Fever therapy for arthritis.
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Biomedical subjects
Publications and source records attributed to Daniel J Wallace.
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Nearly 80% of patients with systemic lupus erythematosus (SLE) are treated with NSAIDs for fever, arthritis, serositis and headaches. This article reviews currently available literature on non-selective and selective inhibitors of cyclooxygenases, with an emphasis on the efficacy and safety profile reported in SLE patients. All NSAIDs, regardless of their cyclooxygenase selectivity, induced renal side effects including sodium retention and reduction in glomerular filtration rate. In addition, lupus nephritis is a risk factor for NSAID-induced acute renal failure. NSAID-induced hepatotoxicity is increased in SLE patients in addition to cutaneous and allergic reactions. Finally, aseptic meningitis has been reported more frequently in NSAID-treated SLE patients. Nevertheless, NSAIDs can safely be prescribed to most lupus patients provided that their administration is re-evaluated on a regular basis and the patient is closely monitored.
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OBJECTIVE: CD40-CD40 ligand (CD40L) interactions play a significant role in the production of autoantibodies and tissue injury in lupus nephritis. We performed an open-label, multiple-dose study to evaluate the safety, efficacy, and pharmacokinetics of BG9588, a humanized anti-CD40L antibody, in patients with proliferative lupus nephritis. The primary outcome measure was 50% reduction in proteinuria without worsening of renal function. METHODS: Twenty-eight patients with active proliferative lupus nephritis were scheduled to receive 20 mg/kg of BG9588 at biweekly intervals for the first 3 doses and at monthly intervals for 4 additional doses. Safety evaluations were performed on all patients. Eighteen patients receiving at least 3 doses were evaluated for efficacy. RESULTS: The study was terminated prematurely because of thromboembolic events occurring in patients in this and other BG9588 protocols (2 myocardial infarctions in this study). Of the 18 patients for whom efficacy could be evaluated, 2 had a 50% reduction in proteinuria without worsening of renal function. Mean reductions of 38.9% (P < 0.005), 50.1% (P < 0.005), and 25.3% (P < 0.05) in anti-double-stranded DNA (anti-dsDNA) antibody titers were observed at 1, 2, and 3 months, respectively, after the last treatment. There was a significant increase in serum C3 concentrations at 1 month after the last dose (P < 0.005), and hematuria disappeared in all 5 patients with significant hematuria at baseline. There were no statistically significant reductions in lymphocyte count or serum immunoglobulin, anticardiolipin antibody, or rubella IgG antibody concentrations after therapy. CONCLUSION: A short course of BG9588 treatment in patients with proliferative lupus nephritis reduces anti-dsDNA antibodies, increases C3 concentrations, and decreases hematuria, suggesting that the drug has immunomodulatory action. Additional studies will be needed to evaluate its long-term effects.
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OBJECTIVE: Crimes against humanity by Nazi Germany led to the codification of procedures for trying medical professionals. The principles detailed in the Nuremberg Code formulated by the Allies represented their effort to prevent future excesses and embody today's Institutional Review Boards. Reactive arthritis is often termed Reiter's syndrome, after Hans Reiter, who was incarcerated at Nuremberg. METHODS: The authors reviewed Dr Hans Reiter's Nuremberg file at the National Archives in Washington, DC, and present chronologic excerpts of his interrogations between 1945 and 1947, with interpretative commentary. RESULTS: Reiter was involved with or knowledgeable of involuntary sterilization and euthanasia undertaken by the Nazi regime. He also played an active role in the design of a study that inoculated concentration camp internees at Buchenwald with an experimental typhus vaccine, which resulted in hundreds of deaths. CONCLUSIONS: A brilliant investigator and erudite intellectual, the career of Hans Reiter shows the importance and the relevance of scientific inquiry to adhere to principles enumerated in the Nuremberg Code. Because he was not the first to describe reactive arthritis, and in view of the above, Reiter's syndrome should only be used to cite an older reference that uses the term or in a historical context.
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OBJECTIVE: To evaluate familiality of 15 clinical and laboratory features in systemic lupus erythematosus (SLE)-affected sibpairs, and to estimate correlations with the age at SLE diagnosis in affected sibpairs and parent-offspring pairs. METHODS: Concordance rates and sibling risk ratios were used as indicators of familiality for 15 manifestations of SLE. Pearson's correlations and paired t-tests were used to compare the age at SLE diagnosis in affected sibpairs and in parent-offspring pairs. RESULTS: Increased sibling risk ratios (1.9-3.9) for thrombocytopenia, discoid rash, neurologic disorder (defined as seizure or psychosis), and hemolytic anemia were observed in 159 SLE-affected sibpairs. Among these clinical features, paired expression of hemolytic anemia plus thrombocytopenia and hemolytic anemia plus neurologic disorder appeared to be more frequent in 709 SLE patients than would be expected by chance (P < 0.00001 and P < 0.007, respectively). The ratio of the presence of both hemolytic anemia and neurologic disorder was approximately 13 times higher in the younger affected sib than in the older affected sib (P < 0.02). Familiality of patient age at SLE diagnosis, as observed by relative correlations, was greater in 125 affected sibpairs (r = 0.67, P < 0.0001) than in 37 affected parent-offspring pairs (r = 0.47, P = 0.003). The median +/- SD age at SLE diagnosis was significantly lower in offspring (21.5 +/- 10.1 years) than in their parents (41.6 +/- 15.8 years) (P < 0.0001) but was not different in sibpairs. The combined non-Caucasian sibpairs had a younger mean age at SLE diagnosis compared with Caucasian sibpairs (P = 0.014). CONCLUSION: Evidence for familiality of thrombocytopenia, discoid rash, neurologic disorder, hemolytic anemia, and co-occurring neurologic disorder plus hemolytic anemia in SLE was observed in 159 affected sibpairs. Familiality of the age at SLE diagnosis in relative pairs suggests that shared genes and/or shared environmental exposures impact disease susceptibility. Shared immediate environmental triggers appear less compelling, because the average time between dates of diagnosis was 11 years in parent-offspring pairs and 7.5 years in affected sibpairs. The significantly earlier age at disease diagnosis in offspring compared with their parents suggests that some forms of anticipation might play a role in susceptibility to SLE. Stratifying families by subphenotypes that are familial may reduce heterogeneity and facilitate identification of genetic risk factors for SLE.
OBJECTIVE: Six recent genome scans of different systemic lupus erythematosus (SLE) multiplex family cohorts showed multiple putative susceptibility loci. In the present study, we examined 4 previously identified loci to replicate findings of significant linkage to 1q23 and 16q12, and to support findings of suggestive linkage to 14q21-23 and 20p12 in a cohort of 115 multiethnic nuclear families containing 145 SLE-affected sibpairs. METHODS: Model-free, multipoint linkage analyses (SIBPAL2, SAGE version 4.0) and exclusion mapping (GeneHunter) were performed. RESULTS: Linkages to 1q23 (peak at D1S2675, mean allele sharing [MAS] 0.56; P = 0.003) and to 16q12 (peaks between D16S753 and D16S757, MAS 0.57; P = 0.003) were confirmed, but linkage evidence at 20p12 was weak and inconsistent (MAS 0.52-0.56; from P = 0.005 to P not significant). Evidence for linkage to 1q23 and 16q12 was stronger in 68 non-Caucasian affected sibpairs than in 77 Caucasian affected sibpairs. Exclusion mapping ruled out linkage at 14q21-23 (lambda(s) [sib recurrence risk or genotypic risk ratio] = 1.8). Because the pericentromeric region of chromosome 16 has been identified by genome scans in several autoimmune diseases, we postulated that it might harbor an autoimmune modifier gene. To explore this possibility, we tested for an interaction between 16q12 and 1q23, and between 16q12 and 20p12. Haplotype sharing at 1q23 increased concomitantly with increased haplotype sharing at 16q12 (P = 0.008 by nonparametric Jonckheere-Terpstra exact statistical test). No evidence supporting an interaction between 16q12 and 20p12 was observed. Analysis of sibpairs sharing 2 alleles at 16q12 also showed increased allele sharing at 1q23 (MAS from 0.56 to 0.65). CONCLUSION: These data support the presence of SLE susceptibility genes at 1q23 and 16q12, particularly in non-Caucasians. The skewed distribution of haplotypes suggests that genetic interaction of these two loci may affect SLE susceptibility.
Most of the six million Americans with fibromyalgia have at least one associated syndrome which mandates specialized attention in addition to traditional therapeutic approaches. These include localized procedures, regional blocks, antiinflammatory or antimicrobial regimens, attention to non soft tissue sources of psychosocial distress, and classes of medicines not usually prescribed for fibromyalgia. The successful treatment of fibromyalgia-associated syndromes improves the symptoms, quality of life, and prognosis of fibromyalgia.
A new understanding of the pathogenesis of autoimmunity, the mechanisms of action of older drugs, the advent of target-specific biological therapies and pharmacogenomics has created multiple treatment options for the patient with systemic lupus erythematosus. These include topical therapies, more selective non-steroidal anti-inflammatory agents, hormonal interventions and a new generation of immune suppressives. Currently available strategies also include the use of intravenous gamma globulin, apheresis, stem-cell transplantation and antileprosy preparations alone or in combination with immune suppressives. A handful of biologicals have been studied in clinical trials. After two decades without new options for lupus patients practitioners now have a full menu of improved therapeutic options.