Can skin disease cause neuropathic pain? A study in pachyonychia congenita.

INTRODUCTION: Pachyonychia congenita (PC) is a rare skin disorder caused by an autosomal dominant mutation in one of five genes encoding keratin (K6a, K6b, K6c, K16 or K17; each defining one PC subtype). Pain is a prominent symptom, but its severity and type are poorly characterized. METHODS: In total, 35 genotyped US patients with PC consented to clinical assessment including the quality of life (QoL) questionnaire EQ-5D-3L, the Brief Pain Inventory (BPI) and painDETECT. Abbreviated quantitative sensory testing (QST) was also performed, and included mechanical detection threshold (MDT), mechanical pain threshold (MPT), wind-up pain ratio (WUR) and vibration detection threshold (VDT). RESULTS: Significant pain in patients with PC was confirmed, as indicated by mean BPI severity and interference of 4.2 ± 1.7 and 4.4 ± 2.2, respectively, as well as QoL impairment, as indicated by mean EQ-5D index of 0.69 ± 0.18. PD identified neuropathic pain in 62% of patients, the remainder being nociceptive. The painDETECT score was most significantly related to EQ-5D index (R(2)  = 0.26, P = 0.02). The K17 and K6a subtypes exhibited significantly worse QoL (0.584 and 0.613 respectively) than the K16 and K6b subtypes (P = 0.02). In QST analysis, abnormal pressure pain (assessed as MPT) was frequently observed, with more than half of patients with PC affected (54%), and 57% of patients with K17 also exhibiting abnormality in minimum touch threshold (assessed as MDT, P < 0.05). Very few patients were receiving analgesic therapy appropriate for neuropathic pain. CONCLUSION: Significant neuropathic pain was observed in PC, which warrants appropriate treatment. The health states observed in this sample are at a level that the average US citizen would forfeit one-third of their remaining lifespan to avoid.

Cost-effectiveness and budget impact of Empirical vitamin D therapy on unintentional falls in older adults in the UK.

OBJECTIVES: To evaluate the health outcomes and economics associated with the current guidance relating to the prevention of falls in the elderly through vitamin D supplementation. SETTING: UK. PARTICIPANTS: UK population aged 60 years and above. INTERVENTIONS: A Markov health state transition model simulated patient transitions between key fall-related outcomes using a 5-year horizon and annual cycles to assess the costs and benefits of empirical treatment with colecalciferol 800 iu daily. PRIMARY AND SECONDARY OUTCOME MEASURES: Costs and health outcomes attributable to fall prevention following vitamin D supplementation. RESULTS: Our model shows that treating the UK population aged 60 years and above with 800 iu colecalciferol would, over a 5-year period: (1) prevent in excess of 430,000 minor falls; (2) avoid 190,000 major falls; (3) prevent 1579 acute deaths; (4) avoid 84,000 person-years of long-term care and (5) prevent 8300 deaths associated with increased mortality in long-term care. The greatest gains are seen among those 75 years and older. Based on reduction in falls alone, the intervention in all adults aged 65+ is cost-saving and leads to increased quality adjusted life years. Treating all adults aged 60+ incurs an intervention cost of £2.70bn over 5 years, yet produces a -£3.12bn reduction in fall-related costs; a net saving of £420M. Increasing the lower bound age limit by 5-year increments increases budget impact to -£1.17bn, -£1.75bn, and -£2.06bn for adults 65+, 70+ and 75+, respectively. CONCLUSIONS: This study shows that treatment of the elderly UK population with colecalciferol 800 iu daily would be associated with reductions in mortality and substantial cost-savings through fall prevention.

Use of 5% lidocaine medicated plasters for the treatment of pain in routine hospital practice: patient reported pain, functioning and satisfaction.

OBJECTIVE: 5% lidocaine medicated plasters are a topical option in the treatment of peripheral neuropathic pain, as monotherapy or as an adjunct to systemic medication. This study sought to determine the impact of lidocaine plaster use on self-reported pain, functioning and patient satisfaction within a large teaching hospital. RESEARCH DESIGN AND METHODS: Patients were selected from the pain and rheumatology outpatient departments in Cardiff, Wales (2008-9). Postal surveys were sent to patients prescribed lidocaine plaster asking whether patients currently used the plaster and, if not, reason for discontinuation. Patients were asked to record pain score before and after therapy initiation, percentage pain relief, duration of effectiveness and impact on functioning. MAIN OUTCOME MEASURES: Pain scores, pain relief and levels of functioning before and after treatment. RESULTS: A total of 850 surveys were dispatched; 408 (48.0%) responses received; 197 (48.3%) patients were current users at survey completion. Median pain score prior to plaster use was 8 (IQR 7-9). One month after initiation, median pain score was 6 (4-8, p < 0.001) overall and 5 (4-7, p < 0.001) for current users. Median pain relief, after initial month of plaster use, was 30% (10-60%) for all patients and 50% (30-70%) for current users, whilst pain relief at time of survey was 30% (0-60%) and 50% (30-70%), respectively. A total of 181 (93.3%) current users claimed the plasters were effective. All three measures of functioning were significantly improved in current users: sleep (63.3% versus 20.1%, p < 0.001), mood (59.2% versus 18.6%, p < 0.001) and activity level (50.0% versus 19.5%, p < 0.001). Median satisfaction was 5 (IQR 1-8) for all patients and 7 (5-9) for current plaster users. CONCLUSIONS: The results of this study need to be considered within the context of a self-reported survey. However, pain, functioning and patient satisfaction were significantly improved in current users of 5% lidocaine medicated plasters.

The incidence of type 2 diabetes in the United Kingdom from 1991 to 2010.

AIMS: To characterize the incidence of type 2 diabetes in the UK over the previous 20 years; and determine if there has been an increase in people aged 40 years or less at diagnosis. METHODS: For this retrospective cohort study, patients newly diagnosed with type 2 diabetes between 1991 and 2010 were identified from the UK Clinical Practice Research Datalink (CPRD). Patient data were grouped into 5-year intervals by year of diagnosis and age at diagnosis. A standardized incidence ratio (SIR) was determined (1991-1995 = 100). The percentage of newly diagnosed patients for each age group and aged ≤40 years was calculated for each 5-year calendar period. The incidence rate by age and 5-year calendar period was also determined. RESULTS: In 2010, the crude incidence rate of type 2 diabetes was 515 per 100,000 population. The overall SIR increased to 158 (95% CI 157-160, p < 0.001), 237 (235-238, p < 0.001) and 275 (273-276, p < 0.001) for 1996-2000, 2001-2005 and 2006-2010, respectively. For those ≤40, the respective values were 217 (209-226, p < 0.001), 327 (320-335, p < 0.001) and 598 (589-608, p < 0.001). An increase in incidence occurred with increasing 5-year calendar period. The incidence of type 2 diabetes was higher for males after the age of 40 and higher for females aged ≤40. The percentage of patients aged ≤40 years at diagnosis increased with each increasing 5-year calendar period (5.9, 8.4, 8.5 and 12.4%, respectively). CONCLUSIONS: There was a significant increase in the incidence of diagnosed type 2 diabetes between 1991 and 2010 and the proportion of people diagnosed at a relatively early age has increased markedly.

Weight change in people with type 2 diabetes: secular trends and the impact of alternative antihyperglycaemic drugs.

AIM: This study aimed to describe the pattern of weight change in people with type 2 diabetes (T2DM) over time and when using alternative treatment regimens. METHODS: Data were from routine clinical practice in the UK. The weight trend was determined for each year from 1995 to 2010 for both prevalent and incident cases. Baseline weight was compared to absolute (mean Δ) and relative weights (% Δ) at 6, 12 and 24 months. RESULTS: Mean, standardized weight in prevalent cases increased from 83.4 to 92.1 kg for males and from 73.5 to 79.9 kg for females between 1995 and 2010 (p < 0.0001). For incident cases, the respective figures were 86.7 to 93.6 kg for males and 76.0 to 80.7 kg for females (p < 0.001). Between baseline and 6, 12 and 24 months, there were significant changes in weight for the majority of the treatment regimens selected for analysis. The largest weight increase at 12 months was for the patients who were prescribed a combination therapy with insulin and a thiazolidinedione, with a median increase of 4.1 kg (95% CI -0.60 to 8.0, p < 0.001). The largest weight decrease at 12 months was for the patients who were prescribed a combination therapy of metformin and exenatide, with a median decrease of -7.0 kg (95% CI -12.0 to -2.0, p < 0.001). CONCLUSIONS: There was a continual increase in body weight in people with T2DM over time, and considerable differences in the impact on weight using alternative treatment regimens. At the same time, glycaemic control remained relatively unchanged.

Estimation of primary care treatment costs and treatment efficacy for people with Type 1 and Type 2 diabetes in the United Kingdom from 1997 to 2007*.

AIMS: The purpose of this study was to characterize the financial cost and efficacy of primary care treatment for diabetes in the United Kingdom from 1997 to 2007. METHODS: Retrospective data were analysed for people with Type 1 and Type 2 diabetes along with matched control subjects using data from The Health Improvement Network. Costs were attributed from published sources and adjusted for price inflation. Type 2 diabetes was analysed by five commonly used treatment regimens. RESULTS: It was possible to identify 126 052 people for inclusion: 11 300 (8.9%) with Type 1 diabetes and 114 752 (91.1%) with Type 2. The overall mean prescribing costs per person per year (pppy) increased markedly for people with diabetes from 1997 to 2007: for Type 1, from 573 pounds to 1014 pounds pppy (+77%), and for Type 2, from 39 pounds to 740 pounds pppy (+89%). In 2007, diabetes-treatment-specific prescribing represented 57% of prescribing costs in Type 1 diabetes and 28% in Type 2 diabetes. In Type 2 diabetes there was a mean of 5.4 primary care consultations in 1997, increasing to 11.5 pppy in 2007 (+112%). In 1997 the total mean cost of primary care treatment for Type 2 diabetes was 602 pounds pppy, increasing to 1080 pounds in 2007. In Type 1 diabetes, the mean glycated haemoglobin decreased by 0.1% from 8.8% in 2001 to 8.7% in 2007; the corresponding change using insulin in Type 2 diabetes was also 0.1%. Greater improvement in blood pressure and lipids was evident. CONCLUSIONS: Over the 10 year period to 2007, diabetes-related primary care adjusted costs increased considerably, whereas glycated haemoglobin values did not improve at all over the same period.

Quality of life and health-related utility analysis of adults with moderate and severe atopic dermatitis treated with tacrolimus ointment vs. topical corticosteroids.

BACKGROUND: The purpose of this study was to measure change in quality of life (QoL) and estimate health-related utility in adults with moderate and severe atopic dermatitis (AD) following the use of either tacrolimus ointment or topical corticosteroids. METHODS: Data were analysed from a double-blind, randomized controlled trial comparing the treatment of adults with moderate and severe AD with either tacrolimus ointment or a standard corticosteroid regimen. Following randomisation, patients applied their medication twice-daily for 6 months. Monthly assessments determined response and QoL. Health-related utility (EQ5Dindex) was estimated by Monte Carlo simulation from SF-12 responses via a published mapping algorithm. RESULTS: At baseline, estimated utility data were available for 926 (95%) of the intention-to-treat patients, 57% of whom had AD of moderate severity (43% severe). The mean age at baseline was 32.5 years (SD +/- 11.8), 46.2% were male, with a mean EQ5Dindex for moderate cases of 0.770 (SD +/- 0.157), and 0.665 (SD +/- 0.225) for those with severe disease (P < 0.001). Patients treated with tacrolimus ointment showed significantly greater improvement in all but one domain of the SF-36. At baseline, there was no difference in estimated utility between the two groups; however, a difference in utility in favour of tacrolimus ointment emerged after 1 month's treatment (0.849 vs. 0.820; P = 0.004). Over the 6-month study period, the mean, marginal utility difference between the study arms was 0.032 U (utility) in favour of tacrolimus (P < 0.001). CONCLUSION: Treatment with 0.1% tacrolimus ointment rather than a standard topical corticosteroid ointment regimen was associated with clinically significant, incremental improvement in QoL, sustained over a 6-month period. A within-trial cost-utility estimate based on study medication cost alone suggests that tacrolimus ointment is highly cost-effective given existing willingness-to-pay thresholds.

Quality of life improvements attributed to combination therapy with oral and topical mesalazine in mild-to-moderately active ulcerative colitis.

BACKGROUND/AIM: To investigate patient-reported health-related quality of life (HRQoL) in data collected from a multinational randomized double-blind controlled trial comparing oral mesalazine (4 g) + topical mesalazine enema (1 g) to oral mesalazine alone (4 g). METHODS: HRQoL was collected using the EQ-5D at baseline and weeks 2, 4 and 8. The EQ-5D assesses mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Scores from each dimension were reported individually, and converted into a weighted health state which reflects an individual's perception of their health condition. RESULTS: At week 4, a significant HRQoL improvement was observed for patients on mesalazine enemas compared to placebo enemas, with EQ-5D scores of 0.906 and 0.838, respectively (p < 0.05). Mesalazine enema was found to reduce the probability of impairment at week 4 for mobility (p = 0.049) and anxiety/depression (p = 0.048), and was of borderline significance for pain/discomfort (p = 0.053); there was also an increased probability of influencing HRQoL changes for mobility (p < 0.005), usual activities (p < 0.005), pain/discomfort (p < 0.005) and anxiety/depression (p < 0.005), based on reported HRQoL problems at baseline. CONCLUSIONS: Including 1 g mesalazine enemas with 4 g oral mesalazine significantly improved HRQoL in patients with active ulcerative colitis. The improvement in QoL of patients with UC preceded clinical remission, and this underlines the importance of including QoL instruments in clinical studies.

Health-related utility among adults with atopic dermatitis treated with 0.1% tacrolimus ointment as maintenance therapy over the long term: findings from the Protopic CONTROL study.

BACKGROUND: Long-term maintenance treatment with 0.1% tacrolimus ointment for the prevention of flares has been demonstrated to be well tolerated and effective in adults for the treatment of atopic dermatitis (AD) but its impact on health-related utility has not been reported. OBJECTIVES: The purpose of this study was to estimate utility changes associated with the use of tacrolimus ointment in the maintenance treatment of adults with AD. METHODS: Data were collected from a clinical trial investigating long-term maintenance treatment with 0.1% tacrolimus ointment in adults with AD. All patients were treated with twice-daily tacrolimus ointment during an open-label period (OLP) of up to 6 weeks, with subsequent randomization to a double-blind disease-control period (DCP) of 12 months comparing tacrolimus ointment, used twice weekly as maintenance treatment, vs. the emollient vehicle as standard treatment. Health-related utility (EQ-5D(index)) was estimated by Monte Carlo simulation from SF-12 responses by application of a published response mapping algorithm and the U.K. tariff for EQ-5D responses and SF-6D responses, respectively. RESULTS: Evaluable data were available for 257 patients stratified into mild, moderate or severe AD with a median age at screening of 28 years [interquartile range (IQR) 22-38] and 40% male. At screening the median EQ-5D(index) across the strata was 0.848 units (IQR 0.704-0.882) for mild cases, 0.796 (0.737-0.876) for moderate cases, and 0.760 (0.661-0.823, P < 0.001) for those with severe disease. At the end of the OLP, mean utility improvement across all strata was 0.027 [95% confidence interval (CI) -0.011 to 0.065, P = 0.165] for mild cases, 0.046 (95% CI 0.015-0.064, P = 0.002) for moderate cases and 0.076 (95% CI 0.035-0.118, P < 0.001) for those with severe disease. At the end of the blinded DCP, repeated measures analysis showed an age- and sex-adjusted mean change of 0.045 units (P < 0.001) for subjects treated with tacrolimus ointment over those treated with emollient vehicle. CONCLUSIONS: Patients with AD of all severities showed considerable decrements in health-related utility. However, treatment with 0.1% tacrolimus ointment was associated with clinically significant improvement in health-related utility for patients with moderate and severe AD, which was sustained over a 12-month maintenance period compared with those using standard treatment with an emollient vehicle.

The influence of glucose-lowering therapies on cancer risk in type 2 diabetes.

AIMS/HYPOTHESIS: The risk of developing a range of solid tumours is increased in type 2 diabetes, and may be influenced by glucose-lowering therapies. We examined the risk of development of solid tumours in relation to treatment with oral agents, human insulin and insulin analogues. METHODS: This was a retrospective cohort study of people treated in UK general practices. Those included in the analysis developed diabetes >40 years of age, and started treatment with oral agents or insulin after 2000. A total of 62,809 patients were divided into four groups according to whether they received monotherapy with metformin or sulfonylurea, combined therapy (metformin plus sulfonylurea), or insulin. Insulin users were grouped according to treatment with insulin glargine, long-acting human insulin, biphasic analogue and human biphasic insulin. The outcome measures were progression to any solid tumour, or cancer of the breast, colon, pancreas or prostate. Confounding factors were accounted for using Cox proportional hazards models. RESULTS: Metformin monotherapy carried the lowest risk of cancer. In comparison, the adjusted HR was 1.08 (95% CI 0.96-1.21) for metformin plus sulfonylurea, 1.36 (95% CI 1.19-1.54) for sulfonylurea monotherapy, and 1.42 (95% CI 1.27-1.60) for insulin-based regimens. Adding metformin to insulin reduced progression to cancer (HR 0.54, 95% CI 0.43-0.66). The risk for those on basal human insulin alone vs insulin glargine alone was 1.24 (95% CI 0.90-1.70). Compared with metformin, insulin therapy increased the risk of colorectal (HR 1.69, 95% CI 1.23-2.33) or pancreatic cancer (HR 4.63, 95% CI 2.64-8.10), but did not influence the risk of breast or prostate cancer. Sulfonylureas were associated with a similar pattern of risk as insulin. CONCLUSIONS/INTERPRETATION: Those on insulin or insulin secretagogues were more likely to develop solid cancers than those on metformin, and combination with metformin abolished most of this excess risk. Metformin use was associated with lower risk of cancer of the colon or pancreas, but did not affect the risk of breast or prostate cancer. Use of insulin analogues was not associated with increased cancer risk as compared with human insulin.

An evaluation of the association between C-reactive protein, the change in C-reactive protein over one year, and all-cause mortality in chronic immune-mediated inflammatory disease managed in UK general practice.

OBJECTIVES: To evaluate the association between systemic inflammation, as measured by CRP, and all-cause mortality. To also evaluate the association between change in CRP status (sub-acute, < or =10 mg/l and acute >10 mg/l) and all-cause mortality. METHODS: A cohort of patients was selected from The Health Improvement Network (THIN) data set of anonymized patient-level data from UK general practice. Patients were selected if they had a diagnosis of RA, psoriasis, AS or PsA. Survival was evaluated using Cox proportional hazards regression models (CPHMs). RESULTS: A total of 11 362 cases had at least one CRP measurement. Analysis grouped by each additional unit increase in log-CRP (range 1-6) across the observed range was associated with a 21% increase in the hazard ratio (HR) of death, after controlling for cardiovascular risk factors (P < 0.001). This observation was consistent in separate analysis of cases with either RA or psoriasis. Repeated CRP observations around 1 yr apart were recorded in 2802 subjects. After controlling for confounding factors, in cases whose CRP changed from sub-acute (< or =10 mg/l) to acute (>10 mg/l), the HR for death increased 2-fold (P < 0.001) relative to cases whose CRP remained sub-acute. In comparison, among those subjects whose CRP was reduced from acute to sub-acute, the HR was virtually identical to those who stayed sub-acute (P = 0.571). CONCLUSIONS: CRP level predicted all-cause mortality after standardization for traditional risk factors, as did change in CRP status from sub-acute to acute observed over 1 yr.

Evaluation of the association between the first observation and the longitudinal change in C-reactive protein, and all-cause mortality.

OBJECTIVE: To evaluate the association between vascular inflammation as measured by subacute C-reactive protein (CRP; 1-10 mg/l) and all-cause mortality and the association between change in CRP status (normal 3 mg/l) and all-cause mortality. METHODS: Probabilistic record linkage was used to match hospital episode data, laboratory reports and mortality statistics in a large urban population. Survival was evaluated using Cox proportional hazards regression models. RESULTS: 22 962 patients had their first CRP measurement in the subacute range (1-10 mg/l). Analysis grouped by each additional unit increase in CRP across the subacute range was associated with a 7.3% (95% CI 5.4% to 9.2%) increase in the hazard ratio (HR) of death over 4 years, after controlling for confounding factors (p<0.001). Repeated CRP observations around 1 year apart were recorded in 5811 subjects. After controlling for confounding factors, in patients whose CRP changed from normal (3 mg/l), the HR increased 6.7-fold (p<0.001) relative to cases whose CRP remained normal. By comparison, among those subjects whose CRP was reduced from elevated to normal, the hazard ratio halved to 3.5 (p = 0.018). In an underpowered analysis of time to cardiovascular events, an identical pattern of risk emerged. CONCLUSIONS: CRP level predicted all-cause mortality, and additional inclusion of prior change in CRP level and current CRP level more so. Increasing vascular inflammation, as measured by CRP, increases the likelihood of death.

The financial costs of healthcare treatment for people with Type 1 or Type 2 diabetes in the UK with particular reference to differing severity of peripheral neuropathy.

AIMS: To characterize symptom severity of diabetic peripheral neuropathy (DPN) in people with diabetes and to characterize its association with healthcare resource use. METHODS: The study was undertaken in Cardiff and the Vale of Glamorgan, UK. A postal survey was posted to subjects identified as having diabetes. Demography, quality of life (EQ-5D and SF-36) and symptoms of neuropathy (NTSS-6 and QOL-DN) data were collected. These data were linked to routine healthcare data coded into healthcare resource groups (HRGs) and subsequently costed according to UK National reference costs. RESULTS: Survey responses were received from 1298 patients, a 32% response rate. For patients with a clinically confirmed diagnosis of DPN, the mean NTSS-6-SA score was 6.16 vs. 3.19 (P < 0.001). Duration of diabetes did not change across groups defined by severity of neuropathy symptoms, but mean HbA(1c) and body mass index values did increase with symptom severity (range 7.6-8.1%, P = 0.023; and 28.0-30.9 kg/m(2), P < 0.001, respectively). General linear modelling showed that the NTSS-6-SA score was a significant predictor of both annual health resource costs and yearly prescribed drug costs. On average, each 1-point increase in NTSS-6-SA score predicted a 6% increase in primary and secondary care costs and a 3% increase in log transformed drug costs. CONCLUSION: This study demonstrated that severity of DPN symptoms was associated with increased healthcare resource use, thus costs.

The health-related utility and health-related quality of life of hospital-treated subjects with type 1 or type 2 diabetes with particular reference to differing severity of peripheral neuropathy.

AIMS/HYPOTHESIS: We characterised symptom severity of diabetic peripheral neuropathy (DPN) in people with diabetes, and correlated this with health-related utility and health-related quality of life. MATERIALS AND METHODS: The study was undertaken in Cardiff and the Vale of Glamorgan, Wales. A postal survey was mailed to a random sample of subjects identified as having diabetes. Data were collected on the symptoms of neuropathy using the Neuropathic Total Symptom Score (self-administered) (NTSS-6-6A) and on quality of life using the Quality of Life in Diabetes Neuropathy Instrument (QoL-DN), EueroQoL five dimensions (EQ5D) and Short Form 36 (SF36). Other information, such as demographics and self-reported drug use, was also collected. The anonymised data were linked to routine inpatient and outpatient healthcare data. RESULTS: Responses were received from 1,298 patients. For patients with a clinically confirmed diagnosis of DPN, the mean NTSS-6-SA score was 6.16 vs 3.19 in patients without DPN (p<0.001). Four categories of severity were defined, ranging from none to severe. All quality of life measures showed a deterioration between these groups: the EQ5D(index) fell from an average of 0.81 in those without symptoms to 0.25 in those with severe symptoms, the SF36 general health profile fell from 59.9 to 25.5 (p<0.001) and the QoL-DN increased from 25.8 to 48.1 (p<0.001). Multivariate models also demonstrated that this relationship remained after controlling for other factors. CONCLUSIONS/INTERPRETATION: This study demonstrated that severity of DPN symptoms was predictive of poor health-related utility and decreased quality of life. Furthermore, it provides detailed utility data for economic evaluation of treatment of typical diabetes-related morbidity states. Reducing DPN morbidity should be a priority.

Bend-induced loss for the higher-order spatial mode in a dual-mode fiber.

Measured loss for the LP(11) mode in a dual-mode fiber subjected to a uniform bend shows a strong dependence on the orientation of the mode-field pattern relative to the plane of the fiber bend. Wavelength and bend-radius dependence of the loss indicates that operation within ~40 nm of cutoff is feasible in dispersion compensators based on dual-mode fibers operated in the LP(11) spatial mode near cutoff.