Effects of Teriparatide on Joint Erosions in Rheumatoid Arthritis: A Randomized Controlled Trial.

OBJECTIVE: Articular erosions correlate with disability in rheumatoid arthritis (RA). Biologic agents reduce erosion progression in RA, but erosion healing occurs infrequently. This study was undertaken to assess the effects of the anabolic agent teriparatide on joint erosion volume in RA patients treated with a tumor necrosis factor inhibitor (TNFi). METHODS: We conducted a randomized controlled trial in 24 patients with erosive RA, osteopenia, and disease activity controlled by TNFi treatment for at least 3 months. Half were randomized to receive teriparatide for 1 year and the others constituted a wait-list control group. Subjects and primary rheumatologists were not blinded with regard to treatment assignment, but all outcomes were assessed in a blinded manner. The primary outcome measure was change in erosion volume determined by computed tomography at 6 anatomic sites. Significance within each hand and anatomic site was based on a 2-tailed test, with P values less than 0.05 considered significant. RESULTS: Baseline characteristics of the treatment groups were well balanced. After 52 weeks, the median change in erosion volume in the teriparatide group was -0.4 mm3 (interquartile range [IQR] -34.5, 29.6) and did not differ significantly from that in controls (median change +9.1 mm3 [IQR -29.6, 26.4]) (P = 0.28). No significant difference in change in erosion volume was noted at the radius, ulna, or metacarpophalangeal joints. Bone mineral density improved at the femoral neck and lumbar spine in the teriparatide group. CONCLUSION: Our findings indicate that teriparatide treatment for 1 year does not significantly reduce erosion volume in the hands or wrists of patients with established RA with disease activity controlled by TNFi treatment.

Predictors of very low adherence with medications for osteoporosis: towards development of a clinical prediction rule.

UNLABELLED: We developed a clinical prediction rule score to predict medication non-adherence for women prescribed osteoporosis treatment. When combined into a summative score, 62% with seven or more points on the score demonstrated very low adherence. This compares with 17% subjects with fewer than seven points (c-statistic = 0.74). INTRODUCTION: Medication non-adherence is extremely common for osteoporosis; however, no clear methods exist for identifying patients at risk of this behavior. We developed a clinical prediction rule to predict medication non-adherence for women prescribed osteoporosis treatment. METHODS: Women undergoing bone mineral density testing and fulfilling WHO criteria for osteoporosis were invited to complete a questionnaire and then followed for 1 year. Adjusted logistic regression models were examined to identify variables associated with very low adherence (medication possession ratio <20%). The weighted variables, based on the logistic regression, were summed, and the score was compared with the proportion of subjects with very low adherence. RESULTS: One hundred forty two women participated in the questionnaire and were prescribed an osteoporosis medication. After 1 year, 36% (n = 50) had very low adherence. Variables associated with very low adherence included prior non-adherence with chronic medications, agreement that side effects are concerning, agreement that she is taking too many medications, lack of agreement that osteoporosis is a worry, lack of agreement that a fracture will cause disability, lack of agreement that medications help her stay active, and frequent use of alcohol. When combined into a summative score, 36 of the 58 subjects (62%) with seven or more points on the score demonstrated very low adherence. This compares with 14 of the 84 (17%) subjects with fewer than seven points (c-statistic = 0.74). CONCLUSION: We developed a brief clinical prediction rule that was able to discriminate between women likely (and unlikely) to experience very low adherence with osteoporosis medications.

Sex differences in gout epidemiology: evaluation and treatment.

BACKGROUND: Little is known about the characteristics, evaluation and treatment of women with gout. OBJECTIVE: To examine the epidemiological differences and differences in treatment between men and women in a large patient population. METHODS: The data from approximately 1.4 million people who were members of seven managed care plans in the USA for at least 1 year between 1 January 1999 and 31 December 2003 were examined. Adult members who had pharmacy benefits and at least two ambulatory claims specifying a diagnosis of gout were identified. In addition, men and women who were new users of urate-lowering drugs (ULDs) were identified to assess adherence with recommended surveillance of serum urate levels within 6 months of initiating urate-lowering treatment. RESULTS: A total of 6133 people (4975 men and 1158 women) with two or more International Classification of Disease-9 codes for gout were identified. As compared with men with gout, women were older (mean age 70 (SD 13) v 58 (SD 14), p<0.001) and had comorbidities and received diuretics more often (77% v 40%; p<0.001). Only 37% of new users of urate-lowering treatment had appropriate surveillance of serum urate levels post-initiation of urate-lowering treatment. After controlling for age, comorbidities, gout treatments, number of ULD dispensings and health plan, women were more likely (odds ratio 1.36, 95% confidence interval 1.11 to 1.67) to receive the recommended serum urate level testing. CONCLUSIONS: Women with gout were older, had greater comorbidities and more often used diuretics and received appropriate surveillance of serum urate levels, suggesting that the factors leading to gout as well as monitoring of treatment are very different in women and men.

Prevention of glucocorticoid-induced osteoporosis: experience in a managed care setting.

BACKGROUND: Treatment with glucocorticoids is the leading cause of drug-induced osteoporosis. Currently available guidelines indicate that patients receiving long-term glucocorticoid therapy should receive measures to prevent osteoporosis. OBJECTIVES: To examine whether patients receiving long-term glucocorticoid therapy in a managed care setting received preventive therapy or prescribed medications for osteoporosis and to identify patient and provider characteristics associated with treatment. SUBJECTS AND METHODS: A cohort of 224 health plan enrollees 20 years and older who were dispensed at least 1 oral glucocorticoid prescription per quarter during the period October 1997 through September 1998 was identified from administrative data. Medical charts and administrative data were reviewed to determine use of preventive therapy and prescribed medications for osteoporosis. RESULTS: Of the 224 patients, 62% had at least 1 documented intervention aimed at osteoporosis prevention (counseling about calcium or vitamin D or weight-bearing exercise; prescription for estrogen, calcitonin, or bisphosphonate; or a bone mineral density study). Women were more likely than men to receive intervention (76% vs 44%; prevalence odds ratio, 4.41; 95% confidence interval, 2.17-9.10). Patients receiving a mean daily prednisone dose of 10 mg or more or 5 to less than 10 mg were no more likely to receive intervention than those receiving 5 mg or less prednisone daily. Sixty-two (90%) of 69 patients who were prescribed glucocorticoid therapy by rheumatologists had at least 1 intervention documented compared with 29 (48%) of 60 for internists, 26 (55%) of 47 for pulmonologists, and 22 (46%) of 48 for all other physicians. In a multiple logistic regression model, including patient age, sex, mean daily glucocorticoid dose, and physician specialty, women and patients prescribed glucocorticoids by a rheumatologist were significantly more likely to receive intervention aimed at osteoporosis prevention. CONCLUSIONS: A substantial proportion of patients receiving long-term glucocorticoid therapy do not receive preventive therapy for osteoporosis. Efforts should be made to reduce barriers to such treatment and increase the proportion of patients given preventive therapy.

The diffusion of a novel therapy into clinical practice: the case of sildenafil.

BACKGROUND: Erectile dysfunction is a common condition, yet in the past most affected men did not seek medical treatment. OBJECTIVE: To examine how sildenafil (Viagra), a new medication for the treatment of erectile dysfunction, has been incorporated into general medical practice. SUBJECTS AND METHODS: The study population consisted of all male members of a group-model Massachusetts health maintenance organization (HMO) whose first prescription for sildenafil was dispensed during the first 24 weeks of its availability through the HMO as a plan benefit (April 24, 1998, through October 8, 1998). Data collected on each member in the study population included age, specialty of the prescribing physician, initial dose, use of prior treatments for erectile dysfunction, receipt of medications known to predispose to impotence, filling of a second prescription for sildenafil, and concomitant medical conditions (including hypertension, ischemic heart disease, hyperlipidemia, diabetes mellitus, and history of radical prostatectomy). Cross tabulations and logistic regression models were constructed to evaluate the potential associations between filling a second prescription for sildenafil and other characteristics of sildenafil users. RESULTS: We identified 899 members who filled a first-time sildenafil prescription in the 24-week period of interest. The majority of sildenafil prescriptions that were filled for the first time (85%) occurred in the first 12 weeks of its availability. Most sildenafil users (84%) were between 45 and 74 years of age (average age, 61 years; age range, 23 to 90 years), and approximately 40% had documentation of prior treatment for erectile dysfunction. Use was highest among those aged 55 to 64 years, with almost 5% of all male HMO members in that age group having received at least 1 sildenafil prescription. Our cohort of sildenafil users was significantly more likely to have hypertension (P<.01), hyperlipidemia (P<.01), and diabetes mellitus (P<.01) than persons who participated in a widely publicized clinical trial of the medication. Prescribing physicians were predominantly primary care physicians (78% were internists, and 11% were family practitioners). More than 60% of sildenafil users filled a second prescription within 3 months of the first prescription; in multivariate analyses, factors associated with filling a second prescription included younger age and prior treatment for erectile dysfunction. CONCLUSIONS: Sildenafil was rapidly adopted into the clinical practice of primary care physicians for the treatment of erectile dysfunction in the managed care setting. The patients for whom the drug was prescribed in the general practice setting differed across many medical characteristics from study subjects who participated in clinical trials of the drug. Arch Intern Med. 2000;160:3401-3405.

Evaluating the predictive value of osteoarthritis diagnoses in an administrative database.

OBJECTIVE: To assess the positive and negative predictive values of osteoarthritis (OA) diagnoses contained in an administrative database. METHODS: We identified all members (> or =18 years of age) of a Massachusetts health maintenance organization with documentation of at least one health care encounter associated with an OA diagnosis during the period 1994-1996. From this population, we randomly selected 350 subjects. In addition, we randomly selected 250 enrollees (proportionally by the age and sex of the 350 subjects) who did not have a health care encounter associated with an OA diagnosis. Trained nurse reviewers abstracted OA-related clinical, laboratory, and radiologic data from the medical records of both study groups (all but 1 chart was available for review). Pairs of physician reviewers evaluated the abstracted information for both groups of subjects and rated the evidence for the presence of OA according to 3 levels: definite, possible, and unlikely. RESULTS: Among the group of patients with an administrative diagnosis of OA, 215 (62%) were rated as having definite OA, 36 (10%) possible OA, and 98 (28%) unlikely OA, according to information contained in the medical record. The positive predictive value of an OA diagnosis was 62%. In those without an administrative OA diagnosis, 44 (18%) were assigned a rating of definite OA. The negative predictive value of the absence of an administrative OA diagnosis was 78%. CONCLUSION: Use of administrative data in epidemiologic and health services research on OA may lead to both case misclassification and under ascertainment.

Increments in bone mineral density of the lumbar spine and hip and suppression of bone turnover are maintained after discontinuation of alendronate in postmenopausal women.

PURPOSE: Previously we have reported a significant increase in bone mineral density (BMD) of the spine and the hip and reductions in biochemical indices of bone turnover in postmenopausal women with osteoporosis treated with alendronate at various doses over 1 to 2 years. We have followed BMD and biochemical parameters in these patients for 1 or 2 years after discontinuation of alendronate to determine resolution of alendronate effects. PATIENTS AND METHODS: Participants received daily oral doses of placebo, 5 or 10 mg of alendronate for 2 years, or 20 or 40 mg of alendronate for 1 year followed by 1 year of placebo. No treatment was given in the third year of study. RESULTS: Lumbar spine BMD changes in the 5- and 10-mg groups (-1.4 and -0.4%) were similar to those in the placebo group (-1.2%) 1 year after discontinuation of drug and lumbar spine BMD changes in the 20- and 40-mg groups (-1.2% and 0.8%) were similar to those in the placebo group (-0.9%) 2 years after discontinuation of drug. BMD of the total hip followed the same pattern of resolution. The difference in BMD between alendronate and placebo groups at the end of alendronate treatment was maintained up to 2 years. Residual reductions in the bone resorption markers urinary deoxypyridinoline (D-Pyr) and collagen type 1 cross-linked N telopeptides and the bone formation markers serum bone-specific alkaline phosphatase and osteocalcin remained for 1 year after discontinuation of 5 and 10 mg of alendronate and for 2 years after discontinuation of 20 and 40 mg of alendronate, other than return of D-Pyr to baseline 1 year after cessation of treatment with the 5- and 10-mg doses. CONCLUSIONS: A residual decrease in bone turnover may be found up to 2 years after discontinuation of alendronate. Accelerated bone loss is not observed when treatment is discontinued. However, continuous therapy with alendronate is required to achieve a continuous gain in BMD.

Resource utilization and cost of care for rheumatoid arthritis and osteoarthritis in a managed care setting: the importance of drug and surgery costs.

OBJECTIVE: To describe the frequency and costs of medical services for patients with osteoarthritis (OA) or rheumatoid arthritis (RA) in a managed care setting. METHODS: Individual utilization records of medical and pharmacy services for OA and RA patients were obtained from a group-model health maintenance organization (HMO). Estimates were made for costs of drugs and medical services for arthritis from July 1, 1993 to June 30, 1994 using Medicare reimbursement schedules and average wholesale drug prices. Calculated rates for each population were expressed as counts of events or as dollars per person-year. RESULTS: The average individual cost rate of arthritis-related care for 365 RA patients was $2,162 per year, and the total cost of RA care to the HMO was $703,053. Prescription medications accounted for 62% ($436,440) of the total cost of RA care, while ambulatory care accounted for 21% ($150,938), and hospital visits accounted for 16% ($115,674). With regard to 10,101 OA patients, the average individual cost rate was $543 per year, and total cost to the HMO was $4,728,425. Hospital care accounted for 46% ($2,170,890) of the total cost of OA care, medications accounted for 32% ($1,509,637), and ambulatory care accounted for 22% ($1,047,898). CONCLUSION: RA care, in the setting of this study, was characterized by intensive treatment, especially frequent use of medications that were delivered to most patients. Although the cost of RA care per patient was high, cost to the managed care provider was relatively low, owing to the rarity of RA. OA care tended to be infrequent, and the largest component of cost was hospital care for a small proportion of patients (5%). Owing to the greater prevalence of OA, care of OA was nearly 7 times more costly to the managed care provider than was care of RA.

Alendronate treatment of the postmenopausal osteoporotic woman: effect of multiple dosages on bone mass and bone remodeling.

BACKGROUND: The effects of the aminobisphosphonate alendronate sodium on bone mass and markers of bone remodeling were investigated. PATIENTS AND METHODS: In a multicenter, randomized, double-blind, placebo-controlled, 2-year study, 188 postmenopausal women, aged 42 to 75 years, with low bone mineral density (BMD) of the lumbar spine were randomly assigned to 1 of 6 daily treatment groups: placebo for 2 years, alendronate 5 or 10 mg for 2 years, alendronate 20 or 40 mg for 1 year followed by placebo for 1 year, or alendronate 40 mg for 3 months followed by 2.5 mg for 21 months. All subjects were given 500 mg/d of elemental calcium as calcium carbonate. RESULTS: At each dose, alendronate produced significant reductions in markers of bone resorption and formation, and significantly increased bone mass at the lumbar spine, hip, and total body, as compared with decreases (significant at lumbar spine) in subjects receiving placebo. In the 10-mg group, mean urinary deoxypyridinoline/creatinine had declined by 47% at 3 months, and mean serum osteocalcin by 53% at 6 months. Mean changes in BMD over 24 months with 10 mg alendronate were +7.21% +/- 0.49% for the lumbar spine, +5.27% +/- 0.70% for total hip, and +2.53% +/- 0.68% for total body (each P < 0.01) compared to changes of -1.35% +/- 0.61%, -1.20% +/- 0.64% and -0.31% +/- 0.44% at these sites, respectively, with placebo treatment. Progressive increases in BMD of both lumbar spine and total hip were observed in the second year of treatment with 10 mg alendronate (both P < 0.05). CONCLUSION: Alendronate, a potent inhibitor of bone resorption, reduces markers of bone remodeling and significantly increases BMD at the lumbar spine, hip, and total body, and is well tolerated at therapeutic doses (5 or 10 mg daily) in the treatment of osteoporosis in postmenopausal women.

Lymphocytic interstitial pneumonitis in a patient with systemic lupus erythematosus.

A 34-year-old woman with stable systemic lupus erythematosus (SLE) treated with low-dose prednisone and hydroxychloroquine developed multiple bilateral pulmonary nodules. Open lung biopsy documented lymphocytic interstitial pneumonitis (LIP). LIP should be considered in the differential diagnosis of nodular pulmonary lesions in patients with SLE.

The infrequency of liver function testing in patients using nonsteroidal anti-inflammatory drugs.

OBJECTIVE: To describe the monitoring of liver function for patients using nonsteroidal anti-inflammatory drugs (NSAIDs), we reviewed the patterns of liver function testing in a medium-sized health maintenance organization. METHODS: We examined the interval between start of therapy and first performance of a liver function test during courses of therapy of the NSAIDs diclofenac sodium, naproxen and naproxen sodium, and piroxicam. For comparison, we also studied courses of lovastatin as a "positive control," in which the anticipated frequency of liver function testing was high. RESULTS: The frequency of liver function tests in patients using NSAIDs was generally low, although testing was more common in patients who used diclofenac. The probability of liver function testing was higher for patients treated in recent calendar years, for patients treated by rheumatologists, for patients who previously used NSAIDs, and for patients who had undergone a liver function test sometime in the 6 months preceding the onset of therapy. CONCLUSION: Physicians ordered liver function tests less frequently than recommended, but the observed testing patterns appear rational in light of the very low reported frequency of serious hepatic disease in large, monitored populations of patients using NSAIDs.

The lag time between onset of symptoms and diagnosis of rheumatoid arthritis.

OBJECTIVE: Rheumatoid arthritis (RA) may be biologically reversible if treated in the first several months, yet it is unknown whether patients are diagnosed that early. We investigated the lag time between symptom onset and diagnosis of RA in a population with excellent access to rheumatology care. METHODS: Using review of medical records, we evaluated all patients newly diagnosed as having RA from 1987 through 1990, at a health maintenance organization in central Massachusetts. Total lag time from symptom onset to first definite diagnosis was divided into medical encounter lag time (from symptom onset to first medical encounter) and diagnosis lag time (from first medical encounter to diagnosis). RESULTS: The median total lag time was 36 weeks (range 4 weeks to > 10 years). The median medical encounter lag time was 4 weeks (not all patients included in the analysis). The median diagnosis lag time was 18 weeks. Diagnosis lag time was shorter for patients with progressive disease and positive rheumatoid factor on the initial test. Of 25 patients with symmetric arthritis and positive rheumatoid factor, only 5 (20%) were diagnosed within 2 months, and 10 (40%) were diagnosed more than 6 months after symptom onset. CONCLUSION: RA diagnosis is usually delayed for several months after symptoms begin, in large part because of delay in diagnosis by the physician. Thus, the goal of initiating treatment extremely early may be unrealistic for most patients.

Incidence of rheumatoid arthritis in central Massachusetts.

OBJECTIVE: To determine whether there is a secular decline in the incidence of rheumatoid arthritis (RA), as has been suggested by previous studies. METHODS: In the absence of comprehensive data in the United States population, we estimated RA incidence in a health maintenance organization population from 1987 through 1990 and compared the rates with those in an earlier, similarly performed study from Rochester, Minnesota, which covered the years 1950 through 1974. RA estimates were based on our review of medical records of patients who had been diagnosed as having RA or related diseases during the period of January 1, 1987 through December 31, 1990. RESULTS: Annual age-standardized incidence of classic or definite RA (according to the American College of Rheumatology [formerly, the American Rheumatism Association] 1958 criteria) in patients aged 18 or older was 22 per 100,000 in men and 60 per 100,000 in women. The incidence of RA increased with age, with a marked increase in women older than 50. CONCLUSION: We found no secular change in RA incidence compared with the similarly ascertained historical data.

Quantitation of substance-P and its metabolites in plasma and synovial fluid from patients with arthritis.

Substance-P (SP) and its metabolites, SP-(1-7) and SP-(5-11), were quantitated in arthritic synovial fluids and plasma using a validated procedure. This process involved collection into appropriate enzyme inhibitors, extraction with acid-acetone, high pressure liquid chromatography, and RIA using region-specific antisera. Our results demonstrate that the levels of authentic SP in these fluids are less than 3.5 pmol/L, which is 50- to 10,000-fold less than those previously reported by others. These discrepant findings were not attributable to degradation, because added SP was recovered in good yield, and the measured levels of the metabolites SP-(1-7) and SP-(5-11) were also extremely low. In search of an explanation, we noted that many of the earlier reports involved direct assay of these fluids (without extraction and chromatography). Further work indicated that proteolytic enzymes (e.g. protease 24.11) present in these unextracted fluids can give rise to artifactually high SP measurements. We conclude that if SP is released within the joint space and if it participates in the inflammatory reaction and/or healing process, it most likely does so in a local fashion, which would not involve its accumulation in synovial fluid or plasma.

An equilibrium model of drug utilization.

We propose an equilibrium model to assess the dispensing pattern of non-steroidal anti-inflammatory drugs (NSAIDs) among members of a health maintenance organization. The model incorporates observed patterns of patient switching among NSAIDs and identifies an implicit equilibrium distribution of drug dispensing, which may be used both to identify aberrations in prescription practice and to forecast the expected utilization of newly introduced drugs. NSAID dispensing patterns were stable for most quarters from 1987 to 1990. Introduction of two new NSAIDs and initiation of a pharmacy co-payment coincided with transient perturbation of the patterns. Dispensings of recently introduced NSAIDs achieved their equilibrium values in less than 2 years.

Patterns of interchange in the dispensing of non-steroidal anti-inflammatory drugs.

Patterns of change in dispensings of non-steroidal anti-inflammatory drugs (NSAID) were evaluated from the pharmacy records of a health maintenance organization (HMO). Overall, 52.8% of NSAID prescriptions were followed by another NSAID prescription within 60 days. Among patients for whom NSAIDs were dispensed twice within 60 days, 15% received a different NSAID. Switching between NSAIDs was more frequent in younger age groups; there was no difference between males and females. Chronic and non-chronic indications for NSAID use were associated with similar probabilities of switches between drugs among repeat users. NSAIDs that were frequently switched to for lack of efficacy or for prior toxicity of other NSAIDs were not as a whole themselves associated with more frequent switches for the same reasons.