Recurrent Stroke as a Presenting Feature of Takayasu Arteritis in an Adolescent: A Case Report and Literature Review.

Takayasu arteritis is a large vessel vasculitis, characterized by granulomatous inflammation of arterial vessels, that typically affects the aorta, its main branches and pulmonary arteries. Disease diagnosis is a challenge and requires awareness of the condition, as clinical signs can be not specific. We report a case of an adolescent with recurrent stroke diagnosed with Takayasu arteritis. A diagnosis of Takayasu arteritis was established due to angiographic findings in the magnetic resonance angiography in conjunction with systolic blood pressure discrepancy, arterial hypertension and increased acute phase reactants. Takayasu arteritis is a rare cause of ischemic stroke in children. However, stroke may be the first manifestation of the disease. Clinical experience and multidisciplinary approach, including aggressive treatment, is essential for the favourable outcome of the disease and the reduction of the associated morbidity and mortality.

International Consensus for the Dosing of Corticosteroids in Childhood-Onset Systemic Lupus Erythematosus With Proliferative Lupus Nephritis.

OBJECTIVE: To develop a standardized steroid dosing regimen (SSR) for physicians treating childhood-onset systemic lupus erythematosus (SLE) complicated by lupus nephritis (LN), using consensus formation methodology. METHODS: Parameters influencing corticosteroid (CS) dosing were identified (step 1). Data from children with proliferative LN were used to generate patient profiles (step 2). Physicians rated changes in renal and extrarenal childhood-onset SLE activity between 2 consecutive visits and proposed CS dosing (step 3). The SSR was developed using patient profile ratings (step 4), with refinements achieved in a physician focus group (step 5). A second type of patient profile describing the course of childhood-onset SLE for ≥4 months since kidney biopsy was rated to validate the SSR-recommended oral and intravenous (IV) CS dosages (step 6). Patient profile adjudication was based on majority ratings for both renal and extrarenal disease courses, and consensus level was set at 80%. RESULTS: Degree of proteinuria, estimated glomerular filtration rate, changes in renal and extrarenal disease activity, and time since kidney biopsy influenced CS dosing (steps 1 and 2). Considering these parameters in 5,056 patient profile ratings from 103 raters, and renal and extrarenal course definitions, CS dosing rules of the SSR were developed (steps 3-5). Validation of the SSR for up to 6 months post-kidney biopsy was achieved with 1,838 patient profile ratings from 60 raters who achieved consensus for oral and IV CS dosage in accordance with the SSR (step 6). CONCLUSION: The SSR represents an international consensus on CS dosing for use in patients with childhood-onset SLE and proliferative LN. The SSR is anticipated to be used for clinical care and to standardize CS dosage during clinical trials.

2019 Update of the Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of lupus nephritis.

OBJECTIVE: To update the 2012 EULAR/ERA-EDTA recommendations for the management of lupus nephritis (LN). METHODS: Following the EULAR standardised operating procedures, a systematic literature review was performed. Members of a multidisciplinary Task Force voted independently on their level of agreeement with the formed statements. RESULTS: The changes include recommendations for treatment targets, use of glucocorticoids and calcineurin inhibitors (CNIs) and management of end-stage kidney disease (ESKD). The target of therapy is complete response (proteinuria <0.5-0.7 g/24 hours with (near-)normal glomerular filtration rate) by 12 months, but this can be extended in patients with baseline nephrotic-range proteinuria. Hydroxychloroquine is recommended with regular ophthalmological monitoring. In active proliferative LN, initial (induction) treatment with mycophenolate mofetil (MMF 2-3 g/day or mycophenolic acid (MPA) at equivalent dose) or low-dose intravenous cyclophosphamide (CY; 500 mg × 6 biweekly doses), both combined with glucocorticoids (pulses of intravenous methylprednisolone, then oral prednisone 0.3-0.5 mg/kg/day) is recommended. MMF/CNI (especially tacrolimus) combination and high-dose CY are alternatives, for patients with nephrotic-range proteinuria and adverse prognostic factors. Subsequent long-term maintenance treatment with MMF or azathioprine should follow, with no or low-dose (<7.5 mg/day) glucocorticoids. The choice of agent depends on the initial regimen and plans for pregnancy. In non-responding disease, switch of induction regimens or rituximab are recommended. In pure membranous LN with nephrotic-range proteinuria or proteinuria >1 g/24 hours despite renin-angiotensin-aldosterone blockade, MMF in combination with glucocorticoids is preferred. Assessment for kidney and extra-renal disease activity, and management of comorbidities is lifelong with repeat kidney biopsy in cases of incomplete response or nephritic flares. In ESKD, transplantation is the preferred kidney replacement option with immunosuppression guided by transplant protocols and/or extra-renal manifestations. Treatment of LN in children follows the same principles as adult disease. CONCLUSIONS: We have updated the EULAR recommendations for the management of LN to facilitate homogenization of patient care.

Safety and Effectiveness of Adalimumab in Patients With Polyarticular Course of Juvenile Idiopathic Arthritis: STRIVE Registry Seven-Year Interim Results.

OBJECTIVE: To evaluate safety and effectiveness of adalimumab (ADA) in polyarticular-course juvenile idiopathic arthritis (JIA) in the STRIVE registry. METHODS: STRIVE enrolled patients with polyarticular-course JIA into 2 arms based on treatment with methotrexate (MTX) alone or ADA with/without MTX (ADA ± MTX). Adverse events (AEs) per 100 patient-years of observation time were analyzed by registry arm. Patients who entered the registry within 4 weeks of starting MTX or ADA ± MTX, defined as new users, were evaluated for change in disease activity assessed by the 27-joint Juvenile Arthritis Disease Activity Score with the C-reactive protein level (JADAS-27CRP ). RESULTS: At the 7-year cutoff date (June 1, 2016), data from 838 patients were available (MTX arm n = 301, ADA ± MTX arm n = 537). The most common AEs were nausea (10.3%), sinusitis (4.7%), and vomiting (4.3%) in the MTX arm and arthritis (3.9%), upper respiratory tract infection (3.5%), sinusitis, tonsillitis, and injection site pain (3.0% each) in the ADA ± MTX arm. Rates of serious infection were 1.5 events/100 patient-years in the MTX arm and 2.0 events/100 patient-years in the ADA ± MTX arm. AE and serious AE rates were similar in patients receiving ADA with versus without MTX. No deaths or malignancies were reported. New users in the ADA ± MTX arm showed a trend toward lower mean JADAS-27CRP compared with new users in the MTX arm in the first year of STRIVE. CONCLUSION: The STRIVE registry 7-year interim results support the idea that ADA ± MTX is well tolerated by most children. Registry median ADA exposure was 2.47 (interquartile range 1.0-3.6) years, with 42% of patients continuing ADA at the 7-year cutoff date.

In silico validation of the Autoinflammatory Disease Damage Index.

INTRODUCTION: Autoinflammatory diseases can cause irreversible tissue damage due to systemic inflammation. Recently, the Autoinflammatory Disease Damage Index (ADDI) was developed. The ADDI is the first instrument to quantify damage in familial Mediterranean fever, cryopyrin-associated periodic syndromes, mevalonate kinase deficiency and tumour necrosis factor receptor-associated periodic syndrome. The aim of this study was to validate this tool for its intended use in a clinical/research setting. METHODS: The ADDI was scored on paper clinical cases by at least three physicians per case, independently of each other. Face and content validity were assessed by requesting comments on the ADDI. Reliability was tested by calculating the intraclass correlation coefficient (ICC) using an 'observer-nested-within-subject' design. Construct validity was determined by correlating the ADDI score to the Physician Global Assessment (PGA) of damage and disease activity. Redundancy of individual items was determined with Cronbach's alpha. RESULTS: The ADDI was validated on a total of 110 paper clinical cases by 37 experts in autoinflammatory diseases. This yielded an ICC of 0.84 (95% CI 0.78 to 0.89). The ADDI score correlated strongly with PGA-damage (r=0.92, 95% CI 0.88 to 0.95) and was not strongly influenced by disease activity (r=0.395, 95% CI 0.21 to 0.55). After comments from disease experts, some item definitions were refined. The interitem correlation in all different categories was lower than 0.7, indicating that there was no redundancy between individual damage items. CONCLUSION: The ADDI is a reliable and valid instrument to quantify damage in individual patients and can be used to compare disease outcomes in clinical studies.

Performance of QuantiFERON®-TB Gold In-Tube assay in children receiving disease modifying anti-rheumatic drugs.

BACKGROUND: To evaluate the performance of the Quantiferon®-TB Gold In-Tube (QFT-IT) interferon (IFN)-γ assay for the detection of latent tuberculosis infection (LTBI) in children receiving anti-rheumatic treatment in a tertiary referral hospital of Northern Greece. METHODS: A total of 79 consecutive children receiving anti-rheumatic treatment [of which 18 screened prior to antitumor necrosis factor (TNF)-α treatment] were tested using Mantoux tuberculin skin test (TST) and QFT-IT. Association of both tests with risk factors for latent tuberculosis and Bacillus Calmette-Guerin immunization was determined. Influence of age, TNF-α inhibitors, systemic corticosteroids, conventional disease modifying anti-rheumatic drugs (DMARDs) and total duration of therapy on the QFT-IT mitogen-induced response was evaluated. RESULTS: Agreement between TST and QFT-IT results was moderate (k=0.38). Frequency of QFT-IT indeterminate results was low (2.5%). In patients with risk factors for LTBI, the odds of a positive IFN-γ assay was increased by a factor of 27.6 (P=0.002), whereas there was no positive TST. There was a significant difference in the mitogen-induced IFN-γ secretion among various treatments (P=0.038). TNF-α inhibitors were associated with increased mitogen-induced IFN-γ secretion compared to monotherapy with conventional DMARDs (P=0.008). All children screened prior to anti-TNF-α treatment exhibited a negative QFT-IT and no active TB disease was detected during a 2-year follow-up. CONCLUSIONS: QFT-IT may be a more reliable test than TST for detection of LTBI in children with rheumatic diseases receiving anti-rheumatic treatment. Drug regimen might influence the mitogen-induced IFN-γ secretion and the effect of TNF-α inhibitors might vary according to the specific agent administered.

Development of the autoinflammatory disease damage index (ADDI).

OBJECTIVES: Autoinflammatory diseases cause systemic inflammation that can result in damage to multiple organs. A validated instrument is essential to quantify damage in individual patients and to compare disease outcomes in clinical studies. Currently, there is no such tool. Our objective was to develop a common autoinflammatory disease damage index (ADDI) for familial Mediterranean fever, cryopyrin-associated periodic syndromes, tumour necrosis factor receptor-associated periodic fever syndrome and mevalonate kinase deficiency. METHODS: We developed the ADDI by consensus building. The top 40 enrollers of patients in the Eurofever Registry and 9 experts from the Americas participated in multiple rounds of online surveys to select items and definitions. Further, 22 (parents of) patients rated damage items and suggested new items. A consensus meeting was held to refine the items and definitions, which were then formally weighted in a scoring system derived using decision-making software, known as 1000minds. RESULTS: More than 80% of the experts and patients completed the online surveys. The preliminary ADDI contains 18 items, categorised in the following eight organ systems: reproductive, renal/amyloidosis, developmental, serosal, neurological, ears, ocular and musculoskeletal damage. The categories renal/amyloidosis and neurological damage were assigned the highest number of points, serosal damage the lowest number of points. The involvement of (parents of) patients resulted in the inclusion of, for example, chronic musculoskeletal pain. CONCLUSIONS: An instrument to measure damage caused by autoinflammatory diseases is developed based on consensus building. Patients fulfilled a significant role in this process.

Achievement of clinical remission in patients with juvenile idiopathic arthritis under a 2-10-year Etanercept exposure.

The objective of this retrospective study was to record the achievement of clinical remission (CR) in juvenile idiopathic arthritis patients under a 2-10 years' administration of Etanercept (ETN) and to detect any variables associated with CR. Patients previously resistant to conventional regimens were enrolled. The annual impact of ETN was assessed by: (a) the American College of Rheumatology pediatric criteria (ACRpedi), (b) the pre- and posttreatment disease activity score (juvenile arthritis disease activity score [JADAS71]), and (c) Wallace's criteria for CR. A total of 41 patients (F: 31) were registered. The median age and disease duration at baseline were 10.6 and 4.17 years, respectively, and their disease course was mainly polyarthritis (32/41). In respect to baseline, there was an impressive JADAS71 reduction posttreatment, most prominent after the first year. From year 1 to 5, more than 50 % of the patients achieved and retained CR and 66 % reached an ACRpedi 70, whereas after the 5th year, no patient was withdrawn due to an ACRpedi <30. JADAS71 at baseline was not associated with the subsequent CR achievement. However, JADAS71 1-year posttreatment had a significant association with the CR of the second posttreatment year, (p = 0.028, OR 0.79; 95 % CI 0.63-0.98) and a similar trend was observed for the following years. These findings emphasize the sustained impact of ETN in the achievement of CR. A low JADAS71 score 1-year posttreatment, may be associated with the maintenance of CR over the next treatment year.

Safety and efficacy of rituximab in refractory pediatric systemic lupus erythematosus nephritis: a single-center experience of Northern Greece.

Lupus nephritis (LN) is the major determinant of outcome in pediatric systemic lupus erythematosus (pSLE), and its treatment remains a challenge. The aim of this study was to report the experience of our center in treating with rituximab (RTX) SLE patients with severe LN. Four pSLE patients with biopsy-proven LN, who are refractory to conventional immunosuppressive treatment, received four doses of 375-500 mg/m(2) RTX, 2-3 weeks apart. All patients were concurrently receiving corticosteroids (CSs) and mycophenolate mofetil. Patients' clinical and laboratory findings were recorded at RTX initiation, after each infusion and at 3.4 ± 2.1 month intervals thereafter. pSLE activity was assessed using the European Consensus Lupus Activity Measurement (ECLAM), while LN activity using 24-hour urine protein excretion and serum cystatin C. Patients were followed up for 6-21 months (median: 16 months). Full Β-cell depletion was noticed 2-4 weeks after RTX initiation and lasted 4-7 months. All patients achieved complete LN remission 3.5 months (range: 2-4) after RTX initiation, which was retained in 3 patients through the follow-up period. One patient relapsed 15 months after RTX initiation and received one additional RTX dose. ECLAM scores and CSs doses were markedly reduced in all patients, while complement levels were increased. No side effects or infections were observed. In conclusion, RTX is an alternative, safe and efficient treatment for refractory LN.

Ghrelin levels in patients with juvenile idiopathic arthritis: relation to anti-tumor necrosis factor treatment and disease activity.

Studies in adults with rheumatoid arthritis reported low serum ghrelin that increased following anti-tumor necrosis factor (TNF) infusion. Data on juvenile idiopathic arthritis (JIA) are lacking. The aim of this pilot study was to explore serum ghrelin levels in patients with JIA and the possible association with anti-TNF treatment, disease activity, and nutritional status. Fifty-two patients with JIA (14/52 on anti-TNF treatment) were studied. Juvenile idiopathic arthritis was inactive in 3 of 14 anti-TNF-treated patients and in 11 of 38 non-anti-TNF-treated patients. The nutritional status, energy intake/requirements, appetite, and fasting serum ghrelin levels were assessed. Ghrelin control values were obtained from 50 individuals with minor illness matched for age, sex, and body mass index. Ghrelin levels in patients with JIA were significantly lower than in controls (P < .001, confidence interval [CI] = -101 to -331). Analysis according to anti-TNF treatment and disease activity showed that ghrelin levels were comparable to control values only in 3 patients with anti-TNF-induced remission. Ghrelin in non-anti-TNF-treated patients in remission was low. Multiple regression analysis showed that disease activity (P = .002, CI = -84.16 to -20.01) and anti-TNF treatment (P = .003, CI = -82.51 to -18.33) were significant independent predictors of ghrelin after adjusting for other potential confounders. Ghrelin did not correlate with nutritional status, energy balance, and appetite. Serum ghrelin is low in patients with JIA and is restored to values similar to those in controls following anti-TNF-induced remission. Our study provides evidence that TNF blockade is independently associated with serum ghrelin, which possibly contributes to anti-TNF-induced remission. These preliminary results could form the basis for future research.

Resistant pityriasis lichenoides et varioliformis acuta in a 3-year-old boy: successful treatment with methotrexate.

Pityriasis lichenoides et varioliformis acuta (PLEVA) represents the acute clinical subtype of pityriasis lichenoides (PL) and its occurrence is relatively common during childhood. Diagnosis and treatment may sometimes pose certain difficulties. We present the recalcitrant case of a 3-year-old boy with an asymptomatic polymorphic eruption consisting of multiple, scattered, 0.5 cm, round to ovoid, erythematous papules covered in places with a fine scale, vesicles and superficial erosions with thick hemorrhagic crusts. The correlation of the clinical features with the lesional histopathology favored the diagnosis of PLEVA. No first-line treatment scheme succeeded in controlling the eruption of new lesions. The only therapeutic approach that eventually managed to cease the disease evolution was the combination of prednisolone and methotrexate.

The effect of anti-TNF treatment on the immunogenicity and safety of the 7-valent conjugate pneumococcal vaccine in children with juvenile idiopathic arthritis.

Our aim was to study the effect of anti-TNF treatment on immunogenicity and safety of the 7-valent conjugate pneumococcal vaccine in children with juvenile idiopathic arthritis. Thirty-one children (mean age:12.9+/-4.6 years) treated with anti-TNFs plus Disease Modifying Anti-Rheumatic Drugs (DMARDs) and 32 age-matched children treated only with DMARDs were vaccinated with two doses of PCV7. After the first vaccine dose geometric mean titers (GMTs) were significantly increased for all vaccine serotypes (p<0.0001) in both groups and were found to be protective (>0.35microg/ml) in 87-100% of all children, depending on the serotype. Children receiving anti-TNFs achieved a significantly lower GMTs against serotypes 4, 14 and 23F (p<0.05). A >or=4-fold increase of the baseline titers to >or=5 vaccine serotypes was observed in 50% and 75% of the anti-TNF and control patients, respectively (p=0.0697). No patient developed vaccine-associated serious adverse events or disease flares.

The significance of persistent newly developed autoantibodies in JIA patients under long-term anti-TNF treatment.

OBJECTIVE: To study the significance of persistent (12 months) new autoantibodies, in Juvenile Idiopathic Arthritis (JIA) patients treated with either Infliximab (INFL) or Etanercept (ET) for 2 years. PATIENTS-METHODS: 26 children under INFL (n=12) or ET (n=14) were prospectively studied. A large panel of autoantibodies was tested using indirect immunofluorescence (ANA, anti-dsDNA, anti-ENA, SMA, LKM, AMA, PCA, anti-R1, ATA), ELISA (ANA, anti-ENA, anti-cardiolipin, ANCA), immunoblotting assay (anti-ENA: anti-Ro, anti-La, anti-Sm, anti-URNP, anti-Jo, anti-Scl70, anti-centromere, anti-ribosomal and anti-histone) and rate nephelometry (RF). RESULTS: Apart from the positive patients for ANA (13/26) and RF (2/26) prior to anti-TNF treatment, 6/26 patients (23%) developed new autoantibodies (SMA, anti-R1, ATA) which persisted for 12-50 months. None developed antibodies to nuclear antigens. In only one case, ATA was associated with the development of Hashimoto's thyroiditis. CONCLUSIONS: These findings indicate that in JIA patients in contrast to adult RA patients, development of new autoantibodies to various nuclear antigens is rare. Other non relevant to rheumatic diseases autoantibodies, may appear and persist for >12 months, but very rarely they may be related to clinical entities, especially in the presence of a positive family history of autoimmunity.