A mechanistic basis for converting a receptor tyrosine kinase agonist to an antagonist

Hepatocyte growth factor (HGF) activates the Met receptor tyrosine kinase by binding and promoting receptor dimerization. Here we describe a mechanistic basis for designing Met antagonists based on NK1, a natural variant of HGF containing the N-terminal and the first kringle domain. Through detailed biochemical and structural analyses, we demonstrate that both mouse and human NK1 induce Met dimerization via a conserved NK1 dimer interface. Mutations designed to alter the NK1 dimer interface abolish its ability to promote Met dimerization but retain full Met-binding activity. Importantly, these NK1 mutants act as Met antagonists by inhibiting HGF-mediated cell scattering, proliferation, branching, and invasion. The ability to separate the Met-binding activity of NK1 from its Met dimerization activity thus provides a rational basis for designing Met antagonists. This strategy of antagonist design may be applicable for other growth factor receptors by selectively abolishing the receptor activation ability but not the receptor binding of the growth factors.     

Multidisciplinary approach to fibromyalgia A pilot study

Summary The aim of the study was to instruct a group of fibromyalgia patients how to solve problems related to activities of daily life. Sixteen female fibromyalgia patients completed a ten week multidisciplinary program, consisting of a cognitive and an exercise part. After ten weeks a reduction in general pain intensity (p<0.05) was found. At six months follow-up sensory (somatic) pain intensity was reduced compared to baseline recordings (p=0.05). All patients had made adjustments to their everyday life after ten weeks. Eight patients reported that they regularly practised relaxation techniques, and seven patients had undertaken dietary changes. Thus, the study shows that adjustment of activities in daily living may reduce pain in patients with fibromyalgia. Controlled studies are needed in the future.     

Generalized pain, fibromyalgia and regional pain: an epidemiological view.

Generalized pain, which is one component of the fibromyalgia syndrome, is a common and disabling problem in the general population. Pain at individual sites, such as the lower back and shoulder, has traditionally been considered distinct from generalized pain and studied separately. This chapter considers first the basic definition and distribution of widespread pain in the population, and second examines the evidence as to whether widespread and regional pain are truly or usefully distinguished.     

Clinical evidence and mechanistic basis for vildagliptin's action when added to metformin

Several new oral antidiabetic agents, known as 'gliptins' or 'enzyme dipeptidyl peptidase-IV (DPP-4) inhibitors', have been developed for the treatment of type 2 diabetes and a key clinical use of the gliptins is in combination with metformin. There are important differences in the kinetics of the interaction of different gliptins with the catalytic site of DPP-4, which may lead to varying pharmacokinetics, pharmacodynamics and dosing regimens. Therefore, individual gliptins need to be characterized and here we discuss the extensively studied DPP-4 inhibitor vildagliptin, which has binding characteristics that ensure inhibition of the enzyme beyond the presence of detectable drug levels in plasma. As vildagliptin has been used most often at doses of 50 mg once or twice daily, in combination with metformin, this review focuses on these dose regimens. All clinical trials employing vildagliptin (50 mg once or twice daily) as an add-on therapy to metformin (identified by MEDLINE search using keywords vildagliptin and metformin or known by authors to be in press) are reviewed, as is current knowledge of the mechanism of action of vildagliptin. Vildagliptin added to a stable dose of metformin elicits a dose-related decrease in both HbA1c and fasting plasma glucose. The additional efficacy seen with 50 mg twice daily [ΔHbA1c ～- 1.1% (-12.1 mmol/mol)] relative to 50 mg once daily [ΔHbA1c ～- 0.7% (-7.7 mmol/mol)] is attributable to an overnight effect of the evening dose of vildagliptin, with prolonged DPP-4 inhibition and elevated fasting levels of the intact and insulinotropic form of glucagon-like peptide-1 (GLP-1). Vildagliptin's therapeutic actions are primarily mediated by GLP-1 and metformin enhances vildagliptin's effect to raise plasma levels of intact GLP-1. Vildagliptin is weight-neutral and has a very low hypoglycaemic potential, explained by its remarkable ability to enhance both α-cell and β-cell sensitivity to glucose. Therefore, vildagliptin offers a clinically important outcome when added to metformin with a twice daily dose regimen, taking advantage of its tight binding and slow dissociation characteristics that lead to a sustained overnight effect.     

Psychological disturbance in fibromyalgia: Relation to pain severity

Summary Fibromyalgia is a form of nonarticular rheumatism characterized by musculoskeletal aching and tenderness on palpation. The role of psychological factors in fibromyalgia has been controversial. The aim of this study was to evaluate the relationship of fibromyalgia to the intensity of anxiety and depression and to determine the correlation between psychological disturbances with disease duration and pain severity.Thirty-nine patients with fibromyalgia and 36 healthy controls were included in this study. Beck depression inventory, State and trait anxiety inventory and Beck hopelessness scale were used to evaluate psychological disturbances. Visual analog scale was used to determine pain intensity.We found a significant difference in the psychological status between patients with fibromyalgia and control subjects as measured by Beck depression inventory and trait anxiety inventory; 35.9% of the patients scored higher than the cut-off score on the Beck depression rating scale. Pain severity was found to be correlated with trait anxiety inventory scores. These results suggest that somatic expression of depression is an important difference between fibromyalgia and control groups. The difference between state and trait anxiety inventory reflects that current anxiety is not secondary to pain but trait anxiety is possibly causally related to pain.     

A realistic approach to managing patients with fibromyalgia

Fibromyalgia syndrome is common and variable in impact, with some patients having a milder and shorter duration of symptoms and others suffering significant and prolonged pain. Disability also varies. It is thought that the syndrome arises from a disordered neurophysiology that, through links to central control inputs, involves emotions, thoughts, and cognitions. Social and psychological sequelae contribute to and result from this process. The biopsychosocial model of disease epitomizes fibromyalgia. Although management may be difficult at times, and much needs to be done, the growing appreciation of strategies that use this described model and the knowledge of the potential reversibility of the syndrome are resulting in improved outcomes.     

The cancer-family syndrome: A pragmatic basis for syndrome identification

Summary We report a family manifesting the cancer-family syndrome in which 11 family members had colonic carcinomas (predominantly involving the proximal colon, in the absence of polyposis), with an average age at onset of 35 years. Three women had endometrial or endocervical cancers. The kindred is notable in that its full evaluation was predicated upon the recognition of features consistent with the cancer-family syndrome in only two sisters. The ascertainment and evaluation of the kindred demonstrates the clinical utility of regarding such criteria (early cancer onset, multiple primary cancers, proximal colonic involvement) as a basis for selecting cases for more thorough family-history evaluation. Although such selection criteria are not pathognomonic for the syndrome, identification of a more extensive family cancer history sometimes enables the initiation of a highly specific cancer surveillance program. Specific attention has been given to the problems of screening patients at risk for the development of proximal colonic cancer, an important feature of the cancer-family syndrome. Innovative operative management is also indicated, such as total colectomy for initial colonic cancer, and consideration of prophylactic hysterectomy for women with colonic cancer (because of the high risk of development of endometrial carcinoma).     

Subgrouping of fibromyalgia patients on the basis of pressure‐pain thresholds and psychological factors

Objective

Although the American College of Rheumatology (ACR) criteria for fibromyalgia are used to identify individuals with both widespread pain and tenderness, individuals who meet these criteria are not a homogeneous group. Patients differ in their accompanying clinical symptoms, as well as in the relative contributions of biologic, psychological, and cognitive factors to their symptom expression. Therefore, it seems useful to identify subsets of fibromyalgia patients on the basis of which of these factors are present. Previous attempts at identifying subsets have been based solely on psychological and cognitive features. In this study, we attempt to identify patient subsets by incorporating these features as well as the degree of hyperalgesia/tenderness, which is a key neurobiologic feature of this illness.

Methods

Ninety‐seven individuals meeting the ACR criteria for fibromyalgia finished the same battery of self‐report and evoked‐pain testing. Analyzed variables were obtained from several domains, consisting of 1) mood (evaluated by the Center for Epidemiologic Studies Depression Scale [for depression] and the State‐Trait Personality Inventory [for symptoms of trait‐related anxiety]), 2) cognition (by the catastrophizing and control of pain subscales of the Coping Strategies Questionnaire), and 3) hyperalgesia/tenderness (by dolorimetry and random pressure‐pain applied at suprathreshold values). Cluster analytic procedures were used to distinguish subgroups of fibromyalgia patients based on these domains.

Results

Three clusters best fit the data. Multivariate analysis of variance (ANOVA) confirmed that each variable was differentiated by the cluster solution (Wilks' λ [degrees of freedom 6,89] = 0.123, P < 0.0001), with univariate ANOVAs also indicating significant differences (all P < 0.05). One subgroup of patients (n = 50) was characterized by moderate mood ratings, moderate levels of catastrophizing and perceived control over pain, and low levels of tenderness. A second subgroup (n = 31) displayed significantly elevated values on the mood assessments, the highest values on the catastrophizing subscale, the lowest values for perceived control over pain, and high levels of tenderness. The third group (n = 16) had normal mood ratings, very low levels of catastrophizing, and the highest level of perceived control over pain, but these subjects showed extreme tenderness on evoked‐pain testing.

Conclusion

These data help support the clinical impression that there are distinct subgroups of patients with fibromyalgia. There appears to be a group of fibromyalgia patients who exhibit extreme tenderness but lack any associated psychological/cognitive factors, an intermediate group who display moderate tenderness and have normal mood, and a group in whom mood and cognitive factors may be significantly influencing the symptom report.

     

Psychological therapies for chronic widespread pain and fibromyalgia syndrome

Psychological factors such as adverse childhood experiences, traumatic life events, interpersonal conflicts and psychological distress play an important role in the predisposition, onset and severity of chronic widespread pain (CWP) and fibromyalgia syndrome (FMS). Therefore, psychological therapies might have the potential to reduce disability as well as symptom and economic burden in patients with CWP and FMS. Recent interdisciplinary guidelines have suggested different strengths of recommendation for psychological therapies for FMS. The aims of this narrative review are to summarise:• Mechanisms of actions.• Evidence on efficacy, tolerability and safety.• Knowledge gaps and needs for future researchof psychological therapies for CWP and FMS for non-mental health professionals.     

Tapering biologics in rheumatoid arthritis: a pragmatic approach for clinical practice

Optimal rheumatoid arthritis (RA) therapy in daily clinical practice is based on the treat-to-target strategy. Quicker escalation of therapy and earlier introduction of biological disease-modifying anti-rheumatic drugs have led to improved outcomes in RA. However, chronic immunosuppressive therapy is associated with adverse events and higher costs. In addition, our patients frequently express a desire for lower dosing and drug holidays. Current clinical practice guidelines from the American College of Rheumatology and European League Against Rheumatism suggest that rheumatologists consider tapering treatment after achieving remission. However, the optimal approach for tapering therapy in RA, specifically de-escalation of biologics, remains unknown. This clinical review discusses biologic tapering strategies in RA. We draw our recommendations for everyday clinical practice from the most recent observational, pragmatic, and controlled clinical trials on de-escalation of biologics in RA. For each biologic, we highlight clinically relevant outcomes, such as flare rates, recapture of the disease control with retreatment, radiographic progression, side effects, and functional impact. We discuss the use of musculoskeletal ultrasound to select patients for successful tapering. In conclusion, we provide the reader with a practical guide for tapering biologics in the rheumatology clinic.     

Use of neuroimaging to understand abnormal pain sensitivity in fibromyalgia

This paper examines the use of neuroimaging to measure change in regional cerebral blood flow (rCBF) produced by pain in patients with fibromyalgia and in healthy individuals. Fibromyalgia patients differ from healthy persons in rCBF distribution in several brain structures involved in pain processing and pain modulation both at rest and during experimental pain induction. These abnormalities may contribute to abnormal pain sensitivity as well as the maladaptive pain behaviors that characterize many patients with fibromyalgia. We anticipate that future neuroimaging studies will enhance our understanding of abnormal pain sensitivity and of pain management interventions aimed at altering central nervous system function in patients with fibromyalgia.     

Catastrophizing and pain in arthritis, fibromyalgia, and other rheumatic diseases

OBJECTIVE: Pain is among the most frequently reported, bothersome, and disabling symptoms described by patients with osteoarthritis, rheumatoid arthritis, fibromyalgia, and other musculoskeletal conditions. This review describes a growing body of literature relating catastrophizing, a set of cognitive and emotional processes encompassing magnification of pain-related stimuli, feelings of helplessness, and a generally pessimistic orientation, to the experience of pain and pain-related sequelae across several rheumatic diseases. METHODS: We reviewed published articles in which pain-related catastrophizing was assessed in the context of one or more rheumatic conditions. Because much of the available information on catastrophizing is derived from the more general chronic pain literature, seminal studies in other disease states were also considered. RESULTS: Catastrophizing is positively related, in both cross-sectional and prospective studies across different musculoskeletal conditions, to the reported severity of pain, affective distress, muscle and joint tenderness, pain-related disability, poor outcomes of pain treatment, and, potentially, to inflammatory disease activity. Moreover, these associations generally persist after controlling for symptoms of depression. There appear to be multiple mechanisms by which catastrophizing exerts its harmful effects, from maladaptive influences on the social environment to direct amplification of the central nervous system's processing of pain. CONCLUSION: Catastrophizing is a critically important variable in understanding the experience of pain in rheumatologic disorders as well as other chronic pain conditions. Pain-related catastrophizing may be an important target for both psychosocial and pharmacologic treatment of pain.