Sleep Disturbance May Be Very Early Warning of Bipolar Risk

Severely disturbed sleep patterns may be an early indicator of the risk of developing bipolar disorder (BD) and may allow early intervention, new research shows.

Speaking here at EPA 2012: 20th European Congress of Psychiatry, Phillip Ritter, MBBS, of the Clinic and Polyclinic for Psychiatry and Psychotherapy at University Hospital Carl Gustav Carus of the University of Dresden in Germany, said that sleep is highly altered in mania and depression and is the most common prodromal symptom of mania in patients with BD. Studies have shown that these patients also have a poorer quality of sleep between episodes when they are euthymic.

Even before individuals develop BD, "the picture that emerges from retrospective studies is that sleep disturbances are far more common in bipolar patients in their premorbid state compared to healthy controls," Dr. Ritter said, based on his reading of the literature.

He noted that sleep disturbances emerge in adolescence, occur far more frequently in the offspring of patients with BD, and occur several years before the first affective episode.

Dr. Ritter presented the first results of his own ongoing prospective study, called BipoSleep, which uses a structured interview and actimetry, a wrist-worn device to detect movement, from which sleep and wake periods can be determined.

Consistently Disturbed Sleep

To date, the study includes 59 participants (22 bipolar patients, 9 high-risk individuals, and 28 control participants). High risk was defined as having a first-degree relative with an affective disorder and subsyndromal mood symptoms but no previous manic episode.

For a small study, the groups were reasonably well matched for age (group mean range, 25.4 - 32.7 years), gender (57% - 78% male), and employment or student status (91% - 100%).

Of the 39 questions in the structured interview about sleep, "there was a significant difference in answers for 30 questions," Dr. Ritter reported. "So that alone seemed to be a good indicator that bipolar patients have difficulty sleeping."

When asked to rate the frequency of unrestorative sleep (0 - 6 points), healthy control participants reported a mean of 1; bipolar patients, 3; and people at high risk for BD, just above 4. In answer to a question about insomnia for at least 3 nights in a row, on a 0 - 9 scale, the score by healthy control participants was 0; by bipolar patients, 4; and by high-risk individuals, 3.

Healthy people may have an occasional night of poor sleep, "but they rarely had a series of 3 or more nights," Dr. Ritter said. "This was very common in patients with bipolar disorder, but it was also quite common in patients at high risk of bipolar disorder."

Interestingly, hypersomnia of at least 3 days' duration was also common among the BD patients and high-risk individuals compared with control participants, with average scores of 5, 9, and 0, respectively.

Altered Mood

For each of the items in the questionnaire, Dr. Ritter standardized the scores, setting the scores of healthy control participants as 1, and he plotted the scores for the BD patients, the high-risk individuals, and the control participants for each item in the questionnaire.

The greatest differences from control participants were in terms of recurrent insomnia and a heightened sensitivity to disruptions in daily sleep rhythms for both the patients and the high-risk groups.

He had expected that the high-risk group would fall somewhere between the patients with established BD and the control participants.

"But actually we were a bit surprised to see that...the results of the high-risk participants are much closer to the answers we got from patients with established bipolar disorder, which might be an indication that really sleep is altered prior to the first episode, but it's speculative," he said.

Dr. Ritter also noted that there was more profound effect of altered sleep on mood as well as altered mood on sleep for the patient group and the high-risk group. These groups also had more difficulty in maintaining a regular rhythm after disruptions in sleep rhythms.

The reported differences on the questionnaires among the 3 groups was not so profound for sleep latency (time to get to sleep), sleep duration, and awake periods per hour, and there were fairly wide individual variations within groups.

With regard to the actimetry data for 6 nights in a row, Dr. Ritter said the data did not show much difference among the groups for most of the parameters measured.

Profile Similar to BD

One significant difference was in sleep latency, with BPD patients taking longer to get to sleep, despite many of them receiving sedating medications. But they tended to sleep longer once asleep compared with control participants. They also slept more "efficiently," with little sleep fragmentation.

The fact of greater sleep duration for BD patients has also been reported in the literature, the consensus being that patients sleep ½ hour or 1 hour longer.

Dr. Ritter said that even after correcting for sedating medications in the study, sleep duration was still elevated in the BD group.

The high-risk group also had a mildly elevated length of sleep, even though they were free of medication. For most other measures, they were similar to the control group except that they had a higher level of nighttime activity than either the control participants or the BD group.

He added that a limitation of the study is that 6 nights of actimetry monitoring may not be long enough to detect other differences between the groups.

He concluded that patients with BD differ significantly from healthy control participants regarding most of their nighttime and subjective sleep habits and that "high-risk persons have a profile similar to bipolar subjects, but the differences in actimetry are not really evident over 6 nights."

Potential Risk Factor, Not a Predictor

Cristoph Correll, MD, associate professor at Albert Einstein College of Medicine and a child and adolescent psychiatrist at the Zucker Hillside Hospital in Glen Oaks, New York, chaired the session in which Dr. Ritter presented his study results.

Dr. Correll, who had no relation to the study, told Medscape Medical News that sleep is a very nonspecific item, with up to 50% of the general population having any sleep problem in a given month, so it will be necessary to find subtypes or characteristics of disturbed sleep "that might differentiate bipolar risk from non-risk."

He said using actimetry may not be feasible with every patient suspected of being at risk but may be a predictive tool for certain high-risk individuals.

"The question and the worry is always how specific are these findings?" he said. "I would at the moment see [disturbed sleep] as a risk factor or warning sign but not as a definite predictor of the illness."

Even if people at particularly high risk of developing BD could reliably be identified, Dr. Correll said it is hard to know if or what interventions could prevent the illness.

"The hope is that once you identify high-risk people and you do some general preventive measures or early targeted measures, which would include healthy lifestyle, no substance use, sleep hygiene, and then also stress reduction and targeting anxiety and depression, maybe even with nonpharmacologic treatments, that should already help. Then more pharmacologic interventions can only be tested and developed once we can validly identify high-risk people," he said.

He added that no one yet knows how circadian rhythm and BD risk interact — whether underlying illness exists first and then disrupts circadian rhythm or whether circadian rhythm disruption is 1 factor that pushes people into mania and BD.

"We don't know that," Dr. Correll said. "We just know that circadian rhythm abnormalities are associated with mood disorders, and we need to try to get that under control in order to hopefully then also attenuate the risk and the expression of the illness."

The study did not receive any commercial funding. Dr. Ritter has disclosed no relevant financial relationships. Dr. Correll has been a consultant and/or advisor to or has received honoraria from Actelion, Alexza, the American Academy of Child and Adolescent Psychiatry, AstraZeneca, Biotis, Bristol-Myers Squibb, Cephalon, Desitin, Eli Lilly, Gerson Lehrman Group, GSK, IntraCellular Therapies, Lundbeck, Medavante, Medscape, Merck, Novartis, Ortho-McNeill/Janssen/J&J, Otsuka, Pfizer, ProPhase, Sunovion, Takeda, and Teva. He has received grant support from BMS, Feinstein Institute for Medical Research, Janssen/Johnson & Johnson, the National Institute of Mental Health, the National Alliance for Research in Schizophrenia and Depression, and Otsuka.

EPA 2012: 20th European Congress of Psychiatry. Abstract AS04-01. Presented March 4, 2012.

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Oral Vitamin D Boosts Intranasal Steroid Effect in Rhinitis

Adding an oral vitamin D supplement to regular intranasal corticosteroid dosing can improve symptoms of seasonal allergic rhinitis beyond that seen with corticosteroids alone in patients who are not vitamin D deficient, according to study results presented here at the American Academy of Allergy, Asthma and Immunology 2012 Annual Meeting.

The findings add to a number of reports at the meeting suggesting that vitamin D supplementation might be beneficial in patients with allergies.

"Vitamin D has been shown to play a role in innate immunity and the generation of antimicrobial peptides. It also has a number of immunological effects on T cells, dendritic cells, and macrophages," said James Lane, BA, a researcher at the University of Chicago, Illinois, who presented the findings.

These findings must be viewed with caution, said lead investigator Fuad Baroody, MD, a pediatric head and neck surgeon at the University of Chicago. "This was a small study, a pilot study. More work needs to be done before people can run out and add vitamin D to intranasal steroids," he said in an interview with Medscape Medical News.

In the double-blind placebo-controlled study, patients 18 to 45 years of age with seasonal allergic rhinitis received fluticasone propionate 200 µg/day, and were randomized to receive either vitamin D 4000 IU/day for 2 weeks (n = 17) or placebo (n = 18).

Subjects had at least a 2-year history of seasonal allergic rhinitis and a positive skin test to tree, grass, and/or ragweed.

At baseline, serum 25-hydroxy-vitamin D levels were within the normal range and similar in the vitamin D and placebo groups (29.6 vs 29.4 ng/dL). After 2 weeks, levels in the vitamin D group rose significantly from baseline to 37.2 ng/dL (P = .001); in the placebo group, there was no rise.

"There's variation on what people consider appropriate levels of vitamin D," explained Dr. Baroody. "Most recommendations are for levels around 30 or so. These were not vitamin-deficient people, but we bumped it up a little bit to within a still reasonable range, and nobody had side effects from having too much vitamin D."

According to daily self-rated nasal symptoms, including sneezing, nasal congestion, and drip, subjects in both groups noted significant daytime improvements from baseline.

However, subjects in the vitamin D group noted a decreased symptom score of 6.9 points from baseline, which was statistically significant and superior to the 3.7 point drop in the placebo group (P = .04).

"Just giving vitamin D on top created a significant drop — almost a 50% drop," said Dr. Baroody. "The magnitude is impressive, actually. If that is duplicated in a big trial, it would be pretty spectacular."

Nighttime symptoms were not presented at the meeting, but Dr. Baroody said they were "not as spectacular." As a result, the reduction in 24-hour symptom relief was not statistically different between the vitamin D and placebo groups (11.3 vs 7.6 points; P = .09).

Similarly, although there was a statistically significant improvement from baseline in quality of life in both groups (P= .0028), there was no significant difference between the vitamin D and placebo groups (2.5 vs 2.0 points).

"A change of 0.5 is considered to be clinically meaningful, and both groups had improvements well beyond that," said Lane.

In response to a comment from the audience, Dr. Baroody acknowledged that perhaps the real strength of vitamin D supplementation in this group was not in better, but rather in faster, symptom control; all measures showed patients in the vitamin D group responding within 2 days and sustaining their response level.

"That's an interesting way of looking at it. I will examine that in more detail," he said.

"I think people don't really know what the vitamin D story is," Rachel Miller, MD, associate professor of medicine in pediatrics and environmental health sciences at Columbia University Medical Center in New York City, toldMedscape Medical News.

"My bias is to do a randomized trial and see what vitamin D supplementation does, because most of the work so far has been observational. I know people are already doing it, but I personally look forward to more evidence from randomized trials."

The study received no funding from industry. Mr. Lane and Dr. Miller have disclosed no relevant financial relationships. Dr. Baroody reports being on the speaker's bureau for Merck and GlaxoSmithKline.

American Academy of Allergy, Asthma and Immunology (AAAAI) 2012 Annual Meeting: Abstract 510. Presented March 4, 2012.

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Frequent Chocolate Consumption Linked to Lower BMI

 A recent study showed that frequent chocolate consumption was associated with lower body mass index (BMI), even when adjusting for calorie intake, saturated fat intake, and mood.

Beatrice A. Golomb, MD, PhD, associate professor of medicine at the University of California, San Diego, and colleagues described their findings in a research letter published in the March 26 issue of the Archives of Internal Medicine.

The authors used data from 1018 patients already being screened for inclusion in a widely sampling clinical study evaluating noncardiac effects of statin medications. Of the 1018 participants, 1017 answered the question, "How many times a week do you consume chocolate?" BMI was calculated for 972 participants (95.6%); and 975 (95.8%) answered the validated Fred Hutchinson Food Frequency Questionnaire.

The investigators performed analyses with and without adjustment for calorie intake, saturated fat (satfat) intake, and mood. Fruit and vegetable intake was not associated with chocolate consumption (β, 0.004; P = .55), but satfat intake was significantly related to both chocolate consumption (β, 0.035; P < .001) and higher BMI.

The amount of chocolate consumed was examined, in addition to the frequency of chocolate consumption. Activity (number of times in a 7-day period the participant engaged in vigorous activity for at least 20 minutes) and mood (Center for Epidemiological Studies Depression scale [CES-D]) were also examined.

The relationship between chocolate consumption frequency and BMI was calculated in unadjusted models, in models adjusted for age and sex, and in models adjusted for activity, satfats, and mood.

Study participants consumed chocolate a mean 2.0 (SD, 2.5) times per week and exercised 3.6 (SD, 3.0) times per week. Frequency of chocolate consumption was associated with greater intake of calories and satfats and higher CES-D scores (P < .001 for each of these 3 associations); these all related positively to BMI. Chocolate consumption frequency was not associated with greater activity (P = .41), but it was associated with lower BMI (unadjusted P = .01). This association remained with and without adjustment for age and sex, as well as for calories, satfats, and depression.

Although chocolate consumption frequency was associated with lower BMI, the amount of chocolate consumed was not (eg, per medium chocolate serving or 1 oz [28 g], β, 0.00057 and P = .97, in an age- and sex-adjusted model).

"The connection of higher chocolate consumption frequency to lower BMI is opposite to associations presumed based on calories alone, but concordant with a growing body of literature suggesting that the character — as well as the quantity — of calories has an impact on [metabolic syndrome (MetS)] factors," write the authors.

They further explain that as chocolate products are frequently high in sugar and fat, they are often assumed to contribute to an increased BMI. The authors note that this may still be true in some cases.

"[O]ur findings — that more frequent chocolate intake is linked to lower BMI — are intriguing," write the authors. "They accord with other findings suggesting that diet composition, as well as calorie number, may influence BMI. They comport with reported benefits of chocolate to other elements of MetS," the authors write, noting that a randomized trial studying the metabolic benefits of chocolate in humans may be warranted.

This study was funded by a grant from the National Heart, Lung and Blood Institute, National Institutes of Health, and was supported by the University of California, San Diego, General Clinical Research Center. The authors have disclosed no relevant financial relationships.

Arch Int Med. 2012;172:519-523.

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Guidelines Define Hemoglobin Levels for Transfusion

Red blood cell (RBC) transfusions in most hospitalized patients should be performed based on "restrictive," rather than "liberal," hemoglobin levels (7 - 8 g/dL), according to new clinical guidelines from the American Association of Blood Banks (AABB).

The new guidelines are based on a systematic literature review and were formulated by a multinstitutional panel of 20 experts led by Jeffrey L. Carson, MD, from the University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School in New Brunswick, and were published online March 26 in the Annals of Internal Medicine.

"Many small trials have addressed the question of optimal use of RBC transfusions," Dr. Carson and colleagues write. "Recently, 2 additional trials were published that expanded by 30% the number of patients included in the evidence base of transfusion trials. Thus, it is timely to reexamine the data and provide guidance to the medical community," the authors write.

The new guidelines outline 4 major recommendations based on various levels of evidence. The authors conducted a systematic review of 19 randomized clinical trials (including 6264 patients) evaluating transfusion thresholds. Trials were published from 1950 to February 2011.

The first recommendation is adherence to a restrictive transfusion strategy (7 - 8 g/dL) in hospitalized, stable patients. This is classified as a "strong" recommendation based on high-quality evidence.

The second recommendation is that a restrictive strategy be used in hospitalized patients with preexisting cardiovascular disease with consideration of transfusion for patients with symptoms or a hemoglobin level of 8 g/dL or less. The authors describe this recommendation as "weak," with moderate-quality evidence.

The third recommendation is that the AABB cannot recommend either for or against a liberal or restrictive transfusion threshold for hospitalized, hemodynamically stable patients with acute coronary syndrome. The panel classified this as an uncertain recommendation, with very low-quality evidence.

The fourth recommendation is that transfusion decisions should be influenced by symptoms as well as hemoglobin concentration, although again, this was a weak recommendation with low-quality evidence.

According to the panelists, other guidelines have proposed that transfusion is generally not indicated when the hemoglobin concentration is above 10 g/dL, but is indicated when it is less than 6 to 7 g/dL. "However, none of these guidelines recommended a specific transfusion trigger," they write.

"[I]n the current guidelines we explicitly used an evidence-based process that employed the [Grading of Recommendations Assessment, Development, and Evaluation (GRADE)] method," the authors note. "Although individual clinical factors are important, hemoglobin level is one of the critical elements used daily by physicians in the decision to transfuse. Thus, specific evidence-based recommendations on use of hemoglobin levels will help standardize transfusion practice," they conclude.

Transfusing Based on Hemoglobin Levels Alone "Insufficient"

In a related editorial, Jean-Louis Vincent, MD, from the Department of Intensive Care, Erasme Hospital, Université libre de Bruxelles, Belgium, points out that "basing the decision to transfuse only on hemoglobin levels is insufficient."

He adds that he does "not believe that available evidence supports a fixed transfusion trigger. Rather, transfusion decisions need to consider individual patient characteristics, including age and the presence of [coronary artery disease], to estimate a specific patient's likelihood of benefit from transfusion."

He concludes, "The decision to transfuse is too complex and important to be based guided by a single number."

Support for the development of the guidelines was provided by the AABB in Bethesda, Maryland. Dr. Carson reports having a grant or grants pending from Amgen. Conflict-of-interest information for all authors is available on the journal's Web site. Dr. Vincent has disclosed no relevant financial relationships.

Annals Int Med. Published online March 26, 2012. Full text editorial

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Curcumin Holds Promise as Treatment for Brain Tumors

Can a lowly spice help fight the battle against pediatric brain tumors?

Maybe, according to preliminary research published in a recent issue of BMC Cancer. Curcumin, a major component of the spice turmeric, has been shown to have chemopreventive and chemotherapeutic properties. Past research also demonstrates that it has the potential to destroy human medulloblastoma cells cultured in the laboratory.

In the current study, researchers were able to identify a protein as a candidate biomarker in order to better predict which patients might respond favorably to curcumin therapy.

This work is exciting because right now, the prognosis of childhood brain tumors is generally poor, treatment options are limited, and children often have long-term side effects from treatment, explained lead author Sigrid Langhans, PhD, senior research scientist at the Nemours Center for Childhood Cancer Research at the Alfred I. duPont Hospital for Children, Wilmington, Delaware. The team is now planning clinical trials with curcumin.

"The problem is that many drugs which could be effective do not make it across the blood-brain barrier," she pointed out. "The blood-brain barrier protects the brain from toxic substances but unfortunately also prevents therapeutic agents from entering as well."

But one of the interesting things about curcumin is that it can cross the blood-brain barrier, she told Medscape Medical News in an interview.

Selective Apoptosis

Curcumin can induce apoptosis in a variety of tumor cells and has also prevented tumor initiation and growth in experimental models. Dr. Langhans and her team, along with other groups, have previously shown that curcumin induces cell death in medulloblastoma, the most common pediatric brain tumor, and inhibited tumor growth in in vivo medulloblastoma models.

But it is not clear why curcumin selectively targets tumor cells, although it has been suggested that it affects signaling pathways that regulate cell growth and survival and thus preferably will induce apoptosis in highly proliferating cells. "So in this study we followed up on studying the mechanisms which might explain how it can induce cell death," Dr. Landhans explained.

Drawing on their earlier research, the authors found that curcumin specifically binds to and crosslinks to a protein that is involved in cell-cycle regulation. It is known as a checkpoint protein, she said, because it blocks the onset of anaphase until all chromosomes make proper attachments to the spindle. The mitotic checkpoint, or spindle assembly checkpoint (SAC), is the major cell-cycle control mechanism that delays the onset of anaphase during mitosis. One of the primary regulators of the SAC is the anaphase-promoting complex/cyclosome (APC/C).

"But if there is a defect in the checkpoint, this process is disrupted," Dr. Langhans added. "So this study may show why curcumin causes death in tumor cells but not in normal cells. That is the great thing about curcumin because if it only targets tumor cells, then it has very few — if any — side effects."

Because the APC/C not only ensures that the cell cycle will be halted during spindle disruption but also promotes cell death in response to prolonged mitotic arrest, the authors note, it has become an attractive drug target for cancer therapy.

Preference for Phosphorylated Cells

The authors also found that tumors treated with curcumin had lower levels of Cdc27, and subsequently identified Cdc27/APC3, which is a component of the APC/C, as a novel molecular target of curcumin. They found that curcumin binds to and crosslinks Cdc27 to affect APC/C function.

In addition, they found that curcumin binds more resolutely to this specific protein when it is phosphorylated, a modification that is generally seen in rapidly proliferating cells, such as in tumors.

"It much more strongly induces death in these cells, so we can probably use that as a biomarker to predict which patients might respond to curcumin therapy," Dr. Langhans said. "And this isn't just for children but for all patients. We might be able to predict who may respond more favorably to this treatment, and then treatment can be adjusted accordingly."

Knowing the mechanism behind curcumin's antitumor mechanism will help in developing therapeutic agents. "We can then rationally design drugs that may be more effective — that is our long term goal," she explained.

Dr. Langhans noted that the next step is to move their research into the clinic. "We hope to begin clinical trials," she said. "Our first priority will be pediatric brain tumors. We will first see how curcumin responds in pediatric patients and then we will next try to specifically target the patients that might derive the most benefit."

The study was funded by the Nemours Foundation. The authors have disclosed no relevant financial relationships.

BMC Cancer. 2012;12:44. Full text

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Excessive Cured Meat Intake May Be Harmful to COPD Patients

Excessive consumption of cured meat is associated with an increased risk for hospital readmission among patients with chronic obstructive pulmonary disease (COPD), report Jordi de Batlle, BMedBiol, from the Centre for Research in Environmental Epidemiology, Hospital del Mar Research Institute, the CIBER Epidemiología y Salud Pública, and the Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain, and colleagues. Results from their study were scheduled to be published online March 8 in the European Respiratory Journal.

The goal of the Phenotype and Course of COPD Project (PAC-COPD) study was to assess the association between dietary intake of cured meat and risk for COPD readmission among patients with COPD. The researchers calculated the association between cured meat intake and COPD admissions using parametric regression survival-time models.

Researchers demonstrated that higher cured meat consumption was related to a 2-fold increased risk for COPD readmission (adjusted hazard ratio, 2.02; 95% confidence interval [CI], 1.31 - 3.12; P = .001), after adjusting for age, forced expiratory volume in the first second (FEV1), and total calorie intake. In addition, the time to the first COPD readmission was longer in patients with low cured meat intake (P = .028).

COPD researchers have recently turned their sights on the role diet plays in the development of the disease. "Recent studies have shown that a high dietary intake of cured meat increases the risk of COPD development. However, its potential effects on COPD evolution have not been tested," the authors write.

Between January 2004 and March 2006, 274 patients with COPD were recruited from 9 hospitals in Spain during their first COPD hospital admission and were followed-up through December 31, 2007 (median follow-up, 2.6 years). The COPD diagnosis was based on a ratio of postbronchodilator FEV1 to forced vital capacity (FEV1/FVC) equal to 0.70. COPD exacerbations were classified according to the International Classification of Diseases, Ninth Revision, and survival status was obtained for all patients from direct interviews with the patients or their relatives.

Study participants filled out a food frequency questionnaire at the time of enrollment that encompassed dietary habits during the preceding 2 years. Cured meat consumption was defined as the total daily consumption (g/day) of cooked ham, Spanish cured ham, cured and other sausages, and hot dogs.

Using standardized questionnaires, the investigators collected baseline sociodemographic characteristics, respiratory symptoms, drug treatment, and lifestyle information. The team also assessed body mass index (BMI) and fat-free mass index to evaluate participants' nutritional status. In addition, they measured postbronchodilator spirometry (FEV1, FVC, and FEV1/FVC), arterial oxygen and carbon dioxide partial pressures, carbon monoxide diffusing capacity, and serum C-reactive protein.

The mean age of the participants was 68 years, 93% were men, and 42% were current smokers. The mean postbronchodilator FEV1 was 53% predicted, and the median cured meat intake was 23 g/day (equivalent to approximately 1 slice of ham a day).

Most patients had moderate to severe COPD (5% mild, 52% moderate, 37% severe, and 6% very severe); however, median cured meat intake was similar across COPD severity stages. The researchers also noted that a higher daily cured meat intake was positively related to younger age, current working, current smoking, higher levels of regular physical activity, and lower BMI.

The authors hypothesize that cured meats have a deleterious effect on patients with COPD because they contain high level of nitrites. Nitrites used in the preparation of cured meat may lead to an increase in the nitrosative stress burden within the lungs, and lead to the formation of reactive nitrogen species, which results in parenchymal damage and remodeling.

"This study adds new evidence suggesting that in addition to a possible increase in risk of COPD associated with cured meats, these foods may also increase risk of exacerbations, thus supporting the need of considering specific dietary advice to COPD patients," conclude the study authors.

Funding for this study was provided by the Fondo de Investigación Sanitaria, Ministry of Health, Spain; Agéncia d'Avaluació de Tecnologia i Recerca Mèdiques, Catalonia Government; Spanish Society of Pneumology and Thoracic Surgery; Catalan Foundation of Pneumology; Red RESPIRA ; Red RCESP; Fundació La Marató de TV3; DURSI; and an unrestricted educational grant from Novartis Farmacèutica, Spain. CIBERESP and CIBERES are funded by the Instituto de Salud Carlos III, Ministry of Health, Spain. de Batlle has a predoctoral fellowship from the Instituto de Salud Carlos III, and 1 coauthor also has a researcher contract from the Instituto de Salud Carlos III. The other authors have disclosed no relevant financial relationships.

Eur Respir J. Published online March 8, 2012.

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Exercise and Rest Both Effective for Some Patients With Back Pain

Exercise might not always be the best treatment approach for some low back pain sufferers. A new randomized trial shows no difference in pain, disability, or general health among patients with lower back pain and Modic changes (MCs) — edema or fatty degeneration in the vertebral endplate — who followed an exercise regime and those who adopted a routine of rest and load reduction.

The finding that rest results in the same small improvements as a more active treatment approach challenges the idea that exercise should be the "gold standard" for patients with low back pain and MCs, said lead author Rikke K. Jensen, MSc, from the Research Department, Spine Centre of Southern Denmark, in Middelfart. This article is part of her PhD thesis.

The results do not suggest that patients with MCs should not exercise, said Jensen "But I think clinicians should be careful; when patients come back and say this treatment didn't work, it's not because they did it the wrong way or they didn't do it enough. It's very possible that this treatment is just not very effective for this group of patients."

The study was published online February 29 in BioMed Central's open access journal BMC Medicine.

Inhibits Healing

Although MCs are fairly common, affecting some 40% of patients with low back pain (LBP), their precise cause is unknown. One theory has been that they are caused by mechanical stress, and that excessive loading may result in microfractures of the endplate causing inflammation in the vertebral endplate and the adjacent bone marrow.

The severe and persistent pain suffered by patients with MCs is often unresponsive to active treatment, possibly because weight-bearing exercises inhibit microfracture healing. "When you're jumping up and down on microfractures, they tend not to get better," said Jensen. "It was important for us to test the hypothesis that people don't improve with exercise if they have these MCs, and are there other treatment options that could prove to be more effective."

When you're jumping up and down on microfractures, they tend not to get better.

The study enrolled 100 adult patients with persistent LBP (at least 3 on an 11-point scale) and MC confirmed on magnetic resonance imaging that extended beyond the endplate into the vertebral body. The patients were referred from primary care and had had symptoms lasting from 2 to 12 months. They were allocated to either a rest group or an exercise group.

The rest group was instructed to avoid hard physical activity and to rest by lying down for an hour twice daily. They also used a flexible lumbar belt as needed for up to 4 hours a day. After 10 weeks, they were to gradually increase their physical activity. The duration of this intervention was supposed to allow time for microfracture healing.

Subjects in the exercise group did supervised 1-hour exercises once a week for 10 weeks. The regime included exercises for stabilizing muscles in the low back and abdomen, exercises for postural instability, and light physical fitness training. These patients were encouraged to do the same exercises at home 3 times a week and to maintain a "normal" level of activity.

Pain/Disability Assessment

All patients completed questionnaires at baseline, 10 weeks, and 12 months. The study assessed pain using a numerical rating scale (NRS) of back pain ranging from 0 to 10; disability using the 23-item Roland Morris Disability Questionnaire (RMQ) with scores ranging from 0 to 23; general health using the EuroQol, as well as global assessment and depression. Patients also reported any back problems or sick leave.

The study included data on 87 patients at 10 weeks and 96 patients at the end of the study.

After treatment, the mean pain NRS score was 5.0 in the rest group vs 4.5 in the exercise group (difference adjusted for baseline score, age, sex, smoking and physical workload: − 0.07; P = .9). At 1 year, the scores were 4.8 in the rest group and 4.3 in the exercise group (adjusted difference:− 0.3; P = .5).

For disability, the posttreatment NRS score was 11.0 in the rest group and 11.1 in the exercise group (adjusted difference: − 0.6; P = .5) and at 1 year, the scores were identical at 10.7 for both groups (adjusted difference: − 1.2; P = .3).

The study found no significant difference in general health scores. Also no serious problems or adverse events were reported in either group.

The study results do not add anything new to what is already known about the etiology of MCs, said Jensen. "We know that they are part of the degeneration process but we still don't know what causes them."

Spine-related pathoanatomic changes other than MCs, or psychosocial factors, might influence or cause pain, said the authors. And if MCs do cause pain and rest is useful, the amount of rest in the study may have been insufficient. It's also possible that subgroups of type, size, and location of MCs would have responded differently to treatment.

Although rest was not inferior to exercise in the study, it could carry the risk of unwanted behaviors such as poor coping strategies. However, the study found no difference in emotional functioning between the groups.

Jensen stressed that exercise generally has beneficial effects on overall health and well being for all patients. "I don't recommend exercise as a specific treatment for MCs but MCs are not a contraindication for exercise."

However, she added that the study does not bring researchers or clinicians any closer to an effective treatment for MCs. "Actually, we don't know what to do with these patients."

“Excellent” Study

Asked for comment on this study, Vera Bril, MD, from the Division of Clinical Investigation & Human Physiology, Toronto General Research Institute, in Canada, and a member of the American Academy of Neurology, was positive.

"I think that this is an excellent study that does not support the hypothesis that patients with different forms of back pain respond differently to treatment," she told Medscape Medical News. "So the presence of Modic changes at the endplate regions does not predict response to therapy for back pain.

"It is also interesting that both those advised to rest and those to be active had the same outcomes in this study," she added.

The authors have disclosed no relevant financial relationships.

BMC Medicine. 2012. Published online February 29, 2012. Abstract

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SibermedOs 1.0

Tuntutan jaman untuk mengubah budaya kerja berbasis kertas (Paperwork) menjadi tanpa kertas (Paperless) sudah menyentuh ke segala bidang, tak terkecuali bidang kesehatan. Rekam medis elektronik merupakan yang paling hangat dibahas dalam dasawarsa terakhir sebagai salah satu penerapan budaya kerja paperless di bidang kesehatan. Berbagai negara di dunia sudah beralih ke EMR karena memiliki banyak manfaat terutama efisiensi dan efektifitas pelayanan kesehatan kepada masyarakat. SiberMedOS (SiberMedik Operating System) merupakan system operasi sumber terbuka yang termasuk didalamnya sebuah perangkat lunak EMR SiberMRS (Siber Medical Record System), terkemas dalam sebuah flashdisk dan mampu dijalankan di komputer dengan spesifikasi seminimal mungkin.

Download di sini atau sini  

Setelah di download file tersebut diekstrak, nanti menghasilkan file sebesar 3,5 giga, ternyata file ini adalah suatu image hasil backup, kita harus merestorenya ke flashdisk dengan perintah dd

• Siapkan flashdisk sebesar 4 giga
• Colokin ke komputer dengan sistem linux yang sudah terinstall ddrescue
• Buka konsole atau terminal detek letak flashdisk dengan perintah dmesg, dalam hal ini flashdisk terdeteksi di sdd 
• Buka konsole/ terminal, file hasil ekstrakan saya letakan di /home/arch/smos, masukan perintah:

        sudo dd if=/home/arch/smos of=/dev/sdd bs=1024

• Tunggu prosesnya sampai selesai
• Setelah selesai, silahkan booting dengan flashdisk yang kita bikin tadi
• Setelah masuk desktop ternyata SiberMRS ini dibuat berbasiskan distro Puppy Linux Lucid Puppy, untuk memulai SiberMRS, klik icon SiberMRS di desktop
• Masukan username admin, password test

 

• Setelah login anda akan dihadapkan pada form pergantian password, ganti password yang tadi dengan password anda
•  
• Bersambung ....
• Selamat mencoba !!!

Sumber: http://sibermedos.rekansejawat.com/

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Does Drinking Coffee Increase Glaucoma Risk?

An analysis of the health records of more than 75,000 women has found a positive association between heavy coffee drinking and the development of exfoliation glaucoma (EG) or EG suspect, according to data presented here at the American Glaucoma Society 22nd Annual Meeting.

"We believe that coffee consumption is a reasonable candidate to consider," said lead investigator Louis Pasquale, MD, FARVO, associate professor of ophthalmology at Harvard Medical School in Boston, Massachusetts.

Dr. Pasquale explained that previous randomized trials have indicated that homocysteine levels, a risk factor for coronary disease, are increased after coffee consumption, and that patients with EG have elevated homocysteine in the aqueous humor and tears.

Dr. Pasquale and colleagues used data collected in the Nurses' Health Study from 1980 to 2008 for their study. To be included, subjects had to be at least 40 years of age, had to have no history of glaucoma or cancer, and had to have reported eye exams.

Patients were identified as having EG if there was evidence on a slit-lamp exam and 2 or more reliable visual fields showing reproducible loss. For patients with EG suspect, the presence of exfoliation material on the slit-lamp exam was required, as was an intraocular pressure (IOP) above 21 mm Hg or a cup-to-disc ratio of 0.6 or higher.

A validated questionnaire was used to assess total caffeine intake (from coffee, tea, soda, and caffeine-containing food) every 4 years. A multivariate analysis was performed to determine the association between caffeine consumption and the incidence of EG.

The investigators found 300 cases of EG over 1.6 million person-years of follow-up.

Women who consumed 500 mg caffeine or more per day (1 cup of coffee has roughly 150 mg of caffeine) had a nonsignificant but numerically increased risk for EG (P = .06), compared with those who consumed less than 125 mg per day.

People who drank 3 or more cups of coffee daily had a relative risk (RR) for EG of 1.63 (95% confidence interval [CI], 1.03 to 2.57; P = .02), compared with those who abstained from drinking coffee.

The association between coffee intake and EG was stronger in people with a family history of glaucoma (RR, 2.9; CI, 1.16 to 7.47) than in people with no family history (RR, 1.16; CI, 0.27 to 1.88).

"This strongly suggests that there is a gene interaction with the environment at play here," Dr. Pasquale said.

Given these data, which he cautions are preliminary, Dr. Pasquale does not think that routine checking of homocysteine levels or advising changes in coffee consumption are warranted until stronger associations are proven.

Moderation in All Things

A second study reported here at the American Glaucoma Society meeting was an investigation of the effect of modest caffeine intake — one 8 oz (237 mL) cup of coffee — on IOP.

"Studies in the past have shown conflicting evidence about IOP and caffeinated coffee," explained Aliya Jiwani, BA, from the Massachusetts Eye and Ear Infirmary in Boston. "To date, there are no double-blind randomized controlled trials that examine the effect of coffee on IOP, ocular perfusion pressure [OPP], or ocular pulse amplitude [OPA] in those who have glaucoma or those at risk. This is the first trial of its kind."

This prospective investigation involved 106 subjects — 22 with high-tension primary open-angle glaucoma (POAG), 18 with normal-tension POAG, 20 with ocular hypertension, 21 with suspected POAG, and 25 healthy control subjects.

Randomized subjects ingested 8 oz of either caffeinated (182 mg) or decaffeinated (4 mg) coffee at the first clinic visit; at the second clinic visit, they ingested the alternate beverage. Blood pressure, IOP, OPA, and heart rate were measured before and 60 and 90 minutes after coffee consumption. The investigators calculated OPP (from blood pressure) and IOP.

At baseline, there were no differences in IOP, OPP, or OPA between treatment groups. Sixty minutes after caffeinated coffee intake, mean change in IOP was 0.99 mm Hg (P < .001), in OPP was 1.06 mm Hg (P < .001), and in OPA was 1.57 mm Hg (P = .013). Ninety minutes after caffeinated coffee intake, mean change from baseline in IOP was 1.26 mm Hg (P = .039), in OPP was 0.23 mm Hg (P < .001), and in OPA was 0.18 (P = .001).

Regression analysis revealed sporadic and inconsistent associations between caffeine intake and increases in IOP, OPP, and OPA.

"Although caffeine did have an observable effect in this cohort," Ms. Jiwani explained, "these 1-time modest increases are unlikely to have a clinical impact on this population."

American Glaucoma Society 22nd Annual Meeting: Abstracts 83 and 23. Presented March 3, 2012.

Source

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Up-to-date Management of Gout

Abstract

Purpose of review Gout is a true crystal deposition disease, extremely painful and bone and tissue damaging if untreated. It is the only curable form of arthritis. Although we have many treatments to cure gout, it is a disease that is consistently undertreated/mismanaged and perceived by clinicians and the lay public as a 'laughable condition' with the patients' lifestyle often held erroneously to account. This article would give you a good understanding of modern and established pharmacological and nonpharmacological treatments used in the management of acute and chronic gout and how to 'treat to target' to cure the disease.

Recent findings Many of the drugs we use to manage patients with gouty arthritis have been in existence since the 1970s and 1980s. In the past few years, because of the improved physiological understanding of gout, new innovative treatments such as anti-IL inhibitors, a nonxanthine oxidase inhibitor and the uricase enzymes have been developed adding to our armamentarium of drugs.

Summary With the introduction of new research, we have been able to explore how to also use established treatments more effectively, raising the profile of gout and its best management and introducing the principle of treating the patient to urate target.

Introduction

Gout is a true crystal deposition disease [monosodium urate (MSU) crystals] and the commonest inflammatory arthritis in men over the age of 40. It is the only curable form of arthritis. First identified by the Egyptians in 2640 BC, it is recognized as one of the oldest medical conditions. The UK prevalence is 1.4% which does not appear to be rising.^[1,2]

Improved understanding of the pathophysiology of urate including intracellular events and renal handling in hand with the identification of many genetic components of patients with gout has helped facilitate new therapeutic modalities from bench to bedside. They have also enabled older treatment modalities to be included in contemporary research trials giving more detailed analysis of their use in modern day life with the increased comorbidities experienced by many patients with gout. Epidemiological studies on lifestyle components have similarly added to treatment options for patients giving choice. Importantly, those patients who are unable to take or are unresponsive to traditional treatments can be more adequately treated with alternative drugs and modify lifestyle, reducing treatment-resistant gout and helping minimize flare of gout on introduction of uratelowering treatments.

Unfortunately, although an ancient disease, gout is consistently poorly managed by primary and secondary care clinicians, perhaps because of initiation of treatment by nonspecialists in the majority of diagnosed cases. With the advent of newer, more expensive treatments raising the profile of gout, there may be a move back towards more specialist care thereby optimizing treatment and enabling cure for more patients.

In order to improve patient care amongst specialists and nonspecialists, guidelines have been developed by the British Society of Rheumatology (BSR)^[3] and the European League against Rheumatology (EULAR).^[4] These give pragmatic guidance but require updating in light of newer treatment modalities emerging.

This review aims to update the reader of recent evidence-based additions to treatment, adding to previously published British and European guidance.

Management: Lifestyle Factors

Modifications of lifestyle and diet are key components of gout management. Obesity is the commonest comorbid risk factor for gout,^[1] highlighting the need to address over-weight in every patient's management plan.

Numerous previous epidemiological studies^[5–7] have highlighted links with a variety of food and drinks being either protective (coffee, dairy products, and low BMI) or causative (beer, meat and seafood, and fructose) in patients with gout and are outlined in various review articles.

A recent, randomized, crossover trial^[8] explored the effect of dairy products in more detail by studying the effect of drinking milk (cow and soy) on serum urate concentrations. They found intact cows milk (not soy) decreased serum urate by 10% after a 3-h follow-up period. A follow-up controlled trial^[9••] by the same authors has suggested that skimmed milk enriched with glycomacropeptide or milk fat extract significantly reduces the risk of gout flare. Furthermore, a meta-analysis^[10] has confirmed that supplementation with vitamin C significantly reduces serum urate levels. Further study is required, but this may suggest dairy products and vitamin C have a longer term role in the nonpharmacological management of gout patients.

In terms of increasing risk, a study^[11] implicated beer consumption (but not wine) associated with elevated serum urate levels, women more so than men. Also, replicating previous observations seen in men, the NHANES study^[12]confirmed women also have a higher risk of incident gout associated with consumption of fructose-rich beverages. Avoidance/reduction advice can be confidently included in patient consultation and written educational material.

Although adhering to lifestyle advice alone cannot reduce very high levels of serum urate, modification of lifestyle/diet can have a small uratelowering effect and carry additional benefits in terms of overall health, particularly with regard to the metabolic syndrome. Additionally, it provides patients with a degree of autonomy over their disease and choice of adopting lifestyle advice to manage their condition in the first instance.

Further treatment can be divided into the acute and chronic management of gout.

Acute Treatment

The main aim of acute treatment is to provide rapid relief of pain and inflammation and exclude joint sepsis. Without acute treatment, the pain from an attack can last at least a week. Time from treatment to termination of attack is the only guide to efficacy as few placebo-controlled trials exist.

In addition to pharmacological agents, affected joints should be rested and treated with ice, which has a significant anti-inflammatory effect additionally.^[13]

A systematic review looked at pharmacological treatments for acute gout.^[14] Only 26 suitable studies and three abstracts papers were identified demonstrating the lack of published evidence in acute management strategies. The review concluded nonsteroidal anti-inflammatory drugs (NSAIDs) and colchicine are the most frequently used effective treatments, but steroid and anti-IL-1 can be used in those who are treatment resistant.

Nonsteroidal Anti-inflammatory Drugs

NSAIDs are the most commonly used first-line treatment. Head-to-head studies show few differences between drugs.^[15] Full doses of NSAID should be initiated immediately and tapered after resolution of symptoms.^[3,4]

NSAIDs have numerous adverse effects and should be avoided in gastrointestinal ulcer disease, bleeding or perforation, renal insufficiency, heart failure and those taking oral anticoagulants. Adverse events are increased in the elderly and co-administration of a proton pump inhibitor should be considered. When contemplating NSAIDs, premorbid conditions and drug history should be taken into account on an individual patient basis and any current national guidance adhered to.

Colchicine Colchicine is an old-fashioned drug with modern pathophysiological effects derived from the autumn crocus. It blocks microtubule assembly in neutrophils reducing phagocytosis and transport of MSU crystals.^[15] It also affects neutrophil migration into joints by reducing adhesion molecules on endothelial cells and neutrophils in response to IL-1 or TNF-a.^[16] More recently, it has been demonstrated that colchicine also reduces NALP3 inflammasome-driven caspase-1 activation by microtubule inhibition which decreases MSU delivery.^[15]

A RDBPCT compared colchicine low dose (1.8mg over 1 h) and high dose (4.8mg over 6 h) with placebo in 184 patients with acute gout. Low dose was as effective as high dose and both significantly more effective than placebo. The low-dose group had an adverse side-effect profile similar to placebo.^[17] This suggests low-dose colchicine can be utilized effectively and safely in acute gout flare. Further dosing regimes are suggested by the BSR and EULAR.^[3,4]

Adverse events of colchicine include abdominal cramps, nausea, vomiting and rarely bone marrow suppression, neuropathy and myopathy. Colchicine has the narrowest therapeutic window of any gout therapy. Reduced dosing in elderly or those with renal or hepatic impairment is imperative. Colchicine is metabolized by CYP3A4 and excreted by p-glycoprotein. Toxicity can be caused by drugs interacting with its metabolism and clearance, which include macrolides, cyclosporin and protease inhibitors.^[18] Unpublished data from healthy individuals highlight the important interaction between colchicine and clarithromycin, which increases the plasma elimination half-life of colchicine by 233% via p-glycoprotein inhibition.^[19] Intravenous colchicine is no longer licensed in the UK and many clinicians advocate an outright ban as it has a 2% mortality rate. No trials have directly compared NSAIDs and colchicine.

Corticosteroids Corticosteroids act on the cytosolic glucocorticoid receptor to alter gene expression. Steroids also have nongenomic effects mediated by the cytosolic glucocorticoid receptor, membrane-bound glucocorticoid receptor and additional interactions with cellular membrane proteins.^[20]

In gout, corticosteroid can either be given intraarticularly (preferred route if one or two joints affected), orally, intramuscularly or intravenously. Corticosteroids are a good alternative where NSAID and colchicine cannot be used or in refractory cases. A Cochrane review demonstrated equal efficacy between corticosteroid and comparator (NSAID), but commented the studies were of poor-to-moderate quality with numerous types of active comparator making comparison difficult. There were no reported side-effects with short-term use of corticosteroid however.^[21]

Anti IL-1 Therapy Blocking IL-1 is a novel concept in the treatment of acute gout but highly effective. The rationale stems from the discovery that MSU crystals stimulate the inflammasome in gout leading to IL-1b secretion.^[22] In current experiments, IL-1 inhibitors prevent IL-1 secretion via this mechanism and also block IL-1 secretion by macrophages via a toll-like receptor-dependent mechanism.^[23]

The anti-IL-1 drugs anakinra, canakinumab and rilonacept have all been studied in patients with acute gout.

A case report^[22] and an open-labelled pilot study^[23] have shown subcutaneous injections of anakinra 100mg daily to be a well tolerated and efficacious treatment of flares. Ten patients featured in the open-label study were unable to take other gout medications because of renal impairment, allergies, gastrointestinal haemorrhage and history of renal stones. Pain decreased by 79% on average after three injections.^[23] No side-effects were noted during the trial, and clinical examination showed complete resolution in 9 of 10 patients on day 3.

Phase III studies have been completed using both canakinumab and rilonacept in the management of acute gout flare. In two 12 week trials (b-relieved and b-relieved II), 416 gouty arthritis patients in flare were randomized to either canakinumab 150mg subcutaneously or triamcinolone acetate 40mg intramuscularly. Superiority was significantly demonstrated over triamcinolone acetate at 12 weeks. A total of 317 patients then completed a 12-week extension study. Over the full 24-week study period, canakinumab delayed time to new flare with risk reduction of 52% (b-relieved) and 60% (b-relieved II), respectively, compared with triamcinolone acetate.^[24] In the same patient population, inflammation markers (CRP and SAA) and joint tenderness and swelling were significantly diminished by 24 h as compared with triamcinolone acetate and response was sustained.^[25]

In a pooled analysis of one phase II and three phase III RDBPCTs, weekly subcutaneous injection of rilonacept 80mg (n = 162) or 160mg (n = 1191) or placebo (n = 533) was given in patients at risk of flare on initiation of urate-lowering therapy (ULT). The study period was 16 weeks and assessed the side-effects. The rate of serious infections was low, with site reaction the most common adverse event, mainly in the high-dose rilonacept group.^[26]The three phase III study results were then pooled to assess prevention of gout flare on initiation of ULT. Rilonacept 160 and 80mg resulted in a 69.2 and 62.3% reduction in rate of gout flare, respectively, as compared with placebo.^[27]

Anti-IL-1 treatments are highly effective in terminating de novo flares in those unresponsive to NSAID and colchicine and also reducing the risk of flare on initiation of ULT; the effect is long lasting over several weeks. However, they are extremely expensive when compared with traditional acute treatment modalities, and therefore their place in management is still to be determined.

Chronic Treatment

The main aims of chronic treatment are to

1. prevent recurrent attacks by using ULT and thereby alleviate complications of chronic gouty arthritis;
2. 'treat to target' to prevent MSU crystal saturation and dissolve crystals already deposited in joints and soft tissue by reducing serum urate effectively (BSR <0.3 mmol/l; EULAR <0.36mmol/l);
3. assess and modify contributing risk factors [e.g. hypertension, diabetes mellitus, hyperlipidaemia, heart failure, obesity, osteoarthritis, drugs (diuretics and ciclosporin)];
4. provide long-term follow-up and monitoring of gout including serum urate (sUA) checks.

Complications of gout are as follows:

1. tophi and soft tissue damage;
2. erosive bone damage;
3. renal disease:
   • uric acid calculi;
   • chronic urate nephropathy;
   • acute uric acid nephropathy (usually secondary to chemotherapy);
   • disability and work absence;
   • avascular necrosis of the femoral head.

ULTs can be divided into uricostatic agents that decrease sUA production, uricosuric agents that increase renal excretion or uricolytic agents that metabolize sUA.

Uricostatic Agents: Xanthine Oxidase Inhibitors

Allopurinol Since the 1970s, allopurinol has been the mainstay of chronic treatment. It reduces sUA by inhibiting xanthine oxidase preventing xanthine being converted to uric acid. The most commonly used dose is 300mg daily, with the maximum dose of 900mg daily. However, it is thought introducing allopurinol at a dose of 100mg daily and increased by 100mg titrated against sUA and creatinine clearance may reduce flare on initiation.^[3,4] Additionally, commencing at a low dose and slowly incrementing can reduce the risk of allopurinol hypersensitivity reaction.^[28]

Adverse events of allopurinol include rash (2%), vasculitis, eosinophilia, life-threatening hypersensitivity reaction, hepatitis, decreased renal function and bone-marrow suppression. Allopurinol requires reduced dosing in renal impairment, this being its route of excretion.

Febuxostat Febuxostat is a new nonpurine selective xanthine oxidase inhibitor. It is a potent hypouricaemic agent primarily metabolized in the liver and therefore no dose reduction in moderate renal function is required.

A Phase 3 trial compared febuxostat 80 and 120mg with allopurinol 300mg for 52 weeks with the same sUA target.^[29] The largest reduction in sUA was achieved in those receiving febuxostat 120mg (P<0.001); however, more patients in this group discontinued treatment (P<0.003). The primary end-point was reached in 53% of the patients on 80mg of febuxostat, 62% on 120mg of febuxostat and only 21% in those receiving allopurinol. However, overall rates of discontinuation were higher in both the groups of patients on febuxostat, most commonly because of deranged liver function tests (LFTs) or acute flares.

Results from a 5-year febuxostat trial^[30] provide longer term safety and efficacy results.

At 5 years, 93% of the patients achieved the target of sUA less than 6.0 mg/dl with daily doses between 40 and 120 mg. Twenty-two percent (n = 26) had palpable tophi and the majority resolved. Efficacy in renal impairment was demonstrated with no significant relationship between renal function and urate-lowering efficacy found. The most common adverse event leading to withdrawal from the study was reversible LFT derangement. However, the exclusion criteria of not prescribing in patients consuming over 14 alcoholic drinks a week must be noted. The most frequently encountered serious adverse event was atrial fibrillation, but this was not attributed to febuxostat.

It is difficult to make a direct comparison on the efficacy of febuxostat in comparison with allopurinol because of the doses used and lack of escalation above 300mg allopurinol daily. Its place in treatment should be as a second-line agent where allopurinol has failed to reduce sUA or contraindicated.

Uricosuric Agents

These drugs enhance the renal clearance of urate. They are utilized much less frequently than xanthine oxidase inhibitors and are largely ineffective in patients with renal insufficiency (except benzbromarone) and should not be used in patients with nephrolithiais.

Benzbromarone Benzbromarone is metabolized by cytochrome P450 and was withdrawn from widespread use because of hepatic toxicity. It can now be used on a named patient basis in much of Europe. It is a highly effective drug at reducing sUA levels and can be used in patients with renal transplant and in combination with xanthine oxidase inhibitors.

The most recent randomized controlled trial assessing benzbromarone compared it with probenecid in patients who could not tolerate allopurinol or failed to achieve sUA of less than 0.30 mmol/l on allopurinol.^[31] Twenty-four percent of the patients were successfully treated with allopurinol 300 mg/day within 2 months. In those who failed on allopurinol and were assigned to the benzbromarone (200mg once daily) arm, 92% (n = 24) achieved the sUA target compared with 65% (n = 31) in the probencid 1 g twice a day arm.

Sulphinpyrazone Sulphinpyrazone inhibits prostaglandin synthesis much like the NSAIDs and therefore its adverse events are similar including gastrointestinal ulceration, acute renal failure, fluid retention and rarely elevation of liver enzymes and blood disorders. Daily divided doses of 200–800mg are given.

Probenecid Probenecid can be effective as an add-in therapy when allopurinol alone is insufficient, but is ineffective in renal impairment. Divided doses of 0.50– 2.0 g are used, but it is rarely utilized because of difficulties with supply.

Lesinurad Lesinurad (RDEA594) is a novel uricosuric agent and has been studied in combination with allopurinol in allopurinol refractory gout patients in a phase II dosing study using 200, 400 or 600mg lesinurad plus a stable dose of allopurinol. Reduced sUA and increased response rates occurred in a doserelated manner when lesinurad was combined with allopurinol, and the findings were highly statistically significant at all combination doses when compared with allopurinol plus placebo. Lesinurad was also well tolerated.^[32••] Further studies are required to explore this drug as mono and combination therapy.

Uricolytics

The human uricase gene underwent two separate mutations that independently resulted in truncation of gene transcription. This decreased uricase function, but may have increased antioxidant activity, increased intelligence and improved the ability of humans to retain salt.^[33] The action of uricase converts urate to allantoin, which is 10 times more soluble and thus more readily excreted.

Rasburicase In 1996, rasburicase was developed by recombinant DNA technique from a genetically modified strain of Saccharomyces cerevisiae. The efficacy of rasburicase in prevention and treatment of tumour lysis syndrome (TLS) has been well demonstrated despite its cost.^[34] However, allergenicity and development of antibodies compromise its effectiveness, the risk of which increases with repeated use.^[34] Rasburicase is given intravenously at a dose of 0.20 mg/kg for 5–7 days to treat TLS. No trials have assessed rasburicase efficacy in gout, but a small study^[35] compared monthly and daily regimes.

After 6 monthly infusions, sUA decreased from 612.6–162.4 mmol/l at baseline to 341.2– 91.8mmol/l (P = 0.001). Daily infusions did not produce a significantly sustained reduction, and the incidence of hypersensitivity was higher in the once daily group.

Poly(ethylene) Glycol-uricase PEGylation forms a covalent link between a protein and PEG, and has the advantageous properties of prolonging the drug half-life and decreasing antigenicity.^[34] The mean termination half-life of PEG-uricase is 2 weeks compared with 19 h for rasburicase.

PEG-uricase is better tolerated intravenously than by subcutaneous injection, and postinfusion uricase activity increases in a linear fashion up to 8mg.^[36] Phase 1 trials demonstrated that intravenous administration is superior to subcutaneous administration in achieving more rapid, significant and prolonged lowering of sUA.^[36] PEG-uricase reduces or eliminates uric acid excretion, which is an attractive property potentially benefiting patients with uric acid nephrolithiasis. Phase 2 trials from 2004 to 2005 showed that the most effective dose is 8mg every 2 weeks, and the detection of antibodies against PEG-uricase does not appear to limit treatment either by increasing drug clearance, neutralizing treatment, or increasing adverse events.^[37] If antibodies limit the efficacy of PEG-uricase, then a next generation could be developed with different coupling of uricase to PEG.

Two placebo-controlled, randomized trials in gouty patients who have failed conventional treatment are reported totalling 225 patients. Pooled results demonstrate pegloticase 8mg each fortnight and monthly, respectively, resulted in reducing sUA less than 0.36 mmol/l in 42 and 35% of patients, respectively. No patients in the placebo arm reached the endpoint.^[38]

The most common adverse event of PEG-uricase is inducing an acute flare and infusion reactions. Infusion-related events included nausea, vomiting, dizziness, respiratory symptoms, myalgias and rash, but not anaphylaxis.^[36]

PEG-uricase is another potentially powerful agent for treating refractory gout in those who are unable to tolerate other treatments and could have a role in 'debulking' tophi in advanced gout before switching to another agent for maintenance treatment.

Conclusion

There have been many innovations in treatment for patients with gout over recent years with additional new drugs currently in development that will help in the management of treatment resistant gout. This has raised the profile of gout as a disease entity and highlighted the current poor management experienced by many patients.

The concept of treat-to-target has been established with clear serum urate cut off, enabling practitioners and their patients to monitor treatment successfully.

Increased research into health-related quality of life for gout sufferers demonstrates a definite need for better care and if provided, clearly shows health improves.^[39]

However, the main barrier to more successful treatment is altering the image of gout as a purely acute disease that is humorous and educating fellow healthcare professionals and patients to utilize the treatment armamentarium we already have available optimally.

References

1. Annemans L, Spaepen E, Gaskin M, et al. Gout in the UK and Germany: prevalence, comorbidities and management in general practice 2000–2005. Ann Rheum Dis 2008; 67:906–966.
2. Mikuls TR, Farrar J, Bilker WB, et al. Gout epidemiology: results from the UK general practice research database, 1990–1999. Ann Rheum Dis 2005; 64:267–272.
3. Jordan KM, Cameron JS, Snaith M, et al. British Society for Rheumatology and British Health Professionals in Rheumatology guidelines for the management of gout. Rheumatology 2007; 46:1372–1374.
4. Zang W, Doherty M, Bardin T, et al. EULAR evidence based recommendations for gout. Part II. Management. Report task force of the EULAR standing committee for international clinical studies including therapeutics (ESCISIT). Ann Rheum Dis 2006; 65:1312–1324.
5. Rider TG, Jordan KM. The modern management of gout. Rheumatology 2010; 49:5–14.
6. Singh JA, Reddy SG, Kundukulam J. Risk factors for gout and prevention: a systematic review of the literature. Curr Opin Rheumatol 2011; 23:192–202, 1531–6963.
7. Li S, Micheletti R. Role of diet in rheumatic disease. Rheum Dis Clin North Am 2011; 37:119–133.
8. Dalbeth N, Wong S, Gamble GD, et al. Acute effect of milk on serum urate concentrations: a randomised controlled crossover trial. Ann Rheum Dis 2010; 69:1677–1682.
9. Dalbeth N, Ames R, Gamble G, et al. Daily intake of skim milk powder enriched with glycomacropeptide and G600 milk fat extract may reduce frequency of gout flares; results from a randomized, controlled trial. In: ACR Conference Proceedings; abstract 207; 2011.
   ••The first reported trial of a dietary intervention reducing urate levels.
10. Juraschek SP, Miller ER 3rd, Gelber AC. Effect of oral vitamin C supplementation on serum uric acid: a meta-analysis of randomized controlled trials. Arthritis Care Res 2011; 63:1295–1306.
11. Gaffo AL, Roseman JM, Jacobs DR Jr, et al. Serum urate and its relationship with alcoholic beverage intake in men and women: findings from the Coronary Artery Risk Development in Young Adults (CARDIA) cohort. Ann Rheum Dis 2010; 69:1965–1970.
12. Choi HK, Willett W, Curhan G. Fructose rich beverages and risk of gout in women. JAMA 2010; 304:2270–2278.
13. Schlesinger N. Response to application of ice may help differentiate between gouty arthritis and other inflammatory arthritides. J Clin Rheumatol 2006; 12:275–276.
14. Khanna P, Singh MK, Fitzgerald JD, et al. Pharmacological treatment of acute gout: a systematic review. In: ACR Conference Proceedings, abstract 1025; 2011.
15. Cronstein BN, Terkeltaub R. The inflammatory process of gout and its treatment. Arthritis Res Ther 2006; 8:S1.
16. Choi HK, Mount DB, Reginato AM. Pathogenesis of gout. Ann Intern Med 2005; 143:499–516.
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    Papers of particular interest, published within the annual period of review, have been highlighted as:
    • of special interest
    •• of outstanding interest
    Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 239–241).

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