Catherine A. Williams

Nonsteroidal anti-inflammatory drug-associated gastropathy: Incidence and risk factor models

PURPOSE The most prevalent serious drug toxicity in the United States is increasingly recognized as gastrointestinal (GI) pathology associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs). The incidence of serious GI events (hospitalization or death) associated with NSAID use was therefore prospectively analyzed in patients with rheumatoid arthritis (RA) and patients with osteoarthritis. PATIENTS, METHODS, AND RESULTS The study consisted of 2,747 patients with RA and 1,091 patients with osteoarthritis. The yearly hospitalization incidence during NSAID treatment was 1.58% in RA patients and was similar in all five populations studied. The hazard ratio of patients taking NSAIDs to those not taking NSAIDs was 5.2. The incidence in osteoarthritis may be less. The risk of GI-related death in RA patients was 0.19% per year with NSAIDs. Multivariate analyses assessing risk factors for serious GI events were performed in the 1,694 (98 with an event) RA patients taking NSAIDs at the predictive visit. The main risk factors were higher age, use of prednisone, previous NSAID GI side effects, prior GI hospitalization, level of disability, and NSAID dose. A rule is presented that allows estimation of the risk for the individual patient with RA. CONCLUSION Knowledge of the risk factors for NSAID-associated gastropathy and their inter-relationships provides a tool for identification of the patient at high risk and for initiation of appropriate therapeutic action.

Toward an Epidemiology of Gastropathy Associated With Nonsteroidal Antiinflammatory Drug Use

The thesis of this paper is that gastropathy associated with nonsteroidal antiinflammatory drugs (NSAIDs) is the most frequent and, in aggregate, the most severe drug side effect in the United States. This work is based on a consecutive series of 2400 patients with rheumatoid arthritis followed prospectively for an average of 3.5 yr by ARAMIS, the American Rheumatism Association Medical Information System. We present a preliminary exploration of the magnitude of the problem, the population at risk, and the patients within that population who are at particularly high risk. Patients on NSAIDs had a hazard ratio for gastrointestinal (GI) hospitalization that was 6.45 times that of patients not on NSAIDs. Characteristically, high-risk patients for GI hospitalization and GI death are older, have had previous upper abdominal pain, have previously stopped NSAIDs for GI side effects, and have previously used antacids or H2-receptor antagonists for GI side effects. They also are frequently on corticosteroids. In contrast, patients attributing relatively minor symptoms to the drug tend to be younger and more frequently female. Our preliminary analysis is univariate and, as these variables are interdependent, firm conclusions regarding the relative importance of these risk factors will require reevaluating our data base as it is expanded using multivariate analysis. The syndrome of NSAID-associated gastropathy can be estimated to account for at least 2600 deaths and 20,000 hospitalizations each year in patients with rheumatoid arthritis alone.

Lymphoma and luekemia in rheumatoid arthritis: are they associated with azathioprine, cyclophosphamide, or methotrexate?

Incident cases of lymphoma and leukemia in a cohort of 3824 rheumatoid arthritis (RA) patients from the Arthritis, Rheumatism and Aging Medical Information System (ARAMIS) database were identified, and the use of azathioprine, cyclophosphamide, and methotrexate was compared in a matched case-control study. Controls were matched on age, sex, year of study entry, disease duration, center, and years of follow-up. Twenty-four cases of lymphoma and 10 cases of leukemia were identified: 21% of patients with cancer versus 9% of controls had taken azathioprine [McNemar statistic 1.50 (p = 0.22), odds ratio 5.0 (95% confidence interval 0.6,236.5)]. Equal numbers of cases and controls (6% each) had taken cyclophosphamide and 18% of cases and 12% of controls had taken methotrexate [McNemar statistic 0.13 (p = 0.72), odds ratio 1.7 (0.3, 10.7)]. Results suggest but do not prove that RA patients taking azathioprine and methotrexate may have an increased risk of developing lymphoma. However, even if this increased risk can be confirmed, it accounts for only a small proportion of the greatly increased incidence of these malignancies in RA.

The relative toxicity of alternative therapies for rheumatoid arthritis: Implications for the therapeutic progression

The traditional pyramid for the therapeutic progression in rheumatoid arthritis (RA) is based on assumptions that RA is a mild disease, that nonsteroidal antiinflammatory drugs (NSAIDs) have low toxicity, and that disease-modifying antirheumatic drugs (DMARDs) are extremely toxic. This article reviews data from ARAMIS (Arthritis, Rheumatism, and Aging Medical Information System), casting strong doubt on these assumptions. NSAIDs result in 1.3% excess gastrointestinal hospitalizations per year. Mortality rates in RA are far above those expected from age- and sex-matched populations. Individual NSAIDs show widely different overall quantitative toxicity indices, as do individual DMARDs. However, the ranges of toxicity of the two classes of drugs show nearly complete overlap. It is suggested that the new therapeutic progression in RA should emphasize initial use of DMARDs, beginning with the least toxic.

Marginally Trapped Tubes Generated from Nonlinear Scalar Field Initial Data

We show that the maximal future development of asymptotically flat spherically symmetric black hole initial data for a self-gravitating nonlinear scalar field, also called a Higgs field, contains a connected, achronal, spherically symmetric marginally trapped tube which is asymptotic to the event horizon of the black hole, provided the initial data is sufficiently small and decays like

On blow-up solutions of the Jang equation in spherical symmetry

{O(r^{-\frac{1}{2}})}

Radiographic assessment of progression in osteoarthritis.

, and the potential function V is nonnegative with bounded second derivative. This result can be loosely interpreted as a statement about the stability of ‘nice’ asymptotic behavior of marginally trapped tubes under certain small perturbations of Schwarzschild.

Reduction in long-term disability in patients with rheumatoid arthritis by disease-modifying antirheumatic drug-based treatment strategies.

Differences in health status between subjects, their parents, and their children were analyzed in 2206 subjects who had attended the University of Pennsylvania during the 1939 to 1940 school year. Subjects compared their overall health status at the average age of 70 with that of their same-sex parent at the same age and with that of their same-sex child at the approximate average age of 45, providing reasons for reported differences. Thus, health status in family members of the same sex at the same age in 1988 was compared with that in approximately 1963. Subject health was strikingly improved compared with that of their parents a generation earlier, with 58% reporting their health to be better or much better, and only 9% reporting it to be worse or much worse (P less than .001). The major reasons for the difference were decreased prevalence of chronic conditions and healthier life-styles. The same results were observed in a community-based population of 317 subjects and, even more strikingly, in a group of 422 aging long-distance runners. These observations suggest substantial improvement in senior health status over the past quarter century in selected populations, and they contrast with equivocal changes that have been noted with traditional serial survey techniques.