Recruitment of TRADD, FADD, and caspase 8 to double-stranded RNA-triggered death inducing signaling complexes (dsRNA-DISCs).

Rapid elimination of virus-infected cells by apoptosis is an efficient anti-viral strategy. Double-stranded RNA (dsRNA), a viral product, is potently and rapidly apoptogenic in susceptible cells. Caspase 8 plays an important role in the dsRNA-induced apoptosis; however, the mechanisms of caspase 8 activation in response to dsRNA are unknown. We demonstrate here that, in HeLa cells, the dsRNA-triggered activation of caspase 8 is independent of ongoing proteins synthesis (and is, therefore, independent of changes in pro- and anti-apoptotic gene expression) and involves the formation of multiprotein dsRNA-triggered death inducing signaling complexes (dsRNA-DISCs). DsRNA-DISCs contain FADD, TRADD, and caspase 8; however, several experimental approaches suggest that death ligands and death receptors (such as Fas/Apo1 and DR4/Apo2) are not involved in the formation of dsRNA-DISCs.

Isolated spleen agenesis: a rare cause of thrombocytosis mimicking essential thrombocythemia.

Thrombocytosis is a common feature of myeloproliferative disorders but may also result from various conditions including chronic iron deficiency, hemorrhage, chronic inflammation and splenectomy. We report two cases of secondary thrombocytosis caused by isolated and congenital asplenia, mimicking essential thrombocythemia. These two adult cases of spleen agenesis were unexpected. We conclude that in thrombocytosis without clinical evidence of splenomegaly, attentive screening of blood in search of Howell-Jolly bodies and abdominal ultrasonography should always be performed not only to detect mild spleen enlargement but also to make sure of the presence of this organ.

Parenteral ketorolac and risk of gastrointestinal and operative site bleeding. A postmarketing surveillance study.

OBJECTIVE: To evaluate the risk of gastrointestinal and operative site bleeding associated with the use of parenteral ketorolac tromethamine. DESIGN: Postmarketing surveillance inception cohort study. SETTING: A total of 35 hospitals throughout the Philadelphia, Pa, region, 1991 to 1993. PATIENTS: Patients administered 10,272 courses of parenteral ketorolac therapy were compared with patients administered 10,247 courses of a parenteral opiate who were matched to the ketorolac patients by hospital, admitting service, and date of initiation of study drug. MAIN OUTCOME MEASURES: Medical records were reviewed for demographics, medical history, doses and duration of study drug, various aspects of the hospital course including surgery and concomitant medications, and adverse events. RESULTS: The multivariate adjusted odds ratio (OR) comparing ketorolac with opiates for gastrointestinal bleeding was 1.30 (95% confidence interval [CI], 1.11 to 1.52); for operative site bleeding, the OR was 1.02 (95% CI, 0.95 to 1.10). The OR was elevated further in subjects 75 years of age or older for both gastrointestinal bleeding (OR = 1.66; 95% CI, 1.23 to 2.25) and operative site bleeding (OR = 1.12; 95% CI, 0.94 to 1.35). A dose-response relationship was evident between average daily ketorolac dose and both gastrointestinal bleeding and operative site bleeding (trend test P < .001 for both). When analgesic therapy lasted 5 or fewer days, ketorolac was associated with only a small increased risk of gastrointestinal bleeding (OR = 1.17; 95% CI, 0.99 to 1.30); when therapy was prolonged beyond 5 days, the OR was 2.20 (95% CI, 1.36 to 3.57). The association of ketorolac with operative site bleeding was not affected by duration of therapy. CONCLUSIONS: The overall associations between ketorolac use and both gastrointestinal bleeding and operative site bleeding are small. However, the risk associated with the drug is larger and clinically important when ketorolac is used in higher doses, in older subjects, and for more than 5 days. Improving physicians' prescribing practices by limiting the dose and duration of ketorolac use, especially in the elderly, should enhance its overall risk-benefit balance.

Concurrent validity of the Health Assessment Questionnaire Disability Index in Scleroderma.

OBJECTIVE: To establish the concurrent validity of the Health Assessment Questionnaire (HAQ) Disability Index in systemic sclerosis (SSc; scleroderma). METHODS: Eighty subjects with SSc completed the HAQ Disability Index questionnaire. An occupational therapist, who was blind to the subjects' responses, observed each subject's performance on 10 of the items. RESULTS: Paired t-tests showed significant differences between the observer and subjects' responses for tying shoes, buttoning, gripping, and walking. Intra-class correlations between observer and subjects ranged from 0.38 to 0.76. CONCLUSION: The results support the validity of the HAQ Disability Index in patients with systemic sclerosis.

The mortality of rheumatoid arthritis.

OBJECTIVE: To determine the risk and causes of death and to quantify mortality predictors in patients with rheumatoid arthritis (RA). METHODS: RA patients (n = 3,501) from 4 centers (Saskatoon n = 905, Wichita n = 1,405, Stanford n = 886, and Santa Clara n = 305) were followed for up to 35 years; 922 patients died. RESULTS: The overall standardized mortality ratio (SMR) was 2.26 (Saskatoon 2.24, Wichita 1.98, Stanford 3.08, Santa Clara 2.18) and increased with time. Mortality was strikingly increased for specific causes: infection, lymphoproliferative malignancy, gastroenterologic, and RA. In addition, as an effect of the SMR of 2.26, the expected number of deaths was increased nonspecifically across all causes (except cancer), with a large excess of deaths attributable to cardiovascular and cerebrovascular diseases. Independent predictors of mortality included age, education, male sex, function, rheumatoid factor, nodules, erythrocyte sedimentation rate, joint count, and prednisone use. CONCLUSION: Mortality rates are increased at least 2-fold in RA, and are linked to clinical severity.

Toxicity profiles of disease modifying antirheumatic drugs in rheumatoid arthritis.

The toxicity profiles of 7 disease modifying antirheumatic drugs (DMARD) (hydroxychloroquine, intramuscular (im) gold, D-penicillamine, oral gold, methotrexate (MTX), azathioprine and cyclophosphamide) were evaluated in 2,479 patients with rheumatoid arthritis consecutively enrolled at 5 centers in the Arthritis, Rheumatism and Aging Medical Information System (ARAMIS) program. Incidence rates for side effects are reported as events/1000 patient-years. Our descriptive study revealed an individual profile of prevalent toxicities for each drug. Oral gold was characterized by substantial lower gastrointestinal (GI) toxicity (diarrhea 391 events/1000 patient-years, loose bowel movement 148, lower abdominal pain 76), MTX by hepatotoxicity (47) while D-penicillamine had the only clinically significant incidence of altered taste (40). MTX users reported the most mucosal ulcers (87), followed by oral gold (76), im gold (55) and D-penicillamine (38). Rash was frequently seen with gold compounds and D-penicillamine, while upper GI toxicity was common with immunosuppressive agents. Cyclophosphamide had 48% discontinuations within 6 months. MTX had the lowest discontinuation rate in the first 6 months, but then showed little difference from im gold. A preliminary similarity index was developed to compare the toxicity profiles of various DMARD. Close similarities were found between toxicity profiles of im gold and D-penicillamine, and between azathioprine and MTX. Oral gold had a unique toxicity pattern. Knowledge of these different toxicity patterns can enable more appropriate selection of agents for particular patients.

Identification of patients at risk for gastropathy associated with NSAID use.

It is suggested that gastropathy associated with nonsteroidal antiinflammatory drugs (NSAID) 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 2,400 patients with rheumatoid arthritis (RA) followed prospectively for an average of 3.5 years by 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 NSAID had a hazard ratio for gastrointestinal (GI) hospitalization that was 6.45 times that of patients not on NSAID. Characteristically, patients at high risk for GI hospitalization and GI death are older, have had previous upper abdominal pain, have previously stopped NSAID due to GI side effects and have previously used antacids or histamine2-receptor antagonists for GI side effects. These patients also frequently take corticosteroids. Patients attributing relatively minor symptoms to NSAID tend to be younger and female. Our preliminary analysis is univariate; since these variables are interdependent, firm conclusions regarding the relative importance of these risk factors require development of multivariate risk factor models. The syndrome of NSAID-associated gastropathy can be estimated to account for at least 2,600 deaths and 20,000 hospitalizations each year in patients with RA alone.

Toxic effects of azathioprine in rheumatoid arthritis. A national post-marketing perspective.

Concerns about the short-term and long-term toxic effects of azathioprine (AZA) have limited its use. Accordingly, we surveyed 393 AZA-treated rheumatoid arthritis (RA) patients, who were recruited and enrolled through a nationwide call to rheumatologists. Findings in these patients were compared with the findings, retrieved from the databank of the American Rheumatism Association Medical Information System, on 153 similarly treated RA patients. All 546 patients were surveyed prospectively, using the Health Assessment Questionnaire and information abstracted from hospital records. The 2 groups were closely similar in clinical characteristics. The most frequently reported side effects of AZA treatment were nausea, vomiting, and leukopenia. Gastrointestinal intolerance accounted for nearly 60% of therapy interruptions in 95 patients. Of 81 hospitalizations for all causes, only 8 may have been related in part to AZA, and no deaths were attributed to AZA therapy. No lymphomas or leukemias were encountered and the overall frequency of neoplasms was not significantly different from that seen in RA patients receiving conventional therapy. As used in the treatment of RA, AZA has a surprisingly benign profile with relatively few serious therapeutic mishaps.

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.

The clinical value of the Stanford Health Assessment Questionnaire Functional Disability Index in patients with rheumatoid arthritis.

We administered the Stanford Health Assessment Questionnaire functional disability questionnaire to a cohort of 400 patients with rheumatoid arthritis (RA) every 6 months during a mean followup of 3.1 years. Simple classification into 3 groups based on Functional Disability Index (FDI) scores (0-1, 1.1-2, 2.1-3) identified patients with increasingly more severe scores for clinical, psychological, and demographic variables; and FDI scores at entry predicted increased inpatient and outpatient utilization of services, and mortality. The FDI provided important and clinically useful current and predictive information regarding RA status, utilization of services, and mortality that was not available through conventional testing. Our data suggest that such information can be easily and inexpensively obtained.

Postmarketing surveillance in rheumatology: analysis of purpura and upper abdominal pain.

A system of postmarketing surveillance of antirheumatic drugs employing prospective protocol based consecutive patient cohorts is described, together with use of recursive partitioning techniques for statistical adjustment for potentially confounding variables. An analysis of 2 side effects (purpura and upper abdominal pain) is presented. Purpura was found to be associated with age, sex, disease duration, and amount of disability. The combination of aspirin and prednisone was associated with the highest prevalence of purpura. Upper abdominal pain also varied across drug classes. Within the nonsteroidal antiinflammatory drug category, there were clinically important differences in the relative prevalence of upper gastrointestinal pain between specific drugs.

The present and future of comprehensive outcome measures for rheumatic diseases.

In recent years, outcome, or health status, measurement has received wide attention in rheumatology. These measures are based on the concept of maintaining or improving health as the goal of medical care, the World Health Organization (WHO) definition of health, and measurement of those factors that directly impact the patient rather than the traditional measures of disease process. Within this framework, outcomes important to the patient with rheumatic diseases have been identified. They have been conceptualized in general terms of physical, psychological and social functioning or specifically by dimensions of death, disability, discomfort, side effects and economic costs. Two widely used outcome measures, the health assessment questionnaire (HAQ) and the arthritis impact measurement scales (AIMS), are described. Outcomes are measured by patient self-reported questionnaires which have been rigorously tested to establish the measurement properties of reliability and validity. Results show that patient self-report is valid, outcomes are accurately measured, correlate with traditional endpoints, and are sensitive to change over time. These measures are particularly suited for use in follow-up studies because of their simplicity, ease of administration, and cost. Future directions include additional study to define clinically meaningful change, extension of validations to many of the rheumatic diseases, the design of special purpose questionnaires and the development of the cumulative outcome concept.

Salicylate toxicity in elderly patients with rheumatoid arthritis.

Using the American Rheumatism Association Medical Information System, we studied the effect of age upon salicylate toxicity in elderly patients with rheumatoid arthritis. Data were gathered from 545 patients by self-reported questionnaires for the 6 months and also the 7 days before the visit of interest. With one week data and weight adjusted doses in 253 patients in whom data were available, age related differences in lower gastrointestinal symptoms (p = 0.05) and tinnitus (p = 0.01) were found, despite the fact that elderly patients (E) took less salicylate than younger ones (y)--E [39.1 +/- 2.4 (SD) mg/kg/day] vs Y [49.8 +/- 3.89 mg/kg/day] (p = 0.02). Our data indicate a difference in salicylate dynamics among the elderly (i.e., increased toxicity in the face of decreased salicylate doses).

Survival, prognosis, and causes of death in rheumatoid arthritis.

The factors associated with mortality were examined in a prospective longitudinal study, over an average of 12 years, with 94% followup of patients diagnosed as having rheumatoid arthritis. Of 805 patients, 233 died during the period of the study. Survivorship of rheumatoid arthritis patients was approximately 50% less than that of population controls. Survivorship was decreased by the traditional demographic variables of greater age and male sex; however, a significant independent effect of variables reflecting disease severity (American Rheumatism Association functional class, rheumatoid factor titer, number of involved joints) was identified by multivariate analysis. Seventy-nine excess deaths (i.e., those that would not have been expected in a control population) were due in part to disease-related causes, to infections, and to gastrointestinal complications of therapy. Treatment with gold or prednisone did not seem to affect survivorship or cause of death, except for the clustering of deaths of patients with vasculitis within the prednisone group. Our findings indicate that rheumatoid arthritis, a chronic disabling disease, is also associated with a major decrease in survivorship.

A multicenter study of hospitalization in rheumatoid arthritis. Frequency, medical-surgical admissions, and charges.

During 1981, 123 of 816 patients (15.1%) with rheumatoid arthritis were hospitalized 160 times because of the disease. The mean length of hospitalization was 13.1 days, and the cost $7,845. Surgery accounted for 54.4% of admissions, but 69.2% of costs. The average cost for total joint surgery was $12,287. Most medical admissions (46.6%) were for the diagnosis or treatment of articular disease, but 42.5% were for treatment of side effects of therapy, and 11.0% for complications of RA. The most commonly performed surgical procedures included reconstructive surgery of the hand/wrist (n = 35) and foot (n = 22), followed by total knee replacement (n = 18).

Impact of specific therapy upon rheumatoid arthritis.

We performed a prospective, parallel, descriptive study of 737 consecutive new uses for 11 drugs prescribed for patients with definite or classic rheumatoid arthritis. The patients were from 5 geographically dispersed sites. Researchers used validated outcome assessment instruments to measure endpoints of disability, pain, patient global assessment, medication costs, laboratory costs, and number of physician visits. Patients were studied by strict prospective protocol at 6-month intervals for 3 years. Controls included parallel results with other drugs, and before and after values for the individual patient. Beneficial effects were observed with the "disease-modifying" drugs: intramuscular gold, penicillamine, and methotrexate. Of these, gold had the most apparent effect. An average of 9 months of gold therapy resulted in highly significant reductions in disability (P less than 0.005), pain (P less than 0.001), and patient global assessment (P less than 0.005). However, patients receiving gold and methotrexate had nearly twice as many visits to physicians. In addition, drug costs increased strikingly with gold, and laboratory costs tripled. Relatively minor differences among nonsteroidal antiinflammatory agents were difficult to interpret. The outcome assessment techniques used in the study are sensitive measures, which confirm the results of experimental studies and extend observations to new outcomes, including cost and disability.

A multicenter study of hospitalization in rheumatoid arthritis: effect of health care system, severity, and regional difference.

During 1981, centers in Phoenix, Saskatoon, Stanford and Wichita monitored hospitalizations for 816 patients with rheumatoid arthritis. Admission rates varied 2-fold, and admissions for evaluation and treatment 10-fold across centers. Admissions were related primarily to disease severity, but in US centers, were reduced by a factor of 3 by prepaid health care. Length of stay was shortest in California (7.3 days), and longest in Saskatoon (16.3) where designated arthritis beds and government prepaid health care existed. Average charges for surgery were as high as $10,000 in Phoenix and as low as $4550 in Wichita. Charges and length of stay were unrelated to disease severity, but were responsive to health care delivery system, availability of facilities, and geographic and center variation.