Tophus burden reduction with pegloticase: results from phase 3 randomized trials and open-label extension in patients with chronic gout refractory to conventional therapy.

INTRODUCTION: Two replicate randomized, placebo-controlled six-month trials (RCTs) and an open-label treatment extension (OLE) comprised the pegloticase development program in patients with gout refractory to conventional therapy. In the RCTs, approximately 40% of patients treated with the approved dose saw complete response (CR) of at least one tophus. Here we describe the temporal course of tophus resolution, total tophus burden in patients with multiple tophi, tophus size at baseline, and the relationship between tophus response and urate-lowering efficacy. METHODS: Baseline subcutaneous tophi were analyzed quantitatively using computer-assisted digital images in patients receiving pegloticase (8 mg biweekly or monthly) or placebo in the RCTs, and pegloticase in the OLE. Tophus response, a secondary endpoint in the trials, was evaluated two ways. Overall tophus CR was the proportion of patients achieving a best response of CR (without any new/enlarging tophi) and target tophus complete response (TT-CR) was the proportion of all tophi with CR. RESULTS: Among 212 patients randomized in the RCTs, 155 (73%) had ≥ 1 tophus and 547 visible tophi were recorded at baseline. Overall tophus CR was recorded in 45% of patients in the biweekly group (P = 0.002 versus placebo), 26% in the monthly group, and 8% in the placebo group after six months of RCT therapy. TT-CR rates at six months were 28%, 19%, and 2% of tophi, respectively. Patients meeting the primary endpoint of sustained urate-lowering response to therapy (responders) were more likely than nonresponders to have an overall tophus CR at six months (54% vs 20%, respectively and 8% with placebo). CONCLUSIONS: Pegloticase reduced tophus burden in patients with refractory tophaceous gout, especially those achieving sustained urate-lowering. Complete resolution of tophi occurred in some patients by 13 weeks and in others with longer-term therapy. TRIAL REGISTRATIONS: NCT00325195, NCT01356498.

Efficacy and tolerability of pegloticase for the treatment of chronic gout in patients refractory to conventional treatment: two randomized controlled trials.

CONTEXT: Patients with chronic disabling gout refractory to conventional urate-lowering therapy need timely treatment to control disease manifestations related to tissue urate crystal deposition. Pegloticase, monomethoxypoly(ethylene glycol)-conjugated mammalian recombinant uricase, was developed to fulfill this need. OBJECTIVE: To assess the efficacy and tolerability of pegloticase in managing refractory chronic gout. DESIGN, SETTING, AND PATIENTS: Two replicate, randomized, double-blind, placebo-controlled trials (C0405 and C0406) were conducted between June 2006 and October 2007 at 56 rheumatology practices in the United States, Canada, and Mexico in patients with severe gout, allopurinol intolerance or refractoriness, and serum uric acid concentration of 8.0 mg/dL or greater. A total of 225 patients participated: 109 in trial C0405 and 116 in trial C0406. INTERVENTION: Twelve biweekly intravenous infusions containing either pegloticase 8 mg at each infusion (biweekly treatment group), pegloticase alternating with placebo at successive infusions (monthly treatment group), or placebo (placebo group). MAIN OUTCOME MEASURE: Primary end point was plasma uric acid levels of less than 6.0 mg/dL in months 3 and 6. RESULTS: In trial C0405 the primary end point was reached in 20 of 43 patients in the biweekly group (47%; 95% CI, 31%-62%), 8 of 41 patients in the monthly group (20%; 95% CI, 9%-35%), and in 0 patients treated with placebo (0/20; 95% CI, 0%-17%; P < .001 and <.04 for comparisons between biweekly and monthly groups vs placebo, respectively). Among patients treated with pegloticase in trial C0406, 16 of 42 in the biweekly group (38%; 95% CI, 24%-54%) and 21 of 43 in the monthly group (49%; 95% CI, 33%-65%) achieved the primary end point; no placebo-treated patients reached the primary end point (0/23; 95% CI, 0%-15%; P = .001 and < .001, respectively). When data in the 2 trials were pooled, the primary end point was achieved in 36 of 85 patients in the biweekly group (42%; 95% CI, 32%-54%), 29 of 84 patients in the monthly group (35%; 95% CI, 24%-46%), and 0 of 43 patients in the placebo group (0%; 95% CI, 0%-8%; P < .001 for each comparison). Seven deaths (4 in patients receiving pegloticase and 3 in the placebo group) occurred between randomization and closure of the study database (February 15, 2008). CONCLUSION: Among patients with chronic gout, elevated serum uric acid level, and allopurinol intolerance or refractoriness, the use of pegloticase 8 mg either every 2 weeks or every 4 weeks for 6 months resulted in lower uric acid levels compared with placebo. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00325195.

The dynamics of chronic gout treatment: medication gaps and return to therapy.

OBJECTIVE: To identify gaps in therapy with urate-lowering drugs for the treatment of gout as well as factors associated with resuming therapy. METHODS: From 2 integrated delivery systems, we identified patients 18 years or older with a diagnosis of gout who initiated use of a urate-lowering drug from January 1, 2000 through June 30, 2006 and who had a gap in therapy. A gap was defined as a period of over 60 days after the completion of 1 prescription in which no refill for a urate-lowering drug was obtained. Survival curves were used to assess return to therapy of urate-lowering drugs. Cox proportional hazards analysis estimated the association between covariates and return to therapy. RESULTS: There were 4166 new users of urate-lowering drugs (97% received allopurinol), of whom 2929 (70%) had a gap in therapy. Among those with a gap, in 75% it occurred in the first year of therapy. Fifty percent of patients with a gap returned to therapy within 8 months, and by 4 years it was 75%. Age 45-74 years (<45 referent) and greater duration of urate-lowering drug use before the gap was associated with resuming treatment within 1 year. In contrast, receipt of nonsteroidal anti-inflammatory drugs or glucocorticoids in the year before the gap was associated with a reduced likelihood of resuming therapy. CONCLUSIONS: The majority of gout patients with gaps in urate-lowering drug use returned to treatment. More investigation is needed to better understand why patients may go for months without refilling prescriptions, given the clinical consequences of nonadherence.

Adherence with urate-lowering therapies for the treatment of gout.

INTRODUCTION: Adherence to urate-lowering drugs (ULDs) has not been well evaluated among those with gout. Our aim was to assess the level and determinants of non-adherence with ULDs prescribed for gout. METHODS: We identified persons using two integrated delivery systems aged 18 years or older with a diagnosis of gout who initiated use of allopurinol, probenecid or sulfinpyrazone from 1 January 2000 to 30 June 2006. Non-adherence was measured using the medication possession ratio (MPR) over the first year of therapy and defined as an MPR < 0.8. Descriptive statistics were calculated and logistic regression was used to estimate the strength of the association between patient characteristics and non-adherence. RESULTS: A total of 4,166 gout patients initiated ULDs; 97% received allopurinol. Median MPR for any ULD use was 0.68 (interquartile range (IQR) 0.64). Over half of the patients (56%) were non-adherent (MPR < 0.8). In adjusted analyses, predictors of poor adherence included younger age (odds ratio (OR) 2.43, 95% confidence interval (CI) 1.86 to 3.18 for ages <45 and OR 1.44, 95% CI 1.08 to 1.93 for ages 45 to 49), fewer comorbid conditions (OR 1.46, 95% CI 1.20 to 1.77), no provider visits for gout prior to urate-lowering drug initiation (OR 1.28, 95% CI 1.05 to 1.55), and use of non-steroidal anti-inflammatory drugs in the year prior to urate-lowering drug initiation (OR 1.15, 95% CI 1.00 to 1.31). CONCLUSIONS: Non-adherence amongst gout patients initiating ULDs is exceedingly common, particularly in younger patients with less comorbidity and no provider visits for gout prior to ULD initiation. Providers should be aware of the magnitude of non-adherence with ULDs.

Asthma drug use and the development of Churg-Strauss syndrome (CSS).

PURPOSE: Case reports suggest that leukotriene modifier use may be associated with the onset of Churg-Strauss syndrome (CSS). Using pooled data from two nested case-control studies, we examined the association between asthma drug use and the development of CSS. METHODS: The study was performed in three US managed care organizations and a US national health plan with chart access and complete electronic pharmacy data, with a covered population of 13.9 million. There were 47 cases of possible or definite CSS and 4700 asthma drug user controls identified between January 1, 1995 and December 31, 2002. We examined exposure to asthma drugs in cases and controls, including leukotriene modifiers (6 cases and 202 controls), in the two to 6 months prior to the onset of adjudicated CSS. RESULTS: While the crude association between use of leukotriene modifiers and CSS was strong (odds ratio (OR) 4.00, 95% confidence interval (CI): 1.49-10.60), in a multivariable analysis controlling for use of oral corticosteroids, inhaled corticosteroids, and number of categories of asthma drugs dispensed, there was no significant association (OR 1.32, 95% CI: 0.44-3.96). Use of inhaled and oral corticosteroids, evaluated as markers of asthma severity, were associated with CSS (OR 3.07, 95% CI: 1.34-7.03 and OR 5.36, 95% CI: 2.51-11.45, respectively). CONCLUSIONS: No association was found between CSS and leukotriene modifiers after controlling for asthma drug use However, it is not possible to rule out modest associations with asthma treatments given CSS is so rare and so highly correlated with asthma severity, suggesting further investigation is warranted.

Effect of hormone therapy on risk of hip and knee joint replacement in the Women's Health Initiative.

OBJECTIVE: To determine the effect of hormone therapy on arthroplasty rates. METHODS: We examined data from the Women's Health Initiative placebo-controlled, double-blind, randomized trials. Community-dwelling women ages 50-79 years were enrolled at 40 US clinics. Women with prior arthroplasty were excluded, yielding a sample size of 26,321 subjects. Women who had had hysterectomies (n = 10,272) were randomly assigned to receive 0.625 mg/day conjugated equine estrogens (n = 5,076), or placebo (n = 5,196), with a mean followup of 7.1 years. Those who had not had hysterectomies (n = 16,049) were randomly assigned to receive estrogen plus progestin (n = 8,240), given as 0.625 mg/day conjugated equine estrogens plus 2.5 mg/day medroxyprogesterone acetate, or placebo (n = 7,809), with a mean followup of 5.6 years. Participants reported hospitalizations, and arthroplasties were identified by procedure codes. Arthroplasties due to hip fracture were censored. Cox proportional hazards regression was used to assess hazard ratios (HRs) and 95% confidence intervals (95% CIs) using intent-to-treat methods and outcome of time to first procedure. RESULTS: In the estrogen-alone trial, women receiving hormone therapy had significantly lower rates of any arthroplasty (HR 0.84 [95% CI 0.70-1.00], P = 0.05). However, this effect was borderline statistically significant for hip arthroplasty (HR 0.73 [95% CI 0.52-1.03], P = 0.07), and not significant for knee arthroplasty (HR 0.87 [95% CI 0.71-1.07], P = 0.19). In the estrogen-plus-progestin trial, there was no association for total arthroplasty (HR 0.99 [95% CI 0.82-1.20], P = 0.92) or for individual hip (HR 1.14 [95% CI 0.83-1.57], P = 0.41) or knee (HR 0.91 [95% CI 0.72-1.15], P = 0.41) arthroplasties. CONCLUSION: These data suggest that hormone therapy may influence joint health, but this observed decrease in risk may be limited to unopposed estrogen and may possibly be more important in hip than in knee osteoarthritis.

Disclosure of medical errors: what factors influence how patients respond?

BACKGROUND: Disclosure of medical errors is encouraged, but research on how patients respond to specific practices is limited. OBJECTIVE: This study sought to determine whether full disclosure, an existing positive physician-patient relationship, an offer to waive associated costs, and the severity of the clinical outcome influenced patients' responses to medical errors. PARTICIPANTS: Four hundred and seven health plan members participated in a randomized experiment in which they viewed video depictions of medical error and disclosure. DESIGN: Subjects were randomly assigned to experimental condition. Conditions varied in type of medication error, level of disclosure, reference to a prior positive physician-patient relationship, an offer to waive costs, and clinical outcome. MEASURES: Self-reported likelihood of changing physicians and of seeking legal advice; satisfaction, trust, and emotional response. RESULTS: Nondisclosure increased the likelihood of changing physicians, and reduced satisfaction and trust in both error conditions. Nondisclosure increased the likelihood of seeking legal advice and was associated with a more negative emotional response in the missed allergy error condition, but did not have a statistically significant impact on seeking legal advice or emotional response in the monitoring error condition. Neither the existence of a positive relationship nor an offer to waive costs had a statistically significant impact. CONCLUSIONS: This study provides evidence that full disclosure is likely to have a positive effect or no effect on how patients respond to medical errors. The clinical outcome also influences patients' responses. The impact of an existing positive physician-patient relationship, or of waiving costs associated with the error remains uncertain.

Identifying unrecognized peripheral arterial disease among asymptomatic patients in the primary care setting.

National initiatives to enhance recognition of the detrimental impact of peripheral arterial disease on the health of adult Americans have been advocated. The objective of this study was to evaluate a strategy for identifying patients with unrecognized peripheral arterial disease from among persons without known atherosclerotic disease in the primary care setting. A cross-sectional design was used. Participants were patients receiving care from a multispecialty group practice in Massachusetts between July 2002 and July 2003, with a scheduled appointment with a primary care physician. Persons 70 years of age or older who were not already known to have atherosclerotic disease were enrolled. In addition, persons aged 50-69 with a diagnosis of diabetes mellitus, dyslipidemia, hypertension, and/or smoking based on information derived from administrative databases, and not known to have atherosclerotic disease, were enrolled. Before the scheduled appointment, potential study participants completed a telephone interview to ascertain their medical history. The ankle-brachial index (ABI) of eligible patients was measured at the time of the scheduled primary care office visit. Peripheral arterial disease was diagnosed if 1 or both legs had an ABI of or=70 years, 45 (12.5%) were diagnosed with peripheral arterial disease. Nine (2.5%) of 358 subjects aged 50-69 years were diagnosed with peripheral arterial disease. The average total time (n = 52) for ABI testing was 13.7 (SD: +/-3.3) minutes. Patients aged >or=70 years required more time for ABI testing compared to those aged 50-69 (mean: 15.0 vs 13.0 minutes, p=0.04). Unrecognized asymptomatic peripheral arterial disease can be commonly detected among patients in the primary care setting who are not already known to have atherosclerotic disease. The yield from screening is substantially greater among unselected older patients compared with younger patients specifically identified as having risk factors for PAD. These findings should help inform the development and implementation of new initiatives to enhance the early detection of peripheral arterial disease among asymptomatic patients in the primary care setting.

Incidence of Churg-Strauss syndrome in asthma drug users: a population-based perspective.

OBJECTIVE: To estimate the incidence of Churg-Strauss syndrome (CSS) among a large population of asthma drug users. METHODS: A retrospective study was conducted among patients who had been dispensed asthma drugs at 3 managed care organizations. Adults who received >or =3 dispensings of an asthma drug during any consecutive 12-month period between January 1, 1995 and June 30, 2000 were identified. Information on patient age, gender, enrollment status, asthma drugs dispensed, and inpatient and outpatient diagnoses and procedures was obtained from automated databases. Chart reviews were performed on persons identified by combinations of diagnostic and billing codes indicative of CSS. A rheumatologist reviewed abstracted information on all subjects; those who met >or =2 American College of Rheumatology criteria for CSS were reviewed by 2 clinical experts. Each clinical expert independently rated the cases; disagreements were resolved by consensus. Cases classified as having "probable/definite" CSS were included in these analyses. The incidence of CSS was estimated overall and according to patient gender, age, and calendar year. RESULTS: From a population of 184,667 asthma drug users contributing 606,184 person-years of exposure, 21 incident cases of CSS were identified (overall incidence of 34.6 per million person-years; 95% confidence interval 21.4 to 53.0). Incidence rates did not differ by gender and age group. The incidence rates for 1995, 1996, 1997, 1998, 1999, and the first 6 months of 2000 were 0, 22, 52, 75, 14, and 14 per million person-years respectively. CONCLUSIONS: Results from this population-based study suggest a somewhat lower incidence of CSS in asthma drug users than previously reported and provides important information as to the risk of developing CSS from a population-based perspective.

Health plan members' views on forgiving medical errors.

BACKGROUND: How patients respond to medical errors may influence how physicians approach disclosure of medical errors, but information on patients' responses is limited. Research is needed on how the circumstances that surround a medical error affect how patients respond. OBJECTIVE: To investigate whether patients' tendency to forgive a physician following a medical error varied under different circumstances. STUDY DESIGN: Cross-sectional survey. METHODS: We mailed a questionnaire to 1500 randomly selected health plan members; the response rate was 66%. Questionnaire items assessed the likelihood of forgiveness following a medical error under 12 circumstances drawn from a review of the literature. RESULTS: Respondents were most likely to forgive a physician if the patient failed to provide complete information (93% would or might forgive) and least likely to forgive if the error was due to efforts to keep costs down (11% would or might forgive). Most respondents would not forgive a physician when the physician was tired or distracted (68%), was incomplete in data collection (76%), lacked knowledge (78%), or failed to follow up (85%). Men were more likely to forgive than women; the most educated respondents were most likely to forgive. CONCLUSIONS: Our findings suggest that patients are not likely to forgive a physician in circumstances in which they suspect incompetence, inattention, or a lack of caring on the part of the physician involved. A more comprehensive understanding of forgiveness and the effect of forgiveness on the physician-patient relationship following a medical error is needed.

Health plan members' views about disclosure of medical errors.

BACKGROUND: Various authorities and national organizations encourage disclosing medical errors, but there is little information on how patients respond to disclosure. OBJECTIVE: To examine how the type of error, severity of adverse clinical outcome, and level of disclosure affect patients' responses to error and disclosure. DESIGN: Mail questionnaire survey (8 versions were developed) varying 3 factors in a completely crossed, randomized, factorial design. Each questionnaire included a vignette describing 1) a medical error (failure to check for penicillin allergy or inadequate monitoring of antiepileptic medication); 2) an associated clinical outcome (life-threatening or less serious); and 3) a physician-patient dialogue, with either full disclosure (acceptance of responsibility and an apology) or nondisclosure (expression of regret without acceptance of responsibility or an apology). SETTING: New England-based health plan. PARTICIPANTS: Random sample of 1500 adult members received the questionnaire, with a 66% response rate. MEASUREMENTS: Likelihood of changing physicians, likelihood of seeking legal advice, ratings of patient satisfaction, trust and emotional reaction in response to a vignette and dialogue, and views on medical error and disclosure. RESULTS: Full disclosure reduced the reported likelihood of changing physicians and increased patient satisfaction, trust, and positive emotional response. Full disclosure reduced the reported likelihood of seeking legal advice in only 1 error-and-outcome vignette. In the other vignettes, the percentage of patients indicating that they would seek legal advice was relatively high even with full disclosure. Almost all respondents (98.8%) wanted to be told of errors, most (83%) favored financial compensation if harm occurred, and few (12.7%) favored compensation if no harm occurred. LIMITATIONS: Since the study was done in the context of a managed care plan in one geographic area, it could not assess whether the results are generalizable to other populations. In addition, it could not determine whether responses to the simulated situations used predict responses to real situations. CONCLUSIONS: Patients will probably respond more favorably to physicians who fully disclose medical errors than to physicians who are less forthright, but the specifics of the case and the severity of the clinical outcome also affect patients' responses. In some circumstances, the desire to seek legal advice may not diminish despite full disclosure.

Isolated vasculitis of the cervix presenting as vaginal discharge.

A 44-year-old woman previously in excellent health presented with clear vaginal discharge. Pelvic examination revealed a friable cervix that showed small-vessel necrotizing vasculitis on cone biopsy. She had no clinical evidence of systemic vasculitis or any connective tissue disease. Laboratory findings of inflammation (raised erythrocyte sedimentation rate and thrombocytosis) returned to normal after the cone biopsy. She has been symptom-free for over 2 years after the cone biopsy and a subsequent hysterectomy that failed to reveal uterine vasculitis. Localized vasculitis of the cervix can present as vaginal discharge or menorrhagia without evidence of vasculitis elsewhere and does not require systemic therapy.

Compliance with pharmacologic therapy for osteoporosis.

There is little information available concerning compliance with pharmacologic therapy for osteoporosis in the usual care setting. We evaluated 176 consecutive, previously untreated women whose physicians initiated treatment for osteoporosis following a bone mineral density (BMD) test obtained as part of routine medical practice. All patients were contacted >/=1 year after the initial BMD test and offered a follow-up BMD. Compliance with therapy was defined as the percent of time that a patient filled a prescription for osteoporosis treatment. Ninety-three (53%) patients received estrogen (ERT), 93 (53%) bisphosphonates, 8 (5%) calcitonin, and 17 (10%) received more than one therapy. Ninety-one of the 176 (52%) agreed to a follow-up BMD at a mean of 590 days after the first study (participants); 85 declined a follow-up BMD (refusers). Participants and refusers were similar for age, treatment patterns, and compliance with therapy. For all patients, compliance for those given bisphosphonate was similar to those given ERT (70.7% (95% CI 63.5-77.9%) versus 69.2% (95% CI 61.7-76.8%). For participants, the change in spine BMD was similar for those treated with bisphosphonate [mean increase 3.53 (+/-2.64)%/year (mean+/-SD)] and those treated with ERT [mean increase 3.00 (+/-2.75)%/year]. For those participants whose compliance with therapy was >/=66%, the mean increase in spine bone density was 3.80 (+/-2.59)%/year compared to 2.11 (+/-2.64)%/year ( p<0.005) for those whose compliance was <66%. Compliance with ERT and bisphosphonate therapy initiated in routine practice after a BMD was similar over a mean of 590 days. Compliance less than 66% with drug treatment results in suboptimal improvement in bone density.