Pediatric Rheumatology Centers Research Articles

SP0038 Chronic nonbacterial osteomyelitis

Chronic nonbacterial osteomyelitis CNO is an inflammatory disorder of the musculoskeletal system with yet unknown etiology. In addition to bone inflammation, patients may present with inflammation of other tissues including...

SP0138 The Long Term Outcome of Juvenile Idiopathic Arthritis

Over the past four decades, a number of studies have evaluated the long-term outcome of juvenile idiopathic arthritis (JIA) and some of them have also attempted to identify early prognostic...

Geographical Clustering of Juvenile Onset Systemic Lupus Erythematosus within the Sultanate of Oman

While SLE is found worldwide, there is diversity in clinical presentation of the disease according to geographical variations. The aim of this study is to describe geographical distributions of childhood onset SLE within Oman to identify geographical clustering and to compare the demographic, clinical, and immunological characteristics of this cluster against the rest of Oman. We retrospectively reviewed the hospital charts of 104 consecutive children with childhood onset SLE who were seen in pediatric rheumatology centers in the Sultanate of Oman over a 15-year period between 1995 and 2010. Geographical clustering of childhood onset SLE was identified in Sharqiya region, which constituted 41% (n=43) of all cases in Oman. This cohort of patients had characteristic disease features which consisted of significantly more boys affected with SLE compared to the rest of the country (42% versus 15%; p=0.002). These children also tended to be younger (10.3 versus 16.5 years; p=0.001), diagnosed at an earlier age (6.4 versus 9.4 years; p<0.001) with a stronger family history of SLE (58% versus 33%; p=0.010). These children also had increased incidence of mucocutanous changes (81% versus 62%; p=0.036) and decreased hematological abnormalities (30% versus 51%; p=0.036). We identified geographical clustering of childhood onset SLE to Sharqiya region in Oman which is associated with unique demographical and clinical features. Whether increased prevalence of disease in this region is due to geographical, environmental, ethnic or genetic factors is yet to be determined. However, it is likely to be interplay of known and other unrecognized factors.

Seeking insights into the EPidemiology, treatment and Outcome of Childhood Arthritis through a multinational collaborative effort: Introduction of the EPOCA study

The epidemiology of juvenile idiopathic arthritis (JIA) is variable worldwide. In particular, a wide disparity exists in the prevalence of the diverse disease subtypes across different geographic areas. The therapeutic approach to JIA is not standardized and no established and widely accepted guidelines are available. In the past decade, there have been important progresses in the management of the disease, but the availability of the novel and costly biologic medications is not uniform throughout the world. This issue may have significant impact on disease prognosis, with children living in poorer countries being at greater risk of accumulating disease- and treatment-related damage than children followed in Western pediatric rheumatology centers. The multinational study of the EPidemiology, treatment and Outcome of Childhood Arthritis (EPOCA study) is aimed to obtain information on the frequency of JIA subtypes in different geographic areas, the therapeutic approaches adopted by pediatric rheumatologists practicing in diverse countries or continents, and the disease and health status of children with JIA currently followed worldwide. Parent- and child-reported outcomes are meant to be recorded through the administration of a new multidimensional questionnaire, the Juvenile Arthritis Multidimensional Assessment Report (JAMAR). The first step of the study is based on the translation and cross-cultural adaptation of the questionnaire in the national language of each participating country. Each center is, then, asked to enroll a sample of consecutive JIA patients, who should undergo a retrospective assessment and a cross-sectional evaluation, including completion of the JAMAR, a standardized joint examination, and the assessment of articular and extra-articular damage. At the end of May 2012, 124 centers in 55 countries have agreed to participate in the study. The JAMAR has been or is currently being translated in 38 national languages. The target patient sample is more than 10,000 JIA children worldwide.

Clinical remission in juvenile idiopathic arthritis after termination of etanercept

Biologicals are very effective for inhibiting disease progression in active juvenile idiopathic arthritis (JIA). To date, there have been no recommendations on how and when to stop therapy with TNF inhibitors. Our objective was to analyze characteristics and the disease course of JIA patients who discontinued etanercept due to achievement of inactive disease. Data of 39 patients with JIA from two clinical pediatric rheumatology centers in Bydgoszcz and Lublin (Poland) were analyzed retrospectively. All patients discontinued etanercept due to a remission on treatment. Etanercept was started after a mean 33.7 ± 36 (range 3–137) months of disease. The mean duration of therapy with etanercept was 34.7 ± 16.7 (range 6–72) months, with a mean duration of remission on medication 21.3 ± 9.6 (range 4–42) months before withdrawal of etanercept. The mean duration of remission after etanercept discontinuation was 14.2 ± 12.1 (range of 1–60) months. Only 12/39 (30.8 %) patients did not develop a disease exacerbation until the end of the study. Early flares, that is less than 6 months after termination of etanercept, were observed in 15/39 (38.5 %) patients. Twelve (30.8 %) patients restarted etanercept after exacerbation—all patients responded satisfactorily. Our data show that etanercept discontinuation in a substantial proportion of JIA patients results in early disease exacerbation. In many cases, reintroduction of etanercept is needed. Patients, in whom etanercept was restarted, responded satisfactorily.

Treatment of autoinflammatory diseases: results from the Eurofever Registry and a literature review

ObjectiveTo evaluate the response to treatment of autoinflammatory diseases from an international registry and an up-to-date literature review.MethodsThe response to treatment was studied in a web-based registry in which clinical...

Timing of uveitis onset in oligoarticular juvenile idiopathic arthritis (JIA) is the main predictor of severe course uveitis

Aim of the present study was to validate a statistical model to predict a severe course of anterior uveitis (AU) in patients with juvenile idiopathic arthritis (JIA). Consecutive patients with newly diagnosed uveitis have been followed for at least 1 year with a standardized protocol. For each patient, demographic, clinical and laboratory characteristics, including time interval between arthritis and uveitis onset, α(2)-globulins level at arthritis onset, number of uveitis relapses/year, ocular complications and therapy and visual acuity, have reported. The validation procedure included the assessment of sensitivity, specificity and efficiency of previously published statistical model (Zulian et al. J Rheumatol 2002; 29: 2446-2453) in a new inception cohort of patients during a short length follow-up. Sixty patients with JIA, followed at 14 paediatric rheumatology-ophthalmology centres in Italy, entered the study. The mean age at arthritis onset was 4.4 years (range 1.2-15.8 years), and the mean interval time between arthritis and uveitis onset was 1.8 years (range: 0.0-14.2 years). After the first AU, patients, followed for a mean of 3.2 years, had a mean of 2.9 uveitis relapses. Twenty-two patients (36.7%) presented at least one complication. Using a probability cut-off value = 0.7, the statistical model revealed 80% sensitivity, 58% specificity and 65% efficiency. The time interval between arthritis and uveitis onset resulted as the main predictor of severe course uveitis in JIA. The statistical model was able to predict the development of a severe course in 8 of 10 patients.

Systemic Lupus Erythematosus (SLE) Complicated by Neuromyelitis Optica: Case Series from a Tertiary Paediatric Rheumatology Centre

Objective: To identify the presence of Neuromyelitis optica (NMO) in juvenile SLE patients.Background: NMO is a rare autoimmune demyelinating disease of the central nervous system, manifesting with transverse myelitis involving three or more continuous spinal segments and optic neuritis in the presence of NMO-IgG antibodies.Methods: Retrospective study of SLE patients with CNS symptoms, diagnosed from 2000 to2010 and review of clinical data, laboratory and MRI findings.Setting: A tertiary referral centre for juvenile SLE.Results: A total of 210 SLE patients were indentified, 39 of which had manifestations of potential CNS involvement and underwent CNS imaging including the spinal cord. Three were indentified with probable NMO, which was confirmed in two (0.9%). Both patients were adolescent females of Caucasian origin. In one patient NMO was the first manifestation of SLE. In the other NMO developed three years following diagnosis of SLE. They both presented with deterioration of visual acuity, localized spinal tenderness and malaise. NMO was confirmed based on MRI findings and the presence of raised Aquaporin-4-IgG-antibodies. NMO had a relapsing course and interestingly NMO relapses coincided with SLE disease flare-up, both of which responded to treatment simultaneously.Discussion: SLE is a multisystemic autoimmune disease and 25% of patients develop CNS involvement. While NMO has been described in adult patients with SLE, these cases derive specifically from a paediatric population. We believe that SLE and NMO are parts of the same disease spectrum. When this condition is noticed in patients with refractory, long standing SLE, prognosis is guarded.

Effectiveness of dexamethasone iontophoresis for temporomandibular joint involvement in juvenile idiopathic arthritis

Temporomandibular joint (TMJ) involvement is common in juvenile idiopathic arthritis (JIA). Dexamethasone iontophoresis (DIP) uses low-grade electric currents for transdermal dexamethasone delivery into deeper anatomic structures. The purpose of this study was to assess the safety and effectiveness of DIP for the treatment of TMJ involvement in JIA, and to delineate variables that are associated with improvement after DIP. Medical records of all JIA patients who underwent DIP for TMJ involvement at a larger tertiary pediatric rheumatology center from 1997-2011 were reviewed. DIP was performed using a standard protocol. The effectiveness of DIP was assessed by comparing the maximal interincisor opening (MIO(TMJ) ) and the maximal lateral excursion (MLE(TMJ) ) before and after treatment. Twenty-eight patients (ages 2-21 years) who received an average of 8 DIP treatment sessions per involved TMJ were included in the analysis. Statistically significant improvement in the median MIO(TMJ) (P < 0.0001) was observed in 68%. The median MLE(TMJ) (P = 0.03) improved in 69%, and resolution of TMJ pain occurred in 73% of the patients who had TMJ pain at baseline. Side effects of DIP were transient site erythema (86%), skin blister (4%), and metallic taste (4%). Improvement in TMJ range of motion from DIP is associated with lower MIO(TMJ) , lower MLE(TMJ) , and absence of TMJ crepitus at baseline. In this pilot study, DIP appeared to be an effective and safe initial treatment of TMJ involvement in JIA, especially among patients with decreased TMJ measurements. Prospective controlled studies are needed.

Pediatric regional examination of the musculoskeletal system: A practice‐ and consensus‐based approach

Competent examination of the pediatric musculoskeletal (MSK) system is a vital component of clinical assessment of children with MSK presentations. The aim was to develop a regional MSK examination for school-age children that is age appropriate and reflects clinical practice. Qualitative and quantitative analyses involving video observation of clinical examination technique, systematic review, and expert consensus were employed to reveal descriptions, frequencies, and variations in technique for joint regions in various clinical scenarios. Systematic review and data from clinical observation were combined with feedback from a group of pediatric MSK experts through a web-based survey. All results were collated and discussed by consensus development groups to derive the pediatric Regional Examination of the Musculoskeletal System (pREMS). A total of 48 pediatric MSK expert clinicians were involved to derive pREMS. Systematic review revealed a paucity of evidence about regional pediatric MSK examination. Video observations of MSK examinations (a total of 2,901 maneuvers) performed by pediatric MSK experts (n = 11 doctors and 8 therapists) of 89 school-age children attending outpatient clinics in 7 UK pediatric rheumatology centers were followed by semistructured interviews with 14 of 19 clinicians. Video observation showed variation in examination techniques, most frequently at the hip and knee in the context of mechanical and inflammatory clinical scenarios. pREMS is the first practice- and consensus-based regional pediatric MSK examination for school-age children. The structured approach is an important step toward improved pediatric MSK clinical skills relevant to clinical training.

Brazilian multicentre study of Takayasu’s arteritis in children and adolescents – preliminary results of a clinical, imaging and therapeutic study

We retrospectively evaluated 55 patients with Takayasu’s arteritis from 8 Pediatric Rheumatology centers in Brazil. All patients fulfilled the specific classification criteria for TA that have most recently been developed for the pediatric age group. Clinical, data were collected at two time points (at disease onset and at the last available visit). Results The majority of patients were girls (84%), with mean age at disease onset of 9.3 years, mean age at diagnosis of 10.6 years and a mean follow-up period of 5.6 years. The most common initial clinica lm anifestations included headache (56.3%), malaise (56.3%), weight loss (45.4%), dyspnea (41.8%) and limb pain (41.8%). The most common cardiovascular finding was hypertension (85.4%). The most frequent laboratory abnormality was an increased erythrocyte sedimentation rate (70.9%). The Mantoux test was positive in 38% of patients. The most common alteration was narrowing or stenosis. The most involved vessels were abdominal aorta (71.8%) followed by left (56.2%) and right renal artery (53.1%). At the last visit the most common clinical manifestations were: headache (22%), inferior limb claudication (14%) and arthralgias (12%); Cardiovascular finding included the absence or decrease of the inferior limb pulses (52%). The treatment included imunossupressors other than corticosteroids in 83.6% and anti-TNF antagonists in 7.2% of patients. Seventeen (30.9%) patients underwent surgical intervention and 5 (9%) died of complication from treatment or from disease related complications. Conclusion In this large survey of children and adolescents with Takayasu’s arteritis from Brazil a delay in the diagnosis and a high rate of Mantoux test positivity were observed. A death rate similar to the described in literature was found.

Off-label use of biological agents in the management of uveitis: experience from a pediatric rheumatology centre

Background Uveitis is a common extra-articular feature in juvenile idiopathic arthritis (JIA), particularly in female patients with the extended oligoarticular subtype. A significant number of patients already have ocular complications at time of diagnosis of uveitis. JIA-associated uveitis carries significant ocular morbidity that can progress into adulthood. Treatment with immunosuppressive agents can reduce the risk of ocular complications. Although controlled clinical trials are under way to assess the efficacy of biologic agents in JIA-associated uveitis, therapies with these agents seem to have encouraging results.

Therapy of autoinflammatory diseases: results from an international registry

Methods A web-based registry collecting baseline and clinical information of autoinflammatory diseases was located at the member area of the PRINTO website (www.printo. it). Participating hospitals included pediatric rheumatology centers of the PRINTO network and adult centers with a specific interest in autoinflammatory diseases. Data was collected on Blau’s syndrome, Behcet’s disease, CAPS, CRMO, DIRA, FMF, MKD, NLRP12-mediated periodic fever, PAPA, PFAPA TRAPS and undefined periodic fevers. In total, 704 patients were included in this retrospective study on therapy.

Comparison of data from the juvenile dermatomyositis national (UK &amp; Ireland) cohort biomarker study and repository for idiopathic inflammatory myopathies with a survey of current practice throughout the UK and Ireland

Results Fifteen of 16 Paediatric Rheumatology centres responded to the survey. For initial treatment of patients with mild disease 13/15 centres report using a combination of steroids and methotrexate and 8/15 would also use IV methylprednisolone. For moderately severe disease all centres use steroids and methotrexate and 11/15 also use IV methylprednisolone. With severe weakness, ulceration or systemic disease all centres use IV methylprednisolone as initial treatment, 13/15 use methotrexate and 9/15 use cyclophosphamide. Prospective data were analysed from 98 patients in the UK JDM cohort study. A combination of steroids and methotrexate was used in the first year of treatment in 78% of patients with mild disease (PGA 03.3cm), 89% of patients with moderately severe disease (PGA 3.4-6.7cm) and 100% of patients with severe disease (PGA 6.8-10cm). Cyclophosphamide was used within the first year of diagnosis in 16% of patients with mild disease at presentation, 19% of patients with moderately severe disease and 38% of those with severe disease (p=0.05). There was no significant association between severity of disease at diagnosis and the use of intravenous steroids.

Systemic Lupus Erythematosus complicated by Neuromyelitis Optica (Devic’s Syndrome): case series from a single paediatric rheumatology centre

Results A total of 210 (161 females, 49 males) SLE patients were indentified, 39 of which had manifestations of potential CNS involvement and underwent imaging of their CNS including spinal cord. Three were indentified with probable Devic syndrome, which was confirmed in two (0.9%). Both patients were adolescent females and of Caucasian origin. In one patient NMO was the first manifestation of SLE. In the other NMO developed three years following diagnosis of SLE. They both presented with deterioration of visual acuity, localized spine tenderness and malaise. NMO was confirmed based on MRI findings and the presence of raised Aquaporin-4 IgG antibodies in the plasma. On both occasions NMO had a relapsing course and interestingly NMO relapses coincided with SLE disease flare-up, which responded to treatment simultaneously. The patient with ongoing SLE had a more severe course and required more intensive immunosuppressive treatment. Both patients developed depression following diagnosis of NMO.

Malignancies in Juvenile Idiopathic Arthritis: A Preliminary Report: Table 1.

To present preliminary data on incidence of malignancy in juvenile idiopathic arthritis (JIA), compared to general population rates. We examined cancer occurrence within JIA registries at 3 Canadian pediatric rheumatology centers. The subjects in the clinic registries were linked to regional tumor registries to determine the occurrence of invasive cancers over the observation period (spanning 1974-2006). The total number of cancers expected was determined by multiplying the person-years in the cohort by age, sex, and calendar year-specific cancer rates. The standardized incidence ratio (SIR, ratio of cancers observed to expected) was generated, with 95% confidence intervals. The study sample consisted of 1834 patients. The female proportion was 67.6%; average age at entry to cohort was 8.6 years (SD 5.1). The majority were Caucasian. Subjects contributed 22,341 patient-years (average 12.2, SD 7.8). Within this observation period, one invasive cancer occurred, compared to 7.9 expected (SIR 0.12, 95% CI 0.0, 0.70). This was a hematological cancer (Hodgkin's lymphoma), representing a SIR for hematological malignancies of 0.76 (95% CI 0.02, 4.21). Only one invasive cancer was identified in this large sample of individuals with JIA, observed for an average of 12.2 years each. These data suggest that, at least in the initial years following diagnosis of JIA, the risk of invasive cancers overall is not markedly increased. The results do not rule out the possibility of a baseline increased risk of hematological malignancies.

Perfil da doença de Kawasaki em crianças encaminhadas para dois serviços de reumatologia pediátrica do Rio de Janeiro, Brasil

To describe a population of children diagnosed with Kawasaki's disease (KD) in pediatric rheumatology centers of Rio de Janeiro, Brazil, defining the magnitude of the delay period in diagnosing KD and initiating treatment due to confusion with common childhood febrile illnesses and the impact of this delay on the frequency of coronary sequels. Data analysis from hospital records summarized in a dedicated form, including name, gender, age, date of first recorded clinical signs, date of admission to the specialty service, information about symptoms, clinical evolution, intravenous immunoglobulin (IVIG) use and coronary sequels. Of 125 patients, 63% were males. 40% were under 2 years at diagnosis. Average lapse between earliest signs and KD diagnosis was 12 days (mean fever duration, 14 d). Only 22.4% had a diagnosis of KD before entering the specialty service. For the remainder, initial hipotheses included: bacterial (60%) and viral infections (12%), rheumatological diseases (4%) and adverse vaccination reactions (1.6%). Hence, prevalent febrile illnesses of childhood were major confounding factors. For records (85.6%) mentioning treatment, 46.7% reported IVIG treatment, beginning after day 10 in 23 cases (21.5%). 20 patients (16%) presented coronary sequels, 9 of which were diagnosed late, including 3 given IVIG after day 10, and 6 given no IVIG. We found no significant association between the frequency of coronary sequels and: a) sex; b) age; c) clinical criteria; d) initiation of IVIG treatment (before or after day 10). Common febrile illnesses of childhood often confound the diagnosis of KD.

Factors Associated with a Longer Time to Access Pediatric Rheumatologists in Canadian Children with Juvenile Idiopathic Arthritis

The Research on Arthritis in Canadian Children Emphasizing Outcomes (ReACCh Out) cohort is a prospective inception cohort of patients with newly diagnosed juvenile idiopathic arthritis (JIA) seen in 16 Canadian pediatric rheumatology (PR) centers. We used data from this cohort to explore factors associated with longer time from symptom onset to the first visit to (PR), and with longer time from first visit to a diagnosis of JIA. We included children enrolled in ReACCh Out within 6 months of JIA diagnosis, for whom the dates of symptom onset and first PR visit were recorded. We used Cox proportional hazard modeling to investigate the effects of history, physical examination, and laboratory evaluation on the interval from JIA symptom onset to first PR assessment. In total, 319 children from the cohort were included. Having a fever (hazard ratio 1.80, 95% CI 1.10, 2.93), any part South Asian ethnicity (HR 1.75, 95% CI 1.04, 2.95), highly educated parents (HR 1.69, 95% CI 1.18, 2.44), and limp (HR 1.55, 95% 1.16, 2.06) were significantly associated with shorter time from symptom onset to first PR assessment, while a history of heel pain or enthesitis (HR 0.61, 95% 0.38, 0.97) was significantly associated with a longer time to first PR visit. Children with a history of a fever, limp, any part South Asian ethnicity, or highly educated parents were more likely to see PR sooner than patients without these features, while children with a history of enthesitis received PR care later than those without enthesitis.

PFAPA syndrome is not a sporadic disease

To determine whether PFAPA (periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis) patients have a positive family history (FH) for recurrent fever syndromes. For all patients with PFAPA seen in two paediatric rheumatology centres (Romandy, Switzerland and Bordeaux, France), parents were interviewed to record the FH for periodic fever. As controls, we interviewed a group of children without history of recurrent fever. We recruited 84 patients with PFAPA and 47 healthy children. The FH for recurrent fever (without an infectious cause and recurring for at least half a year) was positive in 38/84 (45%), and was positive for PFAPA (diagnosis confirmed by a physician) in 10/84 (12%) of the PFAPA patients. For 29 of the 38 patients with positive FH, the affected person was a sibling or a parent. None of the healthy children had a positive FH for recurrent fever or PFAPA. A positive FH for rheumatological diseases was seen in both groups of children. These data show that a significant percentage of PFAPA patients present a positive FH of recurrent fever and PFAPA. This familial susceptibility suggests a potential genetic origin for this syndrome.

Risk factors for development of uveitis differ between girls and boys with juvenile idiopathic arthritis

Uveitis is the most common extraarticular manifestation of juvenile idiopathic arthritis (JIA) and is associated with considerable morbidity. The aim of this study was to examine the risk factors associated with uveitis in JIA. We conducted a chart review of 1,047 patients with JIA from a single tertiary care pediatric rheumatology center for factors associated with the development of uveitis. Special emphasis was put on the following known risk factors: oligoarthritis, antinuclear antibody (ANA) status, sex, and age at the time of onset of JIA. The risk of uveitis developing was age dependent in girls but not in boys. Among girls, the risk was maximal (47%) in those who were ANA positive and were ages 1-2 years at the time of the onset of JIA; this risk decreased to <10% in those in whom the age at onset was >7 years. Only girls had an age-dependent and ANA-associated increased risk of uveitis. The time interval from the diagnosis of JIA to the diagnosis of uveitis was statistically significantly longer in patients in whom the onset of JIA occurred at a younger age (P = 0.04). This effect was even more pronounced in ANA-positive patients (P = 0.004). The JIA subtype did not influence a patient's risk of the development of uveitis. An age-associated risk of uveitis was observed only in girls who were younger than 7 years of age at the time of the onset of JIA. The duration of time between the diagnosis of JIA and the onset of uveitis was longer in patients in whom JIA was diagnosed at a younger age, especially in those who were ANA positive. We suggest that our findings have implications for uveitis screening in patients with JIA.