Background Neutralization of tumor necrosis factor α (TNF-α) for three to six months reduces the symptoms and signs of rheumatoid arthritis. However, the capacity of this approach to effect a more sustained benefit and its effect on joint damage are not known. Methods We treated 428 patients who had active rheumatoid arthritis despite methotrexate therapy with placebo or infliximab, a chimeric monoclonal antibody against TNF-α, in intravenous doses of 3 or 10 mg per kilogram of body weight every 4 or 8 weeks in combination with oral methotrexate for 54 weeks. We assessed clinical responses with use of the criteria of the American College of Rheumatology, the quality of life with a health-status questionnaire, and the effect on joint damage radiographically. Results The combination of infliximab and methotrexate was well tolerated and resulted in a sustained reduction in the symptoms and signs of rheumatoid arthritis that was significantly greater than the reduction associated with methotrexate therapy alo...

Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group.

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Infliximab and methotrexate in the treatment of rheumatoid arthritis

Platelet-Active Drugs: The Relationships Among Dose, Effectiveness, and Side Effects

When microsomes of sheep or bovine seminal vesicles are incubated with [acetyl-3H]aspirin (acetyl salicylic acid), 200 Ci/mol, we observe acetylation of a single protein, as measured by sodium dodecyl sulfate/polyacrylamide gel electrophoresis. The protein has a molecular weight of 85,000 and corresponds to a similar acetylated protein found in the particulate fraction of aspirin-treated human platelets. The aspirin-mediated acetylation reaction proceeds with the same time course and at the same concentration as does the inhibition of prostaglandin synthase (cyclo-oxygenase) (EC 1.14.99.1; 8,11,14-eicosatrienoate, hydrogen-donor:oxygen oxidoreductase) by the drug. At 100 muM aspirin, 50% inhibition of prostaglandin synthase and 50% of maximal acetylation are observed after 15 min at 37 degrees. Furthermore, the substrate for cyclo-oxygenase, arachidonic acid, inhibits protein acetylation by aspirin at concentrations (50% inhibition at 10-30 muM) which correlate with the Michaelis constant of arachidonic acid as a substrate for cyclooxygenase. Arachidonic acid analogues and indomethacin inhibit the acetylation reaction in proportion to their effectiveness as cyclo-oxygenase inhibitors. The results suggest that aspirin acts as an active-site acetylating agent for the enzyme cyclo-oxygenase. This action of aspirin may account for its anti-inflammatory and anti-platelet action.

https://www.pnas.org/content/pnas/72/8/3073.full.pdf

Acetylation of prostaglandin synthase by aspirin

Publisher Summary Autoantibodies to nuclear antigens (ANAs) have assumed an important place in the diagnostic armamentarium of the clinician because of distinct profiles of ANAs in different diseases. Profiles of ANAs have, therefore, been extremely useful in differential diagnosis, where the disease does not have classical or full-blown manifestations.. Immune complexes formed in the circulation or in situ mediate tissue injury by the activation of complement and other inflammatory mediators. Not only do these antibodies precipitate their respective antigens but also other proteins or nuclear RNAs that might be associated with them in special ways. The reasons for these special associations of protein antigens with specific sets of nuclear RNAs is unknown, but the possibility that there might be functional relationships in these complexed particles is not unreasonable. The key question that pervades the minds of many investigators in this field is the reason for the appearance of ANAs in certain individuals. It is highly improbable that the phenomenon is a random immune response to nuclear breakdown products, because the types of ANAs in different diseases are strikingly different. Some known environmental agents are drugs, such as hydralazine and procainamide, that together with lower levels of hepatic acetyltransferase enzyme predispose the host to the development of ANAs. Another agent may be the Epstein–Barr virus that is a ubiquitous environmental agent.

Autoantibodies to nuclear antigens (ANA): their immunobiology and medicine.

Antibody to DNA in human serums can be detected by the ammonium sulfate method. This sensitive and specific technique, which measures the primary interaction between DNA and antibody to DNA, is based on the observation that free DNA is soluble in 50-percent saturated ammonium sulfate whereas antibody-bound DNA is insoluble.

https://science.sciencemag.org/content/sci/161/3843/806.full.pdf

Deoxyribonucleic Acid Antibody: A Method to Detect Its Primary Interaction with Deoxyribonucleic Acid

EXISTING evidence suggests that the concentrations of IgG immunoglobulin* in maternal and cord sera are essentially the same. In 1963 von Muralt1 concluded that no significant difference existed in the absolute concentration of gamma globulin in paired maternal-cord sera after reviewing forty-three published studies in which gamma globulin was quantitated in 1,542 maternal-cord pairs by a variety of methods. Recently, Gitlin et al.2 reported cord IgG to be equal to or slightly lower than maternal. They did observe, however, that IgG labelled with iodine-131 was present in higher concentrations in cord than in maternal serum if the iodinated protein had been administered to the mother 25 or more days before parturition. The higher cord 131I-IgG levels were felt to be a consequence of tracer kinetics and not an indication of higher cord endogenous IgG concentrations2.

Elevation of Cord over Maternal IgG Immunoglobulin: Evidence for an Active Placental IgG Transport

HUMAN serum albumin (HSA) is permanently altered after exposure to therapeutic concentrations of acetylsalicylic acid (ASA, aspirin) either in vitro or in vivo1–3. Recently we showed that this structural alteration was the result of the acetylation of the HSA molecule by aspirin4,5. Because the acetylation of HSA by aspirin could occur by aminolysis resulting in an N-acetyl-HSA derivative, we decided to determine whether aspirin could acetylate other biological materials. We now report that aspirin acetylates a variety of body constituents in vitro.

In vitro Acetylation of Plasma Proteins, Enzymes and DNA by Aspirin

Human serum albumin is acetylated when exposed to acetylsalicylic acid (aspirin) under physiologic conditions in vitro. Indications are that a similar phenomenon occurs in vivo after ingestion of aspirin.

Acetylation of human serum albumin by acetylsalicylic acid

Summary The immune responses of rabbits fed low concentrations of bovine serum albumin (BSA) have been characterized and compared to the immune responses of rabbits injected with BSA either i.v. or s.c. in oil. The qualities of the antibodies produced were evaluated by the following criteria: 1 ) the average strength of the antibody-antigen bond as measured by the effect of dilution on the antigen-binding capacity; 2 ) the changes in strength of the antibody-antigen bond during immunization; 3 ) the association of BSA binding with heavy and light immunoglobulin fractions; 4 ) the association of BSA binding with the γA-immunoglobulins; 5 ) passive hemagglutinating capacities; 6 ) antigen-precipitating capacities and efficiencies; and 7 ) alteration of antibody activity by treatment with 2-mercaptoethanol. Despite possible alteration of the antigen by digestive functions, local initiation of antibody production in lymphoid tissue associated with the gastrointestinal tract and quantitative differences among the three groups, the antibodies present in the sera from orally immunized animals qualitatively were similar to antibodies produced following parenteral immunization, as judged by the above criteria. Light as well as heavy immunoglobulins with anti-BSA activity were present in the earliest antisera from all three immunization groups. These findings and the previous demonstration that antibodies produced following oral or s.c. in oil immunization have similar immunologic specificities, suggest that most of the cellular mechanisms of antibody production basic to parenteral immunization are operative during oral immunization.

Richard S. Farr

Papers

Deoxyribonucleic Acid Antibody: A Method to Detect Its Primary Interaction with Deoxyribonucleic Acid

Elevation of Cord over Maternal IgG Immunoglobulin: Evidence for an Active Placental IgG Transport

In vitro Acetylation of Plasma Proteins, Enzymes and DNA by Aspirin

Acetylation of human serum albumin by acetylsalicylic acid

Similarities between Rabbit Antibodies Produced Following Ingestion of Bovine Serum Albumin and Following Parenteral Immunization