Recent advances in Pediatric Rheumatology: July 2015–June 2016

1. Analysis of published criteria for clinically inactive disease in a large juvenile dermatomyositis cohort shows that skin disease is underestimated Almeida B, Campanilho-Marques R, Arnold K, Pilkington CA, Wedderburn LR, Nistala K; Juvenile Dermatomyositis Research Group Arthritis Rheumatol 2015 Sep; 67(9), 2495–502 There is no gainsaying the fact that juvenile dermatomyositis (JDM) is a complex disease. Assessment of disease activity can be difficult. The Pediatric Rheumatology International Trials Organization (PRINTO) has recently proposed criteria for classifying patients as having 'clinically inactive disease'. The authors of this multicentric study, from the Juvenile Dermatomyositis Research Group, evaluated 1114 visits of children with JDM. This, in itself, is no mean achievement considering the rarity of this condition in pediatric practice. The authors observed that even in children classified as having 'clinically inactive disease', a significant proportion continued to have skin manifestations in the form of rash (65.8%) or abnormalities in nail-fold capillaries (35.2%). However, when physician global activity (PGA) assessment was made, an essential criterion to assess disease activity, the number of children with 'active' skin changes was much lower. It is apparent, therefore, that both muscle disease and skin disease need to be assessed individually before it is concluded that JDM is indeed inactive. 2. Medically significant infections are increased in patients with juvenile idiopathic arthritis treated with etanercept: Results from the British Society for Paediatric and Adolescent Rheumatology Etanercept Cohort Study Davies R, Southwood TR, Kearsley-Fleet L, Lunt M, Hyrich KL; British Society for Paediatric and Adolescent Rheumatology Etanercept Cohort Study Arthritis Rheumatol 2015 Sep; 67(9), 2487–94 Anti-tumour necrosis factor-α (TNF-α) medications have been the standard of care for children with juvenile idiopathic arthritis (JIA) who do not respond satisfactorily to methotrexate alone. These medications are associated with an increased risk of infections. However, the risk is not well documented in children. In this cohort study from the United Kingdom, Davies et al. have quantified the risk of medically significant infections (MSIs) in children treated with etanercept (either alone or in combination with methotrexate) and compared it with children treated with methotrexate alone. Of the 1112 children enrolled in this study, 399 received etanercept alone, 453 received etanercept with methotrexate and 260 received only methotrexate. One hundred and eighty-four patients developed MSIs during the study period. It was found that the risk of MSIs was significantly higher in children receiving etanercept. Within the etanercept group, children on monotherapy had a lower incidence of MSI than those receiving etanercept with methotrexate. However, there was no significant difference across the groups when only serious infections were considered. 3. Predictors of kidney disease in a cohort of pediatric patients with lupus Sule SD, Moodalbail DG, Burnham J, Fivush B, Furth SL Lupus 2015 Jul; 24(8), 862–8 Involvement of kidneys in systemic lupus erythematosus (SLE) is more common in children as compared to adults. Lupus nephritis is an independent and important risk factor for mortality in children. However, it is difficult to predict if a given child with lupus would go on to develop nephritis. Sule et al. have tried to develop some 'predictors' based on retrospective analysis of data on 47 children and adolescents with lupus. The authors found that chances of developing nephritis were higher in boys and they developed it within a month of diagnosis. Other predictors include presence of low serum albumin and 'isolated sterile pyuria'. Presence of malar rash and anti-Ro antibodies were found to have negative predictive values for nephritis. These findings need to be replicated on bigger, and preferably multicentric cohorts, before firm conclusions can be drawn. 4. Similarities and differences between pediatric and adult patients with systemic lupus erythematosus Tarr T, Dérfalvi B, Győri N, Szántó A, Siminszky Z, Malik A, Szabó AJ, Szegedi G, Zeher M Lupus 2015 Jul; 24(8), 796–803 It is well known that pediatric and juvenile-onset lupus is more severe than adult-onset disease. In this Hungarian study, the clinical course of 342 adult patients with lupus was compared with that of 79 children. Children had higher prevalence of lupus nephritis, hematological disorders, photosensitivity, malar rash and mucosal ulceration. Neurological symptoms and polyarthritis were more common in adults. Similarly the titres of anti-Ro, anti-La and antiphospholipid antibodies were significantly higher in adults as compared to children. Further, children were more likely to be treated with intravenous immunoglobulin and mycophenolate mofetil than adults. However, the authors have not commented on differences in morbidity and mortality between children and adults. 5. A randomized study of local anesthesia for pain control during intra-articular corticosteroid injection in children with arthritis Weiss JE, Haines KA, Chalom EC, Li SC, Walco GA, Nyirenda TL, Edelheit B, Kimura Y Pediatr Rheumatol Online J 2015 Aug 27; 13, 36 Administration of intra-articular corticosteroids is now the standard of care for children with oligoarthritis. However, it may not always be easy to inject a joint in a small child who is already in agony, is irritable and not co-operative. There are no specific recommendations for sedation and analgesia to be used for this procedure. In this multicentric study, Weiss et al. randomized their cohort of 63 patients into two groups prior to administration of intra-articular steroids: topical anesthetic alone or topical anesthetic along with subcutaneous lidocaine. It was found that addition of lidocaine to the topical anesthetic resulted in significant reduction in pain and anxiety when compared with topical anesthetic alone. The results of this study would help in formulating guidelines for control of pain during this procedure. 6. Predictors of hospital length of stay in pediatric Henoch-Schönlein purpura. Cohen N, Mimouni FB, Friedel N, Amarilyo G Rheumatol Int 2015 Sep; 35(9), 1561–4 Henoch-Schönlein purpura (HSP) is a common vasculitic disorder in children. Like other vasculitides it can have protean manifestations. Disease severity can vary from the clinically mild (and requiring nothing more than outpatient care) to a rapidly progressive glomerulonephritis (requiring aggressive immunosuppression). In this single centre study from Israel, Cohen et al. have attempted to derive an HSP Severity Score Index based on retrospective analysis of hospital records of 89 children with HSP. It was found that factors which were associated with a prolonged (> 4 days) hospital stay included abdominal pain as initial sole presentation, presence of fever, a C-reactive protein level of 45 mg/dL and age above 6 years. This index may help in assessment of disease severity at initial presentation. However, the results of this study need to be validated on a larger sample size for any meaningful conclusions to be drawn. It is also not clear why the authors have not included significant renal involvement at presentation as one of the variables for formulating the HSP Severity Score Index. 7. Chronic active disease pattern predicts early damage in juvenile systemic lupus erythematosus. Sato JO, Corrente JE, Saad-Magalhães C Lupus 2015; 24, 1421–28 There is a paucity of literature on predictors of long-term adverse outcomes in pediatric and juvenile systemic lupus erythematosus (SLE). Identification of risk factors for early damage would result in improved patient outcomes. In this retrospective analysis of 37 patients with juvenile SLE with a mean follow-up period of 3.2 years, Sato et al. found that 67.5% of them had a relapsing-remitting pattern, 29.8% had a chronic active pattern and 2.7% had long quiescent activity according to modified SLE Disease Activity Index (SLEDAI)-2K. Damage accrual, as assessed by Pediatric Systemic Lupus International Collaborating Clinics (SLICC)/ American College of Rheumatology (ACR) Damage Index (Ped-SDI), was noted in 20 (62.5%) and growth failure was noted in 10 (31.3%) patients. Progression to damage was noted significantly earlier in chronic active disease pattern (3.3 years) than in relapsing-remitting pattern (5.1 years). Duration of disease, thrombocytopenia and alopecia at the disease onset predicted damage. Further, duration of disease and presence of renal failure predicted growth failure in juvenile SLE patients. 8. Methotrexate polyglutamates as a potential marker of adherence to long-term therapy in children with juvenile idiopathic arthritis and juvenile dermatomyositis: An observational, cross-sectional study Hawwa AF, AlBawab A, Rooney M, Wedderburn LR, Beresford MW, McElnay JC Arthritis Res Ther 2015; 17, 295 Weekly administration of methotrexate is the standard of care for both JIA and JDM. However, the drug can be associated with significant gastrointestinal side effects which may interfere with compliance, especially in children. It is important to develop an objective laboratory assay for assessment of drug compliance. Hawwa et al. prospectively studied a cohort of 48 children with JIA/JDMS who were on oral or subcutaneous methotrexate for at least 2 months duration. Dried blood spot samples were obtained for assay of methotrexate polyglutamate (MTXPG) concentrations. Non-adherence was presumed when there was ≥ two-fold variation in MTXPG levels in two consecutive assays carried out at 4-weekly intervals. Subcutaneous administration of methotrexate was found to have a significantly better adherence profile as compared to the oral route. Adolescents and older children are found to be more non-adherent than younger children. Higher methotrexate dosages tend to result in higher MTXPG levels. This is a landmark study, the results of which would impact on clinical management of patients. 9. Consensus classification criteria for paediatric Behçet's disease from a prospective observational cohort: PEDBD Koné-Paut I, Shahram F, Darce-Bello M, Cantarini L, Cimaz R, Gattorno M, Anton J, Hofer M, Chkirate B, Bouayed K, Tugal-Tutkun I, Kuemmerle-Deschner J, Agostini H, Federici S, Arnoux A, Piedvache C, Ozen S, PEDBD group Ann Rheum Dis 2015 Dec 23. [Epub ahead of print] Pediatric Behçet's disease (PEDBD) is an uncommon condition that defies clinical classification. Published criteria for diagnosis have been adapted from adult guidelines and may not be valid for children as clinical manifestations in this age group may be quite different. An International Expert Consensus Group on PEDBD recruited 230 patients from 42 centers in 12 countries (European and non-European), based on the following criteria: recurrent oral aphthous ulcers at least three times a year, accompanied by one of the following: genital ulcers, vessel thrombosis or aneurysm, acneiform lesions, erythema nodosum, skin ulcerations, papulopustular lesions, positive pathergy test, posterior or panuveitis, retinal vasculitis and family history of BD. Of these, 156 (71.2%) were classified as confirmed BD by the experts. The mean age of diagnosis for confirmed BD was 13.87 ± 3.84 years. While cutaneous, ocular and vascular symptoms were more common in boys, genital ulcers were more common in girls. Most common presenting symptom was oral aphthosis (81%), followed by genital ulcers, skin symptoms and fever. One hundred and fifteen of the 156 patients with confirmed BD fulfilled the previous International Study Group criteria (sensitivity 73.7%, specificity 100%). The proposed consensus classification criteria for PEDBD entail presence of at least three of the following six features: recurrent oral aphthosis (at least three times a year); genital ulcers with scar; skin involvement (necrotic folliculitis, acneiform lesions, erythema nodosum); eye involvement (anterior or posterior uveitis, retinal vasculitis); neurological signs (with exception of isolated headaches); vascular signs (arterial or venous thrombosis, arterial aneurysm). The proposed new criteria had a sensitivity of 91.7% and a specificity of 42.9%. Addition of pathergy test was not found to improve the sensitivity, and hence was not included in the criteria. This study represents a major advance in our understanding of PEDBD. 10. The outcomes of juvenile idiopathic arthritis in children managed with contemporary treatments: Results from the ReACCh-Out cohort Guzman J, Oen K, Tucker LB, Huber AM, Shiff N, Boire G, Scuccimarri R, Berard R, Tse SM, Morishita K, Stringer E, Johnson N, Levy DM, Duffy KW, Cabral DA, Rosenberg AM, Larché M, Dancey P, Petty RE, Laxer RM, Silverman E, Miettunen P, Chetaille AL, Haddad E, Houghton K, Spiegel L, Turvey SL, Schmeling H, Lang B, Ellsworth J, Ramsey S, Bruns A, Campillo S, Benseler S, Chédeville G, Schneider R, Yeung R, Duffy CM, ReACCh-Out investigators. Ann Rheum Dis 2015; 74(10), 1854–60 The last two decades have seen a major transformation in development of management protocols for JIA. These include incorporation of biological as first-line therapy for some forms of JIA. However, there is a paucity of data on long-term outcomes of conventional treatment in JIA. Guzman et al. have carried out a prospective analysis of a cohort of 1104 children with newly diagnosed JIA at 16 Canadian pediatric rheumatology centers from 2005 to 2010. Children with oligoarthritis received non-steroidal anti-inflammatory drugs (NSAIDs) and intra-articular corticosteroids while those with polyarthritis received disease-modifying anti-rheumatic drugs (DMARDs) followed by biological agents if DMARDs alone were not sufficient for disease control. Glucocorticoids were the mainstay of therapy for patients with systemic JIA. Probability of attaining inactive disease within 2 years was found to be more than 70% for all JIA categories, except for rheumatoid factor positive polyarticular JIA (48%). Almost two-thirds of the children were able to discontinue treatment at least once within 5 years after initiation. Approximately half of the cohort achieved disease remission rates within 5 years. However, the corresponding figures were understandably much lower in children with polyarthritis. This is an important study and would impact on clinical decision-making in JIA the world over. 11. Myositis autoantibodies, clinical features, and environmental exposures at illness onset are associated with disease course in juvenile myositis Habers GE, Huber AM, Mamyrova G, Targoff IN, O'Hanlon TP, Adams S, Pandey JP, Boonacker C, van Brussel M, Miller FW, van Royen-Kerkhof A, Rider LG, Childhood Myositis Heterogeneity Study Group Arthritis Rheumatol 2015 Oct 16. [Epub ahead of print] The term juvenile idiopathic inflammatory myopathies (JIIM) encompasses several disorders such as JDM, juvenile polymyositis and juvenile connective tissue myositis. Of these, JDM is the most common in the pediatric age group. The etiology is unknown and pathogenesis remains poorly understood. In this comprehensive study, Habers et al. report on 365 patients with probable or definite JIIM. The authors have analyzed demography, early clinical features, myositis autoantibodies, environmental exposure and immunogenetic polymorphisms in the context of subsequent disease course. The authors found that a chronic or polycyclic course was more likely to be associated with anti-p155/140 antibodies and presence of infection within 6 months of disease onset, when compared with the monocyclic course. Photosensitivity, 'V' sign or 'shawl' sign rashes, and cuticular overgrowth were also correlated with a more chronic disease course. Further, a higher ultra-violet index in the month before diagnosis was more likely to be associated with a chronic disease course, especially in boys. Clearly, the last word has not been said on this subject. The clinical spectrum of JIIM is wide and the course of disease is often unpredictable. 12. High-dose aspirin is associated with anemia and does not confer benefit to disease outcomes in Kawasaki disease Kuo HC, Lo MH, Hsieh KS, Guo MM, Huang YH PLoS One 2015; 10(12), e0144603 High-dose aspirin (50–80 mg/kg/day) has been conventionally used for treatment of Kawasaki disease (KD) during the acute febrile period. Besides antipyretic action, high-dose aspirin has been thought to have 'synergistic' anti-inflammatory effects with intravenous immunoglobulin (IVIg) in reducing the risk of coronary artery abnormalities (CAA). However, this hypothesis remains unproven. Kuo et al. retrospectively analyzed 851 children with KD from 1999 to 2009. All children received the standard treatment regimen, namely IVIg at 2 g/kg. While group 1 (n = 305) received high-dose aspirin (> 30 mg/kg/day) till fever subsidence followed by low-dose aspirin (3–5 mg/kg/day), in group 2 (n = 546) low-dose aspirin (3–5 mg/kg/day) was used throughout the acute phase. The authors found that there was no statistical difference in duration of hospitalization, incidence of IVIg resistance, and development of CAA between the two groups. Further, children in group 1 had significantly lower hemoglobin values and higher C-reactive protein levels compared to group 2, after treatment with IVIg. Children in group 1 also had higher plasma hepcidin levels as compared to group 2. This study has confirmed the widely held belief that high-dose aspirin may not bequeath any additional benefits for children with KD treated with IVIg. However, as KD has a strong genetic basis, the results of this study need to be replicated from other parts of the world before a definitive conclusion can be drawn. 13. 2016 Classification Criteria for Macrophage Activation Syndrome complicating systemic juvenile idiopathic arthritis Ravelli A, Minoia F, Davì S, Horne A, Bovis F, Pistorio A, Aricò M, Avcin T, Behrens EM, De Benedetti F, Filipovic L, Grom AA, Henter JI, Ilowite NT, Jordan MB, Khubchandani R, Kitoh T, Lehmberg K, Lovell DJ, Miettunen P, Nichols KE, Ozen S, Pachlopnik Schmid J, Ramanan AV, Russo R, Schneider R, Sterba G, Uziel Y, Wallace C, Wouters C, Wulffraat N, Demirkaya E, Brunner HI, Martini A, Ruperto N, Cron RQ, Paediatric Rheumatology International Trials Organisation, the Childhood Arthritis and Rheumatology Research Alliance, the Pediatric Rheumatology Collaborative Study Group, and the Histiocyte Society, Paediatric Rheumatology International Trials Organisation the Childhood Arthritis and Rheumatology Research Alliance the Pediatric Rheumatology Collaborative Study Group and the Histiocyte Society Arthritis Rheumatol 2016 Mar; 68(3), 566–76 Macrophage activation syndrome (MAS) is a serious and life-threatening complication of many pediatric rheumatological disorders and is now being increasingly recognized. However, there is lot of debate on what constitutes MAS. The hemophagocytic lymphohistiocytosis (HLH)-2004 criteria have been widely used in clinical practice but have several limitations. The purpose of this multicentric collaborative project, involving 28 experts, was to try and develop a set of classification criteria for MAS complicating systemic JIA. The experts took patients with JIA and classified patients as having or not having MAS based on their clinical and laboratory Consensus criteria were based on These included fever as a criterion along with laboratory namely and These classification criteria have a sensitivity of specificity of and a positive predictive of for MAS complicating systemic JIA. The study by Ravelli et al. is a major advance in our understanding of this However, criteria would valid for other rheumatological associated with MAS remains a of of paediatric patients with systemic lupus erythematosus and symptoms S, R, G, G, L, G, E, G, G, G Lupus involvement in children with lupus is uncommon but can result in significant morbidity and However, our for assessment of involvement have been as have been to and both of which have limitations. et al. have in children with lupus who had symptoms but had findings on on of and the authors were able to in several children in their There was a significant between disease duration and findings on represents a significant advance in the of children with lupus and and to Kawasaki disease from other febrile Kawasaki Disease Research Group PLoS One after decades in KD remains an is even to the most based as it is on a set of clinical findings that may from to of clinical findings other febrile in children. Li et al. have tried to children with KD from febrile a on a genetic the a of that KD from febrile with a sensitivity of and a specificity of is now being increasingly evaluated for in diagnosis of KD but the remains 16. methotrexate in juvenile dermatomyositis: A Ruperto N, Pistorio A, S, F, R, Ravelli A, M, B, Sterba G, Avcin T, K, F, F, C, A, Cimaz R, G, R, P, Russo R, M, Wulffraat N, B, P, B, T, M, A, E, Pilkington C, Wouters C, S, Martini A, Paediatric Rheumatology International Trials Organisation (PRINTO) 2016 of children with JDM remains a in of significant in our understanding of this Ruperto et al. report on a randomized in patients with JDM based on data from across The treatment included the following: alone and methotrexate Results of this study that combination treatment with methotrexate or was better than alone and that methotrexate had than Methotrexate has as the disease-modifying drug for several in pediatric Children this drug much better than adults and serious are in combination with of outcomes in juvenile dermatomyositis S, Arnold KA, SL, H, Pilkington CA, Nistala K, Wedderburn LR, on of the Juvenile Dermatomyositis Research Group Arthritis Rheumatol 2016 23. [Epub ahead of print] JDM is a disease by chronic of muscle and disease course is often unpredictable. is on clinical and laboratory findings based on muscle and the of muscle is not for of clinical especially in children. In the study, et al. have that this practice may need to be The authors have evaluated validated muscle in children with definite or probable JDM in the context of not only correlated with some more were predictive of the for long-term A was often predictive of the for of This study shows that muscle and can be in children with JDM. alone may not be abnormalities in systemic lupus erythematosus patients L, C, CA, JC Lupus 2016 It is well known that children with lupus have more severe disease as compared to adults. mortality is also higher in children. While some of differences be to a for neurological and hematological involvement in involvement in pediatric lupus is not well and may well some of the et al. enrolled children with lupus and analyzed their of and abnormalities in patients with in the being the most in were noted in of patients. This study shows that manifestations are common in lupus and may result in manifestations can impact morbidity and mortality in children remains a of of lupus nephritis in onset SLE in and centre years P, B, R, A, A Lupus 2016 SLE is a Children with SLE have more severe disease and more prevalence of lupus nephritis is higher in children as compared to adults. to treatment as well as of patients with has been to vary groups. The authors to study the long-term of in children with hundred and children criteria for SLE with age of onset years were was renal disease need for renal therapy was as was seen in out of children at a mean age of years at disease was in patients. was the most common seen in of followed by seen in of in and in a mean of years, and remission was seen in and of while active nephritis was seen in of and in of children. of SLE were seen in of of children were at 5 years, at 10 years and at years. in of children on with infections being the most common and serum at onset was significantly associated with this study concluded a better in children with as compared to literature from

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