Reasons for Dermatology Consultations in Nursing Homes and the Estimated Potential of Teledermatology as a Triage Tool.

Considering the limited availability of dermatologists to perform live consultations in nursing homes, teledermatology could be used as a triage tool for selection of cases for which live consultations are considered to be of added value compared with teledermatology. This prospective, multicentre observational study aimed to determine the reasons for dermatology consultations in nursing homes and the estimated value of teledermatology as a triage tool, including potential predictors. Skin tumours were the most common reason (n = 161/270; 59.6%) for dermatology consultations in nursing homes. Dermatologists estimated that live consultations added value compared with teledermatology in 67.8% of cases (n = 183). Multivariable logistic regression showed that predictors for this added value of live consultations were: consultations because of a skin tumour; consultations during which a diagnostic or treatment procedure was performed; consultations during which a secondary diagnosis was made; and the dermatologist involved. These results indicate that using teledermatology as a triage tool potentially reduces the need for additional live consultations in one-third of patients, whereas live consultations are estimated to have added value over teledermatology in two-thirds of cases. To make optimal use of the limited capacity for live consultations by dermatologists, it could therefore be helpful if elderly care physicians use teledermatology more frequently.

High-Dose Intravenous Pulse Methotrexate in Patients With Eosinophilic Fasciitis.

Importance: Eosinophilic fasciitis (EF) is a connective tissue disorder in which conventional treatment leads to disappointing results in a proportion of patients. Therefore, we investigated high-dose intravenous (IV) pulse methotrexate (MTX) as a treatment for EF. Objective: To examine safety and effects of monthly high-dose IV pulse MTX in EF. Design, Setting, and Participants: For this prospective single-arm study, we recruited 12 patients diagnosed with biopsy specimen-proven EF between 2006 and 2009 from the Department of Dermatology and Rheumatology at the Radboud University Medical Centre. Interventions: Intravenous MTX (4 mg/kg) monthly for 5 months with folinic acid rescue 24 hours after MTX administration. Main Outcomes and Measures: The primary outcome was improvement of the modified skin score at month 5 vs baseline. Secondary outcomes were durometry, range of motion, visual analog scale scores for disease activity, and 36-Item Short Form Survey health questionnaires. Results: Overall, 12 patients (11 women between 37-69 years old) received a median (range) monthly dose of 288 (230-336) mg MTX. Median (range) modified skin score improved from 17.5 (8.0-24.0) at baseline to 8.5 (1.0-20.0) at month 5 (P = .001). Secondary outcome measures improved significantly, except for durometer scores and range of motion of the elbows. Adverse events included gastrointestinal symptoms (n = 9), mild stomatitis (n = 5), and alopecia (n = 4). Conclusions and Relevance: High-dose IV pulse MTX is a safe and effective treatment option in EF. Trial Registration: clinicaltrials.gov Identifier: NCT00441961.

Are ultrasonographic signs of inflammation predictors for response to intra-articular glucocorticoids in knee osteoarthritis?

OBJECTIVES: To investigate the predictive value of ultrasound (US) characteristics for the effect of intra-articular glucocorticoids in knee osteoarthritis (OA). METHODS: In this prospective cohort study, 62 patients with symptomatic knee OA (clinical knee OA criteria, pain>4 on a Numerical Rating Scale (NRS; 0-10)) received an intra-articular glucocorticoid injection (40 mg triamcinolone acetonide). Patients with NRS pain ≤4 at 4 weeks were defined as responders. On inclusion, demographics, clinical data (body mass index, local swelling) knee x-rays and knee injury and Osteoarthritis Outcome Score (KOOS) questionnaire were collected. Six US features were assessed including: effusion, synovial hypertrophy, Baker's cyst, infrapatellar bursitis, meniscal protrusion and cartilage thickness. Stepwise multiple logistic regression analyses with forward selection were conducted to identify possible predictors. RESULTS: At 4 weeks, 42% of the study participants reached a NRS ≤4; an effect comparable to existing literature. Regression analyses showed that patients who used analgesics at baseline were less likely to have a good response. The small proportion of patients with infrapatellar bursitis was more likely to respond to the injection. CONCLUSIONS: No patient, disease or US characteristic of inflammation, turned out to be a reliable and clinically meaningful predictor for the effect of intra-articular glucocorticoids after four weeks in knee OA.

Ultrasonographic analysis in knee osteoarthritis: evaluation of inter-observer reliability.

OBJECTIVES: Evidence for the validity of US in detecting structural joint pathology in OA is increasing. However, despite the rapidly emerging field of US in OA, few studies have reported on the inter-observer reliability of US to date. The objective of this study was to assess inter-observer reliability of ultrasonography (US) in the evaluation of specifically defined features in osteoarthritis (OA) of the knee. METHODS: US was performed independently by two rheumatologists in 60 outpatients fulfilling the American College of Rheumatology clinical criteria for knee OA. The acquisition protocol comprised medial meniscus protrusion, synovial hypertrophy, effusion, infrapatellar bursitis and cartilage thickness. Cartilage thickness and meniscal protrusion (if >3 mm) were measured on a continuous scale, all other variables were scored dichotomously. RESULTS: Inter-observer agreement (κ-value) was moderate for protrusion of the medial meniscus (0.54), good for infrapatellar bursitis (0.66) and effusion (0.74), excellent for Bakers' cyst (0.85) and poor for the detection of synovial hypertrophy (-0.08). Inter-observer reliability was good for the measurement of medial meniscus protrusion (correlation coefficient 0.80, 95% limits of agreement -1.93 to 1.94 mm) and cartilage thickness (correlation coefficient 0.62 and 0.68, 95% limits of agreement -0.87 to 0.84 mm and -0.77 to 0.96 mm at the medial and lateral condyle respectively). CONCLUSIONS: This study demonstrated good reproducibility of US in the assessment of the majority of the investigated mechanical, inflammatory and degenerative features of knee OA, and contributes to exploring the use of US in knee OA as a useful tool in research as well as in clinical practice.

Celecoxib: considerations regarding its potential disease-modifying properties in osteoarthritis.

Osteoarthritis (OA) is a degenerative joint disease characterized by progressive loss of articular cartilage, subchondral bone sclerosis, osteophyte formation, and synovial inflammation, causing substantial physical disability, impaired quality of life, and significant health care utilization. Traditionally, non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase (COX)-2 inhibitors, have been used to treat pain and inflammation in OA. Besides its anti-inflammatory properties, evidence is accumulating that celecoxib, one of the selective COX-2 inhibitors, has additional disease-modifying effects. Celecoxib was shown to affect all structures involved in OA pathogenesis: cartilage, bone, and synovium. As well as COX-2 inhibition, evidence indicates that celecoxib also modulates COX-2-independent signal transduction pathways. These findings raise the question of whether celecoxib, and potentially other coxibs, is more than just an anti-inflammatory and analgesic drug. Can celecoxib be considered a disease-modifying osteoarthritic drug? In this review, these direct effects of celecoxib on cartilage, bone, and synoviocytes in OA treatment are discussed.

Collagen XXIII, novel ligand for integrin alpha2beta1 in the epidermis.

Cellular receptors for collagens belong to the family of ß(1) integrins. In the epidermis, integrin α(2)ß(1) is the only collagen-binding integrin present. Its expression is restricted to basal keratinocytes with uniform distribution on the cell surface of those cells. Although α(2)ß(1) receptors localized at the basal surface interact with basement membrane proteins collagen IV and laminin 111 and 332, no interaction partners have been reported for these integrin molecules at the lateral and apical membranes of basal keratinocytes. Solid phase binding and surface plasmon resonance spectroscopy demonstrate that collagen XXIII, a member of the transmembrane collagens, directly interacts with integrin α(2)ß(1) in an ion- and conformation-dependent manner. The two proteins co-localize on the surface of basal keratinocytes. Furthermore, collagen XXIII is sufficient to induce adhesion and spreading of keratinocytes, a process that is significantly reduced in the absence of functional integrin α(2)ß(1).

Defective granulation tissue formation in mice with specific ablation of integrin-linked kinase in fibroblasts - role of TGFß1 levels and RhoA activity.

Wound healing crucially relies on the mechanical activity of fibroblasts responding to TGFß1 and to forces transmitted across focal adhesions. Integrin-linked kinase (ILK) is a central adapter recruited to integrin ß1 tails in focal adhesions mediating the communication between cells and extracellular matrix. Here, we show that fibroblast-restricted inactivation of ILK in mice leads to impaired healing due to a severe reduction in the number of myofibroblasts, whereas inflammatory infiltrate and vascularization of the granulation tissue are unaffected. Primary ILK-deficient fibroblasts exhibit severely reduced levels of extracellular TGFß1, α-smooth muscle actin (αSMA) production and myofibroblast conversion, which are rescued by exogenous TGFß1. They are further characterized by elevated RhoA and low Rac1 activities, resulting in abnormal shape and reduced directional migration. Interference with RhoA-ROCK signaling largely restores morphology, migration and TGFß1 levels. We conclude that, in fibroblasts, ILK is crucial for limiting RhoA activity, thus promoting TGFß1 production, which is essential for dermal repair following injury.

Integrin alpha2beta1 is required for regulation of murine wound angiogenesis but is dispensable for reepithelialization.

The alpha2beta1 integrin functions as the major receptor for collagen type I on a large number of different cell types, including keratinocytes, fibroblasts, endothelial cells, and a variety of inflammatory cells. Recently, we demonstrated that adhesion of keratinocytes to collagen critically depends on alpha2beta1, whereas fibroblasts can partly compensate for loss of alpha2beta1 in simple adhesion to collagen. However, in three-dimensional collagen matrices, alpha2beta1-null fibroblasts are hampered in generating mechanical forces. These data suggested a pivotal role for alpha2beta1 during wound healing in vivo. Unexpectedly, reepithelialization of excisional wounds of alpha2beta1-null mice was not impaired, indicating that keratinocytes do not require adhesion to or migration on collagen for wound closure. Whereas wound contraction and myofibroblast differentiation were similar, wound tensile strain was reduced in alpha2beta1-null mice, suggesting subtle changes in organization of the extracellular matrix. In addition, we observed reduced influx of mast cells into the granulation tissue, whereas infiltration of other inflammatory cells was not impaired. Interestingly, ablation of alpha2beta1 resulted in strong enhancement of neovascularization of granulation tissue and sponge implants. Both ultrastructurally and functionally, these new blood vessels appeared intact. In conclusion, our data show unique and overlapping functions of alpha2beta1 integrin during murine cutaneous wound healing.

Mechanical tension and integrin alpha 2 beta 1 regulate fibroblast functions.

The extracellular matrix (ECM) environment in connective tissues provides fibroblasts with a structural scaffold and modulates cell shape, but it also profoundly influences the fibroblast phenotype. Here we studied fibroblasts cultured in a three-dimensional network of native collagen, which was either mechanically stressed or relaxed. Mechanical load induces fibroblasts that synthesize abundant ECM and a characteristic array of cytokines/chemokines. This phenotype is reminiscent of late granulation tissue or scleroderma fibroblasts. By contrast, relaxed fibroblasts are characterized by induction of proteases and a subset of cytokines that does not overlap with that of mechanically stimulated cells. Thus, the biochemical composition and physical nature of the ECM exert powerful control over the phenotypes of fibroblasts, ranging from "synthetic" to "inflammatory" phenotypes. Interactions between fibroblasts and collagen fibrils are mostly mediated by a subset of beta 1 integrin receptors. Fibroblasts utilize alpha 1 beta 1, alpha 2 beta 1, and alpha 11 beta 1 integrins for establishing collagen contacts and transducing signals. In vitro assays and mouse genetics have demonstrated individual tasks served by each receptor, but also functional redundancy. Unraveling the integrated functions of fibroblasts, collagen integrin receptors, collagen fibrils, and mechanical tension will be important to understand the molecular mechanisms underlying tissue repair and fibrosis.

Integrin alpha2beta1 deficiency does not affect contact hypersensitivity.

Collagens in the extracellular matrix are thought to play an important role in regulating inflammatory responses by affecting cell adhesion and migration. The contact between collagens and cells is established mainly by alpha1beta1, alpha2beta1 and alpha11beta1integrin receptors. Here, we analyzed the contact hypersensitivity (CHS) reaction in mice that were genetically deficient in the collagen receptor alpha2beta1. Integrin alpha2beta1 is widely expressed and has been suggested to play an important role in mediating inflammatory responses. CHS was induced by applying dinitrofluorobenzene to abdominal skin and challenging with the same reagent on ear skin. Macroscopically and histologically, ear swelling in alpha2beta1-deficient mice did not differ from that in wild-type control mice. Immunohistological detection of infiltrated T lymphocytes, neutrophils and mast cells in inflamed ear skin revealed similar numbers in controls and integrin alpha2beta1-deficient animals. Our results suggest that the adhesive functions of integrin alpha2beta1 are dispensable for the CHS response; they may be compensated for by the collagen receptor alpha1beta1 or other collagen receptors.

Abdominal aortic aneurysm is associated with high serum levels of tenascin-X and decreased aneurysmal tissue tenascin-X.

BACKGROUND: Tenascin-X is a large extracellular matrix protein that is abundantly expressed in several connective tissues. A 140-kDa C-terminal fragment of tenascin-X is present in human serum. Complete deficiency of tenascin-X is associated with Ehlers-Danlos syndrome, and these patients show major connective tissue alterations in their skin, as well as blood vessel fragility. In this study, we investigated whether tenascin-X is present in normal human aorta and abdominal aortic aneurysm (AAA) tissues and whether an association exists between serum tenascin-X levels and AAA. METHODS AND RESULTS: Five normal aortas and 5 AAA tissues were immunostained for tenascin-X and elastin. Tenascin-X was present throughout the entire aorta and was especially abundant near the elastic lamellae, whereas tenascin-X expression was strongly decreased in AAA tissue. Measurement of tenascin-X serum concentration by enzyme-linked immunosorbent assay (ELISA) in 87 AAA patients and 86 controls demonstrated an increasing risk for AAA with increasing tenascin-X serum concentrations. After adjustment for established risk factors, tenascin-X serum concentrations in the highest quartile were associated with a 5-fold increase in risk of AAA (odds ratio, 5.3; 95% confidence interval, 2.0 to 13.8). CONCLUSIONS: Tenascin-X expression is markedly decreased in AAA tissue, and AAA is associated with high serum concentrations of tenascin-X.

Transplantation of reconstructed human skin on nude mice: a model system to study expression of human tenascin-X and elastic fiber components.

Tenascin-X is a large extracellular matrix protein that is widely expressed in connective tissues during development and in the adult. Genetically determined deficiency of tenascin-X causes the connective tissue disease Ehlers-Danlos syndrome. These patients show reduced collagen density and fragmentation of elastic fibers in their skin. In vitro studies on the role of tenascin-X in elastic fiber biology are hampered because monolayers of fibroblasts do not deposit tenascin-X and elastic fibers into the extracellular matrix. Here, we applied an organotypic culture model of fibroblasts and keratinocytes to address this issue. We investigated the deposition of tenascin-X and elastin into skin-equivalent in vitro and also in vivo after transplantation onto immunodeficient mice. Whereas tenascin-C and fibrillin-1 were readily expressed in the skin-equivalents before transplantation, tenascin-X and elastin were not present. Three weeks post-grafting, a network of elastin was observed that coincided with the appearance of tenascin-X. At the ultrastructural level, microfibrils were observed, some of which were associated with elastin. Transplanted skin-equivalents containing tenascin-X-deficient fibroblasts showed deposition of immunoreactive elastin in similar quantities and distribution as those containing control fibroblasts. This suggests that tenascin-X is important for the stability and maintenance of established elastin fibers, rather than for the initial phase of elastogenesis. Thus, the transplantation of reconstructed skin on nude mice allows the study of tenascin-X and elastin expression and could be used as a model system to study the potential role of tenascin-X in matrix assembly and stability.

Deficiency of tenascin-X causes abnormalities in dermal elastic fiber morphology.

Deficiency of the extracellular matrix protein tenascin-X (TNX) was recently described as the molecular basis of a new, recessive type of Ehlers-Danlos syndrome. Here we report gross abnormalities of the elastic fibers and microfibrils in the dermis of these patients, and reduced dermal collagen content, as determined by quantitative image analysis. The ascending, fine elastic fibers in the papillary dermis were absent or inconspicuous and had few branches. The coarse elastic fibers of the reticular dermis were fragmented and clumped. At the ultrastructural level, irregular and immature elastin fibers and fibers devoid of microfibrils were observed. In TNX-deficient patients the dermal collagen density was reduced, but no structural abnormalities in the collagen fibrils were found. These findings suggest that both elastic fiber abnormalities and reduced collagen content contribute to the observed phenotype in TNX-deficient patients.