Periodontitis and gingivitis in inflammatory bowel disease: a case-control study.

BACKGROUND: The oral cavity is frequently affected in patients with inflammatory bowel disease (IBD), especially in patients with Crohn's disease (CD). Periodontitis is thought to influence systemic autoimmune or inflammatory diseases. We aimed to analyze the relationship of periodontitis and gingivitis markers with specific disease characteristics in patients with IBD and to compare these data with healthy controls. METHODS: In a prospective 8-month study, systematic oral examinations were performed in 113 patients with IBD, including 69 patients with CD and 44 patients with ulcerative colitis. For all patients, a structured personal history was taken. One hundred thirteen healthy volunteers served as a control group. Oral examination focussed on established oral health markers for periodontitis (bleeding on probing, loss of attachment, and periodontal pocket depth) and gingivitis (papilla bleeding index). Additionally, visible oral lesions were documented. RESULTS: Both gingivitis and periodontitis markers were higher in patients with IBD than in healthy control. In univariate analysis and logistic regression analysis, perianal disease was a risk factor for periodontitis. Nonsmoking decreased the risk of having periodontitis. No clear association was found between clinical activity and periodontitis in IBD. In only the CD subgroup, high clinical activity (Harvey-Bradshaw index > 10) was associated with 1 periodontitis marker, the loss of attachment at sites of maximal periodontal pocket depth. Oral lesions besides periodontitis and gingivitis were not common, but nevertheless observed in about 10% of patients with IBD. CONCLUSIONS: IBD, and especially perianal disease in CD, is associated with periodontitis. Optimal therapeutic strategies should probably focus on treating both local oral and systemic inflammation.

Subclinical hyperthyroidism and the risk of coronary heart disease and mortality.

BACKGROUND: Data from prospective cohort studies regarding the association between subclinical hyperthyroidism and cardiovascular outcomes are conflicting.We aimed to assess the risks of total and coronary heart disease (CHD) mortality, CHD events, and atrial fibrillation (AF) associated with endogenous subclinical hyperthyroidism among all available large prospective cohorts. METHODS: Individual data on 52 674 participants were pooled from 10 cohorts. Coronary heart disease events were analyzed in 22 437 participants from 6 cohorts with available data, and incident AF was analyzed in 8711 participants from 5 cohorts. Euthyroidism was defined as thyrotropin level between 0.45 and 4.49 mIU/L and endogenous subclinical hyperthyroidism as thyrotropin level lower than 0.45 mIU/L with normal free thyroxine levels, after excluding those receiving thyroid-altering medications. RESULTS: Of 52 674 participants, 2188 (4.2%) had subclinical hyperthyroidism. During follow-up, 8527 participants died (including 1896 from CHD), 3653 of 22 437 had CHD events, and 785 of 8711 developed AF. In age- and sex-adjusted analyses, subclinical hyperthyroidism was associated with increased total mortality (hazard ratio[HR], 1.24, 95% CI, 1.06-1.46), CHD mortality (HR,1.29; 95% CI, 1.02-1.62), CHD events (HR, 1.21; 95%CI, 0.99-1.46), and AF (HR, 1.68; 95% CI, 1.16-2.43).Risks did not differ significantly by age, sex, or preexisting cardiovascular disease and were similar after further adjustment for cardiovascular risk factors, with attributable risk of 14.5% for total mortality to 41.5% forAF in those with subclinical hyperthyroidism. Risks for CHD mortality and AF (but not other outcomes) were higher for thyrotropin level lower than 0.10 mIU/L compared with thyrotropin level between 0.10 and 0.44 mIU/L(for both, P value for trend, .03). CONCLUSION: Endogenous subclinical hyperthyroidism is associated with increased risks of total, CHD mortality, and incident AF, with highest risks of CHD mortality and AF when thyrotropin level is lower than 0.10 mIU/L.

Fecal calprotectin more accurately reflects endoscopic activity of ulcerative colitis than the Lichtiger Index, C-reactive protein, platelets, hemoglobin, and blood leukocytes.

BACKGROUND: The correlation between noninvasive markers with endoscopic activity according to the modified Baron Index in patients with ulcerative colitis (UC) is unknown. We aimed to evaluate the correlation between endoscopic activity and fecal calprotectin (FC), C-reactive protein (CRP), hemoglobin, platelets, blood leukocytes, and the Lichtiger Index (clinical score). METHODS: UC patients undergoing complete colonoscopy were prospectively enrolled and scored clinically and endoscopically. Samples from feces and blood were analyzed in UC patients and controls. RESULTS: We enrolled 228 UC patients and 52 healthy controls. Endoscopic disease activity correlated best with FC (Spearman's rank correlation coefficient r = 0.821), followed by the Lichtiger Index (r = 0.682), CRP (r = 0.556), platelets (r = 0.488), blood leukocytes (r = 0.401), and hemoglobin (r = -0.388). FC was the only marker that could discriminate between different grades of endoscopic activity (grade 0, 16 [10-30] μg/g; grade 1, 35 [25-48] μg/g; grade 2, 102 [44-159] μg/g; grade 3, 235 [176-319] μg/g; grade 4, 611 [406-868] μg/g; P < 0.001 for discriminating the different grades). FC with a cutoff of 57 μg/g had a sensitivity of 91% and a specificity of 90% to detect endoscopically active disease (modified Baron Index ≥ 2). CONCLUSIONS: FC correlated better with endoscopic disease activity than clinical activity, CRP, platelets, hemoglobin, and blood leukocytes. The strong correlation with endoscopic disease activity suggests that FC represents a useful biomarker for noninvasive monitoring of disease activity in UC patients.

Impact of genetic polymorphisms in cytomegalovirus glycoprotein B on outcomes in solid-organ transplant recipients with cytomegalovirus disease.

BACKGROUND:It is unknown whether specific viral polymorphisms affect in vivo therapeutic response in patients with cytomegalovirus (CMV) disease. Polymorphisms in the CMV glycoprotein B (gB) gene allow discrimination of 4 distinct genotypes (gB1-gB4). We assessed the influence of gB genotypes on the clinical and virologic outcome of CMV disease. METHODS:Solid-organ transplant recipients enrolled in a multicenter trial of CMV disease treatment (VICTOR study) were included in this study. CMV gB genotyping was performed using quantitative real-time polymerase chain reaction at day 0 (start of antiviral therapy). RESULTS:Among 239 patients with CMV disease, the prevalence of gB strain types was 26% for gB1, 10% for gB2, 10% for gB3, and 5% for gB4, whereas mixed infections were present in 49%. Donor-seropositive/recipient-seropositive patients were more likely to have mixed gB infection than donor-seropositive/recipient-seronegative patients (40% vs. 12%; P = .001). Median baseline viral loads were higher and time to viral eradication was longer ( P = .006 and P = .026 , respectively) for mixed infection versus infection with a single genotype. In a multivariate model, mixed gB infection was a significant predictor of failure to eradicate virus by day 21 (mixed vs single genotype; odds ratio, 2.66; 95% confidence interval, 1.31-5.38; P = .007 ) after controlling for baseline viral load, CMV serostatus at baseline, ganciclovir resistance, and antiviral treatment. No effect of gB genotype was seen on virologic or clinical CMV recurrence. CONCLUSIONS:No specific gB genotype appears to confer a specific CMV virulence advantage. However, mixed gB genotype infections are associated with higher viral loads and delayed viral clearance.

Evidence for a role of sphingosine-1 phosphate in cardiovascular remodelling in Fabry disease.

AIMS: A hallmark of Fabry disease is the concomitant development of left-ventricular hypertrophy and arterial intima-media thickening, the pathogenesis of which is thought to be related to the presence of a plasmatic circulating growth-promoting factor. We therefore characterized the plasma of patients with Fabry disease in order to identify this factor. METHODS AND RESULTS: Using a classical biochemical strategy, we isolated and identified sphingosine-1 phosphate (S1P) as a proliferative factor present in the plasma of patients with Fabry disease. Plasma S1P levels were significantly higher in 17 patients with Fabry disease compared with 17 healthy controls (225 +/- 40 vs. 164 +/- 17 ng/mL; P = 0.005). There was a positive correlation between plasma S1P levels and both common carotid artery intima-media thickness and left-ventricular mass index (r(2) = 0.47; P = 0.006 and r(2) = 0.53; P = 0.0007, respectively). In an experimental model, mice treated with S1P developed cardiovascular remodelling similar to that observed in patients with Fabry disease. CONCLUSION: Sphingosine-1 phosphate participates in cardiovascular remodelling in Fabry disease. Our findings have implications for the treatment of cardiovascular involvement in Fabry disease.

Efficacy and safety of certolizumab pegol in an unselected crohn's disease population: 26-week data of the FACTS II survey.

BACKGROUND: Certolizumab pegol (Cimzia, CZP) was approved for the treatment of Crohn's disease (CD) patients in 2007 in Switzerland as the first country worldwide. This prospective phase IV study aimed to evaluate the efficacy and safety of CZP over 26 weeks in a multicenter cohort of practice-based patients. METHODS: Evaluation questionnaires at baseline, week 6, and week 26 were completed by gastroenterologists in hospitals and private practices. Adverse events were evaluated according to World Health Organization (WHO) guidelines. RESULTS: Sixty patients (38F/22M) were included; 53% had complicated disease (stricturing or penetrating), 45% had undergone prior CD-related surgery. All patients had prior exposure to systemic steroids, 96% to immunomodulators, 73% to infliximab, and 43% to adalimumab. A significant decrease of the Harvey-Bradshaw Index (HBI) was observed under CZP therapy (12.2 ± 4.9 at week 0 versus 6.3 ± 4.7 at week 6 and 6.7 ± 5.3 at week 26, both P < 0.001). Response and remission rates were 70% and 40% (week 6) and 67% and 36%, respectively (week 26). The complete perianal fistula closure rate was 36% at week 6 and 55% at week 26. The frequency of adverse drug reactions attributed to CZP was 5%. CZP was continued in 88% of patients beyond week 6 and in 67% beyond week 26. CONCLUSIONS: In a population of CD patients with predominantly complicated disease behavior, CZP proved to be effective in induction and maintenance of response and remission. This series provides the first evidence of CZP's effectiveness in perianal fistulizing CD in clinical practice.

Severe and steroid-resistant Crohn's disease.

Patients with moderate to severe disease and patients with steroid-refractory or steroid-dependent disease differ in their management, as the latter groups usually include patients with less acute situations. Systemic corticosteroids represent the mainstay of the management of moderate to severe disease and remain the first-line therapy in this setting. Infliximab is the choice alternative for patients who do not respond to steroids or in whom steroids are contraindicated. Purine analogues, methotrexate and infliximab have shown efficacy in achieving steroid-free remission in patients with steroid-refractory or -dependent disease. Other fast-acting immunosuppressors showed little benefit. Surgery may be indicated in this setting. Nataluzimab may prove useful in patients refractory to infliximab.

Enzyme replacement therapy with agalsidase alfa in patients with Fabry's disease: an analysis of registry data.

BACKGROUND: We analysed 5-year treatment with agalsidase alfa enzyme replacement therapy in patients with Fabry's disease who were enrolled in the Fabry Outcome Survey observational database (FOS). METHODS: Baseline and 5-year data were available for up to 181 adults (126 men) in FOS. Serial data for cardiac mass and function, renal function, pain, and quality of life were assessed. Safety and sensitivity analyses were done in patients with baseline and at least one relevant follow-up measurement during the 5 years (n=555 and n=475, respectively). FINDINGS: In patients with baseline cardiac hypertrophy, treatment resulted in a sustained reduction in left ventricular mass (LVM) index after 5 years (from 71.4 [SD 22.5] g/m(2.7) to 64.1 [18.7] g/m(2.7), p=0.0111) and a significant increase in midwall fractional shortening (MFS) from 14.3% (2.3) to 16.0% (3.8) after 3 years (p=0.02). In patients without baseline hypertrophy, LVM index and MFS remained stable. Mean yearly fall in estimated glomerular filtration rate versus baseline after 5 years of enzyme replacement therapy was -3.17 mL/min per 1.73 m(2) for men and -0.89 mL/min per 1.73 m(2) for women. Average pain, measured by Brief Pain Inventory score, improved significantly, from 3.7 (2.3) at baseline to 2.5 (2.4) after 5 years (p=0.0023). Quality of life, measured by deviation scores from normal EuroQol values, improved significantly, from -0.24 (0.3) at baseline to -0.17 (0.3) after 5 years (p=0.0483). Findings were confirmed by sensitivity analysis. No unexpected safety concerns were identified. INTERPRETATION: By comparison with historical natural history data for patients with Fabry's disease who were not treated with enzyme replacement therapy, long-term treatment with agalsidase alfa leads to substantial and sustained clinical benefits. FUNDING: Shire Human Genetic Therapies AB.

Prevalence and risk factors for gastro-esophageal reflux disease in the North-Eastern part of Bangladesh.

Despite a common disorder population-based data on gastro-esophageal reflux disease (GERD) in Bangladesh is lacking. This epidemiological study was designed to determine the prevalence of GERD and its association with lifestyle factors. This population-based cross-sectional study was done by door to door interview of randomly selected persons in both urban and rural areas of North Eastern part of Bangladesh by using a validated questionnaire. A cutoff point 3 was chosen as a valid and reliable scale to confirm GERD. Statistical analysis was done by SPSS-12 version and the level of significance was set at P < or = 0.05. A total of 2000 persons with an age range of 15 to 85 years were interviewed; 1000 subjects from urban area and 1000 from rural area. Among the study subjects 1064 were male and 936 were female. A total of 110 persons (5.5%) were found to have GERD symptoms and among them 47 were men and 67 were women. The monthly, weekly and daily prevalence of heart-burn and or acid regurgitation was 5.5%, 5.25% and 2.5% respectively. Female sex, increased age and lower level of education were significantly associated with GERD symptoms. Prevalence was found more among city dwellers (approximately 6.0% versus 4.8%), married (6.23%, n = 86), widowed/widowers (16.83%, n = 17) and day labourer (8.78%). Level of education inversely influenced the prevalence. No significant association of GERD was found with body mass index (BMI) and smoking. Prevalence of GERD in North-Eastern part of Bangladesh was lower than that of western world. Prevalence was found higher in urban population, women, married, widowed/widowers and in poor an dilliterate persons. BMI and smoking had no significant association with GERD.

Sentinel lymph node involvement and a high Breslow index are independent factors of risk for early relapse of melanoma.

AIM: The clinical relevance of sentinel lymph node (SLN) analysis was evaluated prospectively and compared with other known risk factors of relapse in early stage melanoma. METHODS: Surgery was guided by lymphoscintigraphy, blue dye and gamma probe detection. SLN were analysed by haematoxylin eosin (HE) histochemistry and multimarker immunohistochemistry (IHC). Disease free survival (DFS) was evaluated with Kaplan-Meier plots according to different parameters and Cox analyses of variance. RESULTS: From 210 patients a total of 381 SLN were excised. Lymphoscintigraphy identified all excised SLN with only 2 false positive lymphatic lakes. Fifty patients (24%) had tumour positive SLN. With a mean follow-up of 31.3 months, 29 tumour recurrences were observed, 19 (38%) in 50 SLN positive and 10 (6%) in 160 SLN negative patients. Strong predictive factors for early relapse (p < 0.0005) were SLN positivity and a high Breslow index. CONCLUSION: SLN tumour positivity is an independent factor of high risk for early relapse with a higher power of discrimination than the Breslow index.

Fecal calprotectin more accurately reflects endoscopic activity of ulcerative colitis than the Lichtiger Index, CRP, or blood leukocytes

Background: Mucosal healing in ulcerative colitis (UC) is reported to be associated with favourable clinical outcomes such as reduced hospitalization and surgery rates. Activity monitoring by endoscopy has its shortcomings due to invasiveness, costs, and potential patient discomfort. Data on the correlation of noninvasive biomarkers with endoscopic severity in UC are scarce. Aim: to evaluate the correlation between endoscopic activity according to the modified Baron Index and fecal calprotectin, C-reactive protein (CRP), blood leukocytes, and the Lichtiger Index (clinical score). Methods: UC patients with leftsided and extensive colitis undergoing complete colonoscopy were prospectively enrolled and scored clinically and endoscopically. Fecal and blood samples were analyzed in UC patients (in a blinded fashion) and controls. The modified Baron score describes the following 5 endoscopic conditions: 0 = normal, 1 = granular mucosa, edema, 2 = friable mucosa but no spontaneous bleeding, 3 = microulcerations with spontaneous bleeding, 4 = gross ulceration, denuded mucosa. Results: We enrolled 228 UC patients (mean age 41 ± 13 years, 39 female) and 52 healthy controls. Disease was located in 40% in the left colon, 21% had an extensive and 39% a pancolitis. Endoscopic disease activity correlated best with fecal calprotectin (Spearman's rank correlation coefficient r = 0.821), followed by the Lichtiger Index (r = 0.682), CRP (r = 0.556), and blood leukocytes (r = 0.401). Fecal calprotectin was the only marker that could discriminate between different grades of endoscopic activity (grade 0, 25 ± 11 μg/g; grade 1, 44 ± 34 μg/g; grade 2, 111 ± 74 μg/g; grade 3, 330 ± 332 μg/g; grade 4, 659 ± 319 μg/g; P = 0.002 for discriminating grade 0 vs. 1, and P < 0.001 for discriminating grade 1 vs. 2, grade 2 vs. 3, and grade 3 vs. 4). Fecal calprotectin had the highest overall accuracy (91%) to detect endoscopically active disease (modified Baron Index ≥ 2), followed by the Lichtiger Index score of ≥ 4 (77%), CRP > 5 mg/L (69%) and blood leukocytosis (58%). Conclusions: Fecal calprotectin better correlated with endoscopic disease activity than clinical activity, CRP, and blood leukocytes. The strong correlation with endoscopic disease activity suggests that FC represents a useful biomarker for noninvasive monitoring of disease activity in UC patients.

Vedolizumab as induction and maintenance therapy for Crohn's disease.

BACKGROUND: The efficacy of vedolizumab, an α4β7 integrin antibody, in Crohn's disease is unknown. METHODS: In an integrated study with separate induction and maintenance trials, we assessed intravenous vedolizumab therapy (300 mg) in adults with active Crohn's disease. In the induction trial, 368 patients were randomly assigned to receive vedolizumab or placebo at weeks 0 and 2 (cohort 1), and 747 patients received open-label vedolizumab at weeks 0 and 2 (cohort 2); disease status was assessed at week 6. In the maintenance trial, 461 patients who had had a response to vedolizumab were randomly assigned to receive placebo or vedolizumab every 8 or 4 weeks until week 52. RESULTS: At week 6, a total of 14.5% of the patients in cohort 1 who received vedolizumab and 6.8% who received placebo were in clinical remission (i.e., had a score on the Crohn's Disease Activity Index [CDAI] of ≤150, with scores ranging from 0 to approximately 600 and higher scores indicating greater disease activity) (P=0.02); a total of 31.4% and 25.7% of the patients, respectively, had a CDAI-100 response (≥100-point decrease in the CDAI score) (P=0.23). Among patients in cohorts 1 and 2 who had a response to induction therapy, 39.0% and 36.4% of those assigned to vedolizumab every 8 weeks and every 4 weeks, respectively, were in clinical remission at week 52, as compared with 21.6% assigned to placebo (P<0.001 and P=0.004 for the two vedolizumab groups, respectively, vs. placebo). Antibodies against vedolizumab developed in 4.0% of the patients. Nasopharyngitis occurred more frequently, and headache and abdominal pain less frequently, in patients receiving vedolizumab than in patients receiving placebo. Vedolizumab, as compared with placebo, was associated with a higher rate of serious adverse events (24.4% vs. 15.3%), infections (44.1% vs. 40.2%), and serious infections (5.5% vs. 3.0%). CONCLUSIONS: Vedolizumab-treated patients with active Crohn's disease were more likely than patients receiving placebo to have a remission, but not a CDAI-100 response, at week 6; patients with a response to induction therapy who continued to receive vedolizumab (rather than switching to placebo) were more likely to be in remission at week 52. Adverse events were more common with vedolizumab. (Funded by Millennium Pharmaceuticals; GEMINI 2 ClinicalTrials.gov number, NCT00783692.).

Clinical experience with Adalimumab in a multicenter Swiss cohort of patients with Crohn's disease

Background. Des études précédentes ont démontré l'efficacité et la tolérance de l'adalimumab chez les patients avec maladie de Crohn modérée ou sévère. Les patients qu'on rencontre dans la pratique quotidienne peuvent être différents des patients rigoureusement sélectionnés dans les études contrôlées.But. Dans ce travail, nous résumons notre expérience avec l'adalimumab durant une période de 3 ans.Méthodes. Nous avons analysé rétrospectivement les dossiers de 55 patients atteints d'une maladie de Crohn modérée ou sévère et traités par adalimumab dans les hôpitaux universitaires de Bâle, Zurich, Genève et Lausanne, ainsi que dans un cabinet médical à Olten. Les informations collectées étaient les suivantes : données démographiques, localisation, phénotype et durée de la maladie, traitements chirurgicaux précédents, traitements précédents par anti-TNF alpha ou immunosuppresseur, le traitement concomitant et l'activité de la maladie à la « baseline » et durant le traitement. La sévérité de la maladie à l'inclusion a été établie en utilisant le score Harvey- Bradshaw Index (HBI). Durant le traitement, la rémission a été définie avec un HBI<4 et la réponse comme une réduction de l'HBI de plus de 3 points. L'analyse de régression logistique univariée a été utilisée pour déterminer si les variables étudiées étaient associées à la réponse ou à la rémission durant le traitement.Résultats. L'âge moyen des patients a été de 37.5 ± 11.4 ans et la durée moyenne de maladie à été de 12.7 ans. 29 des 55 patients étaient des fumeurs. Le traitement d'induction a été effectué chez 31 patients avec l'adalimumab en sous-cutané 160 mg à la semaine 0 et 80 mg à la semaine 2 et chez 24 patients avec 80 mg à la semaine 0 et 40 mg à la semaine 2. Le traitement d'entretien a été de 40 mg en sous-cutané toutes les 2 semaines. 13 patients (23.6%) ont nécessité l'augmentation de la dose d'adalimumab pour maintenir la rémission ou la réponse.Le taux de rémission et de réponse à la semaine 4-6 était de 52.7%, respectivement 83.6%. La rémission a été maintenue aux semaines 12, 24 et 52 chez 89.6%, 72.4%, respectivement 44.7% des patients. Le taux de rémission et de réponse n'a pas été influencé par le tabagisme, la location ou la durée de la maladie, la dose totale donnée durant le premier mois de traitement, la dose d'adalimumab par kilogramme-corps ou par le traitement précédent par infliximab. La rémission à la semaine 4-6 a été significativement plus élevée chez les patients intolérants à l'infliximab comparativement à ceux qui avaient perdu la réponse à l'infliximab (78.9% vs 42.1%, p=0.02). Le traitement par adalimumab a été bien toléré. Les effets secondaires les plus signalés ont été : la douleur au site d'injection (10.9%), l'asthénie (9%) et des infections (7.2%).Conclusions. L'adalimumab a démontré une bonne efficacité et tolérance dans la pratique quotidienne chez les patients avec une maladie de Crohn modérée ou sévère.

Appropriate treatment for Crohn's disease: methodology and summary results of a multidisciplinary international expert panel approach--EPACT.

BACKGROUND/AIMS: For many therapeutic decisions in Crohn's disease (CD), high-grade evidence is lacking. To assist clinical decision-making, explicit panel-based appropriateness criteria were developed by an international, multidisciplinary expert panel. METHODS: 10 gastroenterologists, 3 surgeons and 2 general practitioners from 12 European countries assessed the appropriateness of therapy for CD using the RAND Appropriateness Method. Their assessment was based on the study of a recent literature review of the subject, combined with their own expert clinical judgment. Panelists rated clinical indications and treatment options using a 9-point scale (1 = extremely inappropriate; 9 = extremely appropriate). These scenarios were then discussed in detail at the panel meeting and re-rated. Median ratings and disagreement were used to aggregate ratings into three assessment categories: appropriate (A), uncertain (U) and inappropriate (I). RESULTS: 569 specific indications were rated, dealing with 9 clinical presentations: mild/moderate luminal CD (n = 104), severe CD (n = 126), steroid-dependent CD (n = 25), steroid-refractory CD (n = 37), fistulizing CD (n = 49), fibrostenotic CD (n = 35), maintenance of medical remission of CD (n = 84), maintenance of surgical remission (n = 78), drug safety in pregnancy (n = 24) and use of infliximab (n = 7). Overall, 146 indications (26%) were judged appropriate, 129 (23%) uncertain and 294 (52%) inappropriate. Frank disagreement was low (14% overall) with the greatest disagreement (54% of scenarios) being observed for treatment of steroid-refractory disease. CONCLUSIONS: Detailed explicit appropriateness criteria for the appropriate use of therapy for CD were developed for the first time by a European expert panel. Disease location, severity and previous treatments were the main factors taken into account. User-friendly access to EPACT criteria is available via an Internet site, www.epact.ch, allowing prospective evaluation and improvement of appropriateness of current CD therapy.

Recombinant human insulin-like growth factor I (rhIGF-I) for the treatment of amyotrophic lateral sclerosis/motor neuron disease.

BACKGROUND: Recombinant human insulin-like growth factor I (rhIGF-I) is a possible disease modifying therapy for amyotrophic lateral sclerosis (ALS, which is also known as motor neuron disease (MND)). OBJECTIVES: To examine the efficacy of rhIGF-I in affecting disease progression, impact on measures of functional health status, prolonging survival and delaying the use of surrogates (tracheostomy and mechanical ventilation) to sustain survival in ALS. Occurrence of adverse events was also reviewed. SEARCH METHODS: We searched the Cochrane Neuromuscular Disease Group Specialized Register (21 November 2011), CENTRAL (2011, Issue 4), MEDLINE (January 1966 to November 2011) and EMBASE (January 1980 to November 2011) and sought information from the authors of randomised clinical trials and manufacturers of rhIGF-I. SELECTION CRITERIA: We considered all randomised controlled clinical trials involving rhIGF-I treatment of adults with definite or probable ALS according to the El Escorial Criteria. The primary outcome measure was change in Appel Amyotrophic Lateral Sclerosis Rating Scale (AALSRS) total score after nine months of treatment and secondary outcome measures were change in AALSRS at 1, 2, 3, 4, 5, 6, 7, 8, 9 months, change in quality of life (Sickness Impact Profile scale), survival and adverse events. DATA COLLECTION AND ANALYSIS: Each author independently graded the risk of bias in the included studies. The lead author extracted data and the other authors checked them. We generated some missing data by making ruler measurements of data in published graphs. We collected data about adverse events from the included trials. MAIN RESULTS: We identified three randomised controlled trials (RCTs) of rhIGF-I, involving 779 participants, for inclusion in the analysis. In a European trial (183 participants) the mean difference (MD) in change in AALSRS total score after nine months was -3.30 (95% confidence interval (CI) -8.68 to 2.08). In a North American trial (266 participants), the MD after nine months was -6.00 (95% CI -10.99 to -1.01). The combined analysis from both RCTs showed a MD after nine months of -4.75 (95% CI -8.41 to -1.09), a significant difference in favour of the treated group. The secondary outcome measures showed non-significant trends favouring rhIGF-I. There was an increased risk of injection site reactions with rhIGF-I (risk ratio 1.26, 95% CI 1.04 to 1.54). . A second North American trial (330 participants) used a novel primary end point involving manual muscle strength testing. No differences were demonstrated between the treated and placebo groups in this study. All three trials were at high risk of bias. AUTHORS' CONCLUSIONS: Meta-analysis revealed a significant difference in favour of rhIGF-I treatment; however, the quality of the evidence from the two included trials was low. A third study showed no difference between treatment and placebo. There is no evidence for increase in survival with IGF1. All three included trials were at high risk of bias.