Competitive insulin autoantibody assay. Prospective evaluation of subjects at high risk for development of type I diabetes mellitus.

A quantitative fluid-phase radioassay for autoantibodies reacting with insulin (competitive insulin autoantibody assay, CIAA) was developed. The assay's features include 1) use of a physiologic amount of 125I-labeled insulin, 2) parallel incubations with supraphysiologic cold insulin (competitive), and 3) an incubation time of 7 days and a single-step multiple-wash polyethylene glycol separation. Mean +/- SE CIAA levels in 50 controls were 8 +/- 1.4 nU/ml (range -16-33.3). In 36 cytoplasmic islet cell antibody (ICA)-positive nondiabetic first-degree relatives of type I (insulin-dependent) patients less than 30 yr of age, CIAA levels exceeded the normal range in 20 (55.6%) of 36 (mean 86.8 +/- 17.1 nU/ml). In 26 ICA-positive relatives greater than 30 yr of age, only 5 (19.2%) of 26 exceeded the normal range (mean 26.1 +/- 9.4 nU/ml); P less than .001 compared with younger ICA-positive relatives). Six ICA-negative HLA-identical siblings of type I diabetic patients had normal CIAA levels (mean 3.6 +/- 5.8 nU/ml), and only 2 of 13 ICA-negative identical twins discordant for diabetes (mean 15.4 +/- 6.6 nU/ml) exceeded the normal range. Nine (50%) of 18 ICA-positive schoolchildren exceeded the normal range (mean 105.3 +/- 36.7 nU/ml). Genetically susceptible subjects negative for CIAA (with only 3 exceptions) remained negative for CIAA on multiple determinations (3 conversions observed), and CIAA levels of positive subjects were relatively stable. Linear regression of the first CIAA level versus last (interval between sampling 1 mo to 10 yr) in genetically susceptible individuals showed a highly significant correlation (r = .95, P less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)

Attitudes and behaviors of primary care physicians regarding tight control of blood glucose in IDDM patients.

OBJECTIVE--To evaluate attitudes and practices of primary-care physicians toward tight blood glucose control in IDDM. RESEARCH DESIGN AND METHODS--A mail and telephone questionnaire survey was conducted on a systematic, stratified sample of 1429 family-practice physicians, general practitioners, internists, and pediatricians in active practice in the United States who treated patients with IDDM. Physicians were asked about methods they used for clinical and laboratory assessment of blood glucose control and about their attitudes and beliefs in treating IDDM. They were asked also what they consider to be acceptable ranges for blood glucose and HbA1 in IDDM patients. A score was developed reflecting three criteria for tight blood glucose control: fasting glucose 70-120 mg/dl (3.9-6.7 mM), 2-h postprandial glucose < 180 mg/dl (< 10 mM), and HbA1 < or = 8% (the nondiabetic value was specified as 5-7%). Physicians were accorded one point when their acceptable range agreed with an intensive treatment criterion (range for score 0-3). RESULTS--Only 31% of physicians agreed with all three criteria for tight control of blood glucose; 37% agreed with none or only one of the standards. Pediatricians were particularly low in their agreement with the HbA1 standard. Physicians who agreed with one of the three criteria often did not agree with the other two. With increasing value for the score, there was a greater proportion of physicians whose management practices (e.g., frequent measurement of HbA1, multiple insulin injections, patient SMBG, use of dietitian/educator in care of patients) are conducive toward tight control of blood glucose. However, even among physicians with a score of 3, HbA1 was ordered infrequently, three or more insulin injections/day was prescribed rarely, patient SMBG was less than fully endorsed, and both a dietitian and diabetes educator were used by a minority of physicians. CONCLUSIONS--It appears that primary-care physicians are not fully aware of recommended criteria for intensive treatment of blood glucose in IDDM patients or of the importance of multiple insulin injections, use of HbA1, and patient SMBG. Physician practice behaviors are less than optimal for intensive management of IDDM patients, even among physicians who agree with all three standards for intensive treatment of blood glucose in IDDM.

Meaningful improvement criteria sets in a rheumatoid arthritis clinical trial. MIRA Trial Group. Minocycline in Rheumatoid Arthritis.

OBJECTIVE: To compare 3 sets of criteria for meaningful improvement in a rheumatoid arthritis (RA) clinical trial, and to evaluate the implications of these criteria sets for RA trial design. METHODS: Data were obtained from the Minocycline in Rheumatoid Arthritis (MIRA) trial (primary outcome measures: 50% improvement in joint tenderness and 50% improvement in joint swelling, based on joint scores). These MIRA data were evaluated against 1) the Paulus criteria (20% improvement in 4 of 6 measures: joint tenderness scores, joint swelling scores, physician's and patient's global assessments, erythrocyte sedimentation rate [ESR], and morning stiffness); and 2) the American College of Rheumatology (ACR) criteria (20% improvement in joint tenderness and joint swelling counts, and in 3 of 5 other measures: physician's and patient's global assessments, ESR, modified Health Assessment Questionnaire, and patient's pain assessment). The ACR criteria were modified using 3 of 4 remaining measures, since baseline pain assessment data were not available. RESULTS: Percentages of minocycline-treated patients versus placebo-treated patients showing meaningful improvement were as follows: by MIRA criteria, for joint tenderness, 56% versus 41% (P = 0.021), and for joint swelling, 54% versus 39% (P = 0.023); by Paulus criteria, 41% versus 28% (P = 0.040); and by ACR criteria, 44% versus 26% (P = 0.004). Both the modified ACR criteria and the Paulus criteria demonstrated a reduced placebo response rate. Compared with the MIRA criteria, the ACR criteria increased, and the Paulus criteria decreased, absolute between-group differences in improvement; however, both criteria sets increased relative percentages of patients showing improvement in the minocycline group versus the placebo group. Study design considerations indicated that application of the ACR criteria would reduce the required sample size. CONCLUSION: Different placebo response rates and treatment group differences were found using the 3 RA improvement criteria sets. These findings support the use of the ACR criteria for defining improvement in RA clinical trials.

International variation in the incidence of hip fractures: cross-national project on osteoporosis for the World Health Organization Program for Research on Aging.

A cross-national study of hip fracture incidence was carried out in five geographic areas--Beijing, China; Budapest, Hungary; Hong Kong; Porto Alegre, Brazil; and Reykjavik, Iceland--during the years 1990-1992. Cases of hip fracture among women and men of age 20 years and older were identified using hospital discharge data in conjunction with medical records, operating room logs, and radiology logs. Estimated incidence rates varied widely, with Beijing reporting the lowest rates (age-adjusted rate per 100,000 population for men 20 years and older = 45.4; women = 39.6) and Reykjavik the highest rates (man = 141.3; women = 274.1). Rates were higher for women than for men in every area except Beijing. In every area except Budapest, review of the operating room or radiology logs identified additional cases that were not reported in the discharge list, increasing the estimated number of hip fractures by 11% to 62%, depending on the area. Review of medical records identified miscoding of hip fractures (ICD 9820) as 'shaft of femur and other femur fractures' (ICD 9821) in the discharge lists of every area except Budapest, increasing the estimated number of hip fractures by 1% to 30%. The final estimates of hip fracture incidence taking into account all investigated sources of undercount and overcount ranged from 15% lower to 89% higher than an estimate based on the discharge diagnoses alone. Although these results indicate substantial limitations in relying on hospital discharge data alone to estimate hip fracture incidence rates, the extent of errors found in the discharge lists is smaller than the large international variation found here and previously reported in incidence rates. The findings support the conclusion that the differences reported among countries mainly reflect genuine variation in the hip fracture incidence rates.

A cross sectional assessment of health status instruments in patients with rheumatoid arthritis participating in a clinical trial. Minocycline in Rheumatoid Arthritis Trial Group.

OBJECTIVE: To (1) validate the Short-Form Health Survey (SF-36) as a generic functional health status measure in patients with rheumatoid arthritis (RA); and (2) assess correlations between the SF-36 and other outcome measures used in the Minocycline in Rheumatoid Arthritis (MIRA) Trial. METHODS: We conducted a cross sectional analysis of the final visit outcome measures from the 48 week, multicenter, placebo controlled, double blind MIRA trial. Multitrait scaling analyses assessed convergent and discriminant validity and internal consistency reliability of the SF-36 in the study patients. Responses to comparable items on the SF-36 and modified Health Assessment Questionnaire (M-HAQ) regarding physical functioning were compared and questions from both instruments were also compared to other RA outcome measures. RESULTS: In patients with RA, the SF-36 had high internal consistency and reliability, high discriminant and high convergent validity. Moderate correlations were observed (r = -0.46 to -0.61, p < 0.01 in each case) for comparable items on the SF-36 and M-HAQ regarding dressing, walking, and bending. Joint tenderness score correlations with items on the M-HAQ and SF-36, and joint tenderness score correlations with the SF-36 scales were higher than for joint swelling scores. Physician and patient global assessments were most highly correlated (r = 0.58 and 0.66; p < 0.01, respectively) with the SF-36 bodily pain item. CONCLUSION: The SF-36 is a valid instrument for this RA population. The SF-36 correlates with the M-HAQ and the physician and patient global assessments. The usefulness of the SF-36 in measuring change in RA clinical trials requires testing in longitudinal studies.

Radiographic results from the Minocycline in Rheumatoid Arthritis (MIRA) Trial.

OBJECTIVE: To assess radiographically determined disease progression in patients in the Minocycline in Rheumatoid Arthritis (MIRA) Trial. METHODS: A double blind, randomized, multicenter, 48 week trial of oral minocycline (200 mg/day) or placebo in 6 clinical centers in the United States. Patients include 219 adults with active RA previously receiving limited treatment with disease modifying drugs. Posteroanterior films of the hands from baseline and final visits, blinded for sequence, were read for erosions and joint space narrowing by trained observers. Outcomes included rate of disease progression (change/month) and percentage of patients with progression from baseline, newly involved joints, and newly erosive disease. RESULTS: Using intent-to-treat analyses, progression rates for erosions (0.11 +/- 0.42 minocycline, 0.17 +/- 0.41 placebo; p = 0.47) and joint space narrowing (0.16 +/- 0.55 minocycline and 0.23 +/- 0.71 placebo; p = 0.14) were similar. (Power 43% to detect a 50% difference.) Newly erosive joints occurred more frequently in the placebo group (44 vs 32%; p = 0.08), not a statistically significant difference. CONCLUSION: Radiographic measurement of disease progression using 4 measures failed to show a significant difference between minocycline and placebo treatment, although for all methods there was a trend toward treatment benefit, consistent with reported clinical results. A one year trial duration, high measurement variability, and slow rate of radiographic progression in this cohort may explain the low power to detect a treatment effect. The measurement that denoted "newly involved" joints was most sensitive in detecting change. In future trials longer term assessment (minimum 2 years) of radiographic changes and further comparison of measures of disease progression are warranted.

HLA-DRB1 genes and disease severity in rheumatoid arthritis. The MIRA Trial Group. Minocycline in Rheumatoid Arthritis.

OBJECTIVE: To examine the effect of alleles encoding the "shared"/"rheumatoid" epitope on rheumatoid arthritis (RA) disease severity in patients who participated in the minocycline in RA (MIRA) trial. METHODS: Of 205 patients with a week-48 visit, blood was available for typing of HLA-DRB1 and HLA-DQB1 in 174 (85%) and successfully completed in 169 (82%). Baseline erosions were used to assess disease severity and new erosions at the last visit served as a proxy for progression. RESULTS: At baseline, there was no association between the presence of erosive disease or rheumatoid factor status and the dose of rheumatoid epitope (homozygous, heterozygous, none) or the specific alleles identified. At the final visit, a gradient was observed for the 3 allelic subgroups (and their gene doses) in the occurrence of new erosions among the Caucasian placebo-treated, but not the minocycline-treated, patients. A treatment group/HLA-DR4 epitope interaction was demonstrated in multivariate analyses. Approximately two-thirds of African-American patients did not have the rheumatoid epitope. CONCLUSION: HLA-DRB1 oligotyping may be useful in predicting the progression of disease in some Caucasian patients. Our study corroborates the infrequency of the epitope among African-American patients with RA.

Minocycline in rheumatoid arthritis. A 48-week, double-blind, placebo-controlled trial. MIRA Trial Group.

OBJECTIVE: To assess the safety and efficacy of minocycline in the treatment of rheumatoid arthritis. DESIGN: A double-blind, randomized, multicenter, 48-week trial of oral minocycline (200 mg/d) or placebo. SETTING: 6 clinical centers in the United States. PATIENTS: 219 adults with active rheumatoid arthritis who had previous limited treatment with disease-modifying drugs. MEASUREMENTS: As the primary outcomes, 60 diarthrodial joints were examined for tenderness, and 58 joints were examined for swelling (hips excluded). Grip strength, evaluator's global assessment, morning stiffness, Modified Health Assessment Questionnaire, patient's global assessment, hematocrit, erythrocyte sedimentation rate, platelet count, and IgM rheumatoid factor levels were also assessed; radiographs of both hands and wrists were taken. RESULTS: 109 and 110 patients were randomly assigned to receive minocycline and placebo, respectively. At entry, demographic, clinical, and laboratory measurements were similar in both groups. Most patients had mild to moderate disease activity and some evidence of destructive disease. At the week 48 visit, 79% of the minocycline group and 78% of the placebo group continued to receive the study medication. At 48 weeks, more patients in the minocycline group than in the placebo group showed improvement in joint swelling (54% and 39%) and joint tenderness (56% and 41%) (P < 0.023 for both comparisons). The minocycline group also showed greater improvement in hematocrit, erythrocyte sedimentation rate, platelet count, and IgM rheumatoid factor levels (all P values < 0.001), and more patients receiving minocycline had laboratory values within normal ranges at 48 weeks. For the remaining outcomes, P values ranged from 0.04 to 0.76, all greater than the critical value of 0.005 (Bonferroni adjustment for multiple comparisons). The frequency of reported side effects was similar in both groups, and no serious toxicity occurred. CONCLUSIONS: Minocycline was safe and effective for patients with mild to moderate rheumatoid arthritis. Its mechanisms of action remain to be determined.