Arthritis (JIA). Here we summarized the studies conducted on JIA patients in which a pro-arthritogenic microbial profiles has been observed; this, together with a depletion of microbial biodiversity, clearly distinguish patients' from healthy subjects' microbiota. Further studies are however needed to better clarify the role of microbiota in JIA pathogenesis.

Innate immune system represents the ancestral defense against infectious agents preserved along the evolution and species; it is phylogenetically older than the adaptive immune system, which exists only in the vertebrates. Cells with phagocytic activity such as neutrophils, macrophages, and natural killer (NK) cells play a key role in innate immunity. In 1999 Kastner et al. first introduced the term “autoinflammation” describing two diseases characterized by recurrent episodes of systemic inflammation without any identifiable infectious trigger: Familial Mediterranean Fever (FMF) and TNF Receptor Associated Periodic Syndrome (TRAPS). Autoinflammatory diseases (AIDs) are caused by self-directed inflammation due to an alteration of innate immunity leading to systemic inflammatory attacks typically in an on/off mode. In addition to inflammasomopathies, nuclear factor (NF)-κB-mediated disorders (also known as Rhelopathies) and type 1 interferonopathies are subjects of more recent studies. This review aims to provide an overview of the field with the most recent updates (see “Most recent developments in..” paragraphs) and a description of the newly identified AIDs., Highlights • Autoinflammatory diseases are caused by self-directed inflammation. • Alteration of innate immunity leads to systemic inflammation attacks. • The autoinflammatory field is exponentially expanding. • The advances in AIDs have led to new insights into immune system understanding. • Autoimmunity and autoinflammation features may be simultaneously present.

Background In this retrospective Italian study, which involved all major national interstitial lung diseases centers, we evaluated the effect of pirfenidone on disease progression in patients with IPF. Methods We retrospectively studied 128 patients diagnosed with mild, moderate or severe IPF, and the decline in lung function monitored during the one-year treatment with pirfenidone was compared with the decline measured during the one-year pre-treatment period. Results At baseline (first pirfenidone prescription), the mean percentage forced vital capacity (FVC) was 75% (35-143%) of predicted, and the mean percentage diffuse lung capacity (DLCO) was 47% (17-120%) of predicted. Forty-eight patients (37.5%) had mild disease (GAP index stage I), 64 patients (50%) had moderate IPF (stage II), and 8 patients (6.3%) had severe disease (stage III). In the whole population, pirfenidone attenuated the decline in FVC (p = 0.065), but did not influence the decline in DLCO (p = 0.355) in comparison to the pre-treatment period. Stratification of patients into mild and severe disease groups based on %FVC level at baseline (>75% and ≤75%) revealed that attenuation of decline in FVC (p = 0.002) was more pronounced in second group of patients. Stratification of patients according to GAP index at baseline (stage I vs. II/III) also revealed that attenuation of decline in lung function was more pronounced in patients with more severe disease. Conclusions In this national experience, pirfenidone reduced the rate of annual FVC decline (p = 0.065). Since pirfenidone provided significant treatment benefit for patients with moderate-severe disease, our results suggest that the drug may also be effective in patients with more advanced disease. Background In this retrospective Italian study, which involved all major national interstitial lung diseases centers, we evaluated the effect of pirfenidone on disease progression in patients with IPF. Methods We retrospectively studied 128 patients diagnosed with mild, moderate or severe IPF, and the decline in lung function monitored during the one-year treatment with pirfenidone was compared with the decline measured during the one-year pre-treatment period. Results At baseline (first pirfenidone prescription), the mean percentage forced vital capacity (FVC) was 75% (35-143%) of predicted, and the mean percentage diffuse lung capacity (DLCO) was 47% (17-120%) of predicted. Forty-eight patients (37.5%) had mild disease (GAP index stage I), 64 patients (50%) had moderate IPF (stage II), and 8 patients (6.3%) had severe disease (stage III). In the whole population, pirfenidone attenuated the decline in FVC (p = 0.065), but did not influence the decline in DLCO (p = 0.355) in comparison to the pre-treatment period. Stratification of patients into mild and severe disease groups based on %FVC level at baseline (>75% and ≤75%) revealed that attenuation of decline in FVC (p = 0.002) was more pronounced in second group of patients. Stratification of patients according to GAP index at baseline (stage I vs. II/III) also revealed that attenuation of decline in lung function was more pronounced in patients with more severe disease. Conclusions In this national experience, pirfenidone reduced the rate of annual FVC decline (p = 0.065). Since pirfenidone provided significant treatment benefit for patients with moderate-severe disease, our results suggest that the drug may also be effective in patients with more advanced disease.

Bronchiolitis is the main cause of lower respiratory tract infection and hospitalization during the first year of life. It may occasionally lead to respiratory failure requiring admission to an intensive care unit. Until now, supportive therapy with O 2 and hydration has been the main approach recommended by the international guidelines, while the role of pharmacological treatment is still debated. Novel therapeutic strategies, such as nebulized hypertonic saline and high-flow oxygen therapy, have been proposed in recent years. The lack of effective treatments for bronchiolitis makes prevention particularly important in reducing the impact of this disease, especially in subjects at risk (i.e. preterm infants with BPD, congenital heart disease, or immunodeficiency).