Validation of the systemic lupus erythematosus responder index for use in juvenile-onset systemic lupus erythematosus.

OBJECTIVES: This study tested the concurrent validity of the systemic lupus erythematosus responder index (SRI) in assessing improvement in juvenile-onset systemic lupus erythematosus (jSLE). METHODS: The SRI considers changes in the SELENA-SLEDAI, BILAG and a 3-cm visual analogue scale of physician-rated disease activity (PGA) to determine patient improvement. Using prospectively collected data from 760 unique follow-up visit intervals of 274 jSLE patients, we assessed the sensitivity and specificity of the SRI using these external standards: physician-rated improvement (MD-change), patient/parent-rated major improvement of wellbeing (patient-change) and decrease in prescribed systemic corticosteroids (steroid-change). Modifications of the SRI that considered different thresholds for the SELENA-SLEDAI, BILAG and 10-cm PGA were explored and agreement with the American College of Rheumatology/PRINTO provisional criteria for improvement of jSLE (PCI) was examined. RESULTS: The sensitivity/specificity in capturing major improvement by the MD-change were 78%/76% for the SRI and 83%/78% for the PCI, respectively. There was fair agreement between the SRI and PCI (kappa=0.35, 95% CI 0.02 to 0.73) in capturing major improvement by the MD-change. Select modified versions of the SRI had improved accuracy overall. All improvement criteria tested had lower sensitivity when considering patient-change and steroid-change as external standards compared to MD-change. CONCLUSIONS: The SRI and its modified versions based on meaningful changes in jSLE have high specificity but at most modest sensitivity for capturing jSLE improvement. When used as an endpoint of clinical trials in jSLE, the SRI will provide a conservative estimate regarding the efficacy of the therapeutic agent under investigation.

Association of noninvasively measured renal protein biomarkers with histologic features of lupus nephritis.

OBJECTIVE: To investigate the relationship of urinary biomarkers and established measures of renal function to histologic findings in lupus nephritis (LN), and to test whether certain combinations of the above-mentioned laboratory measures are diagnostic for specific histologic features of LN. METHODS: Urine samples from 76 patients were collected within 2 months of kidney biopsy and assayed for the urinary biomarkers lipocalin-like prostaglandin D synthase (L-PGDS), α(1) -acid glycoprotein (AAG), transferrin (TF), ceruloplasmin (CP), neutrophil gelatinase-associated lipocalin (NGAL), and monocyte chemotactic protein 1 (MCP-1). Using nonparametric analyses, levels of urinary biomarkers and established markers of renal function were compared with histologic features seen in LN, i.e., mesangial expansion, capillary proliferation, crescent formation, necrosis, wire loops, fibrosis, tubular atrophy, and epimembranous deposits. The area under the receiver operating characteristic curve (AUC) was calculated to predict LN activity, chronicity, or membranous LN. RESULTS: There was a differential increase in levels of urinary biomarkers that formed a pattern reflective of specific histologic features seen in active LN. The combination of MCP-1, AAG, and CP levels plus protein:creatinine ratio was excellent in predicting LN activity (AUC 0.85). NGAL together with creatinine clearance plus MCP-1 was an excellent diagnostic test for LN chronicity (AUC 0.83), and the combination of MCP-1, AAG, TF, and creatinine clearance plus C4 was a good diagnostic test for membranous LN (AUC 0.75). CONCLUSION: Specific urinary biomarkers are associated with specific tissue changes observed in conjunction with LN activity and chronicity. Especially in combination with select established markers of renal function, urinary biomarkers are well-suited for use in noninvasive measurement of LN activity, LN chronicity, and the presence of membranous LN.

Validation of the Lupus Nephritis Clinical Indices in Childhood-Onset Systemic Lupus Erythematosus.

OBJECTIVE: To validate clinical indices of lupus nephritis activity and damage when used in children against the criterion standard of kidney biopsy findings. METHODS: In 83 children requiring kidney biopsy, the Systemic Lupus Erythematosus Disease Activity Index renal domain (SLEDAI-R), British Isles Lupus Assessment Group index renal domain (BILAG-R), Systemic Lupus International Collaborating Clinics (SLICC) renal activity score (SLICC-RAS), and SLICC Damage Index renal domain (SDI-R) were measured. Fixed effects and logistic models were calculated to predict International Society of Nephrology/Renal Pathology Society (ISN/RPS) class; low-to-moderate versus high lupus nephritis activity (National Institutes of Health [NIH] activity index [AI]) score: ≤10 versus >10; tubulointerstitial activity index (TIAI) score: ≤5 versus >5; or the absence versus presence of lupus nephritis chronicity (NIH chronicity index) score: 0 versus ≥1. RESULTS: There were 10, 50, and 23 patients with ISN/RPS class I/II, III/IV, and V, respectively. Scores of the clinical indices did not differentiate among patients by ISN/RPS class. The SLEDAI-R and SLICC-RAS but not the BILAG-R differed with lupus nephritis activity status defined by NIH-AI scores, while only the SLEDAI-R scores differed between lupus nephritis activity status based on TIAI scores. The sensitivity and specificity of the SDI-R to capture lupus nephritis chronicity was 23.5% and 91.7%, respectively. Despite being designed to measure lupus nephritis activity, SLICC-RAS and SLEDAI-R scores significantly differed with lupus nephritis chronicity status. CONCLUSION: Current clinical indices of lupus nephritis fail to discriminate ISN/RPS class in children. Despite its shortcomings, the SLEDAI-R appears best for measuring lupus nephritis activity in a clinical setting. The SDI-R is a poor correlate of lupus nephritis chronicity.

Initial Benchmarking of the Quality of Medical Care in Childhood-Onset Systemic Lupus Erythematosus.

OBJECTIVE: To assess the quality of medical care in childhood-onset systemic lupus erythematosus (SLE) at tertiary pediatric rheumatology centers as measured by observance of SLE quality indicators (SLE-QIs). METHODS: International consensus has been achieved for childhood-onset SLE-QIs capturing medical care provision in 9 domains: diagnostic testing, education of cardiovascular (CV) risk and lifestyles, lupus nephritis (LN), medication management, bone health, ophthalmologic surveillance, transition, pregnancy, and vaccination. Using medical record information, the level of performance of these childhood-onset SLE-QIs was assessed in childhood-onset SLE populations treated at 4 tertiary pediatric rheumatology centers in the US, 2 in Brazil, and 1 center in India. RESULTS: A total of 483 childhood-onset SLE patients were assessed. Care for the 310 US patients differed markedly for childhood-onset SLE-QIs addressing LN, bone health, vaccinations, education on CV risk, and transition planning. Performance of safety blood testing for medications was high at all centers. Despite often similar performance on the childhood-onset SLE-QI, access to kidney biopsies was lower in Brazil than in the US. Irrespective of the country of practice, larger centers tended to meet the childhood-onset SLE-QIs more often than smaller centers. CONCLUSION: The childhood-onset SLE-QIs, evidence-based minimum standards of medical care, are not consistently met in the US or some other countries outside the US. This has the potential to contribute to suboptimal childhood-onset SLE outcomes.

Update on differences between childhood-onset and adult-onset systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease and occurs worldwide in both children and adults. The estimated annual incidence among children is 2.22/100,000 and among adults is 23.2/100,000 in the United States. There is increasing understanding about differences in disease manifestations, medication use, and disease severity between those with childhood-onset SLE as compared with adult-onset SLE. Children have a more fulminant disease onset and course than adults with SLE, resulting in two to three times higher mortality. In future years, we anticipate more insight into the genetics between childhood-onset SLE and adult-onset SLE to help delineate the best therapies for both subsets of patients.

Inactive disease and remission in childhood-onset systemic lupus erythematosus.

OBJECTIVE: To define inactive disease (ID) and clinical remission (CR) and to delineate variables that can be used to measure ID/CR in childhood-onset systemic lupus erythematosus (cSLE). METHODS: Delphi questionnaires were sent to an international group of pediatric rheumatologists. Respondents provided information about variables to be used in future algorithms to measure ID/CR. The usefulness of these variables was assessed in 35 children with ID and 31 children with minimally active lupus (MAL). RESULTS: While ID reflects cSLE status at a specific point in time, CR requires the presence of ID for >6 months and considers treatment. There was consensus that patients in ID/CR can have <2 mild nonlimiting symptoms (i.e., fatigue, arthralgia, headaches, or myalgia) but not Raynaud's phenomenon, chest pain, or objective physical signs of cSLE; antinuclear antibody positivity and erythrocyte sedimentation rate elevation can be present. Complete blood count, renal function testing, and complement C3 all must be within the normal range. Based on consensus, only damage-related laboratory or clinical findings of cSLE are permissible with ID. The above parameters were suitable to differentiate children with ID/CR from those with MAL (area under the receiver operating characteristic curve >0.85). Disease activity scores with or without the physician global assessment of disease activity and patient symptoms were well suited to differentiate children with ID from those with MAL. CONCLUSION: Consensus has been reached on common definitions of ID/CR with cSLE and relevant patient characteristics with ID/CR. Further studies must assess the usefulness of the data-driven candidate criteria for ID in cSLE.

Consensus treatment plans for induction therapy of newly diagnosed proliferative lupus nephritis in juvenile systemic lupus erythematosus.

OBJECTIVE: To formulate consensus treatment plans (CTPs) for induction therapy of newly diagnosed proliferative lupus nephritis (LN) in juvenile systemic lupus erythematosus (SLE). METHODS: A structured consensus formation process was employed by the members of the Childhood Arthritis and Rheumatology Research Alliance after considering the existing medical evidence and current treatment approaches. RESULTS: After an initial Delphi survey (response rate = 70%), a 2-day consensus conference, and 2 followup Delphi surveys (response rates = 63-79%), consensus was achieved for a limited set of CTPs addressing the induction therapy of proliferative LN. These CTPs were developed for prototypical patients defined by eligibility characteristics, and included immunosuppressive therapy with either mycophenolic acid orally twice per day, or intravenous cyclophosphamide once per month at standardized dosages for 6 months. Additionally, the CTPs describe 3 options for standardized use of glucocorticoids, including a primarily oral, a mixed oral/intravenous, and a primarily intravenous regimen. There was consensus on measures of effectiveness and safety of the CTPs. The CTPs were well accepted by the pediatric rheumatology providers treating children with LN, and up to 300 children per year in North America are expected to be candidates for the treatment with the CTPs. CONCLUSION: CTPs for induction therapy of proliferative LN in juvenile SLE based on the available scientific evidence and pediatric rheumatology group experience have been developed. Consistent use of the CTPs may improve the prognosis of proliferative LN, and support the conduct of comparative effectiveness studies aimed at optimizing therapeutic strategies for proliferative LN in juvenile SLE.

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

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

Identification of urinary metabolites that distinguish membranous lupus nephritis from proliferative lupus nephritis and focal segmental glomerulosclerosis.

INTRODUCTION: Systemic lupus erythematosus (SLE or lupus) is a chronic autoimmune disease, and kidney involvement with SLE, a.k.a. lupus nephritis (LN), is a frequent and severe complication of SLE that increases patient morbidity and mortality. About 50% of patients with SLE encounter renal abnormalities which, if left untreated, can lead to end-stage renal disease. Kidney biopsy is considered the criterion standard for diagnosis and staging of LN using the International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification, which was developed to help predict renal outcomes and assist with medical decision-making. However, kidney biopsy-based classification of LN is highly invasive and impractical for real-time monitoring of LN status. Here, nuclear magnetic resonance (NMR) spectroscopy-based metabolic profiling was used to identify urinary metabolites that discriminated between proliferative and pure membranous LN as defined by the ISN/RPS classification, and between LN and primary focal segmental glomerulosclerosis (FSGS). METHODS: Metabolic profiling was conducted using urine samples of patients with proliferative LN without membranous features (Class III/IV; n = 7) or pure membranous LN (Class V; n = 7). Patients with primary FSGS and proteinuria (n = 10) served as disease controls. For each patient, demographic information and clinical data was obtained and a random urine sample collected to measure NMR spectra. Data and sample collection for patients with LN occurred around the time of kidney biopsy. Metabolic profiling analysis was done by visual inspection and principal component analysis. RESULTS: Urinary citrate levels were 8-fold lower in Class V LN compared to Class III/IV patients, who had normal levels of urinary citrate (P < 0.05). Class III/IV LN patients had > 10-fold lower levels of urinary taurine compared to Class V patients, who had mostly normal levels (P < 0.01). Class V LN patients had normal urinary hippurate levels compared to FSGS patients, who completely lacked urinary hippurate (P < 0.001). CONCLUSIONS: This pilot study indicated differences in urinary metabolites between proliferative LN and pure membranous LN patients, and between LN and FSGS patients. If confirmed in larger studies, these urine metabolites may serve as biomarkers to help discriminate between different classes of LN, and between LN and FSGS.

Preliminary criteria for global flares in childhood-onset systemic lupus erythematosus.

OBJECTIVE: To develop widely acceptable preliminary criteria of global flare for childhood-onset systemic lupus erythematosus (cSLE). METHODS: Pediatric rheumatologists (n = 138) rated a total of 358 unique patient profiles with information about the cSLE flare descriptors from 2 consecutive visits: patient global assessment of well-being, physician global assessment of disease activity (MD-global), health-related quality of life, anti-double-stranded DNA antibodies, disease activity index scores, protein:creatinine (P:C) ratio, complement levels, and erythrocyte sedimentation rate (ESR). Based on 2,996 rater responses about the course of cSLE (baseline versus followup), the accuracy (sensitivity, specificity, and area under the receiver operating characteristic curve) of candidate flare criteria was assessed. An international consensus conference was held to rank these candidate flare criteria as per the American College of Rheumatology recommendations for the development and validation of criteria sets. RESULTS: The highest-ranked candidate criteria considered absolute changes (Δ) of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) or British Isles Lupus Assessment Group (BILAG), MD-global, P:C ratio, and ESR; flare scores can be calculated (0.5 × ΔSLEDAI + 0.45 × ΔP:C ratio + 0.5 × ΔMD-global + 0.02 × ΔESR), where values of ≥1.04 are reflective of a flare. Similarly, BILAG-based flare scores (0.4 × ΔBILAG + 0.65 × ΔP:C ratio + 0.5 × ΔMD-global + 0.02 × ΔESR) of ≥1.15 were diagnostic of a flare. Flare scores increased with flare severity. CONCLUSION: Consensus has been reached on preliminary criteria for global flares in cSLE. Further validation studies are needed to confirm the usefulness of the cSLE flare criteria in research and for clinical care.

Pediatric lupus--are there differences in presentation, genetics, response to therapy, and damage accrual compared with adult lupus?

Some complement deficiencies predispose to systemic lupus erythematosus (SLE) early in life. Currently, there are no known unique physiologic or genetic pathways that can explain the variability in disease phenotypes. Children present with more acute illness and have more frequent renal, hematologic, and central nervous system involvement compared to adults with SLE. Almost all children require corticosteroids during the course of their disease; many are treated with immunosuppressive drugs. Mortality rates remain higher with pediatric SLE. Children and adolescents accrue more damage, especially in the renal, ocular and musculoskeletal organ systems. Conversely, cardiovascular mortality is more prevalent in adults with SLE.

Systemic lupus erythematosus in children with sickle cell disease.

Coexistence of sickle cell disease (SCD) and systemic lupus erythematosus (SLE) has been reported in 11 patients. The authors describe five additional patients with SCD and symptoms initially attributable to SCD who were later found to have SLE. Patients were identified over a 10-year period (1991-2001) in a pediatric sickle cell population numbering approximately 350. All patients are African-American. Age at diagnosis of SLE was 9 to 17 years (median 11 years), and follow-up after diagnosis ranged from 6 months to 10 years (median 3 years). SLE cerebritis (n = 3), serositis (n = 4), and nephritis (n = 2) were common findings. Physicians should be alerted to the possible development of SLE in patients with SCD.