Usefulness of the lupus low disease activity state as a treatment target in childhood-onset SLE.

OBJECTIVE: Treat-to-target (T2T) strategies are advocated to improve prognosis in childhood-onset SLE (cSLE). Proposed T2T states include SLEDAI score of <4 (SLEDAI-LD), limited corticosteroid use (low-CS), and lupus low disease activity state (LLDAS). We sought to compare T2T states for their association with cSLE prognosis under consideration of relevant disease characteristics such as pre-existing damage, race and lupus nephritis (LN). METHODS: Longitudinal data from 165 patients enrolled in the Cincinnati Lupus Registry were included. LN presence was based on renal biopsy, and patients were followed up until 18 years of age. RESULTS: The 165 patients (LN: 45, white: 95) entered the registry within a median of 0 (IQR: 0-1) year post diagnosis and were followed up for a median of 4 (IQR: 2-5) years during which 80%, 92% and 94% achieved LLDAS, low-CS and SLEDAI-LD. Patients with LN were significantly less likely to achieve any T2T state (all p<0.03) and required a significantly longer time to reach them (all p<0.0001). Over the study period, patients maintained low-CS, SLEDAI-LD or LLDAS for a median of 76% (IQR: 48%-100%), 86% (IQR: 55%-100%) or 39% (IQR: 13%-64%) of their follow-up. Significant predictors of failure to maintain LLDAS included LN (p≤0.0062), pre-existing damage (p≤0.0271) and non-white race (p≤0.0013). There were 22%, 20% and 13% of patients who reached SLEDAI-LD, CS-low and LLDAS and nonetheless acquired new damage. Patients with LN had a higher risk of new damage than patients without LN even if achieving low-CS (p=0.009) or LLDAS (p=0.04). CONCLUSIONS: Patients with LN and pre-existing damage are at higher risk of increased future damage acquisition, even if achieving a T2T state such as LLDAS. Among proposed common T2T states, the LLDAS is the hardest to achieve and maintain. The LLDAS may be considered the preferred T2T measure as it conveys the highest protection from acquiring additional disease damage.

Alternative Biologic Therapy in Children Failing Conventional TNFα Inhibitors for Refractory, Noninfectious, Chronic Anterior Uveitis.

PURPOSE: A significant number of children with noninfectious, chronic anterior uveitis (CAU) fail to respond to conventional therapy; however, successful alternative biologic treatments (ABT) have not been well described. This study aims to review the clinical and treatment characteristics of children with CAU who require ABT. DESIGN: Retrospective, nonrandomized clinical study. METHODS: Setting: Tertiary center. STUDY POPULATION: Children with noninfectious CAU. OBSERVATION PROCEDURES: Clinical characteristics, uveitis course, complications, and treatment were compared among patients treated with methotrexate (MTX) monotherapy, conventional TNFα inhibitors (cTNFi), and ABT for >3 months. MAIN OUTCOME MEASURE: Success of ABT (abatacept, tocilizumab, and/or golimumab) in children failing conventional treatment. RESULTS: Of the 52 children with CAU, 75% had juvenile idiopathic arthritis. CAU was controlled in 15 children receiving MTX monotherapy, 28 receiving cTNFi, and 9 receiving ABT (n = 1, abatacept; n = 3, tocilizumab; n = 5, golimumab). Patients in the ABT group had a greater number of total ocular complications per person before ABT than those in the control groups (3.4 vs 0.7 [MTX], P < .001, and 1.5 [cTNFi], P < .001, respectively). In all 9 children on ABT, treatment led to control of CAU and topical glucocorticoids tapered to ≤2 drops/d with no new ocular complications. CONCLUSIONS: In this study, alternative biologics (abatacept, golimumab, and tocilizumab) were useful for treating CAU in children who fail MTX and cTNFi therapy. Patients who were controlled on ABT had more disease activity, ocular complications, and anti-cTNFi neutralizing antibodies (before ABT) than those managed with conventional therapy. Larger studies are required to confirm these findings.

Feasibility and acceptability of an innovative adherence intervention for young adults with childhood-onset systemic Lupus Erythematosus.

BACKGROUND: In Childhood-Onset Systemic Lupus Erythematosus (cSLE), poor medication adherence rates are very high. Interventions targeting this problem in cSLE are limited thus effective interventions are needed. The objective of this study is to examine the feasibility and acceptability an intervention (automated digital reminders + personalized prescribed treatment plan (pPTP)) to improve medication adherence in young adults with cSLE over 3 months. METHOD: This is a proof-of-concept randomized controlled study. All participants received SimpleMed+ pillboxes that track adherence. The treatment group received a pPTP, and in month 2, preselected digital reminders for missed doses. Reminders were discontinued after 30 days and adherence data collected. Data analysis was done using t-tests. RESULTS: Twenty-one participants were approached and nineteen consented to participate, yielding a recruitment rate of 86%. Participants were on average 20.5 years, mostly black (58%) and female (84%). Of the nineteen consented, eleven were randomized to control (57%) and eight to treatment (42%) groups respectively. All participants in the treatment group rated the pillbox as easy to use, notably; none reported boredom with the pillbox or reminders. Also, 88% of participants in the treatment group rated the pillbox as helpful, however, only 50% reported the pPTP taught them new information about lupus or made them more interested in their lupus management. CONCLUSIONS: This is the first use of an electronic pillbox to track adherence to multiple medications in cSLE. The high rating of the pillbox makes it an acceptable method of measuring adherence. Feasibility and acceptability ratings for the intervention were mixed suggesting a there is a subset of cSLE patients for whom this intervention would be beneficial. Future research should focus on a larger trial.

The use of S100 proteins testing in juvenile idiopathic arthritis and autoinflammatory diseases in a pediatric clinical setting: a retrospective analysis.

BACKGROUND: Serum phagocyte-derived alarmins S100A8/9 and S100A12 are considered useful for the assessment of inflammatory diseases. Our study evaluated the use of S100 proteins in a pediatric clinical setting for estimating disease activity and supporting diagnosis. METHODS: Patients (n = 136) who had S100 proteins tested as part of clinical care were included in this study and relevant information obtained from the medical record: C-reactive protein (CRP), disease activity status (inactive: = 0 joint; active: > 0 active joint), systemic symptoms in systemic JIA (sJIA), and symptoms of flare of other autoinflammatory and fever syndromes. Patients were categorized as: sJIA, non-systemic JIA (nsJIA), other defined autoinflammatory syndromes (AID) and systemic undifferentiated recurring fever syndromes (SURFS). RESULTS: Patients with sJIA (n = 21) had significantly higher levels of S100A8/9 and S100A12 compared to patients with nsJIA (n = 49), other AIDs (n = 8) or SURFS (n = 14) (all p < 0.0001). Compared to CRP [area under the receiver operating characteristics curve (AUC) = 0.7], S100 proteins were superior in differentiating sJIA from AID and SURFS [AUC = 0.9]. S100A8/9 and S100A12 levels were not associated with disease activity in nsJIA, AID or SURFS. S100A8/9 and S100A12 levels were significantly higher in active sJIA compared to inactive (p = 0.0002 and p = 0.0002 respectively). CONCLUSION: Compared to other autoinflammatory and fever syndromes, sJIA patients have markedly higher levels of S100A8/9 and S100A12 proteins which may assist with diagnosis. S100 levels slightly outperformed CRP in distinguishing sJIA from other diagnoses and in sJIA disease activity. S100 proteins may aid in monitoring disease activity in sJIA patients.

Serum S100A8/A9 and S100A12 Levels in Children With Polyarticular Forms of Juvenile Idiopathic Arthritis: Relationship to Maintenance of Clinically Inactive Disease During Anti-Tumor Necrosis Factor Therapy and Occurrence of Disease Flare After Discontinuation of Therapy.

OBJECTIVE: To determine the relationship between serum levels of S100A8/A9 and S100A12 and the maintenance of clinically inactive disease during anti-tumor necrosis factor (anti-TNF) therapy and the occurrence of disease flare following withdrawal of anti-TNF therapy in patients with polyarticular forms of juvenile idiopathic arthritis (JIA). METHODS: In this prospective, multicenter study, 137 patients with polyarticular-course JIA whose disease was clinically inactive while receiving anti-TNF therapy were enrolled. Patients were observed for an initial 6-month phase during which anti-TNF treatment was continued. For those patients who maintained clinically inactive disease over the 6 months, anti-TNF was withdrawn and they were followed up for 8 months to assess for the occurrence of flare. Serum S100 levels were measured at baseline and at the time of anti-TNF withdrawal. Spearman's rank correlation test, Mann-Whitney U test, Kruskal-Wallis test, receiver operating characteristic (ROC) curve, and Kaplan-Meier survival analyses were used to assess the relationship between serum S100 levels and maintenance of clinically inactive disease and occurrence of disease flare after anti-TNF withdrawal. RESULTS: Over the 6-month initial phase with anti-TNF therapy, the disease state reverted from clinically inactive to clinically active in 24 (18%) of the 130 evaluable patients with polyarticular-course JIA; following anti-TNF withdrawal, 39 (37%) of the 106 evaluable patients experienced a flare. Serum levels of S100A8/A9 and S100A12 were elevated in up to 45% of patients. Results of the ROC analysis revealed that serum S100 levels did not predict maintenance of clinically inactive disease during anti-TNF therapy nor did they predict disease flare after treatment withdrawal. Elevated levels of S100A8/A9 were not predictive of the occurrence of a disease flare within 30 days, 60 days, 90 days, or 8 months following anti-TNF withdrawal, and elevated S100A12 levels had a modest predictive ability for determining the risk of flare within 30, 60, and 90 days after treatment withdrawal. Serum S100A12 levels at the time of anti-TNF withdrawal were inversely correlated with the time to disease flare (r = -0.36). CONCLUSION: Serum S100 levels did not predict maintenance of clinically inactive disease or occurrence of disease flare in patients with polyarticular-course JIA, and S100A12 levels were only moderately, and inversely, correlated with the time to disease flare.

Validation of the Cutaneous Lupus Erythematosus Disease Area and Severity Index and pSkindex27 for use in childhood-onset systemic lupus erythematosus.

OBJECTIVE: To determine the measurement properties of the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) and the paediatric adaptation of the Skindex29 (pSkindex27) when used in childhood-onset SLE (cSLE). METHODS: Patients with mucocutaneous involvement of cSLE were evaluated at the study entry and 6 months later. Besides the CLASI and pSkindex27, the Pediatric Quality of Life Inventory Generic Core scale (PedsQL-GC), its Rheumatology Module (PedsQL-RM), the SLE Disease Activity Index (SLEDAI) and the SLE Damage Index (SDI) were completed. RESULTS: The CLASI and pSkindex27 had high internal consistency (both Cronbach α >0.82). Children were able to complete the pSkindex27, with self-report and caregiver proxy-reports showing excellent agreement (intraclass correlation coefficient=0.97). The CLASI Activity Score (CLASI-A) was strongly correlated with the mucocutaneous domain score of the SLEDAI as was the CLASI Damage Score (CLASI-D) with that of the SDI (both: Spearman correlation coefficients (rs) >0.68). pSkindex27 summary scores were moderately correlated with those of the PedsQL-GC and PedsQL-RM (all: rs >|0.51|), the CLASI-A and CLASI-D (both: rs > 0.64), respectively. Patients who experienced a >50% improvement of the CLASI-A between study visits had significantly higher PedsQL-GC and pSkindex27 scores than those without improvement of mucocutaneous features. CONCLUSION: Both CLASI and pSkindex27 are useful assessment tools in cSLE, active and chronic mucocutaneous lesions and their changes over time can be measured using the CLASI and the pSkindex27 can capture the impact of mucocutaneous involvement on patient health-related quality of life.

A plausibly causal functional lupus-associated risk variant in the STAT1-STAT4 locus.

Systemic lupus erythematosus (SLE or lupus) (OMIM: 152700) is a chronic autoimmune disease with debilitating inflammation that affects multiple organ systems. The STAT1-STAT4 locus is one of the first and most highly replicated genetic loci associated with lupus risk. We performed a fine-mapping study to identify plausible causal variants within the STAT1-STAT4 locus associated with increased lupus disease risk. Using complementary frequentist and Bayesian approaches in trans-ancestral Discovery and Replication cohorts, we found one variant whose association with lupus risk is supported across ancestries in both the Discovery and Replication cohorts: rs11889341. In B cell lines from patients with lupus and healthy controls, the lupus risk allele of rs11889341 was associated with increased STAT1 expression. We demonstrated that the transcription factor HMGA1, a member of the HMG transcription factor family with an AT-hook DNA-binding domain, has enriched binding to the risk allele compared with the non-risk allele of rs11889341. We identified a genotype-dependent repressive element in the DNA within the intron of STAT4 surrounding rs11889341. Consistent with expression quantitative trait locus (eQTL) analysis, the lupus risk allele of rs11889341 decreased the activity of this putative repressor. Altogether, we present a plausible molecular mechanism for increased lupus risk at the STAT1-STAT4 locus in which the risk allele of rs11889341, the most probable causal variant, leads to elevated STAT1 expression in B cells due to decreased repressor activity mediated by increased binding of HMGA1.

Risk, Timing, and Predictors of Disease Flare After Discontinuation of Anti-Tumor Necrosis Factor Therapy in Children With Polyarticular Forms of Juvenile Idiopathic Arthritis With Clinically Inactive Disease.

OBJECTIVE: To determine the frequency, time to flare, and predictors of disease flare upon withdrawal of anti-tumor necrosis factor (anti-TNF) therapy in children with polyarticular forms of juvenile idiopathic arthritis (JIA) who demonstrated ≥6 months of continuous clinically inactive disease. METHODS: In 16 centers 137 patients with clinically inactive JIA who were receiving anti-TNF therapy (42% of whom were also receiving methotrexate [MTX]) were prospectively followed up. If the disease remained clinically inactive for the initial 6 months of the study, anti-TNF was stopped and patients were assessed for flare at 1, 2, 3, 4, 6, and 8 months. Life-table analysis, t-tests, chi-square test, and Cox regression analysis were used to identify independent variables that could significantly predict flare by 8 months or time to flare. RESULTS: Of 137 patients, 106 (77%) maintained clinically inactive disease while receiving anti-TNF therapy for the initial 6 months and were included in the phase of the study in which anti-TNF therapy was stopped. Stopping anti-TNF resulted in disease flare in 39 (37%) of 106 patients by 8 months. The mean/median ± SEM time to flare was 212/250 ± 9.77 days. Patients with shorter disease duration at enrollment, older age at onset and diagnosis, shorter disease duration prior to experiencing clinically inactive disease, and shorter time from onset of clinically inactive disease to enrollment were found to have significantly lower hazard ratios for likelihood of flare by 8 months (P < 0.05). CONCLUSION: Over one-third of patients with polyarticular JIA with sustained clinically inactive disease will experience a flare by 8 months after discontinuation of anti-TNF therapy. Several predictors of lower likelihood of flare were identified.

Transancestral mapping and genetic load in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (∼50% of these regions have multiple independent associations); these include 24 novel SLE regions (P<5 × 10-8), refined association signals in established regions, extended associations to additional ancestries, and a disentangled complex HLA multigenic effect. The risk allele count (genetic load) exhibits an accelerating pattern of SLE risk, leading us to posit a cumulative hit hypothesis for autoimmune disease. Comparing results across the three ancestries identifies both ancestry-dependent and ancestry-independent contributions to SLE risk. Our results are consistent with the unique and complex histories of the populations sampled, and collectively help clarify the genetic architecture and ethnic disparities in SLE.

Adolescent Vaccination Strategies: Interventions to Increase Coverage.

While vaccines have decreased the burden of disease, many adolescents still remain under-immunized, particularly for human papillomavirus (HPV) and influenza. We review the most current data regarding adolescent immunizations in the United States and discuss proven strategies that work for increasing vaccination rates. Strategies that have been shown to improve rates include provider feedback, immunization information systems (or registries), and enhanced access outside of provider offices, such as school-based immunization programs. Overall, practices may want to consider multimodal quality improvement approaches to enhance practice vaccination rates. The public health and cost benefits of immunizing adolescents are well known, yet recent measles outbreaks in the United States have highlighted issues with state immunization laws and vaccine refusals. Providers should be clear in their advice regarding vaccines and use effective reminder strategies as parents commonly cite not having enough information or knowledge that a vaccine was needed for their adolescent. Additional research is needed regarding adolescent consent for vaccines, as well as adolescent and parental refusal, in order to design systems that will help inform families and allow for widespread vaccine availability.

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.

Pain anxiety, acceptance, and outcomes among individuals with HIV and chronic pain: a preliminary investigation.

The current study investigated the role of during treatment changes in pain anxiety in the relation between during treatment changes in pain acceptance and chronic pain outcomes. Participants included 45 (15 women) adults (M(age) = 50.42, SD = 7.69) who were HIV positive and experienced chronic pain. They were offered 12 weekly, 90-min group CBT sessions to increase understanding about chronic pain and to improve coping skills. Four hierarchical regression analyses were conducted to examine the mediating role of treatment changes in pain anxiety in the relation between treatment changes in pain acceptance and chronic pain outcomes. Results suggest that increases in pain acceptance during treatment were associated with decreased levels of pain anxiety during treatment, as well as decreases in pain-related impairment at treatment completion. Furthermore, decreases in pain anxiety during treatment were associated with decreases in pain-related impairment at treatment completion. Finally, treatment changes in pain anxiety were found to partially mediate the association between treatment changes in pain acceptance and pain-related impairment at treatment completion. Results are discussed within the context of better understanding the processes of change within a CBT model for chronic pain patients.

Allergen immunotherapy.

Allergen immunotherapy (also called allergy vaccine therapy) involves the administration of gradually increasing quantities of specific allergens to patients with IgE-mediated conditions until a dose is reached that is effective in reducing disease severity from natural exposure. The major objectives of allergen immunotherapy are to reduce responses to allergic triggers that precipitate symptoms in the short term and to decrease inflammatory response and prevent development of persistent disease in the long term. Allergen immunotherapy is safe and has been shown to be effective in the treatment of stinging-insect hypersensitivity, allergic rhinitis or conjunctivitis, and allergic asthma. Allergen immunotherapy is not effective in the treatment of atopic dermatitis, urticaria, or headaches and is potentially dangerous if used for food or antibiotic allergies. Safe administration of allergen immunotherapy requires the immediate availability of a health care professional capable of recognizing and treating anaphylaxis. An observation period of 20 to 30 minutes after injection is mandatory. Patients should not be taking beta-adrenergic blocking agents when receiving immunotherapy because these drugs may mask early signs and symptoms of anaphylaxis and make the treatment of anaphylaxis more difficult. Unlike antiallergic medication, allergen immunotherapy has the potential of altering the allergic disease course after three to five years of therapy.