Faculty Bibliography

BACKGROUND: Although the combination of cyclophosphamide and rituximab has been utilized in case reports, there are no previous reports of the long term outcome of SLE treated systematically with this regimen. We report a pilot study to evaluate the efficacy of a systematically administered course of rituximab and cyclophosphamide over an eighteen month period to provide sustained improvement in childhood onset systemic lupus erythematosus (SLE). FINDINGS: Twelve patients with childhood onset lupus nephritis or corticosteroid resistant SLE received systematic treatment with a combination of rituximab (750 mg/M2 up to 1 gram) and cyclophosphamide (750 mg/M2: no patient exceeded 1.8 M2). Two administrations of rituximab and cyclophosphamide, two weeks apart, were administered at the start of study, six months later, and eighteen months later. Clinical data were collected and analyzed after sixty months of follow up. There was sustained improvement in all clinical parameters with a dramatic reduction in both mean SLEDAI score (10.1 to 1 at one year and 0 at five years p<0.005) and mean daily prednisone dosage (29.7 mg/day to 12.7 by one year and 7.0 mg/day at five years p<0.005), with sustained improvement in mean C3 (55.5 mg/ml to 113 at one year and 107.5 at five years p<0.001) which was maintained through sixty months of follow up. Serum immunoglobulin levels were transiently depressed but mean values were within the normal range for both IgG and IgM at one and five years. Few complications were observed (two episodes of febrile neutropenia during the first year of treatment were the only serious adverse events) and patients routinely reported sustained wellbeing. CONCLUSIONS: This pilot study demonstrates that a systematically administered course of rituximab and cyclophosphamide over an eighteen month period provided sustained relief for patients with childhood onset SLE which was maintained over a sixty month period, while minimizing the need for corticosteroids, without excessive toxicity.

OBJECTIVE: Epidemiological associations suggest vitamin D may play a role in inflammation and atherosclerosis. Using frozen serum and data from the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) trial, we assessed associations between 25-hydroxyvitamin D [25(OH)D] and measures of systemic lupus erythematosus (SLE) disease activity and cardiovascular risk. METHODS: Baseline APPLE serum samples were used to measure 25(OH)D levels. Logistic regression models for vitamin D deficiency [25(OH)D levels <20 ng/mL] were constructed using baseline variables collected as part of the trial, including race, season, latitude, disease duration, disease activity, high-sensitivity C-reactive protein (hsCRP), proteinuria, fasting lipids and carotid intima medial thickness (CIMT). RESULTS: Samples were available from 201 of 221 APPLE subjects; 61/201 (30%) had vitamin D deficiency at baseline. In univariable analysis, baseline vitamin D deficiency was associated with season (p<0.01), minority status (p<0.01), body mass index (p=0.04), duration of SLE (p<0.01), SLICC damage index (p=0.04), hsCRP (p<0.01), mean-max CIMT (p=0.01), LDL-cholesterol (p=0.03) and timed urine protein (p=0.03). In multivariable modelling, vitamin D deficiency was associated with age, latitude, season, minority status, proteinuria and hsCRP. CONCLUSIONS: Vitamin D deficiency is common in paediatric lupus and is independently associated with elevated hsCRP, a marker of inflammation that predicts cardiovascular disease risk. Although association is not proof of causation, this association is novel in the paediatric SLE population and suggests that vitamin D deficiency may contribute to heightened inflammation and cardiovascular risk in this population. TRIAL REGISTER NUMBER: NCT00065806.

OBJECTIVE: Epidemiological associations suggest that vitamin D status may play a role in inflammation and progression of atherosclerosis. Using frozen serum, carotid intima medial thickness (CIMT) measurements and other existing data from the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) trial, we assessed interactions between serum 25-hydroxyvitamin D (25(OH)D), atorvastatin randomisation and CIMT progression rate. METHODS: Participants in the 3-year APPLE trial were randomised to placebo or atorvastatin and CIMT progression rate was measured. Baseline frozen serum was used to measure 25(OH)D concentrations. Mixed effect longitudinal models for CIMT progression at 3 years were used to evaluate interaction between vitamin D deficiency (serum 25(OH)D <20 ng/mL) at baseline and atorvastatin or placebo treatment, adjusting for key systemic lupus erythematosus disease variables and cardiovascular risk factors. RESULTS: 201/221 APPLE participants had available samples and were included in this analysis; 61/201 (30%) had vitamin D deficiency at baseline. In adjusted longitudinal modelling, there was significant interaction between baseline vitamin D deficiency and atorvastatin randomisation in 3-year progression of mean-max CIMT. In four out of six carotid segments, there was a greater decrease in mean-max CIMT progression rate in subjects who were treated with atorvastatin compared with placebo if they had baseline serum 25(OH)D levels >/=20 ng/mL. CONCLUSIONS: Subjects with serum 25(OH)D >/=20 ng/mL had less mean-max CIMT progression following 3 years of atorvastatin treatment. Results from secondary analyses must be interpreted cautiously, but findings suggest that underlying vitamin D deficiency may be involved in response to atorvastatin in atherosclerosis prevention. TRIAL REGISTRATION NUMBER: NCT00065806.

Juvenile idiopathic arthritis (JIA) includes several forms of chronic arthritis in childhood with no apparent cause. JIA is the most common rheumatic disease in children, and may result in pain, joint deformity, and growth im- pairment, with possible persistent active arthritis into adulthood. Prior treatment involved non-specific agents, several with significant adverse effects. The recent use of biologics now provides target-specific therapy, which may be better tolerated. Through continued translational research and clinical trials, one better understands the biology mediating disease, with the hope of offering safer, more effective medicine, and potential cure. This review will outline the clinical features of JIA, as well as provide the latest updates in treatment.

OBJECTIVE: To use consensus methods and the considerable expertise contained within the Childhood Arthritis and Rheumatology Research Alliance (CARRA) organization to extend the 3 previously developed treatment plans for moderate juvenile dermatomyositis (DM) to span the full course of treatment. METHODS: A consensus meeting was held in Chicago on April 23-24, 2010, involving 30 pediatric rheumatologists and 4 lay participants. Nominal group technique was used to achieve consensus on treatment plans that represented typical management of moderate juvenile DM. A preconference survey of CARRA, completed by 151 (56%) of 272 members, was used to provide additional guidance to the discussion. RESULTS: Consensus was reached on timing and rate of steroid tapering, duration of steroid therapy, and actions to be taken if patients were unchanged, worsening, or experiencing medication side effects or disease complications. Of particular importance, a single consensus steroid taper was developed. CONCLUSION: We were able to develop consensus treatment plans that describe therapy for moderate juvenile DM throughout the treatment course. These treatment plans can now be used clinically, and data collected prospectively regarding treatment effectiveness and toxicity. This will allow comparison of these treatment plans and facilitate the development of evidence-based treatment recommendations for moderate juvenile DM.

ABSTRACT: OBJECTIVE: Behcet's is an idiopathic multi-organ syndrome, which may have onset during childhood. Vascular involvement is uncommon, with rarely reported coronary aneurysm formation. We present a case report of a teenager girl who developed recalcitrant life-threatening Behcet's vasculitis, involving both small and large venous and arterial systems including a giant coronary aneurysm. CASE REPORT: De-identified data were collected retrospectively in case report format. Although our sixteen year old female with Behcet's vasculitis had resolution of many arterial aneurysms, she had persistent venous thrombosis of large vessels, as well as persistent, giant arterial aneurysms requiring intra-arterial coiling of a lumbar artery and coronary bypass grafting despite intensive immunosuppression including glucocorticoids, cyclophosphamide, infliximab, methotrexate, azathioprine and intravenous immunoglobulin. CONCLUSIONS: Vascular manifestations may be seen in Behcet's syndrome, including asymptomatic coronary aneurysm, which may be refractory to immunosuppression and ultimately require surgical intervention. Increased awareness is essential for prompt diagnosis and management.

Juvenile idiopathic arthritis (JIA) comprises a collection of all forms of chronic arthritis in childhood with no apparent cause. JIA is the most common rheumatic disease in children, and may result in significant pain, joint deformity, and growth impairment, with persistence of active arthritis into adulthood. Prior to the mid 1990s, the therapeutic armamentarium for JIA was more limited, utilizing non- specific agents, many with significant adverse effects. With the relatively recent use of biologics, one can provide more target-specific therapy, which may be better tolerated. Through continued translational research and clinical trials, one better understands the biology mediating disease, with the hope of offering safer, more effective medicine, and potential cure. This review will outline the clinical features of JIA, as well as provide the latest updates in current and future pharmacotherapy.

The objective of the study was to compare clinical features, treatment and disease outcome in patients with early versus later onset of childhood-onset systemic lupus erythematosus (cSLE). A retrospective matched cohort study of cSLE patients diagnosed between 1988 and 2008 and followed for a minimum of one year was conducted. Thirty-four pre-pubertal cSLE patients with disease onset prior to their 12th birthday were matched by ethnicity and year of diagnosis to 34 pubertal cSLE patients. The most common criteria at diagnosis in both groups were malar rash, arthritis, hematologic manifestations, and renal disease. After a mean follow-up of more than six years, a similar proportion of patients in the two groups were still prescribed corticosteroids (47% and 41%); patients in the early onset group required a significantly higher daily dose (0.6 mg/kg prednisone-equivalent versus 0.2 mg/kg, p < 0.05). There were no significant differences in organ involvement, disease activity and disease damage between the two groups, and severe complications occurred at similar rates. There were a greater number of admissions to the pediatric intensive care unit (PICU) in the early onset group (18 versus 5, p = 0.01), with time-to-event analysis demonstrating a significantly shorter disease duration from diagnosis to first PICU admission in the early onset group (p < 0.001). While a similar proportion of patients in the early and later onset groups required treatment with cyclophosphamide, patients in the early onset group received treatment earlier in their disease course (mean 13.7 versus 19.9 months, p < 0.001). Early onset cSLE leads to earlier and more frequent PICU admission, earlier use of cyclophosphamide, and higher corticosteroid dose at long-term follow-up

OBJECTIVE: To assess the prevalence of neurocognitive impairment (NCI) in childhood-onset systemic lupus erythematosus (cSLE) by comparing published classification criteria, and to examine associations between NCI, disease characteristics, psychosocial well-being, and intelligence. METHODS: cSLE patients and ethnicity- and age-matched healthy controls completed a neuropsychological research battery, and results were categorized by 3 different NCI classification criteria with different cutoff scores (e.g., >2, 1.5, or 1 SD below the mean) and the number of required abnormal tests or domains. RESULTS: Forty-one cSLE subjects and 22 controls were included. Subjects were predominantly female (~70%) and Hispanic ( approximately 70%). Executive functioning, psychomotor speed, and fine motor speed were most commonly affected. Method 1 classified 34.1% of cSLE subjects with NCI compared to method 2 (14.6% with decline and 7.3% with NCI) and method 3 (63.4% with NCI). The prevalence of NCI was not significantly different between the controls and patients using any of the categorization methods. NCI was not associated with SLE disease activity or characteristics or with depression. Using method 3, patients in the cognitive impairment group reported significantly lower quality of life estimates (69.7 versus 79.3; P = 0.03). Below average intellectual functioning (intelligence quotient <90) differentiated the number of test scores >1 and >1.5 SDs, but not >2 SDs below the mean. CONCLUSION: NCI was prevalent in cSLE, but varied according to the chosen categorization method. A similar proportion of cSLE patients and controls had NCI, reinforcing the importance of studying an appropriate control group. Categorical classification (i.e., impaired/nonimpaired) may oversimplify the commonly observed deficits in cSLE