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ObjectiveNeonatal lupus erythematosus (NLE) is a passively acquired autoimmune disease in infants born to anti-Ro and/or anti-La autoantibody-positive mothers. Genetics may affect NLE risk. We analyzed the genetics of infants and anti-Ro antibody-positive mothers, with NLE and NLE-specific manifestations.MethodsInfants and mothers from a tertiary care clinic underwent genotyping on the Global Screening Array. We created additive non-HLA and HLA polygenic risk scores (PRS) for systemic lupus erythematosus (SLE), from one of the largest genome-wide association studies. Outcomes were any NLE manifestations, cardiac NLE, and cutaneous NLE. We tested the association between SLE-PRS in the infant, mother, and the PRS difference between the mother and infant with NLE outcomes, in logistic regression and generalized linear mixed models (Bonferroni P< 0.02). We also performed HLA-wide analyses for the outcomes (P< 5.00 × 10–8).ResultsThe study included 332 infants, 270 anti-Ro antibody-positive mothers, and 253 mother-infant pairs. A large proportion of mothers (40.4%) and infants (41.3%) were European, and 50% of infants were female. More than half of the infants had NLE (53%), including 7.2% with cardiac NLE and 11.7% with cutaneous NLE. We did not identify significant associations between infant PRS, maternal PRS, or maternal-infant PRS difference and any NLE outcomes. HLA-wide analyses did not identify NLE risk alleles.ConclusionIn a multiethnic cohort of infants and anti-Ro antibody-positive mothers, we did not identify a significant association between SLE genetics and risk of NLE outcomes.

Childhood-onset systemic lupus erythematosus (cSLE) patients are unique, with hallmarks of Mendelian disorders (early-onset and severe disease) and thus are an ideal population for genetic investigation of SLE. In this study, we use the transmission disequilibrium test (TDT), a family-based genetic association analysis that employs robust methodology, to analyze whole genome sequencing data. We aim to identify novel genetic associations in an ancestrally diverse, international cSLE cohort. Forty-two cSLE patients and 84 unaffected parents from 3 countries underwent whole genome sequencing. First, we performed TDT with single nucleotide variant (SNV)-based (common variants) using PLINK 1.9, and gene-based (rare variants) analyses using Efficient and Parallelizable Association Container Toolbox (EPACTS) and rare variant TDT (rvTDT), which applies multiple gene-based burden tests adapted for TDT, including the burden of rare variants test. Applying the GWAS standard threshold (5.0 × 10−8) to common variants, our SNV-based analysis did not return any genome-wide significant SNVs. The rare variant gene-based TDT analysis identified many novel genes significantly enriched in cSLE patients, including HNRNPUL2, a DNA repair protein, and DNAH11, a ciliary movement protein, among others. Our approach identifies several novel SLE susceptibility genes in an ancestrally diverse childhood-onset lupus cohort.

OBJECTIVES: To determine the health of mothers of offspring with complete congenital heart block (CHB) both at the time of delivery of the affected child and in the long-term, and the percentage of mothers of children with CHB who had anti SSA/RO and/or SSB/LA antibodies. PATIENTS AND METHODS: Sixty-four mothers of 64 children with CHB (seen between 1964 and 1993) were identified through the Cardiology database of The Hospital for Sick Children, Toronto, Canada. Medical information from these of children with CHB was evaluated. Data were obtained from the mothers by mailed questionnaire, telephone interview, and/or from the attending physicians. The presence of anti-Ro antibodies and anti-La antibodies were evaluated by ELISA assay. RESULTS: The mean age at the time of delivery of the first child with CHB was 28 [+ or -]6 years. At the time of delivery 42 (66%) mothers were healthy, 2 (3%) had systemic lupus erythematosus (SLE), 2 (3%) had linear scleroderma, 2(3%) had rheumatoid arthritis; 3(5%) had a history of rheumatic fever (but were otherwise well), 1(2%) had Sjogren's syndrome (SS), and 12(19%) had an undifferentiated autoimmune syndrome (UAS) (arthralgia, myalgia, photosensitivity, skin vasculitis, Raynaud's phenomenon). The mean time to follow-up from delivery to study was 121 [+ or -]88 months. The mean maternal age at study was 38 [+ or -]9 years. Three of 12 mothers who initially had a UAS progressed to SLE (average follow-up time of 80 months, median 96), and 2 developed SS (with average follow-up time 140 months, median 132) and 1 went into remission. The mean follow-up time for the other mothers who did not develop an autoimmune disease was 150 [+ or -]102 months. Thirty-six of the 42 initially healthy mothers remained well. One mother developed SLE; 1 developed hyperthyroidism; 1 developed ankylosing spondylitis; and 3 developed an UAS. The mean follow-up time of the 36 mothers who remained healthy was similar (123 [+ or -]97 months) to the 6 initially healthy mothers who developed an autoimmune disease (121 [+ or -]36 months). Anti-Ro and/or anti-La antibodies were positive in 32 of 53 (60%) mothers tested. Fourteen of the 53 mothers were symptomatic at the time of delivery and 39 were asymptomatic. Anti-Ro and/or anti-La antibodies were positive in 12 of 13 mothers tested at the time of delivery. CONCLUSIONS: The long-term maternal outcome in our cohort was very good as most of the initially healthy mothers remained well at follow-up. Twenty-five percent of the mothers with a UAS and only 2% of the initially healthy mothers developed SLE. The development of an autoimmune disease in an asymptomatic mother identified by the birth of a child with CHB was less common in our study than in previous studies. However, close follow-up of mothers with UAS is warranted.

The aim of this study was to examine the impact of timing of a childhood‐onset systemic lupus erythematosus (SLE) diagnosis relative to menarchal status, on final height, accounting for disease‐associated factors. We conducted a cohort study of female patients age <18 years at childhood‐onset SLE diagnosis, followed at a tertiary care pediatric center from July 1982 to March 2016 and restricted to patients with documented age of menarche and final height. We compared final height between patients diagnosed pre‐ and postmenarche. We tested the association of the timing of childhood‐onset SLE diagnosis with final height, adjusted for ethnicity, in linear regression models. We performed subgroup analyses of patients with growth during follow‐up, additionally adjusting for average daily corticosteroid dose and disease activity. Of 401 female childhood‐onset SLE patients in the study, 115 patients (29%) were diagnosed premenarche and 286 (71%) postmenarche. Patients diagnosed premenarche were older at menarche compared with patients diagnosed postmenarche (mean ± SD age 13.5 ± 1.4 versus 12.5 ± 1.3 years; P< 0.001). The mean ± SD final height for girls diagnosed postmenarche (161.4 ± 6.9 cm) was greater than for those diagnosed premenarche (158.8 ± 7.3 cm; P= 0.001). In regression analysis, those diagnosed postmenarche were significantly taller than those diagnosed premenarche, as adjusted for ethnicity and disease severity (mean ± SD β = 2.6 ± 0.7 cm; P= 0.0006). In this large cohort study of girls with childhood‐onset SLE, patients diagnosed postmenarche achieved a taller final height than those diagnosed premenarche, even after accounting for ethnicity and disease severity.

Misoprostol appears to counteract the adverse gastrointestinal effects of non-steroidal anti-inflammatory drug (NSAID) treatment of rheumatoid diseases in children. Misoprostol is a synthetic analogue of prostaglandin E1. It inhibits flow of stomach acid, increases mucous secretion, which helps protect the stomach lining, and enhances healing of irritated tissues. Twenty-five children ranging in age from 7 to 17 were given misoprostol during NSAID treatment. Of the 88% experiencing stomach pain, nausea, vomiting, or bloating, 82% had complete resolution of symptoms and a further 9% showed improvement. Hemoglobin levels rose even in patients who were not anemic, which suggests that minor injuries contributing to blood loss had healed. One patient experienced diarrhea, which resolved on its own without need to discontinue misoprostol treatment.

Dermatomyositis is a connective tissue disease characterized by muscle inflammation and deterioration, skin inflammation, and accumulation of tissue fluid. This condition is most often treated with prednisone (a steroid), although some patients have little or no response to steroid treatment. Other patients become dependent on steroids or develop drug-related side effects. Patients who do not respond to, or cannot tolerate, steroid treatment are given immunosuppressive agents, which reduce immune function. However, immunosuppressive drugs, such as methotrexate, azathioprine, cyclophosphamide, chlorambucil, and cyclosporin A have not been consistently effective in treating dermatomyositis and may cause toxic effects, particularly in children. High doses of intravenous gammaglobulin (IVGG), an immune protein preparation, have been effective in treating various immune disorders, including one reported case of infantile polymyositis, a condition occurring in children that is similar to dermatomyositis. The effectiveness of IVGG was assessed in five patients with juvenile dermatomyositis. Prior treatment with steroids did not improve muscle weakness in these patients and caused toxic effects in three patients. In addition, previous therapy with immunosuppressive agents caused toxic effects in two patients. Treatment with IVGG increased muscle strength and improved skin inflammation. Muscle strength was increased from 56 to 606 percent in the legs, and from 30 to 186 percent in the arms. The use of IVGG eliminated or reduced the need for steroid therapy. These findings show that IVGG is effective in treating juvenile dermatomyositis, reduces the need for steroid treatment, and may be considered as an alternative to traditional therapy for juvenile polymyositis. (Consumer Summary produced by Reliance Medical Information, Inc.)

Kawasaki disease (KD) causes high fever, rash, and frequent cardiac complications in young children; the cause of disease disorder is unknown. KD is currently treated with aspirin, or other salicylates, and gamma-globulin. The reason that salicylate therapy is effective and the best dosage have been debated, and have not been well-studied. Previous research has suggested that the handling of salicylates in children with KD is altered; absorption is decreased, while excretion is increased during the acute phase of the illness. This has led to treatment with higher doses to keep blood levels of salicylates in the therapeutic range. Aspirin and other drugs are chiefly transported in blood by albumin (a protein). A small portion remains free, or unbound, and this free portion is the therapeutically effective fraction. One study has found decreased salicylate-protein binding in KD patients, which should lead to higher free levels of salicylate, so that more would be available for the therapeutic effect. If this is not accounted for, and salicylate dosage is increased, toxic effects may occur. Salicylate-protein binding was evaluated in 36 patients with KD. Protein binding of salicylate during the acute phase of KD averaged 73 percent, and increased significantly during the subacute phase to 90 percent. Albumin levels were 29.2 grams per liter of blood (gm/L) during the acute phase and 36.7 gm/L during the subacute phase. Normally, total salicylate levels correlate closely with protein-salicylate binding, but patients with KD had lower than normal protein-salicylate binding per level of total salicylates. Protein-salicylate binding in KD patients correlated significantly with albumin levels. Calculations showed that children with low albumin levels had twice as much free salicylates. Tinnitus (ringing in ear), a sign of salicylate toxicity, was not reported in these patients. These findings should be considered when adjusting salicylate dosage in children with KD. (Consumer Summary produced by Reliance Medical Information, Inc.)

This report discusses the case of a two-month-old boy who entered a hospital with fever, pallor, irritability, and cyanosis (blue skin color, indicating reduced hemoglobin in the blood). Three weeks before admission, the infant had a fever and raspy breathing, but a chest X-ray revealed no signs of pneumonia. He was treated with an antibiotic and subsequently developed a widespread red rash and lip bleeding, which disappeared three days after discontinuing the antibiotic. The infant seemed better, but did not sleep well and was constipated; he then developed blood in the stool, cyanotic toes, and a pink stain on his diaper indicated a urinary problem. The infant's course in the hospital and in the critical care unit to which he was transferred is described. An initial diagnosis of meningitis was considered, for which antibiotics were given, but no bacteria could be isolated. The possibility of pneumonia was then considered. The infant had raised levels of white blood cells, continued peripheral cyanosis, but normal heart rate and respiration 10 hours after admission to critical care. He suddenly developed cardiac fibrillation (very fast, ineffective heart beat) and could not be resuscitated. The signs and symptoms are reviewed with reference to possible causes. Sudden death in an infant with no resuscitation of a previously beating heart is very rare. The final diagnosis was infantile polyarteritis nodosa, with involvement of coronary and systemic arteries. The pathologist's report corroborated this diagnosis, which is more appropriately called Kawasaki disease, as the disorder does not resemble the adult form of polyarteritis nodosa. Typical signs of Kawasaki disease normally include five of the six following signs: high fever lasting more than five days; eye inflammation; redness and swelling of the oral cavity; swelling of palms of hands and feet with redness and peeling; trunk rash; or swelling of neck lymph nodes. However, this case history indicates that these signs may not consistently appear in young infants, who have a higher death rate from the disease. Kawasaki disease should be considered as a possible diagnosis in young infants with persisting, unexplained fever. Examination of the heart (by echocardiography) and of the eyes (with a slit lamp) may be helpful in early diagnosis so that treatment can be instituted as soon as possible. (Consumer Summary produced by Reliance Medical Information, Inc.)

Kawasaki syndrome (KS) is an acute febrile (fever-causing) disease that is associated with skin rash, peeling, and swollen lymph nodes. Relatively serious long-term effects are coronary artery disease and aneurysm of the heart wall or arteries. The cause of KS is unknown, but altered immune system function has been implicated. High-dose aspirin therapy has been the accepted treatment, and is effective in reducing fever and inflammation in the acute stage. Intravenously administered gamma globulin (GG), which contains a particular group of antibodies made by the immune system, is effective in decreasing the cardiovascular complications that follow KS when treated with aspirin, but the best dosage and treatment schedule in unknown. Children with KS, aged 9 to 111 months, were put on aspirin therapy, and the effectiveness of two doses and schedules of GG was studied. The first group of 25 children was given a single dose of 1 gram (gm) GG per kilogram (kg) body weight, while the second group of 22 children were given 400 milligrams GG per kg once daily for four days. Alterations in blood levels of several types of immune globulins were observed, the significance of which is unclear. Two patients from the first group developed small coronary artery aneurysms by 21 days after the start of KS, which persisted at least until day 49, but which were not visible by echocardiography at one year. One patient from the second group developed multiple small aneurysms with a similar time course, but after one year, several aneurysms were still visible. Fevers declined more rapidly in the group given 1 gm GG per kg and this led to a decrease in hospitalization by one day, on average. Four children in the first group and three in the second group had mild adverse reactions to treatment with GG. These included flushing, chills, nausea and vomiting, or hypotension. The study indicates that GG given in a single dose of 1 gm per kg is associated with more rapid improvement, but further research on the effects of GG and immune system function in Kawasaki syndrome is needed. (Consumer Summary produced by Reliance Medical Information, Inc.)

Juvenile rheumatoid arthritis (JRA) is a chronic inflammatory systemic disease that effects, but is not limited to the joints; the disease can be very debilitating. Like other rheumatoid diseases, JRA is thought to have an autoimmune component, in which the body makes antibodies against its own tissues. Other dysfunctions of the immune system may be present, including deficiency of some types of antibodies. Drug treatment includes aspirin-like drugs, but steroids, which can retard growth in children, are frequently necessary. Treatment with gamma globulin (GG), a type of antibody, has been successfully used in other autoimmune diseases, and its effects on eight patients with JRA were evaluated in this report. The children had been unresponsive to previous drug therapies. Following six monthly GG injections, arthritis was significantly improved in five children, and seven non-joint symptoms were also improved. One child did not improve in either of these areas. Of the six patients receiving steroids at the start of the study, half were able to discontinue these drugs, and the other half decreased dosage by more than 50 percent. GG treatment caused improvement in anemia and blood protein levels and in blood cell responses, while the children's production of native GG decreased. These results suggest that intravenous GG may benefit patients with JRA. (Consumer Summary produced by Reliance Medical Information, Inc.)

Kawasaki disease is an acute illness, which causes inflammation of blood vessels, especially coronary arteries, and may lead to cardiovascular complications, such as aneurysm. It has been proposed that activation of the immune system contributes to the development of Kawasaki disease. In rheumatic arthritis and other immune diseases, elevated levels of immune factors, such as interleukin-2 (IL-2) and the receptor to which it attaches, have been found. In particular, white blood cells appear to release forms of the IL-2 receptor which are soluble in the blood stream, and in some cases levels of the IL-2 receptor correlate with the disease severity. Early identification of Kawasaki patients in whom coronary arteries may be affected is important, because timely treatment appears to prevent aneurysm formation. Blood samples from 57 patients with Kawasaki disease were studied, and levels of soluble IL-2 receptor were elevated during the acute phase, and remained elevated during the succeeding early subacute stage. IL-2 receptor levels dropped during the subsequent convalescent phase, but were still greater than in control patients. No correlations were found between levels of soluble IL-2 receptor and coronary artery abnormalities or treatment with intravenous gamma globulin. Levels of the receptor decreased with increasing age of patients. Although a marker for coronary complications was not found, soluble IL-2 receptor is a sensitive marker of immune activation in cases of Kawasaki disease. (Consumer Summary produced by Reliance Medical Information, Inc.)

Behcet's syndrome is a chronic, recurring disease characterized by: ulcer formation in the mouth and genitals; iritis, or inflammation of the iris (the colored contracting membrane of the eye that controls the entry of light into the eye); and joint pain. Additional symptoms include inflammation of the skin blood vessels; inflammation of the membrane lining the joints; ulcer formation in the gastrointestinal system; inflammation of the brain and its membranes; inflammation of veins with blood clot formation; and other blood vessel disorders associated with vessel blockage. Behcet's syndrome is rarely complicated by myositis, the inflammation of muscle tissue. A case is described of a 15-year-old girl who developed unusual symptoms of Behcet's syndrome, including myositis affecting the calf muscle, and neutropenia, an abnormally low amount of neutrophils (a type of white blood cell). Behcet's syndrome is rare in children, and is associated with symptoms that are different from those in adults. Complications of the eye tend to occur less frequently in children with Behcet's syndrome than in adult patients. In addition, unusual symptoms occur more often in children with this disorder than in adults with Behcet's syndrome. (Consumer Summary produced by Reliance Medical Information, Inc.)

Objective.Specific risk alleles for childhood-onset systemic lupus erythematosus SLE (cSLE) vs adult-onset SLE (aSLE) patients have not been identified. The aims of this study were to determine if there is an association (1) between non-HLA–related genetic risk score (GRS) and age of SLE diagnosis, and (2) between HLA-related GRS and age of SLE diagnosis.Methods.Genomic DNA was obtained from 2001 multiethnic patients and genotyped using the Immunochip. Following quality control, genetic risk counting (GRCS), weighted (GRWS), standardized counting (GRSCS), and standardized weighted (GRSWS) scores were calculated based on independent single-nucleotide polymorphisms from validated SLE loci. Scores were analyzed in a regression model and adjusted by sex and ancestral population.Results.The analyzed cohort consisted of 1540 patients: 1351 females and 189 males (675 cSLE and 865 aSLE). There were significant negative associations between all non-HLA GRS and age of SLE diagnosis: P= 0.011 and r2= 0.175 for GRWS; P= 0.008 and r2= 0.178 for GRSCS; P= 0.002 and r2= 0.176 for GRSWS (higher GRS correlated with lower age of diagnosis.) All HLA GRS showed significant positive associations with age of diagnosis: P= 0.049 and r2= 0.176 for GRCS; P= 0.022 and r2= 0.176 for GRWS; P= 0.022 and r2= 0.176 for GRSCS; P= 0.011 and r2= 0.177 for GRSWS (higher GRS correlated with higher age of diagnosis).Conclusion.Our data suggest that there is a linear relationship between genetic risk and age of SLE diagnosis and that HLA and non-HLA GRS are associated with age of diagnosis in opposite directions.

ObjectiveMacrophage activation syndrome (MAS), a life-threatening inflammatory complication, is increasingly recognized in childhood-onset systemic lupus erythematosus (cSLE). It can be a challenge to differentiate active cSLE from MAS. We generated decision rules for discriminating MAS from active cSLE in newly diagnosed patients.MethodsWe conducted a retrospective cohort study of consecutive, newly diagnosed, active cSLE patients with fever, requiring hospital admission to The Hospital for Sick Children from January 2003 to December 2007 (cohort 1) and January 2008 to December 2013 (cohort 2). All patients met ≥ 4 American College of Rheumatology or Systemic Lupus International Collaborating Clinics criteria, and were steroid-nai¨ve and infection-free. MAS was diagnosed based on expert opinion. Recursive partitioning was applied to each cohort to derive a decision rule based on clinical and laboratory features, distinguishing MAS from non-MAS cSLE. Each decision rule was applied to the alternate, independent cohort. Sensitivity and specificity of these decision rules were compared to existing criteria.ResultsCohort 1 (n = 34) and cohort 2 (n = 41) each had 10 patients with MAS. Recursive partitioning in cohort 1 identified ferritin ≥ 699 μg/L as the sole best discriminator between MAS and non-MAS patients (R2= 0.48), and in cohort 2, ferritin ≥ 1107 μg/L was the best discriminator for MAS, followed by lymphocytes < 0.72 × 103/mm3(R2= 0.52). Cross-validation of our decision rules maintained 90–100% sensitivity and 65–85% specificity.ConclusionOur decision rule demonstrated improved performance compared to preliminary guidelines for MAS in cSLE from the Lupus Working Group of the Paediatric Rheumatology European Society and familial hemophagocytic lymphohistiocytosis diagnostic criteria. Validation in independent cohorts is required.

ObjectiveTo evaluate the association between ethnicity and neonatal lupus erythematosus (NLE), as well as specific NLE manifestations in a large multiethnic population.MethodsWe conducted a cohort study of the children (≤ 1 yr of age) seen in the NLE clinic at The Hospital for Sick Children (SickKids), between January 2011 and April 2019. The cohort was divided into European, non-European, and mixed European–non-European groups according to parent-reported child’s ethnicity (Canada Census categories). Outcomes were NLE and specific NLE manifestations (cardiac, cutaneous, cytopenias, transaminitis, and macrocephaly). The frequency of NLE and specific manifestations were compared between ethnic groups (Fisher exact test). We tested the association between ethnicity and (1) NLE risk, and (2) specific NLE manifestations with logistic regression models, including covariates for child’s sex, maternal rheumatic disease status during pregnancy, and maternal use of antimalarials during pregnancy (multiple comparisons threshold P< 0.008).ResultsWe included 324 children born to 270 anti-Ro antibody–positive mothers. Median age at first visit was 1.8 (IQR 1.4–2.3) months, and median follow-up time was 12 (IQR 2–24) months. The majority was non-European (48%), with 34% European, and 18% mixed European–non-European. There was no significant association between non-European ethnicity (OR 1.18, 95% CI 0.71–1.94, P= 0.51), mixed European–non-European ethnicity (OR 1.13, 95% CI 0.59–2.16, P= 0.70), and NLE risk compared with European ethnicity. We also did not find an association between ethnicity and specific NLE manifestations in univariate or multivariable-adjusted models.ConclusionIn a large multiethnic cohort, there was no association between a child’s ethnicity and NLE risk or specific NLE manifestations.

Undervaluing the effectiveness of conventional treatments may lead to overtreatment with biologic medications in children with juvenile idiopathic arthritis (JIA). Using data from a nationwide inception cohort and strict methods to control bias, the aim of our study was to estimate the real‐world effectiveness of simple JIAtreatment strategies recommended in current guidelines. Children with JIAwho were recruited at 16 Canadian centers from 2005 to 2010 were followed for up to 5 years. For each child, all observed treatment changes over time were assessed by independent physicians using prospectively collected data and published response criteria. Success was defined as attainment of inactive disease or maintenance of this state when stepping down treatment; minimally active disease was deemed acceptable for children with polyarticular JIA. Success rates were calculated for treatments tried ≥25 times, and logistic regression analysis identified features associated with success. A total of 4,429 treatment episodes were observed in 1,352 children. Nonsteroidal antiinflammatory drug (NSAID) monotherapy was attempted 697 times, mostly as initial treatment when <5 joints were involved, with a 54.4% success rate (95% confidence interval [95% CI] 50.3–58.6). NSAIDs plus joint injections had a 64.7% success rate (95% CI59.8–69.7). Adding methotrexate to NSAIDs and/or joint injections (attempted 566 times) had a 60.5% success rate (95% CI55.7–65.3). In adjusted analyses, each additional active joint reduced chances of success for treatment with NSAIDs (odds ratio [OR] 0.90 [95% CI0.85–0.94]) and for methotrexate combinations (OR0.96 [95% CI0.94–0.99]). Each additional year after disease onset reduced chances of success for treatment with methotrexate combinations (OR0.83 [95% CI0.72–0.95]). These real‐world effectiveness estimates show that conventional nonbiologic treatment strategies that are recommended in current guidelines are effective in achieving treatment targets in many children with JIA.

Various connective tissue disorders, such as systemic lupus erythematosus (SLE), may be complicated by thyroid disease. Thyroid disorders develop in 7.5 to 8.9 percent of patients with SLE, and include hypothyroidism, or decreased activity of the thyroid gland; the production of antithyroid antibodies, or immune proteins, directed against the thyroid gland; or hyperthyroidism, abnormally increased activity of the thyroid glands. Hashimoto thyroiditis, characterized by an enlarged thyroid and hypothyroidism, and Grave's disease, characterized by an enlarged thyroid gland and protrusion of the eyeballs, are autoimmune diseases, conditions in which the immune system attacks the body's own tissues. These autoimmune thyroid disorders are rare in children. The incidence of autoimmune thyroid disorders in children with SLE was assessed. Thyroid abnormalities were detected in six of 35 children with SLE, including four with hypothyroidism and two with elevated levels of the thyroid hormone thyroxine. Antithyroid antibodies were detected in 43 percent of patients. Antibodies directed against microsomes, cell structures found in the nucleus, were detected in 31 percent of patients, whereas 29 percent of patients had antibodies against thyroglobulin, an iodine-containing protein released by the thyroid. There was no relation between the presence of antithyroid antibodies and drug therapy or antibodies associated with SLE. These findings show that thyroid abnormalities and thyroid antibodies are increased in patients with SLE. Thyroid antibodies may serve as an indicator of immune abnormalities or may reflect inflammation of the thyroid gland, which may be suppressed by anti-inflammatory agents used to treat SLE. Patients with SLE should be monitored for the presence of thyroid abnormalities. (Consumer Summary produced by Reliance Medical Information, Inc.)

To estimate the impact of enthesitis on patient‐reported outcomes in children with juvenile idiopathic arthritis (JIA), irrespective of JIAcategory. Children enrolled in the Research in Arthritis in Canadian Children Emphasizing Outcomes cohort were studied. Entheseal tenderness by physician examination in 33 defined locations, Juvenile Arthritis Quality of Life Questionnaire (JAQQ), Quality of My Life (QoML) Questionnaire, Childhood Health Assessment Questionnaire (C‐HAQ), and a pain visual analog scale were completed at enrollment, every 6 months for 2 years, and then yearly up to 5 years. Analyses consisted of descriptive statistics, linear mixed models for longitudinal data, and analysis of covariance. Among 1,371 patients followed for a median of 35.3 months (interquartile range 22.1, 49.2), 214 (16%) had enthesitis, of whom 137 (64%) were classified as having enthesitis‐related arthritis. After adjusting for JIAcategory and covariates, children with enthesitis reported higher JAQQ(mean raw score 2.71 versus 2.16, adjusted difference 0.41 points; 95% confidence interval [95% CI] 0.22, 0.59), higher C‐HAQ(0.47 versus 0.31, adjusted difference 0.14 points; 95% CI0.07, 0.22), higher pain (3.01 versus 1.68, adjusted difference 0.94 points; 95% CI0.64, 1.25), and lower QoML(7.02 versus 8.23, adjusted difference –0.80 points; 95% CI–1.09, –0.51) scores than children without enthesitis. These differences persisted up to 5 years. Children with enthesitis, regardless of JIAcategory, report worse patient‐reported outcomes than those without enthesitis. Thus, enthesitis should be assessed in all children with JIA.

Background/aimsThere is a paucity of large trials investigating the effect of management strategies for paediatric non-infectious uveitis on complications requiring surgery. The purpose of our study is to investigate whether earlier initiation of systemic immunosuppression in paediatric non-infectious uveitis is associated with fewer ophthalmic surgeries.MethodsA retrospective review was conducted on 48 children with non-infectious uveitis assessed in 1998–2013. Patients were divided into uveitis diagnosed before December 2008 (group 1) and after January 2009 (group 2). Duration from uveitis onset to methotrexate initiation (U-MTX) and biological addition (U-Biologic) were reviewed. Follow-up visits with topical corticosteroids >3 times daily and active uveitis (≥1+ cells) during 3.5 years were documented. The main outcome measure was the need for ≥1 ophthalmic surgery at 3.5 years.ResultsIn group 1, 69.5% of patients required ≥1 ophthalmic surgery at 3.5 years versus 26.9% in group 2 (p=0.005). U-MTX was 28.9±11.8 weeks and 14.2±10.0 weeks for groups 1 and 2 (p=0.028). U-Biologic was 134.6±46.0 weeks and 82.3±43.3 weeks for groups 1 and 2 (p=0.0016). Corticosteroid use >3 times daily was 85.9±52.7 weeks and 14.6±11.1 weeks for groups 1 and 2. Multivariate regression showed methotrexate initiation within 6 months of uveitis onset lowered the likelihood of needing ophthalmic surgery at 3.5 years (OR=6.2, 95% CI 1.2 to 33.4; p=0.033). Univariate regression demonstrated biological addition within 18 months of uveitis onset reduced the likelihood of requiring ophthalmic surgery (OR 12.57, 95% CI 1.28 to 123.48; p=0.030).ConclusionEarlier control of uveitis by addition of immunosuppressive therapy reduced the need for ophthalmic surgery.

Objective: To determine differences in clinical characteristics, laboratory findings, and cardiac complications between patients with acute Kawasaki disease who received additional treatment for persistent or recurrent fever vs those who did not. Design: Nonconcurrent case series; medical record review. Setting: Tertiary care pediatric hospital. Patients: One hundred eighty-five consecutive patients diagnosed as having acute Kawasaki disease at The Hospital for Sick Children, Toronto, Ontario, from 1995 to 1997. Main Outcome Measure: Prevalence of cardiac complications. Results: Twenty-one patients (11%) received additional treatment with intravenous gamma globulin (IVGG) with or without intravenous methylprednisolone for persistent fever lasting for more than 48 hours or recurrent fever after initial treatment with IVGG. Patients who received additional treatment did not differ significantly from other patients regarding age, sex, race, or diagnostic criteria. Compared with the patients who did not receive additional therapy, the patients who received additional treatment had shorter median interval from fever onset to initial dose of IVGG (5 vs 6 days; P =.006) and longer total days of fever (9 vs 6 days; P [is less than] .001). Initial laboratory investigations did not differ significantly. On initial echocardiography, patients who received additional therapy were significantly more likely to have pericardial effusion (33% vs 15%; P=.04), ventricular dysfunction (14% vs 2%; P=.002), and coronary artery ectasia (76% vs 43%; P=.004) but not aneurysms (10% vs 5%; P=.47). At 12 months after diagnosis, there were no significant differences between the 2 groups regarding the prevalence of coronary artery ectasia or aneurysms. Conclusion: Patients receiving additional treatment for persistent or recurrent fever have similar demographic and clinical characteristics, greater initial cardiac involvement, and similar overall outcomes. Arch Pediatr Adolesc Med. 2000;154:694-699

Objective.Persistent systemic lupus erythematosus (SLE) disease activity is associated with increased morbidity and mortality. In a multicenter cohort of patients with prevalent SLE, we described persistence, patterns, and predictors of change in disease activity over time.Methods.Based on SLE Disease Activity Index (SLEDAI)-2K scores at cohort entry, patients were classified into 4 groups: low (score < 4; LOW), moderate (4 to < 6; MOD), moderately high (6 to ≤ 10; MHIGH), and very high (> 10; VHIGH). Multivariable linear and longitudinal mixed linear regression models were used to identify predictors of change over time in SLEDAI-2K.Results.There were 2019 participants, with declining followup data over 5 years (1326, 580, 274, 186, and 148 patients, respectively). At cohort entry, mean (± SD) age was 42 (± 17) years, disease duration 11 (± 10) years, and 90% were female. The 4 groups included 44% LOW (n = 891), 20% MOD (n = 400), 22% MHIGH (n = 442), and 14% VHIGH (n = 286); therefore, 36% had clinically important SLE activity. The proportion of patients in the LOW group at entry who moved to a higher activity level varied from 30% (167/557) at 1 year, to 49% (41/83) at 3 years, and 54% (30/56) at 5 years. Among 181 patients with MOD to VHIGH entry activity and 3 years of followup, 116 (64.1%) remained active. In all analyses, only higher SLEDAI-2K at cohort entry remained a significant predictor of higher SLEDAI-2K in subsequent years.Conclusion.Higher SLEDAI-2K at study entry was the single major independent predictor of higher SLEDAI-2K over time, reflecting frequent persistence of active disease, even in patients with longstanding disease. This highlights gaps in the optimal treatment of SLE.

Objective.Currently there are 2 different classification criteria for systemic lupus erythematosus (SLE): American College of Rheumatology (ACR) and Systemic Lupus International Collaborating Clinics (SLICC). The aim of this study was to compare the sensitivities of ACR and SLICC criteria in childhood-onset SLE (cSLE) using a large, multiethnic cohort.Methods.We conducted a retrospective study of 722 patients diagnosed with cSLE at The Hospital for Sick Children (SickKids). Prospectively collected data from SickKids’ Lupus Database were reviewed/validated against medical records prior to ACR and SLICC scoring based on cumulative symptoms up to the last visit. Sensitivities were compared using McNemar’s test. Descriptive statistics were used to identify SLE features unique to each set of criteria and autoantibodies not included in either.Results.ACR and SLICC sensitivities were as follows: 92.4% and 96.3% overall (p = 0.001); 82.5% and 91.3% (p = 0.01) in those scored ≤ 1 year from diagnosis; 92.7% and 97.9% (p = 0.02) in those scored 2–3 years from diagnosis. Forty-eight of 55 (87.3%) patients who did not meet ACR criteria met SLICC criteria through SLICC-specific criterion or renal biopsy. Twenty of 27 (74.1%) patients who did not meet SLICC criteria met ACR criteria as a result of photosensitivity (73.9%) and ACR lymphopenia criteria (26.1%). Six of 7 patients (85.7%) who were clinically diagnosed with cSLE but did not meet either SLICC or ACR criteria had anti-Ro antibodies.Conclusion.SLICC criteria were significantly more sensitive than ACR criteria in cSLE classification, especially early in the disease course. Because of the extreme rarity of primary Sjögren syndrome in children, one may consider adding anti-Ro antibodies to the classification criteria for cSLE because they are present in ∼40% of patents with cSLE.

Diagnosis of systemic autoimmune rheumatic diseases (SARD) relies on the presence of hallmark anti-nuclear antibodies (ANA), many of which can be detected years before clinical manifestations. However, ANAs are also seen in healthy individuals, most of whom will not develop SARD. Here, we examined a unique cohort of asymptomatic ANA+individuals to determine whether they share any of the cellular immunologic features seen in SARD. Healthy ANA−controls and ANA+(ANA ≥1:160 by immunofluorescence) participants with no SARD criteria, with at least one criterion (undifferentiated connective tissue disease (UCTD)), or meeting SARD classification criteria were recruited. Peripheral blood cellular immunological changes were assessed by flow cytometry and transcript levels of BAFF, interferon (IFN)-induced and plasma cell-expressed genes were quantified by NanoString. A number of the immunologic abnormalities seen in SARD, including changes in peripheral B (switched memory) and T (iNKT, T regulatory, activated memory T follicular helper) subsets and B cell activation, were also seen in asymptomatic ANA+subjects and those with UCTD. The extent of these immunologic changes correlated with ANA titer or the number of different specific ANAs produced. Principal component analysis of the cellular data indicated that a significant proportion of asymptomatic ANA+subjects and subjects with UCTD clustered  with patients with early SARD, rather than ANA−healthy controls. ANA production is associated with altered T and B cell activation even in asymptomatic individuals. Some of the currently accepted cellular features of SARD may be associated with ANA production rather than the immunologic events that cause symptoms in SARD.

No previous study has studied the longitudinal disease course of childhood‐onset systemic lupus erythematosus (cSLE). Our objectives are to assess distinguishable differences in disease activity trajectories in cSLEpatients, determine baseline factors predictive of disease trajectory membership, and assess if the different disease activity trajectories are associated with different damage trajectories. This is a retrospective, longitudinal inception cohort of cSLEpatients. Patients were followed from diagnosis as children, until they were adults. SLEdisease activity was modeled as a latent characteristic, jointly using the Systemic Lupus Erythematosus Disease Activity Index 2000 and prednisone in a Bayesian growth mixture model. Baseline factors were tested for membership prediction of the latent classes of disease trajectories. Differences in damage trajectories by disease activity classes were tested using a mixed model. A total of 473 patients (82% females), with median age at diagnosis of 14.1 years, were studied. We studied 11,992 visits (2,666 patient‐years). We identified 5 classes of disease activity trajectories. Baseline major organ involvement, number of American College of Rheumatology criteria, and age at diagnosis predicted memberships into different classes. A higher proportion of Asians was in class 2 compared to class 5. Class 1 was associated with the most accrual of damage, while class 5 was associated with no significant damage accrual, even after 10 years. There are 5 distinct latent classes of disease trajectory in patients with cSLE. Membership within disease trajectories is predicted by baseline clinical and demographic factors. Membership in different disease activity trajectory classes is associated with different damage trajectories.

PurposeGenetic testing is an integral diagnostic component of pediatric medicine. Standard of care is often a time-consuming stepwise approach involving chromosomal microarray analysis and targeted gene sequencing panels, which can be costly and inconclusive. Whole-genome sequencing (WGS) provides a comprehensive testing platform that has the potential to streamline genetic assessments, but there are limited comparative data to guide its clinical use.MethodsWe prospectively recruited 103 patients from pediatric non-genetic subspecialty clinics, each with a clinical phenotype suggestive of an underlying genetic disorder, and compared the diagnostic yield and coverage of WGS with those of conventional genetic testing.ResultsWGS identified diagnostic variants in 41% of individuals, representing a significant increase over conventional testing results (24%; P = 0.01). Genes clinically sequenced in the cohort (n = 1,226) were well covered by WGS, with a median exonic coverage of 40 × ±8 × (mean ±SD). All the molecular diagnoses made by conventional methods were captured by WGS. The 18 new diagnoses made with WGS included structural and non-exonic sequence variants not detectable with whole-exome sequencing, and confirmed recent disease associations with the genes PIGG, RNU4ATAC, TRIO, and UNC13A.ConclusionWGS as a primary clinical test provided a higher diagnostic yield than conventional genetic testing in a clinically heterogeneous cohort.

Objective.To develop recommendations for the assessment of people with systemic lupus erythematosus (SLE) in Canada.Methods.Recommendations were developed using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach. The Canadian SLE Working Group (panel of Canadian rheumatologists and a patient representative from Canadian Arthritis Patient Alliance) was created. Questions for recommendation development were identified based on the results of a previous survey of SLE practice patterns of members of the Canadian Rheumatology Association. Systematic literature reviews of randomized trials and observational studies were conducted. Evidence to Decision tables were prepared and presented to the panel at 2 face-to-face meetings and online.Results.There are 15 recommendations for assessing and monitoring SLE, with varying applicability to adult and pediatric patients. Three recommendations focus on diagnosis, disease activity, and damage assessment, suggesting the use of a validated disease activity score per visit and annual damage score. Strong recommendations were made for cardiovascular risk assessment and measuring anti-Ro and anti-La antibodies in the peripartum period and conditional recommendations for osteoporosis and osteonecrosis. Two conditional recommendations were made for peripartum assessments, 1 for cervical cancer screening and 2 for hepatitis B and C screening. A strong recommendation was made for annual influenza vaccination.Conclusion.These are considered the first guidelines using the GRADE method for the monitoring of SLE. Existing evidence is largely of low to moderate quality, resulting in more conditional than strong recommendations. Additional rigorous studies and special attention to pediatric SLE populations and patient preferences are needed.

Although juvenile‐onset proliferative lupus nephritis (PLN) leads to significant morbidity and mortality, there is no clinical trials–based evidence to support the treatment effectiveness of any therapy for juvenile‐onset PLN. Marginal structural models enable us to estimate treatment effectiveness using observational data while accounting for confounding by indication. We used prospectively collected data to examine the effect of mycophenolate mofetil (MMF), compared to the use of other therapies, on the long‐term outcome of a juvenile‐onset PLNcohort (age at PLNonset <18 years). The major outcome variable was the estimated glomerular filtration rate (GFR) using the revised Schwartz formula. Confounding by indication was corrected for marginal structural model. A total of 172 subjects with juvenile‐onset PLN, with a mean followup duration of approximately 4 years, were included. Overall, MMFwas superior to other therapies, with a relative effect estimate for MMFof 1.06, i.e., 6% better estimated GFRon average (95% confidence interval 0.7, 11.3), corrected for potential confounding by indication. We found that beginning in year 4 there was a significant improvement in estimated GFRin the patients who were treated with MMFversus other therapies. This improvement was maintained until the end of the study. MMFwas more beneficial than other therapies in improving/maintaining long‐term renal function in patients with juvenile‐onset PLNup to a maximum followup of 7 years. This finding is consistent with evidence from adult PLNclinical trials.

Elevated levels of type I interferons (IFNs) are a characteristic feature of the systemic autoimmune rheumatic diseases (SARDs) and are thought to play an important pathogenic role. However, it is unknown whether these elevations are seen in anti-nuclear antibody–positive (ANA+) individuals who lack sufficient criteria for a SARD diagnosis. We examined IFN-induced gene expression in asymptomatic ANA+individuals and patients with undifferentiated connective tissue disease (UCTD) to address this question. Healthy ANA−control subjects and ANA+titre (≥1:160 by immunofluorescence) participants meeting no criteria, meeting at least one criterion (UCTD) or meeting SARD classification criteria were recruited. Whole peripheral blood IFN-induced and BAFFgene expression were quantified using NanoString technology. The normalized levels of five IFN-induced genes were summed to produce an IFN5 score. The mean IFN5 scores were increased in all ANA+participant subsets as compared with healthy control subjects. We found that 36.8% of asymptomatic ANA+and 50% of UCTD participants had IFN5 scores >2 SD above the mean for healthy control subjects. In all ANA+subsets, the IFN5 score correlated with the presence of anti-Ro/La antibodies. In the asymptomatic ANA+subset, this score also correlated with the ANA titre, whereas in the other ANA+subsets, it correlated with the number of different ANA specificities. Development of new SARD criteria was seen in individuals with normal and high IFN5 scores. An IFN signature is seen in a significant proportion of ANA+individuals and appears to be associated with ANA titre and type of autoantibodies, rather than with the presence or development of clinical SARD symptoms.

To determine the longitudinal damage trajectory of patients with juvenile‐onset systemic lupus erythematosus (SLE), and to identify baseline and disease course predictors of damage trajectory. This is a retrospective inception cohort. Longitudinal pediatric‐age data were obtained from a juvenile‐onset SLEresearch database, while adult‐age data were obtained from either a research database or patients' charts. Baseline factors were tested as predictors. Time‐varying factors were lagged 6–24 months before a visit for testing their predictive effects. The longitudinal damage trajectory was modeled using a weighted generalized estimating equation. This study cohort consisted of 473 subjects, with followup to 26 years. A total of 65% of patients were ages >18 years at last followup. Cataracts (14%), avascular necrosis (10%), and osteoporosis (5%) were the most common items of damage. Two patients had myocardial infarctions. Baseline features, self‐reported ethnicity (Afro‐Caribbean), earlier time periods of diagnosis, and the presence of a life‐threatening major organ manifestation (lupus nephritis class III–V, cerebrovascular accidents, major organ vasculitis, pulmonary hemorrhage, or myocarditis), were associated with greater damage. Throughout the disease course, an acute confusional state, lupus headache, and fever predicted subsequent increases in the damage trajectory. A higher prednisone dose and exposure to cyclophosphamide also predicted subsequent increases in the damage trajectory. Antimalarial exposure was protective against an increase in damage trajectory. Patients with juvenile‐onset SLEaccrue damage steadily into adulthood. Baseline factors predict greater damage and/or influence the evolution of the damage trajectory. Additionally, SLEclinical features and therapies during the course of disease predict additional changes in the damage trajectory.

Systemic lupus erythematosus (SLE) is a systemic, autoimmune, multisystem disease with a heterogeneous clinical phenotype. Genome-wide association studies have identified multiple susceptibility loci, but these explain a fraction of the estimated heritability. This is partly because within the broad spectrum of SLE are monogenic diseases that tend to cluster in patients with young age of onset, and in families. This article highlights insights into the pathogenesis of SLE provided by these monogenic diseases. It examines genetic causes of complement deficiency, abnormal interferon production, and abnormalities of tolerance, resulting in monogenic SLE with overlapping clinical features, autoantibodies, and shared inflammatory pathways.

Kawasaki disease, a systemic inflammation of the blood vessels, is a serious and potentially life-threatening disease of infants and young children. This disease causes damage to the blood vessels, such as vasculitis, endothelial tissue death (necrosis), dilation of the blood vessel wall (aneurysm), and clotting on the interior wall of the blood vessel (thrombosis). If left untreated, up to 30 percent of patients develop abnormalities of the arteries of the heart, a small portion of which may cause death. Vascular aneurysms and thrombosis are major long-term complications. Abnormalities of the immune regulating system have been implicated as causes of this disease. Tumor necrosis factor (TNF), an immunoregulatory agent, may cause a change in the inflammation in Kawasaki disease. Production of TNF in 18 patients with Kawasaki disease was measured. Patients studied during the acute phase of the disease showed increased TNF production. Patients studied during the subacute and convalescent phase, beginning about 10 days after the onset of initial symptoms, had TNF levels significantly lower than those of patients in the acute phase of disease. In follow-up studies TNF levels were normal in all patients. It is possible that TNF may contribute to the vascular damage either directly or indirectly through its effects on the immune system. The authors speculate that creating a change in the activity of TNF or its production may decrease vascular tissue damage and reduce the risk of coronary artery aneurysms.

To determine whether socioeconomic status assessed by education is associated with disease activity and the risk of organ damage in systemic lupus erythematosus (SLE). Data from the 1000 Canadian Faces of Lupus, a multicenter database of adult SLE patients, was used to compare education as either low (did not complete high school) or high (completed high school or further) for disease activity and damage. Education was also studied as a continuous variable. The relationships between education and SLE outcomes (any organ damage defined as a Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index [SDI] score ≥1, serious organ damage [SDI score ≥3], and end‐stage renal disease) were evaluated using logistic regression analyses adjusted for age, sex, race/ethnicity, and disease duration. A total of 562 SLE patients met inclusion criteria (mean age 47 years, 91% female, and mean disease duration of 10 years); 81% had high education. The low education group was twice as likely to be work disabled (30%; P< 0.0001); they had higher disease activity and reduced renal function. Linear regression analysis revealed that low education was significantly associated with higher disease activity at enrollment into the 1000 Canadian Faces of Lupus database, after adjustment for age (at entry and at diagnosis), race/ethnicity, and sex (B 1.255 + 0.507 [SE], β = 0.115, P= 0.014). In our adjusted logistic regression models we were unable to demonstrate significant associations between education and SLE damage. Results did not change when varying the education variable. In this cohort, low education was associated cross‐sectionally with higher disease activity and work disability, but not damage.

The 71st Annual Meeting of The Canadian Rheumatology Association (CRA) was held at the Fairmont Chateau Lake Louise, Lake Louise, Alberta, Canada, February 17–20, 2016. The program consisted of presentations covering original research, symposia, awards, and lectures. Highlights of the meeting include the following 2016 Award Winners: Distinguished Rheumatologist, Ronald Laxer; Distinguished Investigator, Proton Rahman; Teacher-Educator, Lori Albert; Young Investigator, Nigil Haroon; Best Abstract on Basic Science Research by a Trainee, Liam O’Neil; Best Abstract on Research by a Rheumatology Resident, Valérie Leclair; Best Abstract by a Medical Student, Matthew Jessome; Best Abstract by a Post-Graduate Resident, Hyein Kim; CRA/Arthritis Research Foundation (ARF) Best Epidemiology/Health Services Research Award, Cheryl Barnabe; Summer Studentship Mentor Award, Ines Colmegna; CRA/ARF Best Paediatric Research Award, Lily Lim; CRA/ARF Best Clinical Research Award, Zahi Touma; CRA/ARF Best Basic Science Research Award, Nigil Haroon; Best Abstract on SLE Research by a Trainee — Ian Watson Award, Stephanie Nantes; Best Abstract on Clinical or Epidemiology Research by a Trainee — Phil Rosen Award, Nicolas Richard; Practice Reflection Award — Gold/Silver/Bronze, Henry Averns/Philip Baer and Jean-Pierre Raynauld/Robert Ferrari. Lectures and other events included the Dunlop-Dottridge Lecture: New Paradigms for Inflammatory Arthritis, by Berent Prakken; Keynote Address by Distinguished Investigator Awardee 2016 Proton Rahman: Role of Precision Medicine in Optimizing Quality in Rheumatology Care; State of the Art Lecture: Everything You Must Know About Sleep but are Too Tired to Ask! by James Maas; and the Great Debate: Be it Resolved that Rheumatologists Get with the Times and Use Social Media for Communication with Patients and Research; arguing for: Jason Kur and Michelle Teo; against: Nadia Luca and Sherry Rohekar. Topics such as rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, Sjögren syndrome, psoriatic arthritis, spondyloarthritis, vasculitis, osteoarthritis, fibromyalgia, and their respective diagnoses, treatments, and outcomes are reflected in the abstracts, which we are pleased to publish in this issue of The Journal.

Objective.Autoantibodies to the dense fine speckled 70 kDa antigen (DFS70) are reported to be more common in individuals who do not have an antinuclear antibody (ANA)-associated rheumatic disease (AARD) than in patients with AARD. The frequency of anti-DFS70 antibodies has been thoroughly studied in adult but not in pediatric populations. The primary objective of this observational study was to determine the frequency of anti-DFS70 in pediatric AARD and reference cohorts.Methods.Sera from 743 children with AARD and related conditions, and 345 samples from reference cohorts (healthy children and those being investigated for AARD) were studied for anti-DFS70 autoantibodies as measured by a chemiluminescence immunoassay. A de-identified administrative database was used to retrieve demographic, serologic, and clinical data.Results.Anti-DFS70 antibodies were seen in 2.1% of healthy children and in 4.5% of sera from pediatric individuals referred for ANA testing. The frequency of anti-DFS70 was highest in juvenile localized scleroderma (LS; 4/29, 13.8%), juvenile dermatomyositis (JDM; 2/11, 18.2%), childhood systemic lupus erythematosus (cSLE; 19/331, 5.7%), diffuse cutaneous systemic sclerosis (1/22, 4.5%), celiac disease (2/49, 4.1%), and juvenile idiopathic arthritis (JIA; 5/202, 2.5%). Of note, anti-DFS70 antibodies were observed in 3/26 children (11.5%) with uveitis and JIA-associated uveitis.Conclusion.The frequency of anti-DFS70 autoantibodies in healthy pediatric subjects is within the lower range of that reported in adults. Anti-DFS70 antibodies can be found in childhood SSc and cSLE, but has a remarkably high frequency in children with LS, JDM, and uveitis.

Objective.To examine the frequency and risk factors for symptomatic avascular necrosis (AVN) in childhood-onset systemic lupus erythematosus (cSLE).Methods.A single-center, nested, matched, case-control design was used. There were 617 patients with cSLE followed at the Hospital for Sick Children (SickKids) Lupus Clinic between July 1982 and June 2013 included in the study. The AVN cohort consisted of 37 patients identified with clinical findings of symptomatic AVN and diagnosis was confirmed by 1 or more imaging modalities. Three controls were matched to each patient with AVN by date and age at diagnosis. Baseline clinical, laboratory, and treatment characteristics were compared between patients with AVN and controls by univariable analyses and if statistically significant, were included in a multivariable logistic regression model.Results.A total of 37/617 patients (6%) developed symptomatic AVN in 91 joints during followup at SickKids. The mean duration to disease was 2.3 years. The hip was the most commonly involved joint (26/37, 70%). Compared with the matched non-AVN cohort, patients with AVN had a higher incidence of central nervous system (CNS) involvement and nephritis, required greater cumulative prednisone (PRED) from cSLE diagnosis to AVN, received a greater maximal daily PRED dose, and had more frequent use of pulse methylprednisolone therapy. Multivariable regression analysis confirmed major organ involvement (CNS disease and/or nephritis) and maximal daily PRED dose as significant predictors of symptomatic AVN development.Conclusion.Patients with cSLE with severe organ involvement including nephritis and CNS disease and higher maximal daily dose of PRED are more likely to develop symptomatic AVN.

The 70th Annual Meeting of The Canadian Rheumatology Association (CRA) was held at the Fairmont Chateau Frontenac, Quebec City, Quebec, Canada, February 4–7, 2015. The program consisted of presentations covering original research, symposia, awards, and lectures. Highlights of the meeting include 2015 Award Winners: Distinguished Rheumatologist Award: Carter Thorne; Distinguished Investigator Award: Hani El-Gabalawy; Teacher-Educator Award: Andrew E. Thompson; Young Investigator Award: Sindhu Johnson; Summer Studentship Mentor Award: Lori Albert; Innovation in Education Award: Henry Averns; Best Abstract for Basic Science Research by a Trainee: Sina Rusta-Sallehy; Best Abstract for Research by an Undergraduate Student: Tristan Kerr; Best Abstract for Research by a Rheumatology Resident: Claire Barber; Best Poster by a Medical Student: Dennis Wong; Best Poster by a Post-Graduate Resident: Zainab Alabdurubalnabi; CRA/ARF Best Epidemiology/Health Services Research Award: Evelyn Vinet; CRA/ARF Best Clinical Research Award: Glen Hazelwood; CRA/ARF Best Basic Science Research Award: Carolina Landolt-Marticorena; Ian Watson Award for Best Abstract for SLE Research by a Trainee: Ripneet Puar; Phil Rosen Award for Best Abstract for Clinical or Epidemiology Research by a Trainee: Liam O’Neil. Lectures and more: The 2015 Dunlop Dottridge Lecture: HLA-B27, the Microbiome, and the Pathogenesis of Spondyloarthritis, by James Rosenbaum; Preventing Rheumatoid Arthritis: What We’ll Need to Know Before We Start Navigating this Uncharted Territory, by Distinguished Investigator Awardee Hani El-Gabalawy; and the 2015 State of the Art Lectures: A Genomic Approach to Understanding Rheumatic Disease, by Dr. Virginia Pascual, and Modifiable Risk Factors in RA: You Can Lead a Horse to Water but …, by Michael Vallis. The Great Debate: Treat Pre-RA vs Not Treat Pre-RA. Arguing for: Volodko Bakowsky and Derek Haaland; Against: Hani El-Gabalawy and Rob McDougall. The contributions presented at the meeting are reflected in the abstracts, which we are pleased to publish in this issue.

Objective.To determine the most effective immunosuppressive therapy for the longterm management of proliferative lupus nephritis (PLN) based on the outcome of renal failure.Methods.A systematic review of randomized controlled trials (RCT) was conducted. MEDLINE and EMBASE were searched. RCT designed to examine the maintenance treatment effectiveness of immunosuppressive agents for PLN were included. A Bayesian network metaanalysis of 2-arm and 3-arm trials was used. A skeptical prior assumption was used in sensitivity analysis. Four immunosuppressive agents were evaluated: cyclophosphamide (CYC), azathioprine (AZA), mycophenolate mofetil (MMF), and prednisone alone. The outcome of interest was renal failure during the study period, defined by serum creatinine (sCr) > 256 µmol/l, doubling of sCr from baseline, and/or endstage renal disease.Results.The OR (95% credible interval) of developing renal failure at 2–3 years was 0.72 (0.11, 4.49) for AZA versus CYC, 0.32 (0.04, 2.25) for MMF versus CYC, 2.40 (0.22, 36.94) for prednisone alone versus CYC, and 0.45 (0.11, 1.48) for MMF versus AZA. The probability (95% credible interval) of developing renal failure at 2 years as expected for each agent was 6% (0.7%, 24%) for MMF, 12% (2%, 37%) for AZA, 16% (5%, 33%) for CYC, and 31% (5%, 81%) for prednisone alone. After applying a skeptical prior in the Bayesian analysis, there was no evidence of benefit for 1 therapy over another.Conclusion.Although the data suggest that MMF may be superior to other treatments for the maintenance treatment of PLN, the evidence is not conclusive.