Martina Finetti

Chronic Non-Bacterial Osteomyelitis (CNO) is an inflammatory disorder that primarily affects children. Although underestimated, its incidence is rare. For these reasons, no diagnostic and no therapeutic guidelines exist. The manuscript wants to give some suggestions on how to deal with these patients in the every-day clinical practice. CNO is characterized by insidious onset of bone pain with local swelling. Systemic symptoms such as fever, skin involvement and arthritis may be sometimes present. Radiological findings are suggestive for osteomyelitis, in particular if multiple sites are involved. CNO predominantly affects metaphyses of long bones, but clavicle and mandible, even if rare localizations of the disease, are very consistent with CNO diagnosis. CNO pathogenesis is still unknown, but recent findings highlighted the crucial role of cytokines such as IL-1β and IL-10 in disease pathogenesis. Moreover, the presence of non-bacterial osteomyelitis among autoinflammatory syndromes suggests that CNO could be considered an autoinflammatory disease itself. Differential diagnosis includes infections, malignancies, benign bone tumors, metabolic disorders and other autoinflammatory disorders. Radiologic findings, either with Magnetic Resonance or with Computer Scan, may be very suggestive. For this reason in patients in good clinical conditions, with multifocal localization and very consistent radiological findings bone biopsy could be avoided. Non-Steroidal Anti-Inflammatory Drugs are the first-choice treatment. Corticosteroids, methotrexate, bisphosphonates, TNFα-inhibitors and IL-1 blockers have also been used with some benefit; but the choice of the second line treatment depends on bone lesions localizations, presence of systemic features and patients’ clinical conditions. CNO may be difficult to identify and no consensus exist on diagnosis and treatment. Multifocal bone lesions with characteristic radiological findings are very suggestive of CNO. No data exist on best treatment option after Non-Steroidal Anti-Inflammatory Drugs failure.

Behçet’s disease is a rare multi-systemic inflammatory disease with unknown etiology which involves principally oral and genital mucosa, skin and eyes. Average age at onset of the disease is about 25-30 years, but it may be diagnosed before the age of 16. It is not very rare in Italy, even though there are limited data concerning epidemiology. Aim of this study is to describe the baseline data of an Italian cohort of patients with as having BD or probable BD. We described the baseline data of the first national epidemiological study on children coming from 16 Italian Pediatric Rheumatologic Centers diagnosed by the treating physicians as having Behçet’s Disease. Data on demographic characteristics, clinical features and therapy were collected. We then compared our findings to those of international pediatric cohort studies and also retrospectively evaluated the ability to diagnose BD using ISG, ICBD and, for the first time, the new PEDBD criteria. The study included 110 patients (62 M, 48F). Average age at onset was 8.34±4.11 years. The frequencies of signs/symptoms were: recurrent oral aphtosis 94.5%, genital ulcers 33.6%, ocular 43.6%, gastrointestinal 42.7%, musculoskeletal 42.7%, neurological 30.9% and vascular involvement 10%. Thirty-two patients (29.1%) fulfilled ISG, 78 (70.9%) ICBD, 50 (45.5%) PEDBD criteria and 31 (28%) didn’t fulfill any of them. The most frequently used treatments were colchicine and corticosteroids followed by immunosuppressants. Four patients received biologic therapy (anti TNF-α and anti-IL-1) to treat severe organ involvement. Recurrent oral aphtosis was the most frequent clinical manifestation, followed by ocular involvement. Gastrointestinal lesions were more frequent in Italy than in non-European countries as opposed to genital ulcers. Skin, ocular and vascular manifestations had a higher frequency in males and genital ulcers in females. Constitutional symptoms were present in 44.5% and recurrent fever in one third of our population.

The Chronic Infantile Neurological Cutaneous and Articular (CINCA, or Neonatal-onset multisystem inflammatory disease NOMID) is a rare autoinflammatory disease identified in 1987 by Prieur et al., typically characterized by the triad of skin rash, arthropathy and central nervous system manifestations. It represents the most severe phenotype of the cryopyrin-associated periodic syndrome (CAPS). The syndrome is due to autosomal dominant gain of function mutations in NLRP3, which encodes a key component of the innate immunity that regulates the activation and secretion of interleukin (IL)-1β. From the first days of life, patients display an urticarial rash in association with chronic inflammation with a typical facies featured by frontal bossing and saddle back nose. The CNS manifestations include chronic aseptic meningitis leading to brain atrophy, mental delay and sensorineural hearing loss. Chronic polyarthritis and alteration of the growth cartilage also may be present. CINCA/NOMID diagnosis is made clinically, based on the presence of characteristic features. The detection of NLRP3 mutations is diagnostic in 65–70% of cases. Indeed, up to 40% of affected patients are negative for germline NLRP3 mutations and several subjects are carriers of somatic mosaicism. Due to the pivotal role of Cryopyrin in the control of Caspase-1 activation and the massive secretion of active IL-1β observed in cryopyrin-mutated individuals, anti-IL1 treatment represents the standard therapy. Prognosis of CINCA/NOMID syndrome has been changed by the availability of anti-IL1 drugs. Nowadays, the use of anti-IL-1 drugs has sensibly reduced the risk of developing main complications such as severe intellectual disability, hearing-loss and amyloidosis, if treatment is started early on.

Acute cerebellar ataxia (ACA) is a relatively common neurological disease in children. Most common types of ACA are acute post-infectious (APCA) and acute disseminated encephalomyelitis (ADEM). Less common but important causes include opsoclonus-myoclonus syndrome (OMS) and acute cerebellitis. Cerebellar neoplasms and acute hydrocephalus are additional causes of paediatric ataxia. APCA is the most common cause of ACA in children, comprising about 30-50% of total cases. This is a report about an immunocompetent 4-yrs-old male affected by APCA, due to co-infection by human herpesvirus-6 (HHV-6) and adenovirus, with symptoms mimicking myositis.

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal dominant autoinflammatory disorder caused by mutations in the TNFRSF1A gene encoding the 55-kDa receptor for tumor necrosis factor (TNF)-α. It is characterized by recurrent prolonged episodes of fever accompanied by abdominal pain, pleuritis, migratory skin rashes, fasciitis, headache, conjunctivitis, and periorbital edema. We report two children, one with a severe mutation in the TNFRSF1A gene causing the typical phenotype. The second patient had a homozygous R92Q-type mutation and displayed a periodic fever with aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome-like phenotype. In the eastern Mediterranean region, TRAPS is probably underdiagnosed because of the overwhelming frequency of familial Mediterranean fever (FMF). However, TRAPS should be sought for in patients with atypical symptoms for FMF.

Introduction: Interleukin-1 (IL-1) blockade is the treatment of choice of cryopyrin associated periodic syndromes (CAPS). Anti-IL-1 monoclonal antibody (canakinumab) was recently registered. However no clear data are available on the optimal schedule of administration of this drug. The aim of the present study was to analyse the impact of canakinumab on CAPS patients in daily clinical practice and to identify the best schedule of administration according to age and phenotype. Methods: 13 CAPS patients (10 children and 3 young adults) treated with canakinumab were followed for 12 months. Clinical and laboratory parameters were collected at each visit. Health-related quality of life (HRQoL) was recorded at month 12. Complete response was defined as absence of clinical manifestations and normal examinations. Clinical and laboratory variables at last follow-up were compared with those registered at the moment of anakinra discontinuation. Results: seven patients with chronic infantile neurological cutaneous articular (CINCA) syndrome, four patients with Muckle-Wells syndrome (MWS) and two patients with an overlapping MWS/CINCA phenotype were analysed. CINCA patients experienced a higher number of modifications of the treatment (increased dosage or decreased dosing interval) in respect to MWS patients. At the end of the follow-up CINCA patients displayed a higher frequency of administration with a median dose of 3.7 mg/kg (2.1 mg/kg for MWS patients). Canakinumab was withdrawn in a patient with CINCA for incomplete response and poor compliance. The effect of canakinumab on HRQoL was similar to that observed during treatment with anakinra, with the exception of an improvement of the psychosocial concepts after the introduction of canakinumab. Conclusions: The use of canakinumab in daily practice is associated with persistent satisfactory control of disease activity but needs progressive dose adjustments in more severe patients. The clinical phenotype, rather than the age, represents the main variable able to determine the need of more frequent administrations of the drug at higher dosage.

Objective.: Tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is an autosomal-dominant multisystemic autoinflammatory condition. Patients display different mutations of the TNF receptor superfamily 1A gene (TNFRSF1A), coding for a nearly ubiquitous TNF receptor (TNFR1). No TNFRSF1A mutation has been identified in a proportion of patients with TRAPS-like phenotype.Methods.: We investigated mechanisms downregulating the TNF-induced inflammatory response such as (1) receptor shedding, producing a secreted form acting as a TNF inhibitor; (2) receptor internalization with subsequent induction of apoptosis; and (3) negative regulation of nuclear factor-κB (NF-κB) transcription. We analyzed the sequence of genes known to play a pivotal role in these pathways, in 5 patients with TRAPS symptoms and showing shedding and/or apoptosis defects, but without mutations of the TNFRSF1A gene.Results.: Sequence analysis of 3 genes involved in TNFR1 shedding (ERAP1, NUCB2, RBMX) and 3 genes involved in negative regulation of NF-κB signaling (TNFAIP3, CARP-2) or NF-κB transcription (ZFP36) revealed only a few unreported variants, apparently neutral.Conclusion.: Our study rules out any involvement in the pathogenesis of TRAPS of some of the genes known to regulate TNFR1 shedding and TNF-induced NF-κB signaling and transcription. Gene(s) responsible for TRAPS-like syndrome remain to be investigated among currently unidentified genes likely involved in these pathways, or by applying the genome-wide function-free sequencing approach.