The Castilian Spanish version of the Juvenile Arthritis Multidimensional Assessment Report (JAMAR).

The Juvenile Arthritis Multidimensional Assessment Report (JAMAR) is a new parent/patient reported outcome measure that enables a thorough assessment of the disease status in children with juvenile idiopathic arthritis (JIA). We report the results of the cross-cultural adaptation and validation of the parent and patient versions of the JAMAR in the Castilian Spanish language. The reading comprehension of the questionnaire was tested in 10 JIA parents and patients. Each participating centre was asked to collect demographic, clinical data and the JAMAR in 100 consecutive JIA patients or all consecutive patients seen in a 6-month period and to administer the JAMAR to 100 healthy children and their parents. The statistical validation phase explored descriptive statistics and the psychometric issues of the JAMAR: the three Likert assumptions, floor/ceiling effects, internal consistency, Cronbach's alpha, interscale correlations, test-retest reliability and construct validity (convergent and discriminant validity). A total of 526 JIA patients (8.6% systemic, 49.4% oligoarticular, 18.2% RF negative polyarthritis, 23.8% other categories) and 78 healthy children, were enrolled in six centres. The JAMAR components discriminated well healthy subjects from JIA patients. All JAMAR components revealed good psychometric performances. In conclusion, the Castilian Spanish version of the JAMAR is a valid tool for the assessment of children with JIA and is suitable for use both in routine clinical practise and clinical research.

Incidence, epidemiology and clinical features of Kawasaki disease in Catalonia, Spain.

OBJECTIVES: To assess the incidence, epidemiology and clinical features of Kawasaki disease (KD) in Catalonia (northeast region of Spain). METHODS: This was an observational population-based study including all Paediatric Units in Catalonia, under both public and private management. Retrospective data retrieval was performed for 10 years (2004-2013). A 12-month (March 2013 to March 2014) prospective collection of new cases of KD was carried out to determine the incidence of KD. RESULTS: Data from 399 patients over the 10-year study period was analysed, revealing that 233 (58.4%) had complete KD, 159 (39.8) incomplete KD and 7 (1.7%) were considered atypical KD. Mean annual incidence was 3.5/105 children <14 years old (yo) and 8/105 children <5 yo (mean age 37±33 months, range 1.3-191.3). KD was more frequent in boys (59.6%, p<0.001) and in rural areas (p<0.001). Patients with IVIG non-responsiveness, need of a 2(nd) IVIG dose, delay of treatment >10(th) day of illness, ages <1 yo and >8 yo and the presence of sterile piuria, aseptic meningitis, abdominal pain and uveitis at diagnosis were found to have higher risk of coronary aneurisms (CAA) (p<0.05). CONCLUSIONS: This is the first population-based study on the epidemiology of KD in the western Mediterranean area. Incidence, clinical features and treatment plans in our cohort are similar to those described in other European studies.

Role of the Egami score to predict immunoglobulin resistance in Kawasaki disease among a Western Mediterranean population.

Kawasaki disease is an acute self-limited systemic vasculitis common in childhood. Intravenous immunoglobulin (IVIG) is an effective treatment, and it reduces the incidence of cardiac complications. Egami score has been validated to identify IVIG non-responder patients in Japanese population, and it has shown high sensitivity and specificity to identify these non-responder patients. Although its effectiveness in Japan, Egami score has shown to be ineffective in non-Japanese populations. The aim of this study was to apply the Egami score in a Western Mediterranean population in Catalonia (Spain). Observational population-based study that includes patients from all Pediatric Units in 33 Catalan hospitals, both public and private management, between January 2004 and March 2014. Sensitivity and specificity for the Egami score was calculated, and a logistic regression analysis of predictors of overall response to IVIG was also developed. Predicting IVIG resistance with a cutoff for Egami score ≥3 obtained 26 % sensitivity and 82 % specificity. Negative predictive value was 85 % and positive predictive value 22 %. This low sensitivity implies that three out of four non-responders will not be identified by the Egami score. Besides, logistic regression models did not found significance for the use of the Egami score to predict IVIG resistance in Catalan population although having an area under the ROC curve of 0.618 (IC 95 % 0.538-0.698, p < 0.001). Although regression models found an area under the ROC curve >0.5 to predict IVIG resistance, the low sensitivity excludes the Egami score as a useful tool to predict IVIG resistance in Catalan population.

Efficacy and safety of canakinumab in cryopyrin-associated periodic syndromes: results from a Spanish cohort.

OBJECTIVES: Cryopyrin-associated periodic syndromes (CAPS) are dominantly-inherited autoinflammatory diseases. The uncontrolled IL-1ß overproduction observed in these patients is the rational basis to treat them with anti-IL-1 drugs. The objective of this study was to evaluate the efficacy and safety of treatment with the long-lasting fully humanised anti-IL-1ß monoclonal antibody canakinumab in a Spanish cohort of patients with CAPS. METHODS: Clinical and laboratory data of CAPS patients carrying a heterozygous germline NLRP3 mutation were obtained. The initial treatment scheme with canakinumab was 150 mg/8 weeks administered subcutaneously in adult patients and 2 mg/kg/8 weeks in paediatric patients. RESULTS: Eight unrelated patients were enrolled. Canakinumab was the first anti-IL-1 drug used in three of them; five were already receiving anakinra. The clinical response to the initial canakinumab scheme was positive in all patients, and was quickly observed in the first 24-72 hours. Four required increasing the frequency and/or dose of canakinumab. A limited or no efficacy in those symptoms related to consequence of the deforming arthropathy and neurosensorial deafness was observed. The adverse side effects were restricted to infectious complications in a small percentage of patients. The treatment was well tolerated by all patients, with no reactions at drug site injections. CONCLUSIONS: Canakinumab caused fast and sustained remissions in most clinical and biochemical manifestations in all enrolled patients, with a limited efficacy in the structural lesions. Dose adjustments seem to be necessary for children and/or for patients with the most severe CAPS phenotypes. Treatment was well tolerated with a low incidence of adverse effects.

Efficacy and safety of TNF-alpha antagonists in children with juvenile idiopathic arthritis who started treatment under 4 years of age.

The aims of the study were to assess efficacy and safety of TNF-alpha antagonists (anti-TNF) in a cohort of patients with juvenile idiopathic arthritis (JIA) who began treatment under 4 years old and to assess relapse rate after methotrexate and/or anti-TNF withdrawal. We made a retrospective charts review of our non-systemic JIA patients treated with anti-TNF under 4 years of age between January 2006 and April 2013. Demographics, epidemiologic, clinical, laboratory data and rate of relapse after treatment withdrawal due to clinical remission were collected. Efficacy and safety end points included side effects (SE) and time to achieve clinical remission. We included 27 patients, 23 received etanercept and 4 adalimumab with a median age of 3.01 (range 0.88-3.97) years at anti-TNF beginning and 1.94 (range 0.18-5.44) and 2.39 (range 0.18-7.24) years of treatment and follow-up, respectively. All patients had previously received disease-modifying antirheumatic drugs at optimal dose. Nineteen patients reached clinical remission on treatment in a median time of 9.1 (range 6.23-21.17) months. Four of those relapsed during treatment. Six developed mild SE, mostly mild infections. No serious SE were described. Eleven patients who reached clinical remission relapsed after treatment withdrawal. None achieved clinical remission off treatment. Most patients reached clinical remission on anti-TNF. In our cohort of patients, etanercept and adalimumab were safe, with mostly mild infections and no serious SE. We observed a high relapse rate during treatment withdrawal.

Clinical management algorithm of uveitis associated with juvenile idiopathic arthritis: interdisciplinary panel consensus.

Uveitis associated with juvenile idiopathic arthritis (JIA) typically involves the anterior chamber segment, follows an indolent chronic course, and presents a high rate of uveitic complications and a worse outcome as compared to other aetiologies of uveitis. Disease assessment, treatment, and outcome measures have not been standardized. Collaboration between pediatric rheumatologists and ophthalmologists is critical for effective management and prevention of morbidity, impaired vision, and irreparable visual loss. Although the Standardization of Uveitis Nomenclature Working Group recommendations have been a great advance to help clinicians to improve consistency in grading and reporting data, difficulties arise at the time of deciding the best treatment approach in the individual patient in routine daily practice. For this reason, recommendations for a systematized control and treatment strategies according to clinical characteristics and disease severity in children with JIA-related uveitis were developed by a panel of experts with special interest in uveitis associated with JIA. A clinical management algorithm organized in a stepwise regimen is here presented.

Diagnosis and classification of Kawasaki disease.

Kawasaki disease is an acute systemic vasculitis of unknown etiology. Diagnosis is based on clinical criteria that include fever, exanthema, conjunctivitis, changes in the extremities, erythema of oral mucosa and lips and cervical lymphadenopathy. However, these criteria have low sensitivity and specificity and therefore, other clinical and laboratory features may be helpful in establishing the diagnosis, especially for cases of atypical or incomplete Kawasaki disease. Prognosis depends on the extent of cardiac involvement; coronary aneurysms develop in 20-25% of untreated patients and these may lead to myocardial infarction and sudden death. Treatment with high-dose intravenous immunoglobulin is effective in reducing the risk of coronary aneurysms in most cases and is the treatment of choice for initial Kawasaki disease.

Treatment of uveitis associated with juvenile idiopathic arthritis.

Chronic anterior uveitis affects 10-30 % of patients with juvenile idiopathic arthritis (JIA) and is still a cause of blindness in childhood. In most patients it is asymptomatic, bilateral, and recurrent, so careful screening and early diagnosis are important to obtain the best long-term prognosis. The treatment of chronic uveitis associated with JIA is challenging. Initial treatment is based on topical steroids and mydriatic drops. Methotrexate is the most common first-line immunomodulatory drug used. For refractory patients, biologicals, mainly the anti-tumor-necrosis-factor (TNF) drugs adalimumab and infliximab, have been revealed to be effective and have changed the outcome for these patients. Collaboration between pediatric rheumatologists and ophthalmologists is important for the successful diagnosis and treatment of patients with uveitis associated with JIA.

Non-systemic juvenile idiopathic arthritis outcome after reaching clinical remission with anti-TNF-α therapy: a clinical practice observational study of patients who discontinued treatment.

TNF-alpha-blocking agents (anti-TNF) used in juvenile idiopathic arthritis (JIA) are well established; however, time to withdraw is unclear. Neither prolonged nor tapering treatment seems to influence risk of relapse. Our aim was to assess relapse percentage after anti-TNF withdrawal of our non-systemic JIA patients after reaching clinical remission. A retrospective review of our non-systemic JIA patients in whom anti-TNF had been withdrawn due to inactive disease was achieved, between December 2000 and November 2011. We analyzed percentages of relapse according to JIA categories and antinuclear antibodies (ANA) positivity. n = 18 patients were included. Eighty-two percentage of patients relapsed after treatment withdrawal, and mean time to relapse was 3.04 months (SD 2.03). The percentage of relapse after anti-TNF discontinuation in the main JIA category was 88 % of negative rheumatoid factor polyarticular JIA and 80 % of persistent oligoarticular JIA. We did not find significant statistical differences according to ANA positivity (9 of 14 were ANA positive), and mean time to relapse (days) was 85.0 (SD 69.4) for ANA-positive versus 102.4 (SD 47.7) for ANA-negative patients (p = NS). Relapse percentage following anti-TNF discontinuation was high (82 %) and occurred within the first 3 months after it. No relationship regarding JIA subtype and ANA positivity was found.

Current situation of osteogenesis imperfecta in Spain: results from a Delphi study.

BACKGROUND: Osteogenesis imperfecta (OI) is a rare disease characterized by low bone mass and bone fragility, associated with an increased risk of fractures, and skeletal and extra-skeletal symptoms that results in an impairment of health-related quality of life of OI patients. Since published studies on OI in Spain are limited, this study aimed to determine the epidemiology, assessed the disease burden, management and unmet needs of OI patients in Spain. Thirty-four experts in the management of patients with osteogenesis imperfecta completed two rounds of online consultation and reported real-life experience and data from Spanish hospitals. Delphi study questionnaires were based on literature review. A working group of nationally recognized clinical experts supported the development of the study questionnaires and the final validation of results. RESULTS: The estimated prevalence of patients diagnosed with OI in Spain is 0.56:10,000 inhabitants (95%CI: 0.54-0.59), which represents that, approximately, 2,669 OI patients are currently managed in Spanish hospitals. It is estimated that approximately 269 new patients would be diagnosed with OI each year in Spain, representing an estimated incidence of 0.06 (95%CI: 0.05-0.06) per 10,000 inhabitants per year. Clinical management of OI in Spain is performed by a range of medical specialists; however, multidisciplinary care is not fully implemented. The absence of an approved curative treatment or a treatment to reduce the clinical features of the disease remains the main unmet need. CONCLUSIONS: This study provides a snapshot of the current situation of patients with OI in Spain reported by clinical experts. The results provide an estimation of the epidemiology of the disease, and complement the available evidence on disease burden, clinical management, and unmet needs of these patients in Spain.

Usefulness of adalimumab in the treatment of refractory uveitis associated with juvenile idiopathic arthritis.

PURPOSE: To assess the efficacy and safety of adalimumab in patients with juvenile idiopathic arthritis (JIA) and associated refractory uveitis. DESIGN: Multicenter, prospective case series. METHODS: Thirty-nine patients (mean [SD] age of 11.5 [7.9] years) with JIA-associated uveitis who were either not responsive to standard immunosuppressive therapy or intolerant to it were enrolled. Patients aged 13-17 years were treated with 40 mg of adalimumab every other week for 6 months and those aged 4-12 years received 24 mg/m(2) body surface. RESULTS: Inflammation of the anterior chamber (2.02 [1.16] versus 0.42 [0.62]) and of the posterior segment (2.38 [2.97] versus 0.35 [0.71] decreased significantly between baseline and the final visit (P < 0.001). The mean (SD) macular thickness at baseline was 304.54 (125.03) µ and at the end of follow-up was 230.87 (31.12) µ (P < 0.014). Baseline immunosuppression load was 8.10 (3.99) as compared with 5.08 (3.76) at the final visit (P < 0.001). The mean dose of corticosteroids also decreased from 0.25 (0.43) to 0 (0.02) mg (P < 0.001). No significant side effects requiring discontinuation of therapy were observed. CONCLUSION: Adalimumab seems to be an effective and safe treatment for JIA-associated refractory uveitis and may reduce steroid requirement.

Real-World Health Care Outcomes and Costs Among Patients With Juvenile Idiopathic Arthritis in Spain.

Background: Juvenile idiopathic arthritis (JIA) is the most frequent chronic rheumatic disease in children. If inflammation is not adequately treated, joint damage, long-term disability, and active disease during adulthood can occur. Identifying and implementing early and adequate therapy are critical for improving clinical outcomes. The burden of JIA on affected children, their families, and the healthcare system in Spain has not been adequately assessed. The greatest contribution to direct costs is medication, but other expenses contribute to the consumption of resources, negatively impacting healthcare cost and the economic conditions of affected families. Objective: To assess the direct healthcare, indirect resource utilization, and associated cost of moderate-to-severe JIA in children in routine clinical practice in Spain. Methods: Children were enrolled in this 24-month observational, multicentric, cross-sectional, retrospective study (N = 107) if they had been treated with biologic disease-modifying anti-rheumatic drugs (bDMARDs), had participated in a previous study (ITACA), and continued to be followed up at pediatric rheumatology units at 3 tertiary Spanish hospitals. Direct costs included medication, specialist and primary care visits, hospitalizations, emergency visits or consultations, surgeries, physiotherapy, and tests. Indirect costs included hospital travel expenses and loss of caregiver working hours. Unitary costs were obtained from official sources (€, 2020). Results: Overall, children had inactive disease/low disease activity according to JADAS-71 score and very low functional disability as measured by Childhood Health Assessment Questionnaire score. Up to 94.4% of children received treatment, mainly with bDMARDs as monotherapy (84.5%). Among anti-TNFα treatments, adalimumab (47.4%) and etanercept (40.2%) were used in similar proportions. Annual mean (SD) total JIA cost was €7516.40 (€5627.30). Average cost of pharmacological treatment was €3021.80 (€3956.20), mainly due to biologic therapy €2789.00 (€3399.80). Direct annual cost (excluding treatments) was €3654.60 (€3899.00). Indirect JIA cost per family was €747.20 (€1452.80). Conclusion: JIA causes significant costs to the Spanish healthcare system and affected families. Public costs are partly due to the high cost of biologic treatments, which nevertheless remain an effective long-term treatment, maintaining inactive disease/low disease activity state; a very low functional disability score; and a good quality of life.

[Kawasaki disease is more prevalent in rural areas of Catalonia (Spain)]. / En Cataluña la enfermedad de Kawasaki es más prevalente en las zonas rurales.

INTRODUCTION: Kawasaki disease (KD) is an acute self-limited systemic vasculitis relatively common in childhood. The etiology of KD is still unknown, although clinical, laboratory and epidemiological features suggest an infectious origin or trigger. Differences on incidence between countries have been related to specific genetic factors, ethnicity, country of birth and some other sociocultural and environmental factors. We present a population-based study on incidence of KD in Catalonia (Spain), focusing on differences between patients in rural and non-rural areas of the region. METHODS: Observational population-based study including all Pediatric Units in Catalan hospitals, between 2004 and 2014. A 12-month (March 2013-March 2014) prospective collection of new cases of KD was carried out to determine the incidence of KD. The rest of the data was retrieved retrospectively. RESULTS: Data from 399 patients over the 10-year study period was analyzed. Among the total KD patients, 353 (88.5%) lived in non-rural areas and 46 (11.5%) in rural areas. It was found that there is a significant difference (P<.001) between the percentage of rural population observed in patients with KD (11.5%), and the expected 5% of the Catalan population. CONCLUSION: This is the first population-based study showing significant differences on KD incidence rates between rural and non-rural areas.

Evidence for Tocilizumab as a Treatment Option in Refractory Uveitis Associated with Juvenile Idiopathic Arthritis.

OBJECTIVE: To report on experience using the anti-interleukin 6 receptor antibody tocilizumab (TCZ) to treat severe and therapy-refractory uveitis associated with juvenile idiopathic arthritis (JIA). METHODS: Retrospective data were gathered from patients with JIA receiving TCZ treatment for uveitis. JIA and related uveitis data (disease onset, activity, structural complications, and topical and systemic antiinflammatory treatment) were evaluated at the start of TCZ (baseline) and every 3 months during TCZ therapy. RESULTS: A total of 17 patients (14 women) with active uveitis were included (mean age 15.3 ± 6.9 yrs, mean followup time 8.5 mos). In all patients, uveitis had been refractory to previous topical and systemic corticosteroids, methotrexate (MTX), and other synthetic and biological disease-modifying antirheumatic drugs, including ≥ 1 tumor necrosis factor-α (TNF-α) inhibitor. Uveitis inactivity was achieved in 10 patients after a mean of 5.7 months of TCZ treatment (in 3 of them, it recurred during followup) and persisted in the remaining 7 patients. By using TCZ, systemic corticosteroids or immunosuppressives could be spared in 7 patients. Macular edema was present in 5 patients at baseline and improved in all of them under TCZ treatment. Arthritis was active in 11 patients at the initial and in 6 at the final followup visit. CONCLUSION: TCZ appears to represent a therapeutic option for severe JIA-associated uveitis that has been refractory to MTX and TNF-α inhibitors in selected patients. The present data indicate that inflammatory macular edema responds well to TCZ in patients with JIA-associated uveitis.