Defining trajectories of response in patients with psoriasis treated with biologic therapies.

BACKGROUND: The effectiveness and cost-effectiveness of biologic therapies for psoriasis are significantly compromised by variable treatment responses. Thus, more precise management of psoriasis is needed. OBJECTIVES: To identify subgroups of patients with psoriasis treated with biologic therapies, based on changes in their disease activity over time, that may better inform patient management. METHODS: We applied latent class mixed modelling to identify trajectory-based patient subgroups from longitudinal, routine clinical data on disease severity, as measured by the Psoriasis Area and Severity Index (PASI), from 3546 patients in the British Association of Dermatologists Biologics and Immunomodulators Register, as well as in an independent cohort of 2889 patients pooled across four clinical trials. RESULTS: We discovered four discrete classes of global response trajectories, each characterized in terms of time to response, size of effect and relapse. Each class was associated with differing clinical characteristics, e.g. body mass index, baseline PASI and prevalence of different manifestations. The results were verified in a second cohort of clinical trial participants, where similar trajectories following the initiation of biologic therapy were identified. Further, we found differential associations of the genetic marker HLA-C*06:02 between our registry-identified trajectories. CONCLUSIONS: These subgroups, defined by change in disease over time, may be indicative of distinct endotypes driven by different biological mechanisms and may help inform the management of patients with psoriasis. Future work will aim to further delineate these mechanisms by extensively characterizing the subgroups with additional molecular and pharmacological data.

Electrical stimulation shifts healing/scarring towards regeneration in a rat limb amputation model.

Different species respond differently to severe injury, such as limb loss. In species that regenerate, limb loss is met with complete restoration of the limbs' form and function, whereas in mammals the amputated limb's stump heals and scars. In in vitro studies, electrical stimulation (EStim) has been shown to promote cell migration, and osteo- and chondrogenesis. In in vivo studies, after limb amputation, EStim causes significant new bone, cartilage and vessel growth. Here, in a rat model, the stumps of amputated rat limbs were exposed to EStim, and we measured extracellular matrix (ECM) deposition, macrophage distribution, cell proliferation and gene expression changes at early (3 and 7 days) and later stages (28 days). We found that EStim caused differences in ECM deposition, with less condensed collagen fibrils, and modified macrophage response by changing M1 to M2 macrophage ratio. The number of proliferating cells was increased in EStim treated stumps 7 days after amputation, and transcriptome data strongly supported our histological findings, with activated gene pathways known to play key roles in embryonic development and regeneration. In conclusion, our findings support the hypothesis that EStim shifts injury response from healing/scarring towards regeneration. A better understanding of if and how EStim controls these changes, could lead to strategies that replace scarring with regeneration.

Potential for in situ chemical oxidation of acid extractable organics in oil sands process affected groundwater.

The process of bitumen extraction from oil sands in Alberta, Canada leads to an accumulation of toxic acid-extractable organics (AEOs) in oil sands process water (OSPW). Infiltration of OSPW from tailings ponds and from their retaining sand dykes and subsequent transport towards surface water has occurred. Given the apparent lack of significant natural attenuation of AEOs in groundwater, remediation may be required. This laboratory study evaluates the potential use of unactivated persulfate and permanganate as in situ oxidation agents for remediation of AEOs in groundwater. Naphthenic acids (NAs; CnH2n+zO2), which are a component of the acutely toxic AEOs, were degraded by both oxidants in OSPW samples. Permanganate oxidation yielded some residual dissolved organic carbon (DOC) whereas persulfate mineralized the AEO compounds with less residual DOC. Acid-extractable organics from oxidized OSPW had essentially no Microtox toxicity.

Assessment and management of methotrexate hepatotoxicity in psoriasis patients: report from a consensus conference to evaluate current practice and identify key questions toward optimizing methotrexate use in the clinic.

Experts in psoriasis, hepatology, pharmacokinetics and pharmacogenetics convened to discuss the safety and monitoring of methotrexate with respect to hepatotoxicity when used in the treatment of psoriasis. Methotrexate is an efficacious and cost-effective treatment for psoriasis, but is associated with significant safety issues, particularly relating to hepatotoxicity. Current British, Dutch, German, EU and US guidelines for baseline evaluations, monitoring and prevention of hepatotoxicity in patients with psoriasis receiving methotrexate were evaluated. Liver safety monitoring is currently reliant upon multiple methods, including biopsy, serological tests for biomarkers such as type III procollagen amino terminal propeptide (PIIINP), and liver function tests based on liver enzymes. Monitoring of patients receiving long-term therapy is expected to be improved by the utilization of serum biomarkers currently in development such as the Enhanced Liver Fibrosis (ELF) panel and other non-invasive tests of hepatic architecture, such as fibroelastography, microbubbles and magnetic resonance imaging. Appropriate studies to determine optimal dosing to maximize efficacy and minimize toxicity, potentially utilizing pharmacogenetic principles, are clearly needed. Key questions for future research are identified including needs for optimal screening and monitoring, identification of appropriate biomarkers, assessment of relationships between dosing and safety, utility of liver biopsy, optimal dosing regimens (including route of administration), methods to measure methotrexate levels in blood, and use of methotrexate as a standardized active comparator in trials of experimental drugs used to treat psoriasis.

A retrospective cohort study of the impact of biologic therapy initiation on medical resource use and costs in patients with moderate to severe psoriasis.

BACKGROUND: Biologic therapy has become established as an important treatment option in patients with severe psoriasis, but is significantly more expensive in terms of drug costs than traditional treatment options. Relatively little is known about the total healthcare cost of treating severe psoriasis in daily clinical practice and what the budgetary impacts of such high-cost drugs are when compared with standard systemic therapy. OBJECTIVES: To describe the impact of biologic therapy introduction on the use of medical resources, costs and where available, outcomes in patients with moderate to severe psoriasis. METHODS: Data were extracted from case notes of a sequential patient cohort with psoriasis attending a tertiary referral severe psoriasis service and initiated on biologics (adalimumab, efalizumab, etanercept or infliximab) for treatment of their psoriasis. Data on hospital resource use (inpatient, outpatient, day ward, accident and emergency visits and phototherapy sessions) and drug usage (systemic nonbiologic and biologic psoriasis therapies and supportive drugs) were collected for 12 months prior to, and at least 6 months following initiation of biologic therapy. Outcome was measured using the Psoriasis Area and Severity Index (PASI). Differences in resource use and associated costs and outcomes, between 12 months before and after initiation of biologic therapy, were tested using Wilcoxon paired sign tests for continuous data and the McNemar test for categorical data. Confidence intervals (CI) around treatment costs were constructed using a 5000-sample bootstrap analysis. RESULTS: The primary analysis population comprised 76 patients completing 12 months of biologic therapy: 71% males; mean age at time of study 47·3 years (range 23-74); mean duration of psoriasis 24·7 years (range 5·3-45·5). Significant reductions (P < 0·05) in the year following initiation of biologic therapy were observed for all hospital resource use categories, with mean annual costs reduced by £1682 (95% CI -3182 to -182·2; P = 0·05). Mean annual drug costs increased by £9456 (95% CI 8732-10,182; P < 0·001). Mean PASI fell by 8·9 points from 18·7 to 9·8 (95% CI -10·8 to -7·1; P < 0·001). CONCLUSIONS: Total healthcare costs associated with treatment of severe psoriasis with biologic therapy are significantly greater than with traditional systemic therapy. However, some of these are offset by substantial reductions in the number and length of hospital admissions and use of photo- and systemic therapy, and result in significantly improved patient outcome (as inferred by improvement in PASI).

European S3-guidelines on the systemic treatment of psoriasis vulgaris.

Of the 131 studies on monotherapy or combination therapy assessed, 56 studies on the different forms of phototherapy fulfilled the criteria for inclusion in the guidelines. Approximately three-quarters of all patients treated with phototherapy attained at least a PASI 75 response after 4 to 6 weeks, and clearance was frequently achieved (levels of evidence 2 and 3). Phototherapy represents a safe and very effective treatment option for moderate to severe forms of psoriasis vulgaris. The onset of clinical effects occurs within 2 weeks. Of the unwanted side effects, UV erythema from overexposure is by far the most common and is observed frequently. With repeated or long-term use, the consequences of high, cumulative UV doses (such as premature aging of the skin) must be taken into consideration. In addition, carcinogenic risk is associated with oral PUVA and is probable for local PUVA and UVB. The practicability of the therapy is limited by spatial, financial, human, and time constraints on the part of the physician, as well as by the amount of time required by the patient. From the perspective of the cost-bearing institution, phototherapy has a good cost-benefit ratio. However, the potentially significant costs for, and time required of, the patient must be considered.

Care of patients with psoriasis: an audit of U.K. services in secondary care.

BACKGROUND: Medical professionals require data about the structure and delivery of dermatological services in primary and secondary care in order to identify and tackle variations in standards and monitor the impact of healthcare reforms. The British Association of Dermatologists (BAD) commissioned an audit of the provision of care for patients with psoriasis. OBJECTIVES: To assess the staffing and facilities in dermatology units in the U.K. with a focus on the provision of care for patients with psoriasis. METHODS: Data were collected from 100 dermatology units in the U.K. for 1 year using a questionnaire and a web-based collection system. RESULTS: Key results are as follows. Eighteen per cent (18/98) of units had fewer than 2.0 whole-time equivalent consultants and 20% had no specialist dermatology nurse. Only 23% of units collected diagnostic data on outpatients, and half were unable to supply details about the number of attendances for psoriasis. Seventy-seven units reported admitting patients to dedicated dermatology beds, general medical beds, or both; three-quarters of units had access to dedicated adult dermatology beds. Pharmacy services were not always available for dermatology patients. Only 21 units (21%) had dedicated clinics for patients with psoriasis and 56% of units lacked a clinical psychology service willing to accept adult dermatology patients; 59% (55/93) lacked psychological services for children. Fifty-five per cent had no systemic drug monitoring clinic. Phototherapy was run by dermatology nurses in 93% (88/95) of the units and by physiotherapists in 11% (10/94). Biologics for psoriasis were prescribed in 75% (73/97) of units and in 88% (64/73) of these the BAD guidelines for the use of biologics were known to be followed. Of the seventy-three units prescribing biologic therapies, 64% had a nurse trained in the assessment and administration of biologics, 71% had facilities for outpatient infusions (e.g. for infliximab) and 39% were restricted in prescribing biologic agents because of financial constraints. A quality-of-life score was either inadequately or never recorded in outpatient records in 81% of units, increasing to 88% for inpatient records. The Psoriasis Area and Severity Index score was inadequately or never recorded in 79% of outpatient records and 82% of inpatient records. CONCLUSIONS: Units varied in their capacity to meet BAD guidelines and standards. Among the most significant deficiencies identified were a shortage of specialist dermatology nurses, treatment delivery by untrained nurses and financial constraints on the prescription of biologics for psoriasis. Gaps in data collection and record keeping jeopardize efforts to improve standards of care.

Fragment based drug discovery using fluorescence correlation: spectroscopy techniques: challenges and solutions.

Novel starting points for medicinal chemistry programmes can be effectively identified by screening libraries of fragment molecules in biochemical assays at high concentration. The key to success with this approach is the combination of a high quality fragment library with sensitive biochemical screening methods. There are an increasing number of literature reports where weakly active fragment molecules have been identified by high concentration biochemical assays. We have successfully demonstrated the use of high concentration screening of fragments, using a portfolio of single-molecule Fluorescence Correlation Spectroscopy (FCS+plus) detection techniques to ensure the highest reproducibility and sensitivity, and have determined the binding mode of active fragments to target proteins by X-ray crystallography. Further biophysical detection methods are reviewed for their applicability to studies of fragment binding.

Biological therapies in the systemic management of psoriasis: International Consensus Conference.

Psoriasis is a chronic, immune-mediated disorder that usually requires long-term treatment for control. Approximately 25% of patients have moderate to severe disease and require phototherapy, systemic therapy or both. Despite the availability of numerous therapeutic options, the long-term management of psoriasis can be complicated by treatment-related limitations. With advances in molecular research and technology, several biological therapies are in various stages of development and approval for psoriasis. Biological therapies are designed to modulate key steps in the pathogenesis of psoriasis. Collectively, biologicals have been evaluated in thousands of patients with psoriasis and have demonstrated significant benefit with favourable safety and tolerability profiles. The limitations of current psoriasis therapies, the value of biological therapies for psoriasis, and guidance regarding the incorporation of biological therapies into clinical practice are discussed.

Multi-channel orbicularis oculi stimulation to restore eye-blink function in facial paralysis.

Facial paralysis due to facial nerve injury results in the loss of function of the muscles of the hemiface. The most serious complication in extreme cases is the loss of vision. In this study, we compared the effectiveness of single- and multiple-channel electrical stimulation to restore a complete and cosmetically acceptable eye blink. We established bilateral orbicularis oculi muscle (OOM) paralysis in eight dogs; the OOM of one side was directly stimulated using single-channel electrical stimulation and the opposite side was stimulated using multi-channel electrical stimulation. The changes in the palpebral fissure and complete palpebral closure were measured. The difference in current intensities between the multi-channel and single-channel simulation groups was significant, while only multi-channel stimulation produced complete eyelid closure. The latest electronic stimulation circuitry with high-quality implantable electrodes will make it possible to regulate precisely OOM contractions and thus generate complete and cosmetically acceptable eye-blink motion in patients with facial paralysis.

Socio-cultural anthropology and alcohol and drug research: towards a unified theory.

The arrival of the millennium has understandably created a growing tendency for social commentators to evaluate the current state of the world, assess prior developments and suggest new and enlightened ways forward. In this time of re-appraisals, we assess the current state of the anthropology of alcohol and drug research, consider its early history, examine the range and theoretical underpinnings of work done today, and propose the elements of a possible future model. In formulating the model, we have borrowed from a number of different theoretical approaches and insights not only from anthropological discussions of alcohol and drug issues but also from anthropological research outside these arenas. In examining these issues, and as a way of attempting to answer the question--where has the field come from and where is it heading--we situate anthropological contributions to this area not merely within the wider context of anthropological thought and research, but more importantly within a wider social and political context that takes account of the organizational, funding and conceptual influences, constraints and pressures that operate on anthropologists who wish to conduct research on alcohol and drug issues.

Primary neural precursor cell expansion, differentiation and cytosolic Ca(2+) response in three-dimensional collagen gel.

To investigate the ability to culture neural precursor cells in a three-dimensional (3D) collagen gel, neuroepithelial cells were isolated from embryonic day 13 rat cortex, dispersed within type I collagen and maintained for up to 30 days in vitro. Cultured in Neuorobasal medium supplemented with B27 containing basic fibroblast growth factor, the collagen-entrapped precursor cells actively expanded and formed clone-like clusters. Many cells in the center of the cluster were proliferating as revealed by 5-bromo-2'-deoxyuridine uptake. Some cells began to migrate away from the center at 5 days and were labeled by either neuronal marker neuron-specific beta-tubulin (TuJ1) or astrocytic marker glial fibrillary acidic protein. The differentiated neurons (TuJ1(+)) exhibited characteristic cytosolic Ca(2+) oscillations in response to excitatory neurotransmitter glutamate. These findings suggest the suitability of the 3D culture system for the proliferation and differentiation of neural precursor cells.

Electrically stimulated detrusor myoplasty.

PURPOSE: Many children with spina bifida and other causes of neurogenic bladder rely on clean intermittent catheterization to empty the hyporeflexic or areflexic bladder. Direct bladder and sacral nerve root stimulation have been met with limited success. We studied the electrical stimulation of a rectus abdominis muscle flap wrapped around the bladder to achieve bladder contractility and emptying. MATERIALS AND METHODS: The feasibility of performing rectus detrusor myoplasty in humans was first studied in 8 cadavers. In male and female cadavers it was possible to wrap the distended bladder completely with the rectus abdominis muscle. The rectus abdominis muscle was surgically dissected with preservation of its insertion on the pubis bone and rotation of its mid section behind the bladder to effect a complete bladder wrap. The deep inferior epigastric artery and veins, and 2 most caudal intercostal nerves were preserved. This unilateral rectus abdominis muscle flap was then electrically stimulated with 2 pairs of bipolar electrodes inserted into the muscle near the nerve entrance. Stimulation frequencies of 40, 60 and 80 Hz. were used in each of the 8 dogs. The increase in intravesical pressure over baseline, compliance and post-void residual were measured. Paired Student's t tests were used for statistical comparisons. RESULTS: The increase in intravesical pressure ranged 35 +/- 5 to 45 +/- 7 cm. H2O at stimulation frequency 40 and 80 Hz., respectively. Post-void residual was 27 +/- 4%, 22 +/- 3% and 26 +/- 3% at stimulation frequencies 40, 60 and 80 Hz., respectively. Intravesical pressure was significantly increased over baseline bladder pressure (p <0.05). CONCLUSIONS: Electrically stimulated detrusor myoplasty results in uniform increases in intravesical pressure and reasonable bladder emptying in an animal model. We are currently investigating detrusor myoplasty in a chronic study to determine whether it can be used for enhanced bladder emptying in children with poor detrusor contractility.

Topical application of cod liver oil ointment accelerates wound healing: an experimental study in wounds in the ears of hairless mice.

The effect of topical cod liver oil ointment on the rate of wound epithelialisation and neovascularisation was studied using the hairless mouse ear wound model (experiment I). The effect of local application of vitamin A in increasing concentrations was tested in the same model (experiment II). Experiment I: Bilateral standardised full thickness dermal wounds were created on the ears of 42 mice divided into three groups: group I: 25% cod liver oil ointment (n = 10) applied topically to one ear and vehicle (vaseline) to the other; group II: 25% cod liver oil ointment (n = 10) and saline; and group III: vehicle (n = 22) and saline. Experiment II: Using the same model and procedures wounds were made on 12 mice randomised to vitamin A treatment in various doses (250-3000 IU/g) on one ear and vehicle (vaseline) on the other ear. Using in-vivo microscopy and digitised planimetry, wound epithelialisation and neovascularisation were measured at regular intervals until the processes were complete. Wounds treated with 25% cod liver oil ointment epithelialized significantly (p < 0.05) faster (mean (SEM) 8.9 (0.7) days) than control ears treated with vehicle alone (13.9 (1.9) days). Neovascularisation developed significantly faster (p < 0.01) in the ears treated with cod liver oil ointment (22.5 (1.3) days) compared with their vehicle control (29.1 (0.6) days). Neovascularisation was also significantly (p < 0.05) faster in the ears treated with cod liver oil ointment (23.1 (1.4) days) than in those treated with saline (26.8 (1.1) days). There was no significant difference in speed of epithelialisation between cod liver oil ointment and saline. The vitamin A dose study showed that epithelialisation and neovascularisation of the vitamin A treated wounds pass at the same rate as wounds treated with cod liver oil ointment. In conclusion, topical 25% cod liver oil ointment significantly accelerated both the epithelial and the vascular component of healing compared with saline. Vitamin A seems to have an important role in accelerating wound healing and could be the active component in cod liver oil.

Vascular delay and administration of basic fibroblast growth factor augment latissimus dorsi muscle flap perfusion and function.

Ischemia of the distal latissimus dorsi muscle flap occurs when the entire muscle is acutely elevated. Although this level of ischemia may not be critical if the muscle is to be used as a conventional muscle flap, the ischemia causes decreased distal muscle function if it is used for dynamic muscle flap transfer. This experiment was designed to determine whether or not the administration of exogenous basic fibroblast growth factor (bFGF), combined with a sublethal ischemic insult (i.e., vascular delay), would further augment muscle perfusion and function. Both latissimus dorsi muscles of nine canines were subjected to a bipedicle vascular delay procedure immediately followed by thoracodorsal intraarterial injection of 100 microg of bFGF on one side and by intraarterial injection of vehicle on the other. Ten days later, both latissimus dorsi muscles were raised as thoracodorsally based island flaps, with perfusion determined by laser-Doppler fluximetry. The muscles were wrapped around silicone chambers, simulating cardiomyoplasty, and stimulating electrodes were placed around each thoracodorsal nerve. The muscles were then subjected to an experimental protocol to determine muscle contractile function. At the end of the experiment, latissimus dorsi muscle biopsies were obtained for measurement of bFGF expression. The results demonstrated that the administration of 100 microg of bFGF immediately after the vascular delay procedure increases expression of native bFGF. In the distal and middle muscle segments, it also significantly increased muscle perfusion by approximately 20 percent and fatigue resistance by approximately 300 percent. The administration of growth factors may serve as an important adjuvant to surgical procedures using dynamic muscle flap transfers.

Atypical pigmented lesions following extensive PUVA therapy.

We report a 38-year-old woman with psoriasis who developed multiple atypical lentigines following psoralen photochemotherapy (PUVA). The lentigines first appeared 12 years ago, 3 years after she commenced intermittent PUVA treatment. New lesions continued to develop over the subsequent years with further photochemotherapy. Clinically, the lentigines were strikingly atypical, deeply pigmented, dark brown or black, large stellate macules. Histology of a representative lesion was consistent with a PUVA lentigo and no atypical melanocytes were seen. At present, a link between malignant melanoma and PUVA lentigines has not been established. Instead, limited evidence suggests that PUVA lentigines may be more closely linked with the risk of nonmelanoma skin cancer.