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Objectives: To develop an easy-to-use and efficient clinical score to identify monogenic lupus based on clinical presentations and to stratify patients who may benefit from confirmatory molecular genetic testing., Methods: A comprehensive literature review identified 55 distinct items across 12 clinical and laboratory domains, narrowed down to the top ten by a panel of 12 expert paediatric rheumatologists with 80% consensus. The proposed score was tested in a pilot study on 10 patients with monogenic lupus and 30 control subjects with various autoimmune and autoinflammatory diseases. All patients, both with monogenic lupus and the control group, were then scored, and a receiver operating characteristic curve was employed to determine the threshold that distinguishes monogenic lupus from non-monogenic lupus., Results: The clinical score comprised 10 items. Among all patients, the most frequent items were antinuclear antibody positivity and consanguinity, followed by early disease onset (<5 years), with no significant differences between monogenic lupus patients and the controls. However, the monogenic lupus patients exhibited significantly higher rates of family history of lupus, failure to thrive, cutaneous lesions, brain imaging changes, a low C1q level, and recurrent infections. Also, they achieved the highest scores compared to the controls. A score of more than three was found to be highly predictive for diagnosing monogenic lupus, with a sensitivity of 90% and a specificity of 90%., Conclusions: Our clinical score appears to be a valuable tool for the early identification of patients with monogenic lupus who may require further molecular genetic testing for confirmation.

Objectives: To describe the clinical phenotype and response to treatment of autoinflammatory disease (AID) patients with the TNFRSF1A-pR92Q variant compared to patients with tumour necrosis factor receptor-associated periodic syndrome (TRAPS) due to pathogenic mutations in the same gene and patients diagnosed with other recurrent fever syndromes including periodic fever with aphthous stomatitis, pharyngitis, and adenitis (PFAPA) and syndrome of undefined recurrent fever (SURF)., Methods: Clinical data from pR92Q variant associated AID, classical TRAPS, PFAPA and SURF patients were obtained from the Eurofever registry, an international, multicentre registry enabling retrospective collection of data on AID patients., Results: In this study, 361 patients were enrolled, including 77 pR92Q variant, 72 classical TRAPS, 152 PFAPA and 60 SURF patients. pR92Q carriers had an older age of disease onset than classical TRAPS and PFAPA patients. Compared to pR92Q variant patients, classical TRAPS patients had more relatives affected and were more likely to have migratory rash and AA-amyloidosis. Despite several differences in disease characteristics and symptoms between pR92Q variant and PFAPA patients, part of the pR92Q variant patients experienced PFAPA-like symptoms. pR92Q variant and SURF patients showed a comparable clinical phenotype. No major differences were observed in response to treatment between the four patient groups. Steroids were most often prescribed and effective in the majority of patients., Conclusions: Patients with AID carrying the TNFRSF1A-pR92Q variant behave more like SURF patients and differ from patients diagnosed with classical TRAPS and PFAPA in clinical phenotype. Hence, they should no longer be diagnosed as having TRAPS and management should differ accordingly.

Objectives: Chronic non-bacterial osteomyelitis (CNO) is a non-infectious inflammatory disease characterised by uni- or multi-focal bone lytic lesions. CNO mainly affects metaphysis of long bones, pelvis and shoulder girdle. Neurocranium lesions are extremely rare. The objective of the study is to describe the prevalence and clinical manifestations of CNO patients with neurocranium involvement in an Italian cohort of CNO patients., Methods: This is a retrospective study. Medical records of patients with CNO admitted to eight paediatric rheumatology centres were reviewed., Results: Among 86 patients with CNO enrolled in the study, three of them were female and presented neurocranium involvement - multifocal lesions. Two out of the 3 patients were completely asymptomatic for cranial involvement, while one of the 3 complained of cranial bossing. Cranial involvement was detected with bone scintigraphy and then confirmed by magnetic resonance imaging and/or computed tomography. Two patients presented fever and two with skin manifestations. Laboratory inflammatory markers were increased in two of them. All patients underwent bone biopsy confirming the diagnosis. They all received NSAIDs. Two patients received corticosteroids and then methotrexate and achieved clinical remission, while one patient received pamidronate., Conclusions: This is the first report of neurocranium involvement in a cohort of patients affected by CNO. In our cohort no patient showed significant signs attributable to cranial involvement.

An apparently unprovoked recurrent inflammation is the quintessential hallmark of autoinflammatory diseases (AIDs), a large and heterogeneous group of disorders in which there is poor regulation of the innate immune system with no clearly demonstrated autoimmune machinery involvement. Innate immunity pathways are diverse and our understanding of their molecular composition and function is continuously expanding. The impaired immune responses we observe in monogenic AIDs, mostly in the hereditary periodic fever syndromes, is officiated by target molecules of microbial origin (pathogen-associated molecular patterns) and also host molecules (danger-associated molecular patterns). Further crucial components of innate immune mechanisms that contribute differently in the deregulated inflammatory patterns of different AIDs include Toll-like receptors, Nod-like receptors, scaffolding proteins (such as the caspase recruitment domain of proteins), cytosolic DNA-sensing molecules, inflammatory multi-protein complexes (referred to as inflammasomes), complement system, and others. In recent years, the knowledge of protean molecular pathways responsible for the most common monogenic AIDs has expanded, in parallel with very recent extraordinary technological advances, allowing the identification and characterisation of some unknown aspects of the innate immunity. This review will list and describe the most common monogenic febrile syndromes belonging to AIDs and will focus on current insights dealing with their pathologic processes.

Autoinflammatory diseases (AIDs) are a distinct group of diseases characterised by a dysregulation of the innate immune response leading to systemic inflammation. The clinical spectrum of these conditions is extremely variable and possibly every system and tissue can be involved, including the central nervous system (CNS). Indeed, neurological manifestations may dominate the clinical picture from disease onset in some rare conditions. However, the involvement of the CNS in AIDs is not a disease in itself, but represents a rare complication which is consequent to a systemic or local immune response, mainly involving cells of the innate immunity. This review will describe neurological manifestations associated with AIDs, including: chronic aseptic meningitis and brain atrophy, sensori-neural hearing loss, early-onset haemorrhagic and ischaemic strokes, mental retardation, cerebellitis, and ataxia, and severe encephalopathy with brain calcifications.

Autoinflammatory diseases (AIDs) encompass a heterogeneous group of disorders pathogenetically related to an abnormal activation of the innate immunity and clinically characterised by aseptic inflammation in the affected organs in the absence of high titer of circulating autoantibodies or autoreactive T cells. In classic monogenic AIDs, the skin is frequently involved with a wide range of cutaneous lesions. Monogenic AIDs result from different mutations in a single gene, which regulates the innate immunity. These mutations cause an uncontrolled activation of the inflammasome, leading to an overexpression of interleukin (IL)- 1β. IL-1β is the pivotal cytokine which is responsible for the exaggerated production of cytokines and chemokines that induce the recruitment of neutrophils, key cells in autoinflammation. Paradigmatic autoinflammatory forms are the cryopyrin-associated periodic syndromes (CAPS), whose skin involvement consists of urticarial lesions. Similar IL-1β-mediated autoinflammatory pathomechanisms also occur in deficiency of IL-1 receptor antagonist (DIRA) and deficiency of IL-36 receptor antagonist (DITRA), whose cutaneous appearance is characterised by pustular lesions, as well as in pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome. Pyoderma gangrenosum, which is the cutaneous hallmark of the PAPA syndrome, is a prototypic neutrophil-mediated skin disease, manifesting as single or multiple ulcers with undermined, raised erythematous to violaceous borders. This review is focused on the CAPS, DIRA/DITRA and PAPA syndromes with emphasis on their cutaneous manifestations, as well as their histology and pathophysiology.

Objectives: In 1966, Goldbloom et al. described two children who developed a peculiar clinical picture characterized by intermittent daily bone pain in the lower limbs, fever spikes, increased acute phase reactants and dysproteinaemia. The syndrome occurred two weeks after a group A β-haemolytic streptococcus infection. So far, only a few cases have been reported in the medical literature in English., Methods: We report two further cases of Goldbloom's syndrome with a review of the literature in English., Results: Our two patients lived in the same Italian region and presented their syndrome onset a week apart. Early use of STIR MRI revealed an atypical metaphyseal hyperintensity in the femurs and tibias. X-ray showed periosteal hyperostosis. A short cycle of corticosteroids led to rapid recovery of symptoms and disappearance of bone changes., Conclusions: The reported cases highlight a likely under-recognised post-streptococcal inflammatory periosteal reaction and emphasise the diagnostic utility of the newer imaging modalities.

Objectives: Tumour necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is a multisystemic autoinflammatory condition associated with heterozygous TNFRSF1A mutations, presenting with a variety of clinical symptoms, many of which yet unexplained. In this work, we aimed at deepening into TRAPS pathogenic mechanisms sustained by monocytes., Methods: Microarray experiments were conducted to identify genes whose expression results altered in patients compared to healthy individuals, both under basal condition and following LPS stimulation., Results: An inflammatory state baseline, characterised by constitutive overexpression of IL1β and IL1R1 receptor, has been shown in TRAPS patients compared to controls, including in non-active disease phases. Following LPS stimulation, IL1RN up-regulation is stronger in controls than in patients and inflammatory pathways and microRNAs undergo differential regulation. Genes involved in post-translational modifications, protein folding and ubiquitination result constitutively up-regulated in TRAPS, while response to interferon types I and II is defective, failing to be up-regulated by LPS. TGFβ pathway is down-regulated in untreated TRAPS monocytes, while genes involved in redox regulation result constitutively over-expressed. Finally, additional molecular alterations seem to reflect organ failures sometime complicating the disease., Conclusions: Gene expression profile in resting TRAPS monocytes has confirmed the patients' chronic inflammatory condition. In addition, pathways not yet associated with the disease have been disclosed, such as interferon types I and II response to LPS stimulation and a downregulation of the TGFβ pathway in basal condition. The role of miRNA, suggested by our results, deserves in-depth analyses in light of the possible development of targeted therapies.

Objectives: To develop and test a new multidimensional questionnaire for assessment of children with auto-inflammatory disease (AID) such as FMF, PFAPA, HIDS, TRAPS in standard clinical care., Methods: The juvenile auto-inflammatory disease multidimensional assessment report (JAIMAR) includes 16 parent or patient-centered measures and four dimensions that assess functional status, pain, therapeutic compliance and health-related quality of life (physical, social, school, emotional status) with disease outcome. It is proposed for use as both a proxy-report and a patient self-report, with the suggested age range of 8-18 years for use as a self-report., Results: 250 children with FMF were included in the study. Total of 179 forms were filled up by parents and patients, and 71 forms were filled up by parents having children less than 8 years. Completing and scoring the JAIMAR can be done in 15 minutes. For the JAIMAR's dimensions, the Cronbach's alpha coefficient for internal consistency was between 0.507-0.998. There was a significant and a positive correlation between the test-retest scale scores (ICC=0.607-0.966). Concerning construct validity, all factors loadings were above 0.30. For the criterion validity, the correlation level between each dimension and the related scale ranged from medium (r=0.329, p<0.0001) to large (r=0.894, p<0.0001). The parents' proxy-reported and children's self-reported data were outstandingly concordant (r=0.770-0.989)., Conclusions: The development of the JAIMAR introduces a new and multi-dimensional approach in paediatric rheumatology practice. It is a new tool for children with auto-inflammatory dis-ease and it may help enhance their quality of care.

Objectives: Eosinophilic fasciitis is an uncommon scleroderma-like disorder characterised by induration and thickening of skin and soft tissue, usually associated with peripheral eosinophilia, poorly characterised in childhood., Methods: We report 3 paediatric cases of eosinophilic fasciitis showing unusual clinical and histopathological features with a review of the literature., Results: All cases presented progressive motility impairment started from upper limbs with no skin abnormalities. All cases showed systemic inflammatory involvement and 2 patients had acute complications. Two patients developed disabling outcomes despite appropriate treatments., Conclusions: Eosinophilic fasciitis may present unusual clinical and histopathological features during childhood and requires early recognition in order to prevent acute complications and disabling outcomes.

In this paper we provide a critical digest of the recent literature on inherited autoinflammatory diseases. We reviewed all the articles published during the last 24 months on monogenic autoinflammatory diseases and selected the most relevant studies regarding the pathogenesis, clinical aspects and management of these conditions. In particular, we focused the attention on the more frequent conditions, familial Mediterranean fever (FMF), cryopyrin-associated periodic syndrome (CAPS) and TNF-receptor associated periodic syndrome (TRAPS).

Objective: CD27 is a member of tumour necrosis factor receptor family. Its expression is predominantly confined to mature lymphocytes and is strongly enhanced after cell activation. Shedding of the CD27 from the surface of activated cells is related to their effector phase. The aim of the present study was to evaluate the levels of soluble CD27 in sera and synovial fluids, together with its expression on circulating and synovial fluid (SF) memory T cells, in children with JIA., Methods: Sera from 40 patients with active JIA were studied for soluble CD27. Paired SF samples were available in 20 patients. Sera from 12 age-matched patients affected with various acute infectious diseases and 12 age-matched healthy subjects were used as controls. In 8 JIA patients freshly isolated circulating and SF lymphocytes were stained for CD27 in CD4+CD45 RO+ T cell subpopulation and analyzed by cytometry., Results: Soluble CD27 serum levels were significantly higher in patients with polyarticular JIA and acute systemic infectious diseases than in patients with active oligoarticular or healthy controls. Both polyarticular and oligoarticular JIA patients showed increased levels of soluble CD27 in SF when compared with paired serum samples (p = 0.01). In all the patients tested a significant enrichment of CD27- T cells was seen in the SF (median 39.5%, range 18-56%) when compared to paired CD4+CD45RO+ peripheral lymphocytes (median 19.5%, range 5-43%; p = 0.01)., Conclusions: A clear enrichment of CD4+ memory SF T cells with a CD27-phenotype is observed when compared to correspondent circulating T lymphocytes. This issue is conceivably related to re-activation and recruitment of memory T cells to the site of inflammation, and to the subsequent expansion of a subpopulation of "effector" memory T cells.

Objective: This study was aimed at evaluating intestinal permeability (IP) in patients with oligoarticular juvenile idiopathic arthritis (o-JIA), spondyloarthropathy (SpA) associated with inflammatory bowel disease (IBD) and other forms of juvenile-onset chronic arthritiis (OIA) using the lactulose/mannitol (L/M) test in comparison with other non-invasive parameters of gut involvement., Methods: A series of 26 children affected with o-JIA and 14 with either SpA/IBD or OIA were assessed for IP. The urinary L/M ratio was measured by gas chromatography. The erythrocyte sedimentation rate (ESR), C reactive protein (CRP), and faecal alpha 1 antitrypsin concentrations were also evaluated. Ten o-JIA patients displayed active arthritis while in 16 the disease was under control. Among the OIA patients, 11 were affected with psoriatic arthritis and the remaining 3 with chronic reactive arthritis. 14 patients with SpA-IBD had active synovitis or spine inflammation. 14 eo-pJCA and 22 OIA and SpA-IBD patients, respectively, were receiving NSAID therapy., Results: The mean L/M ratios for the Spa-IBD (0.07 +/- 0.02, mean +/- SD), OIA (0.05 +/- 0.02) and o-JIA (0.04 +/- 0.02) patients were significantly higher (p < 0.001, p = 0.022 and p = 0.01, respectively) than those found in controls (0.02 +/- 0.01). Logistic regression analysis disclosed a positive correlation between the L/M ratio and the presence of gastrointestinal manifestations (p = 0.011). The type of disease (p = 0.28), the disease activity in the JCA patient group (p = 0.24) and NSAID administration (p = 0.210) did not seem to significantly influence the L/M ratio., Conclusions: All of the subtypes of juvenile chronic arthritides that we studied displayed an increased IP. Hence, gut wall inflammation (albeit asymptomatic) may also be present in o-JIA patients. The SpA-IBD patients with gastrointestinal symptoms displayed the highest mean L/M ratio values. The L/M test seemed to correlate with histopathological features of the gut mucosa. The L/M ratio was shown to be a highly sensitive but poorly specific test for predicting gut inflammatory disease compared to other non-invasive screening tests.

Objective: Gut inflammation is a common feature shared by inflammatory bowel diseases (IBD) and the spondyloarthropathies (SpA). The aim of the present study was to compare the reliability of a number of non-invasive investigations for the detection of an inflammatory process of the intestine., Methods: Forty-two children were studied: (i) patients with a previous diagnosis of IBD (group A); (ii) patients with suspected IBD (group B); and (iii) patients with predominantly rheumatological manifestations associated with gastrointestinal symptoms (group C). All the patients were studied using 99mTechnetium-HMPAO labelled white cell scanning (99mTc-WCS), and abdominal ultrasound (US). In addition the ESR, serum class A immunoglobulins, faecal occult blood (OB) and faecal alpha 1-antitripsin level (F alpha 1-AT) were determined. Colonoscopy plus multiple biopsies and radiological study of the intestine were used as gold standards., Results: 99mTc-WCS showed the highest sensitivity (85%) and specificity (100%) in detecting the presence of gut inflammation. This was followed by ESR and faecal occult blood (63% sensitivity, 44% specificity), F alpha 1-AT (43% sensitivity, 44% specificity) and IgA (42% sensitivity, 88% specificity). Ultrasound was informative in 28% of the active/affected patients, with a specificity of 75%., Conclusion: Although ileo-pancolonscopy remains the gold standard for the histological characterisation of gut inflammation, 99mTc-WCS represents the most reliable non-invasive test for its detection.

A 3-year-old boy with erythema multiforme-like manifestations and severe articular involvement is reported. Because of the unusual onset of the cutaneous lesion a skin biopsy was performed, revealing the typical features of a leukocytoclastic vasculitis. A direct immunofluorescent study revealed C3 and IgM deposition within the wall and around the small vessels. The clinical and immunopathological findings in this patient were similar to those reported for the acute hemorrhagic edema of infancy (AHE) described in children younger than 2 years of age. The present case supports the hypothesis that AHE is a distinctive leukocytoclastic vasculitis of childhood, irrespective of the age at onset.