R Nicolai

Safety and Efficacy of Etanercept in a Cohort of Patients with Juvenile Idiopathic Arthritis Under 4 Years of Age

Objective. To evaluate safety, tolerability, and efficacy of etanercept in a cohort of patients with juvenile idiopathic arthritis (JIA) under 4 years of age. Methods. Data were collected at every visit during treatment with etanercept in 25 children who began treatment at a mean age of 3 years (range 18–48 months). Safety endpoints included the incidence of any adverse events. Efficacy endpoints included the American College of Rheumatology (ACR) Pediatric 30, 50, and 70 criteria for improvement. Results. Data from 25 patients with JIA treated with etanercept for a mean period of 23 months were analyzed. All patients received concomitant medications: 24 methotrexate, 3 cyclosporin A, and 10 corticosteroids. After the first 6 months of treatment, 15 (71.4%) patients achieved an ACR Pedi30 response and at the last observation 20 (80%) achieved ACR Pedi30. ACR Pedi50 and 70 responses were, respectively, 62% and 43% at 6 months and 72% and 64% at the last followup. Five patients (20%) discontinued etanercept for lack of efficacy. Two (8%) developed adverse events, both primary varicella zoster virus (VZV) infections (both not vaccinated). One was hospitalized because of a necrotizing fasciitis secondary to VZV infection. No cases of tuberculosis, opportunistic infections, or malignancies were reported. Conclusion. In our cohort of patients etanercept proved to be safe and efficacious in the majority of children. The response in toddlers was similar to that in older children. We observed only 1 case of severe infection that required hospitalization and stopped treatment temporarily.

Anakinra in Systemic Juvenile Idiopathic Arthritis: A Single-center Experience.

Objective. To assess anakinra as a therapy for systemic juvenile idiopathic arthritis (sJIA) in a single-center series. Methods. We reviewed 25 patients with sJIA treated with anakinra for at least 6 months. The primary outcome was the number of patients who achieved clinically inactive disease at 6 months, according to preliminary criteria for inactive disease and clinical remission of JIA. Results. Among 25 patients evaluated, 14 (56%) met the criteria for inactive disease at 6 months and were classified as responders. For each individual patient, we compared the dose administered with the ideal dose of anakinra and we found that there was no relation with response. We also compared demographic characteristics and clinical and laboratory features at baseline in responders and non-responders: no differences were observed in relation with the number of active joints before starting anakinra or concomitant glucocorticoids treatment. The only variable significantly associated with response was the time from disease onset to receiving anakinra, with earlier treatment being associated with a better outcome. Conclusion. Anakinra is associated with rapid attainment of inactive disease in a significant portion of patients. We found that only the earlier treatment is associated with better outcome. However, formal studies on early treatment and on the pathophysiology and response to treatments, including anakinra, of early- and late-onset sJIA are needed to optimize the management of this challenging disease.

P02-016 - A novel PSMB8 mutation causing candle syndrome

Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome is a newly described autoinflammatory disease, which had been recently reported in 9 patients. It is characterized by onset during the first year of life of recurrent fevers, purpuric skin lesions, arthralgia, progressive lipodystrophy, hypochromic or normocytic anemia, delayed physical development and increased levels of acute phase reactants.

P03-012 - A P268S NOD2 mutation in one Blau patient

Blau syndrome (BS) is a rare autosomal dominant, autoinflammatory syndrome characterized by the clinical triad of granulomatous, recurrent uveitis, dermatitis and symmetric arthritis. The arthritis is usually a polyarticular exuberant synovitis and tenosynovitis and represents the characteristic phenotypic feature. Uveitis occurs in most patients and commonly evolves to a panuveitis. In the majority of patients, the disease is characterized by early onset, usually before 3-4 years of age. The gene responsible for BS has been identified in the caspase recruitment domain gene NOD2/CARD15, and the most common mutations were found in codon 334 (R334Q and R334W) [1]. NOD2 is a member of a family of intracellular proteins with N-terminal caspase recruitment domains (CARDs). Since the first report of an association of the NOD2 variants with Crohn disease by Hugot et al. [2], extensive studies have been focused on an association of NOD2 with inflammatory bowel disease (IBD), pediatric Blau syndrome, NOD2-associated autoinflammatory disease (NAID) and rheumatic disease [3].

Predictors of Flare Following Etanercept Withdrawal in Patients with Rheumatoid Factor–negative Juvenile Idiopathic Arthritis Who Reached Remission while Taking Medication

Objective. To evaluate the rate of flare after etanercept (ETN) withdrawal in patients with juvenile idiopathic arthritis (JIA) who attained clinical remission while taking medication, and to identify predictors of flare. Methods. Patients were included with oligo- (oJIA) and rheumatoid factor–negative polyarticular JIA (pJIA) who received a first course of ETN for at least 18 months, maintained clinically inactive disease (CID) for at least 6 months during treatment, and were followed for 12 months after ETN withdrawal. Demographic and clinical features were collected at onset, at baseline (initiation of ETN), and at time of disease flare. Results. After ETN withdrawal, 66 of the 110 patients enrolled (60%) flared with arthritis (of whom 7 flared with concurrent anterior uveitis; none with uveitis alone). The median time to flare was 4.3 months (interquartile range 2.5–6.4) with no evident differences between oJIA and pJIA. The number and type of joints involved at baseline and characteristics of ETN treatment/discontinuation were not associated with flare. Patients who flared were more frequently males (p = 0.034), positive for antinuclear antibody (ANA; p = 0.047), and had higher values of C-reactive protein (CRP; p = 0.012) at baseline. These variables remained significantly associated with flare in a multivariate logistic analysis, a model accounting for only 14% of the variability of the occurrence of the flare. Conclusion. Our results show that a significant proportion of patients with JIA who maintain CID for at least 6 months experience a relapse after ETN withdrawal. Male sex, presence of ANA, and elevated CRP at baseline were associated with higher risk of flare.

Herpes Virus Infections During Treatment With Etanercept in Juvenile Idiopathic Arthritis

Incidence rates for varicella and herpes zoster were similar in patients with juvenile idiopathic arthritis receiving etanercept/methotrexate (n = 85, 184.9 patient-years [PY]) or methotrexate alone (n = 71, 199.4 PY); no complicated varicella or herpes zoster cases were reported; herpes labialis incidence was higher in patients receiving etanercept/methotrexate versus methotrexate alone (0.38 vs. 0.24 PY).

Cronic non-bacterial osteomyelitis (CNO) in a cohort of pediatric patients: clinical, biological and radiological response to treatment with Anakinra

Chronic nonbacterial osteomyelitis (CNO) is the most common autoinflammatory bone disorder in childhood (1). Diagnostic information is provided by TC-99 bone scintigraphy (BS) and/or whole body MRI. Non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, bisphosphonates and tumour necrosis factor inhibitors have been used until now with variable response (2).

OP0134 Increased Muscle Interferon-γ Expression Levels in Juvenile Dermatomyositis

Background Juvenile dermatomyositis (JDM) is a rare autoimmune disorder characterized by muscle weakness, skin rashes and other systemic features. The immunopathogenesis of JDM is unknown, but recent biomarker studies revealed that up-regulation of several type I interferon (IFN)-related mediators might play a role in the development of JDM. Objectives In this study, we focused our attention on the inflammatory cytokine interferon-γ (IFN-γ), the only member of type II class of interferons. We analysed muscle biopsy samples of JDM-affected children to characterize IFN-γ expression levels and to identify possible correlations with clinical features. Methods We identified a retrospective cohort of patients diagnosed with JDM at our Center between 2001 and 2014 and for whom a muscle biopsy was performed during diagnostic work-up. Expression levels of IFN-γ, chemokine (C-X-C motif) ligand 9 (CXCL-9), chemokine (C-X-C motif) ligand 10 (CXCL-10), chemokine (C-X-C motif) ligand 11 (CXCL-11), class II major histocompatibility complex, transactivator (CIITA) were analysed by real-time PCR on muscle biopsy samples from patients with JMD (n=18) and compared with samples from Duchenne muscular dystrophy (DMD) patients (n=29) by Mann Withney test. Results Median age at diagnosis of JDM patients was 5.4 years (interquartile range, IQR: 4.2-9.1), with a median disease duration at diagnosis of 2.1 months (IQR: 1.2-6.9). For each patient we recorded clinical features at diagnosis, physicians global assessment of the patients overall disease activity on a 100-mm visual analog scale (VAS), serum levels of muscle enzymes (CK, ALT, AST, LDH), erythrocyte sedimentation rate, C-reactive protein level, and antinuclear antibodies status. Six patients were already treated with systemic glucocorticoids before time of biopsy sampling, whereas all DMD patients were untreated. Levels of IFN-γ, CXCL-9, CXCL-10, CXCL-11 and CIITA expression were significantly higher in JDM biopsy samples compared with those of DMD patients (p =0.0004, p =0.0004, p <0.0001, p <0.0001, p =0.0017, respectively). In JDM patients we found that IFN-γ mRNA levels significantly correlated with CXCL-9 and CIITA mRNA levels; on the contrary, we do not observed correlations between IFN-γ mRNA levels and clinical scores. JDM patients treated before biopsy were excluded from final statistics since the molecular analysis resulted strongly influenced by glucocorticoid therapy. Conclusions The increased muscle expression of IFN-γ and IFN-γ-correlated genes in muscle biopsy samples of JDM patients suggests a potential pathogenic role of IFN-γ in JDM. References Bellutti Enders F., et al.; Correlation of CXCL10, Tumor Necrosis Factor Receptor Type II, and Galectin 9 with disease activity in juvenile dermatomyositis; Arthritis & Rheumatology; 2014; 66:2281-2289. Reed A.M., et al.; Changes in novel biomarkers of disease activity in juvenile and adult dermatomyositis are sensitive biomarkers of disease course; Arthritis & Rheumatism; 2012; 64:4078-4086. Disclosure of Interest None declared

FRI0323 Cronic Non-Bacterial Osteomyelitis (CNO) in a Cohort of Pediatric Patients: Clinical, Biological and Radiological Response to Treatment with Anakinra

Background Chronic nonbacterial osteomyelitis (CNO)is the most common autoinflammatory bone disorders in childhood (1). CNO remains a diagnosis of exclusion because of the absence of specific clinical or laboratory findings.An important role in the diagnosis could be provided by whole body imaging techniques as TC-99 bone scintigraphy and/or whole body MRI. The treatment is not standardized;non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, bisphosphonates and tumour necrosis factor neutralizing agents have been used until now with variable response (2). Objectives To describe clinical, biological and radiological response to treatment with IL-1 receptor antagonist (anakinra) in a cohort of patients with CNO. Methods Seven patients with CNO refractory to NSAIDs, glucocorticoids and bisphosphonate (pamidronate) were treated with anakinra for at least 6 months in our institution. Response of treatment was evaluated assessing clinical manifestations (pain, local swelling, functional impairment), laboratory findings (C-reactive protein [CRP], erythrocyte sedimentation rate [ESR] and serum amyloid A level [SAA]) and number of bone lesions on TC-99 bone scintigraphy at the start of treatment and in a 6 months follow-up. Results Seven patients (4 females and 3 males) were included in this study. The median age at diagnosis was 9.7 years (IQR 7.8-14.7) and the median age before starting anakinra treatment was 13.3 years (IQR 8.0-15.9). All the patients were treated with NSAIDs and bisphosphonates as first-line therapy. Glucocorticoid therapy was required in one patients with concomitant recurrent fever and pleural effusion. These patients did not respond satisfactorily and we decide to use anakinra (2 mg/kg/day) to control disease activity. At the start of treatment 7/7 patients (100%) had pain, 3/7 (43%) local swelling and 5/7 (71%) functional impairment; at 6 months of follow up 6/7 patients (86%) were completely asymptomatic, with one patient complaining of arthralgia. Before starting anakinra the median CRP, ESR and SAA were 2.7 mg/dl (IQR 1.7-4.9) 26 mm/h (IQR 12-46) and 53 mg/dl (IQR 27-112); at 6 months 5/7 patients (71%) have normalized CRP, ESR and SAA, 2/7 had a decrease in inflammatory markers. Before anakinra 59 osseous lesions were detected on TC-99 bone scintigraphy. After 6 months of therapy 24/59 lesions (40%) had completely resolved, 1/59 lesions (2%) had partially improved and 29/59 lesions (49%) remained stable. In two patients with persistent high biological inflammatory markers, new lesions (14) developed during treatment. Conclusions Our data suggest that anakinra appears effective in CNO patient, who have not responded to standard of care, in controlling symptoms and laboratory findings, although subclinical bone inflammation was still detectable by bone scintigraphy after 6 months of treatment. Long-term follow-up studies with a larger number of patients are needed. References Sara M. Stern, Polly J. Ferguson. Autoinflammatory Bone Diseases. Rheum Dis Clin N Am 39 (2013) 735-749. H J Girschick, P Raab, S Surbaum, A Trusen, et al. Chronic non-bacterial osteomyelitis in children. Ann Rheum Dis 2005;64:279-285. Disclosure of Interest None declared

Clinical presentation and cytokine production abnormalities in a cohort of patients carrying NLRP12 gene variants

The NLRP12 related autoinflammatory disorder (NLRP12-RD) is a rare autosomal dominant disease,caused by mutations in the NLRP12 gene.Clinical manifestations are extremely heterogeneous.At present,only few cases have been described.Patients occasionally required treatment with steroids and NSAIDS for short periods.Treatment with Anakinra induced an initial good response,that appears to decrease over time.