Sex as a determinant of relapse incidence and progressive course of multiple sclerosis

The aim of this work was to evaluate sex differences in the incidence of multiple sclerosis relapses; assess the relationship between sex and primary progressive disease course; and compare effects of age and disease duration on relapse incidence. Annualized relapse rates were calculated using the MSBase registry. Patients with incomplete data or <1 year of follow-up were excluded. Patients with primary progressive multiple sclerosis were only included in the sex ratio analysis. Relapse incidences over 40 years of multiple sclerosis or 70 years of age were compared between females and males with Andersen-Gill and Tweedie models. Female-to-male ratios stratified by annual relapse count were evaluated across disease duration and patient age and compared between relapse-onset and primary progressive multiple sclerosis. The study cohort consisted of 11 570 eligible patients with relapse-onset and 881 patients with primary progressive multiple sclerosis. Among the relapse-onset patients (82 552 patient-years), 48 362 relapses were recorded. Relapse frequency was 17.7% higher in females compared with males. Within the initial 5 years, the female-to-male ratio increased from 2.3:1 to 3.3:1 in patients with 0 versus ≥4 relapses per year, respectively. The magnitude of this sex effect increased at longer disease duration and older age (P < 10−12). However, the female-to-male ratio in patients with relapse-onset multiple sclerosis and zero relapses in any given year was double that of the patients with primary progressive multiple sclerosis. Patient age was a more important determinant of decline in relapse incidence than disease duration (P < 10−12). Females are predisposed to higher relapse activity than males. However, this difference does not explain the markedly lower female-to-male sex ratio in primary progressive multiple sclerosis. Decline in relapse activity over time is more closely related to patient age than disease duration.

Therapeutic approaches to disease modifying therapy for multiple sclerosis in adults: an Australian and New Zealand perspective: part 2 new and emerging therapies and their efficacy

In Part 2 of this three part review of multiple sclerosis (MS) treatment with a particular focus on the Australian and New Zealand perspective, we review the newer therapies that have recently become available and emerging therapies that have now completed phase III clinical trial programs. We go on to compare the relative efficacies of these newer and emerging therapies alongside the existing therapies. The effectiveness of β-interferon in the treatment of different stages and the different disease courses of MS is critically reviewed with the conclusion that the absolute level of response in term of annualised relapse rates (where relapses occur) and MRI activity are similar, but are disappointing in terms of sustained disability progression for progressive forms of the disease. Finally we review the controversial area of combination therapy for MS. Whilst it remains the case that we have no cure or means of preventing MS, we do have a range of effective therapies that when used appropriately and early in the disease course can have a significant impact on short term and longer term outcomes.

Cognitive-behavioural therapy for inflammatory bowel disease: 24-month data from a randomised controlled trial

PURPOSE: There is ongoing controversy on the effectiveness of psychotherapy in inflammatory bowel disease (IBD). In the few small studies, cognitive-behavioural therapy (CBT) has been shown to alleviate symptoms of anxiety or depression. However, there is little research on the impact of CBT on physical outcomes in IBD and no studies on long-term effectiveness of CBT.

METHODS: The present two-arm pragmatic randomised controlled trial aimed to establish the impact of CBT on disease course after 24 months of observation. The study compared standard care plus CBT (+CBT) with standard care alone (SC). CBT was delivered over 10 weeks, face-to-face (F2F) or online (cCBT). The data were analysed using linear mixed-effects models.

RESULTS: CBT did not significantly influence disease activity as measured by disease activity indices at 24 months (Crohn's Disease Activity Index (CDAI), p = 0.92; Simple Clinical Colitis Activity Index (SCCAI), p = 0.88) or blood parameters (C-reactive protein (CRP), p < 0.62; haemoglobin (Hb), p = 0.77; platelet, p = 0.64; white cell count (WCC), p = 0.59) nor did CBT significantly affect mental health, coping or quality of life (all p > 0.05).

CONCLUSIONS: Therefore, we conclude that CBT does not influence the course of IBD over 24 months. Given the high rate of attrition, particularly in the CBT group, future trials should consider a personalised approach to psychotherapy, perhaps combining online and one-to-one therapist time.

'Just to get it off my chest': Patients' views on psychotherapy in inflammatory bowel disease

Objective: This study aimed to explore patients' experiences and views on psychotherapy in relation to inflammatory bowel disease (IBD), and Crohn's disease (CD) in particular. Method: This descriptive survey study used semi-structured in-depth interviews with open-ended questions and a qualitative content analysis to summarise responses of 12 CD patients with mental health problems undergoing treatment with antidepressants. Results: Of 12 interviewed CD sufferers, only four received any form of psychotherapy. Two psychotherapy users considered it useful and beneficial. Patients who used psychotherapy with good results reported it improved their disease course, most likely due to improving patients' skills in reducing stress and thus, delaying relapse of the disease. Conclusion: Psychotherapy seems to be under used in IBD patients with mental health problems. Psychotherapy may act as a preventer of disease relapse in some patients and this observation needs to be tested with further quantitative studies. Online therapies may be the answer to limited psychotherapeutic resources in gastroenterology clinics.

A magic pill? A qualitative analysis of patients' views on the role of antidepressant therapy in inflammatory bowel disease (IBD).

BACKGROUND: Studies with healthy volunteers have demonstrated that antidepressants can improve immunoregulatory activity and thus they may have a potential to positively impact the disease course in inflammatory bowel disease (IBD), a chronic and incurable condition. However, patients' views on the role of antidepressants in the management of their IBD are unknown. Thus, this study aimed to explore patients' experiences and opinions regarding the effect of antidepressants on IBD course before possibly undertaking future treatment trials with antidepressants. METHODS: Semi-structured in-depth interviews with open-ended questions were conducted with a randomly selected sample of IBD patients recruited at the Australian public hospital IBD clinic and currently receiving antidepressants. A qualitative content analysis was undertaken to summarise patients' responses. A Visual Analogue Scale was used to provide a quantitative assessment of patients' experiences with antidepressants. RESULTS: Overall, 15 IBD sufferers currently on antidepressants (nine females, six males) were interviewed. All 15 reported a positive response to antidepressants reporting they improved their quality of life, with minimal side-effects. Five patients (33.3%) felt the antidepressant had specifically improved their IBD course. Three patients noted how they believed the reduction in feelings of stress mediated the positive influence of the antidepressant on IBD course. Ten patients (66.7%) felt the antidepressants had not specifically influenced their IBD. Nine patients (60.0%) had a generally positive attitude towards antidepressants, four patients (26.7%) were ambivalent, and two patients (13.3%) held a negative view towards antidepressants. Twelve patients (80.0%) stated that they would be willing to participate in clinical trials. CONCLUSIONS: Antidepressants seem to be well tolerated by IBD patients. One third of patients reported an observable improvement of their IBD under the influence of this treatment. The positive attitude towards antidepressants in these participants may make the conduct of clinical trials to further assess for any specific role on IBD course feasible. However, due to a small sample size, a qualitative nature of this study and in light of the results of studies on other populations indicating reluctance to taking antidepressants at least in some patients, these results should be interpreted with caution until confirmed in quantitative studies.

Stress, inflammation, and cellular vulnerability during early stages of affective disorders: biomarker strategies and opportunities for prevention and intervention

The mood disorder prodrome is conceptualized as a symptomatic, but not yet clinically diagnosable stage of an affective disorder. Although a growing area, more focused research is needed in the pediatric population to better characterize psychopathological symptoms and biological markers that can reliably identify this very early stage in the evolution of mood disorder pathology. Such information will facilitate early prevention and intervention, which has the potential to affect a person’s disease course.This review focuses on the prodromal characteristics, risk factors, and neurobiological mechanisms of mood disorders. In particular, we consider the influence of early-life stress, inflammation, and allostatic load in mediating neural mechanisms of neuroprogression. These inherently modifiable factors have known neuroadaptive and neurodegenerative implications, and consequently may provide useful biomarker targets. Identification of these factors early in the course of the disease will accordingly allow for the introduction of early interventions which augment an individual’s capacity for psychological resilience through maintenance of synaptic integrity and cellular resilience. A targeted and complementary approach to boosting both psychological and physiological resilience simultaneously during the prodromal stage of mood disorder pathology has the greatest promise for optimizing the neurodevelopmental potential of those individuals at risk of disabling mood disorders.

First, do no harm: managing the metabolic impacts of androgen deprivation in men with advanced prostate cancer

Androgen deprivation therapy (ADT) is a standard systemic treatment for men with prostate cancer. Men on ADT may be elderly and have comorbidities that are exacerbated by ADT, such as cardiovascular disease, diabetes, obesity, sedentary lifestyle and osteoporosis. Studies on managing the impacts of ADT have focused on men with non-metastatic disease, where ADT is given for a limited duration. However, some men with advanced or metastatic prostate cancer will achieve long-term survival with palliative ADT and therefore also risk morbidity from prolonged ADT. Furthermore, ADT is continued during the use of other survival-prolonging therapies for men with advanced disease, and there is a general trend to use ADT earlier in the disease course. As survival improves, management of the metabolic effects of ADT becomes important for maintaining both quality and quantity of life. This review will outline the current data, offer perspectives for management of ADT complications in men with advanced prostate cancer and discuss avenues for further research.

Gastrointestinal diseases: psycho-social aspects

An interconnection between psychological and gastrointestinal (GI) functioning has long been recognized, incorporating multiple mechanisms and considering bidirectional processes. However, exciting discoveries regarding the role of stress and depression in etiology and disease course have shed new light on the understanding of biopsychosocial processes in chronic GI conditions. This article provides an introduction to GI tract functioning, GI disorders, and stress mechanisms in the gut, followed by an overview and discussion of the psychosocial impact of these disorders, the role of stress and mental comorbidity in GI disorders, and the current knowledge regarding psychological interventions for GI disorders.

Prevention of a chronic progressive form of experimental autoimmune encephalomyelitis by an antibody against mucosal addressin cell adhesion molecule-1, given early in the course of disease progression.

A role for α4 and β7 integrins in mediating leucocyte entry into the central nervous system in the multiple sclerosis (MS)-like disease experimental autoimmune encephalomyelitis (EAE) has been demonstrated. However, the individual contributions of their respective ligands mucosal addressin cell adhesion molecule-1 (MAdCAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-cadherin expressed on the blood-brain barrier has not been determined. In the present paper, it is shown that an antibody directed against MAdCAM-1, the preferential ligand for α4β7, effectively prevented the development of a progressive, non-remitting, form of EAE, actively induced by injection of myelin oligodendrocyte glycoprotein peptide (MOG(_35-55)) autoantigen. Combinational treatment with both anti-MAdCAM-1, VCAM-1, and intercellular adhesion molecule-1 (ICAM-1) (ligand for integrin lymphocyte function-associated antigen (LFA)-1) mAbs led to more rapid remission than that obtained with anti-MAdCAM-1 antibody alone. However, neither MAdCAM-1 monotherapy, nor combinational antibody blockade was preventative when administered late in the course of disease progression. In conclusion, MAdCAM-1 plays a major contributory role in the progression of chronic EAE and is a potential therapeutic target for the treatment of MS. Critically, antivascular addressin therapy must be given eaA role for alpha4 and beta7 integrins in mediating leucocyte entry into the central nervous system in the multiple sclerosis (MS)-like disease experimental autoimmune encephalomyelitis (EAE) has been demonstrated. However, the individual contributions of their respective ligands mucosal addressin cell adhesion molecule-1 (MAdCAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-cadherin expressed on the blood-brain barrier has not been determined. In the present paper, it is shown that an antibody directed against MAdCAM-1, the preferential ligand for alpha4beta7, effectively prevented the development of a progressive, non-remitting, form of EAE, actively induced by injection of myelin oligodendrocyte glycoprotein peptide (MOG(35-55)) autoantigen. Combinational treatment with both anti-MAdCAM-1, VCAM-1, and intercellular adhesion molecule-1 (ICAM-1) (ligand for integrin lymphocyte function-associated antigen (LFA)-1) mAbs led to more rapid remission than that obtained with anti-MAdCAM-1 antibody alone. However, neither MAdCAM-1 monotherapy, nor combinational antibody blockade was preventative when administered late in the course of disease progression. In conclusion, MAdCAM-1 plays a major contributory role in the progression of chronic EAE and is a potential therapeutic target for the treatment of MS. Critically, antivascular addressin therapy must be given early in the course of disease prior to the establishment of irreversible damage if it is to be effective, as a single treatment modality.

The extent and breadth of benefits from participating in chronic disease self-management courses: a national patient-reported outcomes survey

Objective
To quantify the benefits that people receive from participating in self-management courses and identify subgroups that benefit most.

Methods
People with a wide range of chronic conditions attending self-management courses (N = 1341 individuals) were administered the Health Education Impact Questionnaire (heiQ). Baseline and follow-up data were collected resulting in 842 complete responses. Outcomes were categorized as substantial improvement (effect size, ES ≥ 0.5), minimal/no change (ES −0.49 to 0.49) and substantial decline (ES ≤ −0.5).

Results
On average, one third of participants reported substantial benefits at the end of a course and this ranged from 49% in the heiQ subscale Skill and technique acquisition to 27% in the heiQ subscale Health service navigation. Stratification by gender, age and education showed that younger participants were more likely to benefit, particularly young women. No further subgroup differences were observed.

Conclusion
While the well-being of people with chronic diseases tends to decline, about one third of participants from a wide range of backgrounds show substantial improvements in a range of skills that enable them to self-manage.

Practice implications
These data support the application of self-management courses indicating that they are a useful adjunct to usual care for a modest proportion of attendees.

Two-year combination antibiotic therapy with clarithromycin, rifabutin, and clofazimine for Crohn's disease

Background & Aims: Mycobacterium avium subspecies paratuberculosis has been proposed as a cause of Crohn’s disease. We report a prospective, parallel, placebo-controlled, double-blind, randomized trial of 2 years of clarithromycin, rifabutin, and clofazimine in active Crohn’s disease, with a further year of follow-up. Methods: Two hundred thirteen patients were randomized to clarithromycin 750 mg/day, rifabutin 450 mg/day, clofazimine 50 mg/day or placebo, in addition to a 16-week tapering course of prednisolone. Those in remission (Crohn’s Disease Activity Index ≤150) at week 16 continued their study medications in the maintenance phase of the trial. Primary end points were the proportion of patients experiencing at least 1 relapse at 12, 24, and 36 months. Results: At week 16, there were significantly more subjects in remission in the antibiotic arm (66%) than the placebo arm (50%; P = .02). Of 122 subjects entering the maintenance phase, 39% taking antibiotics experienced at least 1 relapse between weeks 16 and 52, compared with 56% taking placebo (P = .054). At week 104, the figures were 26% and 43%, respectively (P = .14). During the following year, 59% of the antibiotic group and 50% of the placebo group relapsed (P = .54). Conclusions: Using combination antibiotic therapy with clarithromycin, rifabutin, and clofazimine for up to 2 years, we did not find evidence of a sustained benefit. This finding does not support a significant role for Mycobacterium avium subspecies paratuberculosis in the pathogenesis of Crohn’s disease in the majority of patients. Short-term improvement was seen when this combination was added to corticosteroids, most likely because of nonspecific antibacterial effects.

Change of perspective: a measurable and desired outcome of chronic disease self-management intervention programs that violates the premise of preintervention/postintervention assessment

Objective: To determine if participants in chronic disease self-management courses have a change of perspective of their health status (a response shift), and if this is measurable with a paper-based questionnaire.

Methods: Nine items were developed to measure potential benefits of self-management courses. These were based on the constructs of a previous questionnaire, the Health Education Impact Questionnaire (HEI-Q). Cognitive interviews elicited spontaneous statements about the reasons for paper-based answers. Sensitivity, specificity, and overall accuracy of items were calculated using the interview as a relative gold standard. Response shift can be negative (i.e., after the course, participants realize that, before the course, they were worse than they thought they were), positive (i.e., participants now realize they were better than they thought they were), or absent (no change).

Results: Interviews (n = 39) reflected that true response shift occurred in approximately half the replies to questionnaire items. Of these, 31% were negative response shift, 20% were positive response shift. Response shift was absent in 32% of replies. Presence or absence of response shift could not be determined in 17% of replies across items. Significant concordance between questionnaires and cognitive interviews (average overall accuracy 0.79) indicated that the HEI-Q Perspective questionnaire detects response shift in participants of self-management courses. The questionnaire revealed that 87% of participants had response shift in at least 1 item.

Conclusion: This study suggests that preintervention/postintervention assessments of interventions such as self-management courses are confounded by a change in perspective of a large proportion of respondents. It also indicates response shift is a valuable outcome of self-management courses that can be measured with a paper-based questionnaire.

Dietary patterns across the life course, mammographic density and implications for breast cancer : results from a British prospective cohort

Background : Previous epidemiological studies have investigated the relationship between individual nutrients such as vitamin D and vitamin B12 and mammographic density, a strong marker of breast cancer risk [1], with varied results. There has been limited research on overall dietary patterns and most studies have focused on adult dietary patterns [2]. We examine prospective data to determine whether dietary patterns from childhood to adult life affect mammographic density.

Methods : The Medical Research Council National Survey of Health and Development is a national representative sample of 2,815 men and 2,547 women followed since their birth in March 1946 [3]. A wealth of medical and social data has been collected in over 25 follow-ups by home visits, medical examinations and postal questionnaires. Dietary intakes at age 4 years were determined by 24-hour recalls and in adulthood (ages 36, 43 years) by 5-day food records. Copies of the mammograms (two views for each breast) taken when the women were closest to age 50 years were obtained from the relevant NHS centres. A total of 1,319 women were followed up since birth in 1946 for whom a mammogram at age 50 years was retrieved, and the percentage mammographic density was measured using the computer-assisted threshold method for all 1,161 women. Breast cancer incidence for the whole cohort is being ascertained through the National Health Service Central Register.

Statistical analysis : Reduced rank regression analysis, a relatively new approach to dietary pattern analysis, is being used to identify dietary patterns associated with mammographic density [4]. This approach identifies patterns in food intake that are predictive of an intermediate outcome of the disease process, such as mammographic density, and subsequently examines the relationship between the identified dietary patterns and breast cancer risk.

Results : Preliminary analyses so far suggest that variations in dietary patterns in adulthood might explain more than 10% of the variation in percentage mammographic density at age 50 years (age 36 years: 13%; age 43 years: 14%), with variations in patterns in childhood explaining slightly less. Further work is being carried out on the characteristics of these dietary patterns and their effects on percentage mammographic density and its two components (that is, absolute areas of dense and nondense tissues) and on breast cancer risk, after adjusting for socioeconomic status, anthropometric variables and reproductive factors.

Conclusion : The present study will provide for the first time information on the relationship between dietary patterns across the life course and mammographic density, and will help to clarify the pathways through which diet may affect breast cancer risk.

Who benefits most from participating in chronic disease self-management programs?

Objectives: To quantify the benefits that people receive from participating in self-management courses and identify subgroups that benefit most.
Research Design: People with a wide range of chronic conditions attending self-management courses (N=1,341 individuals) were administered the generic Health Education Impact Questionnaire (HEI-Q). Data were collected before the first session (baseline) and at the end of courses (follow-up) resulting in 842 complete responses. The median (interquartile range) age was 64 (54 to 73) years and most participants were female (75%). Outcomes were categorized as Substantial improvement (Effect Size, ES ≥ 0.5), Minimal/No change (ES -0.49 to 0.49) and Substantial decline (ES ≤ -0.5).
Results: On average, one third of participants reported substantial benefits after attending a self-management course. Proportions of participants reporting substantial benefits ranged from 49% in Skill and technique acquisition to 27% in Health service navigation. Stratification by gender, age and education showed that younger participants were more likely to benefit, particularly young women. No further subgroup differences were observed.
Conclusions: Given that the health of people with chronic diseases tends to decline, this evaluation is reassuring in that about one third of participants coming from a wide range of backgrounds receive substantial improvements in their self-management skills.