Loss of integrin α3 prevents skin tumor formation by promoting epidermal turnover and depletion of slow-cycling cells.

Progression through the various stages of skin tumorigenesis is correlated with an altered expression of the integrin α3ß1, suggesting that it plays an important role in the tumorigenic process. Using epidermis-specific Itga3 KO mice subjected to the 7,12-dimethylbenzanthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate two-stage skin carcinogenesis protocol, we demonstrate that efficient tumor development is critically dependent on the presence of α3ß1. In the absence of α3ß1, tumor initiation is dramatically decreased because of increased epidermal turnover, leading to a loss of DMBA-initiated label-retaining keratinocytes. Lineage tracing revealed emigration of α3-deficient keratinocytes residing in the bulge of the hair follicle toward the interfollicular epidermis. Furthermore, tumor growth and cell proliferation were strongly reduced in mice with an epidermis-specific deletion of Itga3. However, the rate of progression of α3ß1-null squamous cell carcinomas to undifferentiated, invasive carcinomas was increased. Therefore, α3ß1 critically affects skin carcinogenesis with opposing effects early and late in tumorigenesis.

Meta-analysis of tight control strategies in rheumatoid arthritis: protocolized treatment has additional value with respect to the clinical outcome.

OBJECTIVES: Tight control studies including regular assessments of disease activity have shown that this approach has beneficial effects on disease activity, disability and joint damage in treating RA patients. Some of these studies included tight control with protocolized treatment, while others applied tight control without protocolized treatment. The aim of this study was to compare the effects of tight control with usual care and to compare the effects of tight control studies with and without protocolized treatment adjustments. METHODS: A systematic literature search was performed to identify clinical trials in RA that evaluated tight control strategies in comparison with usual care. Two types of study were compared: (i) those using disease activity monitoring with protocolized treatment adjustments, and (ii) those using disease activity monitoring without protocolized treatment adjustments. The databases PubMed and Cochrane were searched from 1995 up to 2009. Primary outcome measure was the mean change in the 28-joint DAS (DAS-28), which was used in a random-effects meta-analysis. RESULTS: Six controlled trials regarding tight control in RA patients were included in the meta-analysis. In all trials, patients treated in the tight control arms had significantly higher DAS-28 responses than patients treated according to usual care [weighted mean difference (WMD) = 0.59, P < 0.001]. Moreover, tight control was significantly more effective (P < 0.001) by means of protocolized treatment adjustments (WMD = 0.97) compared with non-protocolized monitoring of disease activity (WMD = 0.25). CONCLUSION: Tight control in RA resulted in significantly better clinical outcomes than usual care. It is suggested but not proved that tight control with protocolized treatment adjustments is more beneficial than if no such protocol is used.

How to improve DAS28 use in daily clinical practice?--a pilot study of a nurse-led intervention.

OBJECTIVES: To determine whether DAS28 measurements by a specialized nurse, before the rheumatologist visit, in combination with the advice to rheumatologists to reach a DAS28 < or = 3.2, had beneficial effects on disease activity and medication prescription in patients with RA and to explore possible predictors for variation in medication changes and reasons for non-adherence to the advice to reach a DAS28 < or = 3.2. METHODS: In this pilot study, rheumatologists were randomized to 'usual care' (n = 3) or DAS28 measurement by a nurse prior the rheumatologist visit (n = 4). In the usual care group, the DAS28 was measured but not provided to rheumatologists. Mixed model analyses were used for analysing between-group differences and for the prediction model. Rheumatologists in the intervention group were asked to provide reasons in cases of non-adherence to the advice. RESULTS: After 18 months, DAS28 was reduced by - 0.69 and - 0.66 (P = 0.70) in, respectively, the intervention (144 patients) and the usual care (104 patients) groups. In the intervention group, medication was changed by rheumatologists in 35% of the visits with a DAS28 > 3.2; in the usual care group this was 33% (P = 0.99). Baseline DAS28 (OR 1.6; P< or =0.0001) and HAQ (OR 1.3; P = 0.03) were positively related to a medication change. The most frequently mentioned reason not to change medication was patient refusal (26%). CONCLUSIONS: DAS28 measurement by a nurse was as effective as usual care; however, this intervention without protocolized treatment adjustments is not sufficient to lead to a considerable reduction in disease activity compared with trials with protocolized treatment adjustments.

Disease activity-based management of rheumatoid arthritis in Dutch daily clinical practice has improved over the past decade.

To re-evaluate the adherence to clinical practice guidelines recommended disease activity-based management of rheumatoid arthritis (RA) in daily clinical practice, among Dutch rheumatologists in the past decade. In 2007, disease activity was measured in only 16% of outpatient visits. All rheumatologists that participated in the 2007 study were invited to re-enter our study in 2016/2017. If necessary, data were supplemented with data from other rheumatologists. For all 26 rheumatologists who agreed to participate in our study, data were collected from 30 consecutive patients that visited the outpatient clinic. Per patient, data from four consecutive rheumatologist outpatient visits were collected. Since 2007, disease activity was measured more frequently in Dutch daily clinical practice, increasing from 16 to 79% of visits (2440/3081 visits). In addition, intensification of medication based on disease activity scores increased from 33 to 50% of visits (260/525 visits). DAS/DAS28 was the most frequently used disease activity measure (1596/2440 visits). There was a wide variation among rheumatologists in measuring disease activity and intensification of medication, 20-100% and 0-75% respectively. Over the past years, there has been a large improvement in disease activity assessment in daily clinical practice. Disease activity-based medication intensifications, also called tight control or treat to target, increased to a lesser extent. Large variation between different rheumatologists and clinics indicates that there is still room for improvement. Key Points • Following guideline dissemination disease activity is assessed more frequently (79%). • There is large variation between rheumatologists, indicating room for improvement. • Finding factors that explain variation is necessary to improve tight control in daily practice.

Reduced susceptibility to two-stage skin carcinogenesis in mice with epidermis-specific deletion of CD151.

Altered expression of the tetraspanin CD151 is associated with skin tumorigenesis; however, whether CD151 is causally involved in the tumorigenic process is not known. To evaluate its role in tumor formation, we subjected epidermis-specific Cd151 knockout mice to chemical skin carcinogenesis. Mice lacking epidermal Cd151 developed fewer and smaller tumors than wild-type mice after treatment with 7,12-dimethylbenzanthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA). Furthermore, Cd151-null epidermis showed a reduced hyperproliferative response to short-term treatment with TPA as compared with wild-type skin, whereas epidermal turnover was increased. Tumors were formed in equal numbers after DMBA-only treatment. We suggest that DMBA-initiated keratinocytes lacking Cd151 leave their niches in the epidermis and hair follicles in response to TPA treatment and subsequently are lost by differentiation. Because genetic ablation of Itga3 also reduced skin tumor formation, we tested whether reduced expression of α3 could further suppress tumor formation in epidermis-specific Cd151 knockout mice. Although DMBA/TPA-induced formation of skin tumors was similar in compound heterozygotes for Cd151 and Itga3 to that in wild-type mice, heterozygosity for Itga3 on a Cd151-null background diminished tumorigenesis, suggesting genetic interaction between the two genes. We thus identify CD151 as a critical factor in TPA-dependent skin carcinogenesis.

Factors that influence rheumatologists' decisions to escalate care in rheumatoid arthritis: results from a choice-based conjoint analysis.

OBJECTIVE: In order to improve adherence to treatment guidelines and performance indicators advocating tight control of disease activity in rheumatoid arthritis (RA), it is important to gain insight into the factors influencing rheumatologists' decisions whether or not to escalate care. Our objective was to determine the influence of specific attributes relative to a validated measure of disease activity (the Disease Activity Score [DAS]) on rheumatologists' decisions to escalate care. METHODS: We used a computer-based choice-based conjoint analysis survey to determine the relative importance of 6 attributes on rheumatologists' decisions related to escalation of care in RA. We administered the survey in a convenience sample of rheumatologists attending the 2008 American College of Rheumatology Annual Scientific Meeting. Utilities were calculated using hierarchical Bayes modeling, and these results were used to calculate the relative importance of each attribute. RESULTS: Rheumatologists assigned the most importance to the DAS score (relative importance of 30.7%) in their decision to escalate care. The age of the patient (21.5%) and erosions (20.5%) were rated as equally important in this decision. The decision to escalate care was least influenced by change in symptoms reported by the patient (11.1%), current treatment (8.9%), and disease duration (7.4%). CONCLUSION: Our findings suggest that rheumatologists endorse the DAS as a means to guide decision making in RA. We also found that age and erosions are important influences on rheumatologists' decisions to escalate care in RA. Our results add to the literature supporting age bias in RA and suggest that further research is needed to determine how age affects quality of care in clinical practice.