Broadly HIV-1-neutralizing antibodies (BnAbs) display one or more unusual traits, including a long heavy chain complementarity-determining region 3 (HCDR3), polyreactivity, and high levels of somatic mutations. These shared characteristics suggest that BnAb development might be limited by immune tolerance controls. It has been postulated that HIV-1-infected individuals with autoimmune disease and defective immune tolerance mechanisms may produce BnAbs more readily than those without autoimmune diseases. In this study, we identified an HIV-1-infected individual with SLE who exhibited controlled viral load (<5,000 copies/ml) in the absence of controlling HLA phenotypes and developed plasma HIV-1 neutralization breadth. We collected memory B cells from this individual and isolated a BnAb, CH98, that targets the CD4 binding site (CD4bs) of HIV-1 envelope glycoprotein 120 (gp120). CH98 bound to human antigens including dsDNA, which is specifically associated with SLE. Anti-dsDNA reactivity was also present in the patient's plasma. CH98 had a mutation frequency of 25% and 15% nt somatic mutations in the heavy and light chain variable domains, respectively, a long HCDR3, and a deletion in the light chain CDR1. The occurrence of anti-dsDNA reactivity by a HIV-1 CD4bs BnAb in an individual with SLE raises the possibility that some BnAbs and SLE-associated autoantibodies arise from similar pools of B cells.
Objective
Develop response criteria for juvenile dermatomyositis (JDM).
Methods
We analyzed the performance of 312 definitions that used core set measures (CSM) from either the International Myositis Assessment and Clinical Studies Group (IMACS) or the Pediatric Rheumatology International Trials Organization (PRINTO) and were derived from natural history data and a conjoint-analysis survey. They were further validated in the PRINTO trial of prednisone alone compared to prednisone with methotrexate or cyclosporine and the Rituximab in Myositis trial. Experts considered 14 top-performing candidate criteria based on their performance characteristics and clinical face validity using nominal group technique at a consensus conference.
Results
Consensus was reached for a conjoint analysis–based continuous model with a Total Improvement Score of 0-100, using absolute percent change in CSM with thresholds for minimal (≥30 points), moderate (≥45), and major improvement (≥70). The same criteria were chosen for adult dermatomyositis/polymyositis with differing thresholds for improvement. The sensitivity and specificity were 89% and 91-98% for minimal, 92-94% and 94-99% for moderate, and 91-98% and 85-85% for major improvement, respectively, in JDM patient cohorts using the IMACS and PRINTO CSM. These criteria were validated in the PRINTO trial for differentiating between treatment arms for minimal and moderate improvement (P=0.009–0.057) and in the Rituximab trial for significantly differentiating the physician rating of improvement (P<0.006).
Conclusion
The response criteria for JDM was a conjoint analysis–based model using a continuous improvement score based on absolute percent change in CSM, with thresholds for minimal, moderate, and major improvement.
Objective
Vitamin D modulates the immune response and blocks induction of an interferon signature by SLE sera. We investigated the effects of vitamin D supplementation on the IFN signature in SLE patients.
Methods
57 SLE patients with stable, inactive disease, a serum 25OH vitamin D (25OHD) ≤20ng/ml, elevated anti-DNA antibodies and an IFN signature (determined by measurement of 3 interferon responsive genes) were randomized into a 12 week double-blind placebo controlled trial of 0, 2000IU or 4000IU of vitamin D3. An IFN signature response required a 50% reduction in expression of 1 gene or a 25% decrease in 2 genes. Disease activity, adverse events and endocrine effects were assessed.
Results
Baseline characteristics of the 3 treatment groups were similar. No subjects receiving placebo repleted (achieved 25OHD levels ≥30ng/ml) compared to 16 of 33 subjects receiving vitamin D3. The percent of subjects achieving an IFN signature response did not differ between treatment groups. Moreover, there was no difference in the IFN signature response in vitamin D deficient versus repleted subjects. Modular microarray analysis of a subset (n=40) revealed no changes in any modules including the IFN-inducible module between any treatment group, nor when comparing expression data from vitamin D repleted to persistently deficient subjects. Vitamin D3 was well-tolerated with no safety concerns.
Conclusions
Vitamin D3 supplementation up to 4000IU daily was safe and well-tolerated but failed to diminish the IFN signature in vitamin D deficient SLE patients. Higher 25OHD levels sustained for longer duration may be required to affect immunological outcomes.
This is the largest study to date evaluating G6PDH deficiency with concurrent use of HCQ. Of 11 patients with G6PDH deficiency, 2 had episodes of hemolysis, but these did not occur during HCQ therapy. These data do not support routine measurement of G6PDH levels or withholding HCQ therapy among African American patients with G6PDH deficiency.
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