Philip R.A. Baker

Combination Therapy with Cyclosporine and Methotrexate in Severe Rheumatoid Arthritis

BACKGROUND Patients with severe rheumatoid arthritis who are treated with methotrexate frequently have only partial improvement. METHODS In a six-month randomized, double-blind trial, we compared combination therapy with cyclosporine (2.5 to 5 mg per kilogram of body weight per day in two divided doses at 12-hour intervals) and methotrexate (at the maximal tolerated dose) with methotrexate and placebo in 148 patients with rheumatoid arthritis who had residual inflammation and disability despite partial but substantial responses to prior methotrexate treatment. The primary outcome measure was the change in the number of tender joints. RESULTS The mean (+/- SD) dose of cyclosporine at the final treatment was 2.97 +/- 1.02 mg per kilogram per day. As compared with the placebo group, the patients in the treatment group had a net improvement in the tender-joint count of 25 percent, or 4.8 joints (95 percent confidence interval, 0.7 to 8.9; P = 0.02), and in the swollen-joint count of 25 percent, or 3.8 joints (95 percent confidence interval, 1.3 to 6.3; P = 0.005); improvement in overall disease activity as assessed by the physician (19 percent, P < 0.001) and the patient (21 percent, P < 0.001); and improvement in joint pain (23 percent, P = 0.04) and in the degree of disability (26 percent, P < 0.001). The mean erythrocyte sedimentation rate increased by 4.2 mm per hour in the cyclosporine group and decreased by 4.8 mm per hour in the placebo group (P = 0.006). Thirty-six patients (48 percent) in the cyclosporine group and 12 patients (16 percent) in the placebo group (P < 0.001) met the 1993 criteria for improvement of the American College of Rheumatology (more than 20 percent improvement in the numbers of both swollen and tender joints and improvement in three of five other variables). Seventeen patients in the cyclosporine group and 12 patients in the placebo group were withdrawn from the study; 2 patients in the cyclosporine group died, 1 from viral pneumonia and the other in a motor vehicle accident. Serum creatinine concentrations increased by a mean of 0.14 +/- 0.27 mg per deciliter (12 +/- 24 mmol per liter) in the cyclosporine group and by 0.05 +/- 0.19 mg per deciliter (4 +/- 17 mmol per liter) in the placebo group (P = 0.02). CONCLUSIONS In a six-month study, patients with severe rheumatoid arthritis and only partial responses to methotrexate had clinically important improvement after combination therapy with cyclosporine and methotrexate. Side effects were not substantially increased. Long-term follow-up of patients treated with this combination is needed.

Laboratory Evaluation in the Diagnosis of Lyme Disease

1. Introduction 1.1 Lyme disease is the most common tick-borne disease in North America. From 1982 through 1994, more than 70 000 cases were reported in North America; most of these cases were in the United States [1]. It is important that clinicians diagnose Lyme disease correctly because efficacious therapy is available and delayed or inadequate treatment can lead to many morbid sequelae. Lyme disease is a complex multisystem disease caused by the spirochete Borrelia burgdorferi [2]. It affects persons of all ages and both sexes. Since the disease was recognized in Connecticut in 1975 [3], endemic areas have been identified in several regions in North America. In more restricted areas in some northeastern and upper midwestern U.S. states, the disease has assumed the characteristics of an emerging epidemic [4-9]. The true incidence is almost certainly underestimated because of under-reporting [10, 11]. 1.2 Most patients develop a distinctive rash, erythema migrans, that is accompanied by such flu-like symptoms as fatigue, headache, mild stiff neck, joint and muscle aches, and fever [12]. Some weeks or months after the initial exposure, symptoms and signs of disseminated disease (particularly neurologic, cardiac, or articular disease) may develop in untreated patients [13, 14]. 1.3 Case definitions of Lyme disease have been developed in the United States for national disease surveillance purposes. A positive serologic test result was initially required for patients who had erythema migrans alone and had not been exposed to Lyme disease in endemic areas [15], but the 1990 criteria established in the Centers for Disease Control and Preventions (CDCs) U.S. Lyme disease national surveillance definition reduced this requirement to a recommendation (Table 1) [16]. These criteria were developed for an epidemiologic case definition intended for surveillance purposes only. However, previous national disease surveillance criteria have been used in clinical studies [17, 18], and such definitions do provide standardization. Standardization allows comparisons of clinical studies and permits the performance of meta-analysis to facilitate development of clinically useful guidelines. Table 1. Criteria for Confirmed Lyme Disease 1.4 Requests for laboratory testing for Lyme disease have increased rapidly. In Wisconsin, for example, it was reported that more than 60 000 tests were being done annually [19]; in New Jersey, 5000 tests were done in 1 week in 1989 [20]. According to market projections for the United States, 2.79 million rapid tests were to have been done for Lyme disease in 1995 [21]. Testing is often done in persons who have only nonspecific signs and symptoms of illness, such as headache, fatigue, myalgia, or arthralgia. Even in highly endemic areas, the pretest probability of Lyme disease in such patients is less than 0.20 (usually much lower). Thus, even when highly experienced laboratories are used, the probability of a false-positive test result is higher than that of a true-positive result. This problem is compounded by the lack of standardized serologic tests for Lyme disease. Comparisons of the test results from different laboratories have shown poor reliability and accuracy; up to 21% of standardized positive samples are missed, and up to 7% of samples from persons with no known exposure are incorrectly identified as positive [22]. 1.5 This background paper provides a quantitative and qualitative evaluation of the predictive value of the laboratory diagnosis of Lyme disease. This evaluation forms the basis for guidelines on clinical diagnosis. Practitioners have been confused by the lack of consensus on diagnostic criteria for Lyme disease. The causes of this controversy arise from a combination of factors: the use of different tests in different laboratories, the use of different criteria to set positive and negative cutoff values for the same tests, different degrees of quality control in different laboratories, and differences in the community prevalence of Lyme disease. 1.6 We address each of these factors and make recommendations for the diagnostic workup of patients suspected of having Lyme disease. 2. Methods 2.1 Data Sources Relevant articles from the medical literature were identified by searching the MEDLINE database for English-language articles or articles with English-language abstracts published from 1982 (when the spirochetal cause of Lyme disease was established [23, 24]) to 1996. The keywords used were Lyme disease, Borrelia burgdorferi, diagnosis, ELISA, Western blot, immunofluorescence assay, polymerase chain reaction, urinary antigen detection, and culture. The computerized literature search was complemented by citations from authorities in the field. 2.2 Study Selection All identified articles were reviewed by using a modification of the methodologic criteria for evaluating diagnostic tests developed by Irwig and colleagues [25]. The included studies had to provide the following material: a clear statement on the test of interest, a description of the study characteristics that used a design that permitted the calculation of sensitivity and specificity, reproducible information on the sampling and clinical details of patients with the disease of interest and on controls (that is, data on the presence or absence of the criteria for Lyme disease described in the U.S. Lyme disease national surveillance case definition) (Table 1), and reproducible information on the reference standard (that is, cases diagnosed by experts who were blinded to the results of the diagnostic tests being evaluated). Because there are systematic differences in the strains of B. burgdorferi in different parts of the world, studies were excluded if they described results in patients outside of North America. When the same cohort of patients was described in more than one report, the results for individual patients were included only once. 2.3 Data Extraction Sensitivity, specificity, and likelihood ratios were calculated by using established methods [26]; a random-effects model was used to combine the proportions from the eligible studies [27]. 2.4 Estimates of Prevalence and Incidence Levels of the endemicity of Lyme disease in the United States can be estimated by using the annual incidence of Lyme disease reported to the CDC [1] (Figure 1). Figure 1. Rates of Lyme disease cases in the United States in 1993 as reported by states to the Centers for Disease Control and Prevention. 2.5 Epidemiologic studies of Lyme disease in communities in the eastern United States provide important information on the emergence of the disease in populations newly at risk, as well as some estimates of incidence and prevalence [29]. In two clusters of cases in New Jersey, risk was related to residence in new suburban housing developments and to occupational exposures among outdoor workers at a military reservation [6, 7]. A study on Fire Island, a barrier island off the southern coast of Long Island, New York, reported a seasonal incidence of 1% to 3% and a cumulative prevalence of 7.5% among residents of this summer vacation site [5]. A longitudinal study of a community of about 160 persons on Great Island, Massachusetts, found a slow build-up of incidence to a peak of 3 cases per 100 persons per year and a total cumulative prevalence of 16% over a 20-year period [9]. Two population-based studies in highly endemic suburban communities in Westchester, New York, reported seasonal attack rates of 2.6% and 3% and cumulative prevalences of 8.8% and 17%, respectively [30, 31]. On the basis of these data, we considered four categories of endemicity: low (incidence estimate, 0.01%), moderate (incidence estimate, 0.1%), high (incidence estimate, 1%), and very high (incidence estimate, 3%). 2.6 Likelihood Ratios and Treatment Thresholds of Tests Three of the authors constructed scenarios that describe three hypothetical patients. One had diffuse nonspecific muscle pain (scenario A), one had a rash resembling erythema migrans (scenario B), and one had episodic oligoarticular arthritis (scenario C) (Table 2). These models were used to compute the change in the probability of disease using likelihood ratios (likelihood ratio for positive test result = sensitivity [100 specificity]; likelihood ratio for negative test result = [100 sensitivity] specificity) [26] resulting from the use of enzyme-linked immunosorbent assay (ELISA) and Western blotting. Decision analysis was used to assess the relative cost-effectiveness of the management options in these clinical situations when the clinician must decide whether to perform laboratory testing for Lyme disease [32]. Incremental cost-effectiveness ratios were calculated as costs per quality-adjusted life-year for each scenario. This cost-effectiveness study is described in detail in a forthcoming paper [33]. Table 2. Hypothetical Patient Scenarios 3. Data Synthesis 3.1 Microbial Isolation Cultural isolation of B. burgdorferi is the best diagnostic evidence of Lyme disease. Borrelia burgdorferi grows well in Barbour, Stoenner, Kelly (BSK) medium, but it is difficult to obtain isolates from clinical specimens other than biopsy samples from erythema migrans lesions. 3.2 Thirty-four papers were identified by the literature search. None met the criteria formal analysis, but some case reports were worth noting. In the presence of erythema migrans, material has been collected from cutaneous lesions with various techniques, including direct aspiration of involved skin, aspiration after saline instillation, and skin biopsy. Wormser and colleagues [34] reported success rates of 29% with saline-lavage needle aspiration and 60% with 2-mm punch biopsies of the advancing edge of suspected primary erythema migrans lesions. Berger and colleagues [35] reported a success rate of more than 80% with biopsy specimens obtained from the leading edge of erythema migrans lesions. 3.3 Culture from sites other than the erythem

Secondary Prevention of Renal and Cardiovascular Disease: Results of a Renal and Cardiovascular Treatment Program in an Australian Aboriginal Community

Australian Aborigines are experiencing an epidemic of renal and cardiovascular disease. In late 1995 we introduced a treatment program into the Tiwi community, which has a three- to fivefold increase in death rates and a recent annual incidence of treated ESRD of 2760 per million. Eligible for treatment were people with hypertension, diabetics with micro or overt albuminuria, and all people with overt albuminuria. Treatment centered around use of perindopril (Coversyl, Servier), with other agents added to reach BP goals; attempts to control glucose and lipid levels; and health education. Thirty percent of the adult population, or 267 people, were enrolled, with a mean follow up of 3.39 yr. Clinical parameters were followed every 6 mo, and rates of terminal endpoints were compared with those of 327 historical controls matched for baseline disease severity, followed in the pretreatment program era. There was a dramatic reduction in BP in the treatment group, which was sustained through 3 yr of treatment. Albuminuria and GFR stabilized or improved. Rates of natural deaths were reduced by an estimated 50% (P = 0.012); renal deaths were reduced by 57% (P = 0.038); and nonrenal deaths by 46% (P = 0.085). Survival benefit was suggested at all levels of overt albuminuria, and regardless of diabetes status, baseline BP, or prior administration of angiotensin converting enzyme inhibitors (ACEI). No significant benefit was apparent among people without overt albuminuria, nor among those with GFR less than 60 ml/min. An estimated 13 renal deaths and 10 nonrenal deaths were prevented, with the number-needed-to-treat to avoid one terminal event of only 11.6. Falling deaths and renal failure in the whole community support these estimates. The program was extremely cost-effective. Programs like this should be introduced to all high-risk communities as a matter of urgency.

The benefits and challenges of conducting an overview of systematic reviews in public health:a focus on physical activity

Introduction The ultimate aim of Cochrane systematic reviews is to inform policy and practice decisions for better health outcomes. However, due to the increasing numbers of scientific publications, wading through the available evidence of both individual studies and systematic reviews can be challenging and overwhelming even for avid authors and readers. This paper briefly describes the first overview (a systematic review of reviews) of the Cochrane Public Health Group (CPHG) in development and proposes a way forward for the methodologies under consideration.

Incentive-based interventions for increasing physical activity and fitness

This is the protocol for a review and there is no abstract. The objectives are as follows: The main aim of the review is to determine the effectiveness of using incentive-based approaches (IBAs) (financial and non-financial) to increase physical activity in community-dwelling children and adults. A secondary objective will be to address the use of incentives to improve cardiovascular and metabolic fitness. A final objective will be to explore: - whether there are any adverse effects associated with the use of IBAs for increasing physical activity; - whether there are any differential effects of IBAs within and between study populations by age, gender, education, inequalities and health status; and - whether the use of disincentive/aversive approaches leads to a reduction in sedentary behaviour.

Epidemiologic modeling with FluSurge for pandemic (H1N1) 2009 outbreak, Queensland, Australia

TOC summary: Predictions of the effect of pandemic influenza on hospital resources were helpful for service planning.

Reviewing interventions delivered to whole communities: learnings and recommendations for application to policy, practice and evidence development

*This article is free to read on the publishers website* Several reviews within The Cochrane Library address interventions designed to promote physical activity and exercise.1–3 Interventions investigated in these reviews have generally sought to increase the physical activity of individuals or specific groups of people. A new review published by the Cochrane Public Health Group entitled ‘Community-wide Interventions for Increasing Physical Activity’,4 examines the effectiveness of interventions that aim to improve the physical activity levels of an entire community. We were particularly interested in understanding the effectiveness of such approaches, but also whether they have an impact on inequalities, have potential to be sustainable and are cost-effective. In doing so, one of the most important contributions of this review is considerations and recommendations for the advancement of methods for developing, conducting and evaluating complex interventions, and seeking to synthesize findings relevant for programme development and policy-making. This paper briefly highlights some of these issues.

An interactive method for engaging the public health workforce with evidence

Introduction Systematic review authors are increasingly directing their attention to not only ensuring the robust processes and methods of their syntheses, but also to facilitating the use of their reviews by public health decision-makers and practitioners. This latter activity is known by several terms including knowledge translation, for which one definition is a ‘dynamic and iterative process that includes synthesis, exchange and ethically sound application of knowledge’.1 Unfortunately—and despite good intentions—the successful translation of knowledge has at times been inhibited by the failure of reviews to meet the needs of decision-makers, and the limitations of the traditional avenues by which reviews are disseminated.2 Encouraging the utilization of reviews by the public health workforce is a complex challenge. An unsupportive culture within the workforce, a lack of experience in assessing evidence, the use of traditional academic language in communication and the lack of actionable messages can all act as barriers to successful knowledge translation.3 Improving communication through developing strategies that include summaries, podcasts, webinars and translational tools which target key decision-makers such as HealthEvidence.org should be considered by authors as promising actions to support the uptake of reviews into practice.4,5 Earlier work has also suggested that to better meet the research evidence needs of public health professionals, authors should aim to produce syntheses that are actionable, relevant and timely.2 Further, review authors must interact more with those who will, or could use their reviews; particularly when determining the scope and questions to which a review will be directed.2 Unfortunately, individual engagement, ideal for examining complex issues and addressing particular concerns, is often difficult, particularly when attempting to reach large groups where for efficiency purposes, the strategy tends to be didactic, ‘lecturing’ and therefore less likely to change attitudes or encourage higher order thinking.6 …

Sexual difficulties faced by men in the Solomon Islands: a mixed-methods study

Background To date there has been little research into mens sexual and reproductive health in Pacific Island countries. The aim of this study was to describe mens sexual difficulties and barriers to their seeking reproductive health care in the Solomon Islands. METHODS The study included qualitative inquiry (17 individual interviews and three focus group discussions with a total of 21 men) and a quantitative quasi-randomised quota sample household survey (n=400). The prevalence of sexual difficulties and potential risk factors, such as chronic diseases, health risk behaviours, depression and psychological distress were measured using standardised questions translated into pidgin. RESULTS The most commonly self-reported sexual difficulties were premature ejaculation (39.5%), low sexual desire (29.0%), orgasm difficulty (27.3%) and erectile difficulty (4.3%). More than half (56%) of the men experienced at least one sexual difficulty. Relatively few men (7.3%) had ever sought professional health care for reproductive health problems, and 15.4% of men preferred to use kastom (traditional) medicine for sexual problems. Multivariate analysis revealed that comorbid non-communicable diseases (NCDs), low health-related quality of life and dissatisfaction with sexual relationships were independently correlated with sexual difficulties. Contrary to expectations, self-reported psychological distress was inversely associated with these difficulties. In general, the insights gained from in-depth interviews validated the survey findings. CONCLUSION This study adds the first data on symptoms of sexual dysfunction among men in the Solomon Islands and is one of few studies from the Pacific region. The findings strongly suggest the need for comprehensive health services that are gender-specific and sensitive to the sexual difficulties of Islander men.

Enhancing capacity for ‘systematic’ thinking in public health

The concept of being evidence based or evidence informed is widely acknowledged as an important component of decision-making. It is perhaps most universally referred to in medicine, however has extended into many other disciplines over the past decade, including public health. Evidence-based public health has been defined as the ‘conscientious, explicit and judicious use of current best evidence in making decisions about the care of communities and populations in the domain of health protection, disease prevention, health maintenance and improvement (health promotion)’.1 More recent literature favours the use of the term evidence informed over evidence based to acknowledge the varying influences on decisions in this complex field.2,3 Evidence-informed activities in any discipline require a specific set of skills in critical thinking. These skills include identifying the questions to be resolved, collecting relevant evidence, and assessing, synthesizing and distilling evidence in a way that can inform the set of activities to be undertaken as a result.