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1.  Ultraviolet Phototherapy Management of Moderate-to-Severe Plaque Psoriasis 
Executive Summary
The purpose of this evidence based analysis was to determine the effectiveness and safety of ultraviolet phototherapy for moderate-to-severe plaque psoriasis.
Research Questions
The specific research questions for the evidence review were as follows:
What is the safety of ultraviolet phototherapy for moderate-to-severe plaque psoriasis?
What is the effectiveness of ultraviolet phototherapy for moderate-to-severe plaque psoriasis?
Clinical Need: Target Population and Condition
Psoriasis is a common chronic, systemic inflammatory disease affecting the skin, nails and occasionally the joints and has a lifelong waning and waxing course. It has a worldwide occurrence with a prevalence of at least 2% of the general population, making it one of the most common systemic inflammatory diseases. The immune-mediated disease has several clinical presentations with the most common (85% - 90%) being plaque psoriasis.
Characteristic features of psoriasis include scaling, redness, and elevation of the skin. Patients with psoriasis may also present with a range of disabling symptoms such as pruritus (itching), pain, bleeding, or burning associated with plaque lesions and up to 30% are classified as having moderate-to-severe disease. Further, some psoriasis patients can be complex medical cases in which diabetes, inflammatory bowel disease, and hypertension are more likely to be present than in control populations and 10% also suffer from arthritis (psoriatic arthritis). The etiology of psoriasis is unknown but is thought to result from complex interactions between the environment and predisposing genes.
Management of psoriasis is related to the extent of the skin involvement, although its presence on the hands, feet, face or genitalia can present challenges. Moderate-to-severe psoriasis is managed by phototherapy and a range of systemic agents including traditional immunosuppressants such as methotrexate and cyclospsorin. Treatment with modern immunosuppressant agents known as biologicals, which more specifically target the immune defects of the disease, is usually reserved for patients with contraindications and those failing or unresponsive to treatments with traditional immunosuppressants or phototherapy.
Treatment plans are based on a long-term approach to managing the disease, patient’s expectations, individual responses and risk of complications. The treatment goals are several fold but primarily to:
1) improve physical signs and secondary psychological effects,
2) reduce inflammation and control skin shedding,
3) control physical signs as long as possible, and to
4) avoid factors that can aggravate the condition.
Approaches are generally individualized because of the variable presentation, quality of life implications, co-existent medical conditions, and triggering factors (e.g. stress, infections and medications). Individual responses and commitments to therapy also present possible limitations.
Ultraviolet phototherapy units have been licensed since February 1993 as a class 2 device in Canada. Units are available as hand held devices, hand and foot devices, full-body panel, and booth styles for institutional and home use. Units are also available with a range of ultraviolet A, broad and narrow band ultraviolet B (BB-UVB and NB-UVB) lamps. After establishing appropriate ultraviolet doses, three-times weekly treatment schedules for 20 to 25 treatments are generally needed to control symptoms.
Evidence-Based Analysis Methods
The literature search strategy employed keywords and subject headings to capture the concepts of 1) phototherapy and 2) psoriasis. The search involved runs in the following databases: Ovid MEDLINE (1996 to March Week 3 2009), OVID MEDLINE In-Process and Other Non-Indexed Citations, EMBASE (1980 to 2009 Week 13), the Wiley Cochrane Library, and the Centre for Reviews and Dissemination/International Agency for Health Technology Assessment. Parallel search strategies were developed for the remaining databases. Search results were limited to human and English-language published between January 1999 and March 31, 2009. Search alerts were generated and reviewed for relevant literature up until May 31, 2009.
English language reports and human studies
Ultraviolet phototherapy interventions for plaque-type psoriasis
Reports involving efficacy and/or safety outcome studies
Original reports with defined study methodology
Standardized measurements on outcome events such as technical success, safety, effectiveness, durability, quality of life or patient satisfaction
Non-systematic reviews, letters, comments and editorials
Randomized trials involving side-to-side or half body comparisons
Randomized trials not involving ultraviolet phototherapy intervention for plaque-type psoriasis
Trials involving dosing studies, pilot feasibility studies or lacking control groups
Summary of Findings
A 2000 health technology evidence report on the overall management of psoriasis by The National Institute Health Research (NIHR) Health Technology Assessment Program of the UK was identified in the MAS evidence-based review. The report included 109 RCT studies published between 1966 and June 1999 involving four major treatment approaches – 51 on phototherapy, 32 on oral retinoids, 18 on cyclosporin and five on fumarates.. The absence of RCTs on methotrexate was noted as original studies with this agent had been performed prior to 1966.
Of the 51 RCT studies involving phototherapy, 22 involved UVA, 21 involved UVB, five involved both UVA and UVB and three involved natural light as a source of UV. The RCT studies included comparisons of treatment schedules, ultraviolet source, addition of adjuvant therapies, and comparisons between phototherapy and topical treatment schedules. Because of heterogeneity, no synthesis or meta-analysis could be performed. Overall, the reviewers concluded that the efficacy of only five therapies could be supported from the RCT-based evidence review: photochemotherapy or phototherapy, cyclosporin, systemic retinoids, combination topical vitamin D3 analogues (calcipotriol) and corticosteroids in combination with phototherapy and fumarates. Although there was no RCT evidence supporting methotrexate, it’s efficacy for psoriasis is well known and it continues to be a treatment mainstay.
The conclusion of the NIHR evidence review was that both photochemotherapy and phototherapy were effective treatments for clearing psoriasis, although their comparative effectiveness was unknown. Despite the conclusions on efficacy, a number of issues were identified in the evidence review and several areas for future research were discussed to address these limitations. Trials focusing on comparative effectiveness, either between ultraviolet sources or between classes of treatment such as methotrexate versus phototherapy, were recommended to refine treatment algorithms. The need for better assessment of cost-effectiveness of therapies to consider systemic drug costs and costs of surveillance, as well as drug efficacy, were also noted. Overall, the authors concluded that phototherapy and photochemotherapy had important roles in psoriasis management and were standard therapeutic options for psoriasis offered in dermatology practices.
The MAS evidence-based review focusing on the RCT trial evidence for ultraviolet phototherapy management of moderate-to-severe plaque psoriasis was performed as an update to the NIHR 2000 systemic review on treatments for severe psoriasis. In this review, an additional 26 RCT reports examining phototherapy or photochemotherapy for psoriasis were identified. Among the studies were two RCTs comparing ultraviolet wavelength sources, five RCTs comparing different forms of phototherapy, four RCTs combining phototherapy with prior spa saline bathing, nine RCTs combining phototherapy with topical agents, two RCTs combining phototherapy with the systemic immunosuppressive agents methotrexate or alefacept, one RCT comparing phototherapy with an additional light source (the excimer laser), and one comparing a combination therapy with phototherapy and psychological intervention involving simultaneous audiotape sessions on mindfulness and stress reduction. Two trials also examined the effect of treatment setting on effectiveness of phototherapy, one on inpatient versus outpatient therapy and one on outpatient clinic versus home-based phototherapy.
The conclusions of the MAS evidence-based review are outlined in Table ES1. In summary, phototherapy provides good control of clinical symptoms in the short term for patients with moderate-to-severe plaque-type psoriasis that have failed or are unresponsive to management with topical agents. However, many of the evidence gaps identified in the NIHR 2000 evidence review on psoriasis management persisted. In particular, the lack of evidence on the comparative effectiveness and/or cost-effectiveness between the major treatment options for moderate-to-severe psoriasis remained. The evidence on effectiveness and safety of longer term strategies for disease management has also not been addressed. Evidence for the safety, effectiveness, or cost-effectiveness of phototherapy delivered in various settings is emerging but is limited. In addition, because all available treatments for psoriasis – a disease with a high prevalence, chronicity, and cost – are palliative rather than curative, strategies for disease control and improvements in self-efficacy employed in other chronic disease management strategies should be investigated.
RCT Evidence for Ultraviolet Phototherapy Treatment of Moderate-To-Severe Plaque Psoriasis
Phototherapy is an effective treatment for moderate-to-severe plaque psoriasis
Narrow band PT is more effective than broad band PT for moderate-to-severe plaque psoriasis
Oral-PUVA has a greater clinical response, requires less treatments and has a greater cumulative UV irradiation dose than UVB to achieve treatment effects for moderate-to-severe plaque psoriasis
Spa salt water baths prior to phototherapy did increase short term clinical response of moderate-to-severe plaque psoriasis but did not decrease cumulative UV irradiation dose
Addition of topical agents (vitamin D3 calcipotriol) to NB-UVB did not increase mean clinical response or decrease treatments or cumulative UV irradiation dose
Methotrexate prior to NB-UVB in high need psoriasis patients did significantly increase clinical response, decrease number of treatment sessions and decrease cumulative UV irradiation dose
Phototherapy following alefacept did increase early clinical response in moderate-to-severe plaque psoriasis
Effectiveness and safety of home NB-UVB phototherapy was not inferior to NB-UVB phototherapy provided in a clinic to patients with psoriasis referred for phototherapy. Treatment burden was lower and patient satisfaction was higher with home therapy and patients in both groups preferred future phototherapy treatments at home
Ontario Health System Considerations
A 2006 survey of ultraviolet phototherapy services in Canada identified 26 phototherapy clinics in Ontario for a population of over 12 million. At that time, there were 177 dermatologists and 50 geographic regions in which 28% (14/50) provided phototherapy services. The majority of the phototherapy services were reported to be located in densely populated areas; relatively few patients living in rural communities had access to these services. The inconvenience of multiple weekly visits for optimal phototherapy treatment effects poses additional burdens to those with travel difficulties related to health, job, or family-related responsibilities.
Physician OHIP billing for phototherapy services totaled 117,216 billings in 2007, representing approximately 1,800 patients in the province treated in private clinics. The number of patients treated in hospitals is difficult to estimate as physician costs are not billed directly to OHIP in this setting. Instead, phototherapy units and services provided in hospitals are funded by hospitals’ global budgets. Some hospitals in the province, however, have divested their phototherapy services, so the number of phototherapy clinics and their total capacity is currently unknown.
Technological advances have enabled changes in phototherapy treatment regimens from lengthy hospital inpatient stays to outpatient clinic visits and, more recently, to an at-home basis. When combined with a telemedicine follow-up, home phototherapy may provide an alternative strategy for improved access to service and follow-up care, particularly for those with geographic or mobility barriers. Safety and effectiveness have, however, so far been evaluated for only one phototherapy home-based delivery model. Alternate care models and settings could potentially increase service options and access, but the broader consequences of the varying cost structures and incentives that either increase or decrease phototherapy services are unknown.
Economic Analyses
The focus of the current economic analysis was to characterize the costs associated with the provision of NB-UVB phototherapy for plaque-type, moderate-to-severe psoriasis in different clinical settings, including home therapy. A literature review was conducted and no cost-effectiveness (cost-utility) economic analyses were published in this area.
Hospital, Clinic, and Home Costs of Phototherapy
Costs for NB-UVB phototherapy were based on consultations with equipment manufacturers and dermatologists. Device costs applicable to the provision of NB-UVB phototherapy in hospitals, private clinics and at a patient’s home were estimated. These costs included capital costs of purchasing NB-UVB devices (amortized over 15-20 years), maintenance costs of replacing equipment bulbs, physician costs of phototherapy treatment in private clinics ($7.85 per phototherapy treatment), and medication and laboratory costs associated with treatment of moderate-to-severe psoriasis.
NB-UVB phototherapy services provided in a hospital setting were paid for by hospitals directly. Phototherapy services in private clinic and home settings were paid for by the clinic and patient, respectively, except for physician services covered by OHIP. Indirect funding was provided to hospitals as part of global budgeting and resource allocation. Home therapy services for NB-UVB phototherapy were not covered by the MOHLTC. Coverage for home-based phototherapy however, was in some cases provided by third party insurers.
Device costs for NB-UVB phototherapy were estimated for two types of phototherapy units: a “booth unit” consisting of 48 bulbs used in hospitals and clinics, and a “panel unit” consisting of 10 bulbs for home use. The device costs of the booth and panel units were estimated at approximately $18,600 and $2,900, respectively; simple amortization over 15 and 20 years implied yearly costs of approximately $2,500 and $150, respectively. Replacement cost for individual bulbs was about $120 resulting in total annual cost of maintenance of about $8,640 and $120 for booth and panel units, respectively.
Estimated Total Costs for Ontario
Average annual cost per patient for NB-UVB phototherapy provided in the hospital, private clinic or at home was estimated to be $292, $810 and $365 respectively. For comparison purposes, treatment of moderate-to-severe psoriasis with methotrexate and cyclosporin amounted to $712 and $3,407 annually per patient respectively; yearly costs for biological drugs were estimated to be $18,700 for alefacept and $20,300 for etanercept-based treatments.
Total annual costs of NB-UVB phototherapy were estimated by applying average costs to an estimated proportion of the population (age 18 or older) eligible for phototherapy treatment. The prevalence of psoriasis was estimated to be approximately 2% of the population, of which about 85% was of plaque-type psoriasis and approximately 20% to 30% was considered moderate-to-severe in disease severity. An estimate of 25% for moderate-to-severe psoriasis cases was used in the current economic analysis resulting in a range of 29,400 to 44,200 cases. Approximately 21% of these patients were estimated to be using NB-UVB phototherapy for treatment resulting in a number of cases in the range between 6,200 and 9,300 cases. The average (7,700) number of cases was used to calculate associated costs for Ontario by treatment setting.
Total annual costs were as follows: $2.3 million in a hospital setting, $6.3 million in a private clinic setting, and $2.8 million for home phototherapy. Costs for phototherapy services provided in private clinics were greater ($810 per patient annually; total of $6.3 million annually) and differed from the same services provided in the hospital setting only in terms of additional physician costs associated with phototherapy OHIP fees.
Psoriasis, ultraviolet radiation, phototherapy, photochemotherapy, NB-UVB, BB-UVB PUVA
PMCID: PMC3377497  PMID: 23074532
2.  The Higher Proportion of Men with Psoriasis Treated with Biologics May Be Explained by More Severe Disease in Men 
PLoS ONE  2013;8(5):e63619.
Moderate to severe psoriasis, once regarded as merely a skin disease, is today seen as an inflammatory systemic disease. The sex ratio of the prevalence of psoriasis is balanced. In recent years several reports have documented that men receive more systemic or UV treatment than women, and different hypotheses were made. In PsoReg, the national registry for systemic treatment of psoriasis in Sweden, we have, like other European registries, observed a predominance of men (59%), especially of men treated with biologics (63%). Biologics are a relatively new group of very effective but high-priced drugs. The objective of this study was to analyse if women are discriminated by not having the same access to the high-priced biologics.
Population based cohort study using data from a nationwide quality register of psoriasis patients.
2294 patients with moderate to severe psoriasis receiving systemic treatment from a specialist in dermatology.
Main Outcome Measures
Time to initiation of biologic treatment. A multiple Cox proportional hazard’s regression was performed, with time to initiating a biologic treatment as the outcome in order to assess the independent role of the patient’s sex in initiating such therapy. The psoriasis severity was defined as a time-varying variable.
Men had more severe psoriasis than women according to the Psoriasis Area and Severity Index (PASI), regardless of age at enrolment, and throughout the study period. The analysis in the multiple Cox regression show that age, psoriasis severity and psoriasis arthropathy were relevant factors for initiating biologic therapy, whereas sex is not.
Although as many women as men are believed to suffer from psoriasis, men seem to be more severely affected by psoriasis. The asymmetry in allocation of biologic therapy thereby probably reflects the differing disease activity between the sexes, and is not a discrimination against women per se.
PMCID: PMC3655146  PMID: 23691076
3.  Therapy of moderate and severe psoriasis 
Objective and methods
This health technology assessment (HTA) report synthesises systematically randomized controlled studies (RCT) on the therapy of moderate and severe psoriasis vulgaris which were published between 1999 and 2004; it includes some important clinical studies which have been published after 2004 and thus updates the English HTA report by Griffiths et al. [1]. The major objective is the evaluation of the medical effectiveness of different therapeutical approaches and the cost effectiveness with relevance for Germany.
The major conclusions from the results of medical RCT on moderate and severe psoriasis vulgaris are:
Oral fumarates are effective in the treatment of moderate to severe psoriasis vulgaris. However, fumarates quiet frequently cause moderate side effects. Cyclosporine and methotrexate are both effective in the treatment of severe psoriasis vulgaris. Both substances have a different spectrum of side effects which may limit the individual applicability. Acetritin is only moderately effective in the treatment of severe psoriasis of the plaque type. Calcipotriol or UV-radiation used at the same time can increase the clinical effectiveness of acetritin.
Systemic PUVA, balneo-PUVA and UVB therapy are all effective for the treatment of severe psoriasis. The combination of UV therapy with vitamin D3 analogues or with topical steroids is more effective than the treatment with UV radiation alone. Saltwater baths increase the effectiveness of UVB therapy. No RCT on the therapeutical effects of topical tar or of dithranol in combination with UV therapy have been published so far. A continuous therapy with PUVA should not be applied due to its proven photocarcinogenicity.
Three substances from the group of biologicals (Efalizumab, Etanercept, and Infliximab) are now available in Europe and a further substance (Alefacept) is available in the USA for the treatment of moderate to severe psoriasis. All biologicals have been effective in placebo controlled studies. The substances differ in the times until a clinical effect is observable, in the spectrum of side effects and in their efficiency on psoriasis arthritis.
From health-economic studies considering both costs and clinical efficiency oral fumarates appear to be superior to acitretin or cyclosporine (although cyclosporine appears to be more effective in severe psoriasis). From the health economic view methotrexate is equivalent with UVB or PUVA and superior to cyclosporine. The therapy options UVB, UVB plus calcipotriol and PUVA are equivalent and superior to balneo-phototherapy. Biologicals are cost intensive and should be used when other approaches are not sufficient or are not applicable due to their side effects.
The HTA report summarizes some health-economic studies on dithranol, on calcipotriol and on the combination with tar and UV light. No RCT have been published for the treatment of severe psoriasis with these agents alone but it appears to be certain that these substances are effective in severe psoriasis as well.
The spectrum of therapeutical options has fortunately increased during the last years. It must be emphasized that a number of therapeutical procedures exist which are not discussed in detail in this HTA. This is due to the search strategy of literature: Only RCT performed with patients with moderate and/or severe psoriasis vulgaris were included into this evaluation. This led to the exclusion of a number of substances which are traditionally used alone or in combination for the treatment of moderate or severe psoriasis vulgaris (e.g. dithranol, salicyc acid, tar, corticosteroids and topical retinoids). Moreover, other approaches which include neither drugs nor UV light are not discussed in this HTA although the authors believe in the importance of psychotherapeutical interventions, educational approaches and combined medical and non-medical approaches in rehabilitational medicine in the management of psoriasis vulgaris.
The transferability of the health economic evaluations is strongly limited by the fact that all included health economic evaluations except one were not aligned to a German setting. A future research question will be the evaluation of the duration of remission and relapse ratios in the context of different therapy options of moderate and severe psoriasis. Moreover, the consideration of combined outcomes such as the improvement of psoriatic symptoms and the decrease of symptoms in accompanying psoriasis arthritis represents a future requirement of health assessment.
From the clinical point of view it is positive that the spectrum of therapeutic procedures for a chronic severe skin disease has increased continuously during the last years. In cases of individual contraindications or individual inefficacies it is now possible to try alternative approaches. Moreover the risk of long-term side effects can be reduced by changing the therapeutical procedure after some time (so-called rotation therapy). The therapeutical algorithm for severe psoriasis vulgaris now includes photo(chemo-)therapy in combination with topical substances, oral fumaric acid esters, retinoids (in combination with phototherapy or topical substances), methotrexate, cylosporine and the new biologics.
Future studies should address therapeutical approaches which can not easily be studied by RCT, e.g. physical, balneological, climate approaches, educational programs and complex rehabilitation therapy which all may have positive effects on individuals with severe psoriasis.
As in medical therapy management of moderate and severe psoriasis the economic evaluation also points out the way of a strategic therapy concept which corresponds to a large extent to the algorithm in medical practice.
PMCID: PMC3011355  PMID: 21289958
4.  Initiation of tumor necrosis factor-α antagonists and the risk of hospitalization for infection in patients with autoimmune diseases 
Although tumor necrosis factor alpha (TNF-α) antagonists are increasingly used in place of non-biologic comparator medications, their safety profile remains incomplete.
To determine whether initiation of TNF-α antagonists compared with non-biologic comparators is associated with an increased risk of serious infections.
Design, setting and patients
Within a US multi-institutional collaboration, we assembled retrospective cohorts (1998–2007) of patients with rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and psoriasis, psoriatic arthritis or ankylosing spondylitis (PsO-PsA-AS) combining data from Kaiser Permanente Northern California, New Jersey and Pennsylvania Pharmaceutical Assistance programs, Tennessee Medicaid and National Medicaid/Medicare. TNF-α antagonists and non-biologic regimens were compared in disease specific-propensity score (PS) matched cohorts using Cox regression models with non-biologics as reference. Baseline glucocorticoid use was evaluated as a separate covariate.
Main outcome measure
Infections requiring hospitalization (serious infections) during the first 12 months after initiation of TNF-α antagonists or non-biologic regimens.
Study cohorts included 10484 RA, 2323 IBD and 3213 PsO-PsA-AS PS-matched pairs using TNF-α antagonists and comparator medications. Overall, we identified 1171 serious infections, most of which (53%) were pneumonia and skin and soft tissue infections. Among RA patients, serious infection hospitalization rates were 8.16 (TNF-α antagonists) and 7.78 (comparator regimens) per 100 person-years (adjusted hazard ratio [aHR]: 1.07 (95% CI: 0.93–1.23)). Among IBD patients, rates were 10.91 and 9.60 per 100 person-years (aHR: 1.13, (0.85–1.50)). Among PsO-PsA-AS patients, rates were 5.41 and 5.19 per 100 person-years (aHR: 1.10, (0.80–1.53)). Among RA patients, infliximab was associated with a significant increase in serious infections compared with etanercept and adalimumab (aHRs: 1.27 (1.08–1.49) and 1.23 (1.02–1.48)). Baseline glucocorticoid use was associated with a dose-dependent increase in infections.
Among patients with autoimmune diseases, compared to treatment with non-biologic regimens, initiation of TNF-α antagonists was not associated with an increased risk of hospitalizations for serious infections.
PMCID: PMC3428224  PMID: 22056398
Rheumatoid arthritis; inflammatory bowel disease; psoriasis; psoriatic arthritis; ankylosing spondylitis; infliximab; etanercept; adalimumab; safety; infection
5.  Association between the initiation of anti-TNF therapy and the risk of herpes zoster 
Herpes zoster (HZ) reactivation disproportionately affects patients with rheumatoid arthritis (RA). It is unclear whether anti-tumor necrosis factor (anti-TNF) therapy elevates HZ risk, and whether monoclonal antibodies carry greater risk than etanercept.
To ascertain whether initiation of anti-TNF therapy compared with non-biologic comparators is associated with increased HZ risk
Design, Setting, and Patients
We identified new users of anti-TNF therapy among cohorts of rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and psoriasis-psoriatic arthritis-ankylosing spondylitis (PsO-PsA-AS) patients during 1998–2007 within a large US multi-institutional collaboration combining data from Kaiser Permanente Northern California, Pharmaceutical Assistance Contract for the Elderly, Tennessee Medicaid, and national Medicaid/Medicare programs. We compared HZ incidence between new anti-TNF users and patients initiating non-biologic disease modifying drugs (DMARDs) within each inflammatory disease cohort (last participant follow-up Dec 31, 2007). Within these cohorts, we used Cox regression models to compare propensity-score adjusted HZ incidence between new anti-TNF and non-biologic DMARD users while controlling for baseline corticosteroid use.
Main Outcome Measure
Incidence of herpes zoster cases occurring after initiation of new anti- TNF or non-biologic DMARD therapy
Among 32,208 new users of anti-TNF therapy, we identified 310 HZ cases. Crude incidence rates among anti-TNF users for RA, IBD, and PsO-PsA-AS were 12.1/1000 pt-yrs, (95% CI 10.7–13.6), 11.3/1000 (95% CI 7.7–16.7), and 4.4/1000 (95% CI 2.8–7.0) respectively. Baseline use of corticosteroids of > 10mg/day was associated with elevated risk [adjusted HR 2.13 (1.64, 2.75) compared with no baseline use. For RA patients, adjusted incidence rates were similar between anti-TNF and nonbiologic DMARD initiators [adjusted HR 1.00 (95% CI 0.77–1.29) and comparable between all three anti-TNF therapies studied.
Conclusions and Relevance
Among patients with RA and other select inflammatory diseases, those who initiated anti-TNF therapies were not at higher risk for HZ compared to patients who initiated non-biologic treatment regimens.
PMCID: PMC3773213  PMID: 23462785
shingles; zoster; herpes; biologic therapy; tumor necrosis factor-alpha; rheumatoid arthritis; adverse events; psoriasis
6.  Inflammatory bowel diseases: Current problems and future tasks 
Current knowledge on inflammatory bowel disease (IBD) is mainly endorsed by controlled trials and epidemiologic studies. Yet, we seldom look at the messages from real-world practice. Among a patient population followed since 2008, we looked at an unselected sample of 64 IBD patients [26 Crohn’s disease (CD) and 38 ulcerative colitis (UC)] who had been seen as out-patients in the last year. Inducing remission, mesalamines (86% for UC/69% for CD/33%-16% as MMX formulation) prevailed as prescriptions; steroids (55%/19% for UC/CD) ranked second. Prescription of third-party drugs (antibiotics, NSAIDs, biologics) and adherence, were issues in the maintenance. 34% of CD, and 23% of UC patients showed accompanying immunologic diseases: CD-associated familiar psoriasis (4:9) ranked first. Main Message. The association between IBD (CD mainly) and psoriasis, now found in our practice, matches current basic science gathering IBD together with psoriasis (and perhaps chronic respiratory disease) under the comprehensive term “barrier organ disease” wherein an epithelial surface with sensor systems rules contacts between outer antigens and a reactive underneath tissue, with the balance between inflammation and quiescence kept at any time by mucosal permeability. IBD is thus viewed as a polyfactorial/polygenic/syndromic disorder, embedded into a galaxy of immune conditions offering multiple points of attack. This mindset of splitting the IBDs into pathogenic categories may allow overcoming the uniformly targeting of a single cytokine by biological drugs, in favor of demarcating the boundaries between different disease-subtype-specific indications, and paving the way to future personalized strategies.
PMCID: PMC4133442  PMID: 25133045
Inflammatory bowel disease; Immunopharmacology; Barrier organs; Future trends in inflammatory bowel disease; Microbiome
7.  Peripheral blood gene expression patterns discriminate among chronic inflammatory diseases and healthy controls and identify novel targets 
BMC Medical Genomics  2010;3:15.
Chronic inflammatory diseases including inflammatory bowel disease (IBD; Crohn's disease and ulcerative colitis), psoriasis and rheumatoid arthritis (RA) afflict millions of people worldwide, but their pathogenesis is still not well understood.
It is also not well known if distinct changes in gene expression characterize these diseases and if these patterns can discriminate between diseased and control patients and/or stratify the disease. The main focus of our work was the identification of novel markers that overlap among the 3 diseases or discriminate them from each other.
Diseased (n = 13, n = 15 and n = 12 in IBD, psoriasis and RA respectively) and healthy patients (n = 18) were recruited based on strict inclusion and exclusion criteria; peripheral blood samples were collected by clinicians (30 ml) in Venous Blood Vacuum Collection Tubes containing EDTA and peripheral blood mononuclear cells were separated by Ficoll gradient centrifugation. RNA was extracted using Trizol reagent. Gene expression data was obtained using TaqMan Low Density Array (TLDA) containing 96 genes that were selected by an algorithm and the statistical analyses were performed in Prism by using non-parametric Mann-Whitney U test (P-values < 0.05).
Here we show that using a panel of 96 disease associated genes and measuring mRNA expression levels in peripheral blood derived mononuclear cells; we could identify disease-specific gene panels that separate each disease from healthy controls. In addition, a panel of five genes such as ADM, AQP9, CXCL2, IL10 and NAMPT discriminates between all samples from patients with chronic inflammation and healthy controls. We also found genes that stratify the diseases and separate different subtypes or different states of prognosis in each condition.
These findings and the identification of five universal markers of chronic inflammation suggest that these diseases have a common background in pathomechanism, but still can be separated by peripheral blood gene expression. Importantly, the identified genes can be associated with overlapping biological processes including changed inflammatory response. Gene panels based on such markers can play a major role in the development of personalized medicine, in monitoring disease progression and can lead to the identification of new potential drug targets in chronic inflammation.
PMCID: PMC2874757  PMID: 20444268
8.  Predictors of biologic treatment of psoriasis: a non-interventional study 
Biologic therapies represent a significant advance in the treatment of psoriasis. However, no studies have examined the patient characteristics predictive of biologic treatment of psoriasis. The purpose of this study was to ascertain the frequency and predictors of treatment of psoriasis with biologics in three European countries, ie, France, Spain, and the UK.
This was a cross-sectional analysis of physician-recorded demographic and clinical data on patients receiving either conventional or biologic treatments for psoriasis. Data were drawn from the Adelphi 2007 Psoriasis Disease Specific Program (DSP®), a multinational, real-world survey of patients with psoriasis consulting practicing dermatologists. The numbers of patients treated with biologic and nonbiologic agents were recorded. Data were subjected to bivariate analysis according to treatment regimen (biologic versus nonbiologic). Predictors of treatment with biologics were identified by logistic regression analysis.
A total of 2,509 psoriasis patients were included in this study (1,374 from France, 561 from Spain, and 574 from the UK). Biologic use was most prevalent in Spain (19.4% of patients), followed by the UK (9.1%), and France (8.4%). In the logistic regression analysis, psoriatic arthritis was a statistically significant predictor of increased biologic use in France (odds ratio [OR] 5.38, 95% confidence interval [CI] 3.32–8.77), Spain (OR 2.71, 95% CI 1.16–6.33), and the UK (OR 8.70, 95% CI 3.65–20.83). Physician-assessed moderate-to-severe disease was also a statistically significant predictor of increased biologic use in France (OR 5.08, 95% CI 2.01–12.82), Spain (OR 11.11, 95% CI 4.33–28.57), and the UK (OR 8.55, 95% CI 1.11–66.67).
In this study, an average of about one tenth of psoriasis patients enrolled in Spain, France, and the UK were treated with biologics in 2007. Physician-assessed moderate-to-severe disease and presence of psoriatic arthritis were significantly associated with biologic use in all three countries.
PMCID: PMC3933358  PMID: 24600238
psoriasis; drug therapy; tumor necrosis factor-alpha; antagonists; inhibitors; dermatologic agents; therapeutic use
9.  Analysis of Germline GLI1 Variation Implicates Hedgehog Signalling in the Regulation of Intestinal Inflammatory Pathways 
PLoS Medicine  2008;5(12):e239.
Ulcerative colitis (UC) and Crohn's disease (CD) are polygenic chronic inflammatory bowel diseases (IBD) of high prevalence that are associated with considerable morbidity. The hedgehog (HH) signalling pathway, which includes the transcription factor glioma-associated oncogene homolog 1 (GLI1), plays vital roles in gastrointestinal tract development, homeostasis, and malignancy. We identified a germline variation in GLI1 (within the IBD2 linkage region, 12q13) in patients with IBD. Since this IBD-associated variant encodes a GLI1 protein with reduced function and our expression studies demonstrated down-regulation of the HH response in IBD, we tested whether mice with reduced Gli1 activity demonstrate increased susceptibility to chemically induced colitis.
Methods and Findings
Using a gene-wide haplotype-tagging approach, germline GLI1 variation was examined in three independent populations of IBD patients and healthy controls from Northern Europe (Scotland, England, and Sweden) totalling over 5,000 individuals. On log-likelihood analysis, GLI1 was associated with IBD, predominantly UC, in Scotland and England (p < 0.0001). A nonsynonymous SNP (rs2228226C→G), in exon 12 of GLI1 (Q1100E) was strongly implicated, with pooled odds ratio of 1.194 (confidence interval = 1.09–1.31, p = 0.0002). GLI1 variants were tested in vitro for transcriptional activity in luciferase assays. Q1100E falls within a conserved motif near the C terminus of GLI1; the variant GLI protein exhibited reduced transactivation function in vitro. In complementary expression studies, we noted the colonic HH response, including GLI1, patched (PTCH), and hedgehog-interacting protein (HHIP), to be down-regulated in patients with UC. Finally, Gli1+/lacZ mice were tested for susceptibility to dextran sodium sulphate (DSS)-induced colitis. Clinical response, histology, and expression of inflammatory cytokines and chemokines were recorded. Gli1+/lacZ mice rapidly developed severe intestinal inflammation, with considerable morbidity and mortality compared with wild type. Local myeloid cells were shown to be direct targets of HH signals and cytokine expression studies revealed robust up-regulation of IL-12, IL-17, and IL-23 in this model.
HH signalling through GLI1 is required for appropriate modulation of the intestinal response to acute inflammatory challenge. Reduced GLI1 function predisposes to a heightened myeloid response to inflammatory stimuli, potentially leading to IBD.
Charlie Lees and colleagues identify a reduced-function variant of the hedgehog signaling pathway protein GLI1 that associates with inflammatory bowel disease, and investigate its role in a mouse model of colitis.
Editors' Summary
Inflammatory bowel diseases (IBDs) are common disorders in which parts of the digestive tract become repeatedly or continuously inflamed. The immune system normally protects the body from entities it identifies as foreign, but in IBD it mistakenly recognizes gut tissue, and immune system cells accumulate in the lining of the bowel, which causes inflammation. There are two main types of IBD—Crohn's disease (CD), which mainly affects the small bowel, and ulcerative colitis (UC), which affects only the large bowel (colon). Both types tend to run in families and usually develop between the ages of 15 and 35 years. Symptoms—including diarrhea, abdominal cramps, and unexplained weight loss—can be mild or severe and the disease can develop slowly or suddenly. There is no cure for IBD except surgical removal of the affected part of the digestive tract. However, drugs that modulate the immune system (for example, corticosteroids) or that specifically inhibit “proinflammatory cytokines” (proteins made by the immune system that stimulate inflammation) are often helpful in reducing symptoms.
Why Was This Study Done?
Why the immune system becomes unbalanced in people with IBD is not clear but it is known that IBD is “polygenic,” that is, a disease caused by the combined actions of two or more inherited gene variants. Although UC and CD are clinically different diseases, they share several “susceptibility loci” (regions of the genome that harbor disease-associated gene variants), including the IBD2 locus. The identification of the actual gene within the IBD2 locus that is altered in people who are susceptible to IBD might provide new insights into what causes the immune imbalance in IBD and into how to treat the disease. In this study, the researchers test the hypothesis that a variant of a gene called GLI1, which lies in the IBD2 locus, is associated with IBD susceptibility. GLI1 encodes a transcription factor (a protein that regulates the production of proteins) that is a central component in the signaling pathway named for a protein called “hedgehog.” This pathway is involved in the development of many organs, including the digestive tract.
What Did the Researchers Do and Find?
The researchers used a technique called gene-wide haplotype tagging to look for inherited GLl1 variants in patients with IBD and in healthy people living in Scotland, England, and Sweden. A specific variant of the GLI1 gene, resulting in alteration of a single amino acid component of the GLI1 protein, was associated with IBD (particularly with UC) in both Scotland and England; the same variant was weakly associated with IBD in the Swedish population. The variant GLI1 protein was only half as active as the normal protein in a laboratory assay, and, consistent with this result, the expression of several components of the hedgehog signaling pathway was lower in colon samples taken from patients with UC than in samples taken from healthy individuals. Finally, Gli1+/lacZ mice (which express half the normal amount of Gli1 protein) developed severe intestinal inflammation more rapidly than wild-type mice when they were treated with dextran sodium sulfate (DSS), a chemical that induces acute (sudden) colitis. Cellular analysis revealed that myeloid cells (cells that sense and modify the inflammatory response) are direct targets of the hedgehog signaling pathway. Furthermore, the expression of several pro-inflammatory cytokines (in particular, one called IL-23) increased more markedly in the Gli1+/lacZ mice than in the wild-type mice after DSS treatment.
What Do These Findings Mean?
These findings suggest that the normal response of the mammalian gut to challenge with inflammatory substances involves hedgehog signaling through GLI1 and that reduced GLI1 function might be one trigger for IBD. More specifically, the human genetic studies identify a GLI1 variant that is associated with IBD (at least in certain north European populations), the laboratory experiments indicate that this GLI1 variant encodes a protein with reduced activity, and the animal studies show that a similar reduction in Gli1 activity is sufficient to heighten intestinal inflammatory responses. Although this last result needs to be confirmed in animal models of chronic colitis that more closely resemble human IBD, these findings suggest that drugs that modulate hedgehog signaling might be useful in the treatment of IBD.
Additional Information.
Please access these Web sites via the online version of this summary at
The MedlinePlus Encyclopedia has pages on Crohn's disease and on ulcerative colitis (in English and Spanish)
MedlinePlus provides links to other information Crohn's disease and ulcerative colitis (in English and Spanish)
The US National Institute of Diabetes and Digestive and Kidney Diseases provides information on Crohn's disease and ulcerative colitis
The UK National Health Service Direct Encyclopedia also provides information on Crohn's disease and on ulcerative colitis
Wikipedia has a page on the hedgehog signaling pathway (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
PMCID: PMC2596854  PMID: 19071955
10.  Inflammatory bowel disease: An archetype disorder of outer environment sensor systems 
The pathogenesis of the two inflammatory bowel diseases (IBDs) phenotypes ulcerative colitis (UC) and Crohn’s disease (CD) has remained elusive, thus frustrating attempts at defining a cure. IBD often presents as a complex inflammatory process wherein colon lesions (UC) or widespread ulceration and fissure (CD) might be accompanied by ancillary extra-intestinal manifestations involving the eye, skin, joints or liver, but also by full-blown “autoimmune” disorders from psoriasis and multiple sclerosis to rheumatoid arthritis; attempts at unraveling a link or a hierarchical order in these entities have proven almost fruitless. More recently, the input of genetics has suggested that the IBDs might be multi-organ inflammatory processes, elicited by a large number of low-penetrance susceptibility genes, with environmental factors needed to induce full-blown disease. At a noteworthy exception to this rule, the description of the nucleotide-oligomerization domain (NOD) gene mutations in CD came at the beginning of the 2000s: the NOD-LRR are part of a highly conserved microbial sensor system which respond to bacterial peptidoglycans by mounting an inflammatory response. At least in Caucasian patients, the prevalently loss-of-function mutation of NOD permitted to unexpectedly define CD as an immune deficiency state, and upon its recent description in apparently unrelated disorders such as the Blau syndrome (a granulomatous pediatric syndrome), and perhaps in psoriasis and chronic obstructive pulmonary disorders, has contributed to revolutionize our view of IBD and CD in particular. The latter affection, together with psoriasis and chronic pulmonary disease can now be included into a newly identified category named “barrier organ disease”, wherein a barrier organ is defined as a large mucosal or epithelial surface with an abundant metagenomic microbial population and an underneath reactive tissue, the whole structure being in contact with the outer environment and capable to react to it. Personalized treatments and empowerment of research across different disease phenotypes should be the advantages of this novel mindset.
PMCID: PMC3729865  PMID: 23919214
Inflammatory bowel disease; Psoriasis; Chronic pulmonary disease; Innate immunity; Nucleotide oligomerization domains
11.  Metabolomics in psoriatic disease: pilot study reveals metabolite differences in psoriasis and psoriatic arthritis 
F1000Research  2014;3:248.
Importance: While “omics” studies have advanced our understanding of inflammatory skin diseases, metabolomics is mostly an unexplored field in dermatology.
Objective: We sought to elucidate the pathogenesis of psoriatic diseases by determining the differences in metabolomic profiles among psoriasis patients with or without psoriatic arthritis and healthy controls.
Design: We employed a global metabolomics approach to compare circulating metabolites from patients with psoriasis, psoriasis and psoriatic arthritis, and healthy controls.
Setting: Study participants were recruited from the general community and from the Psoriasis Clinic at the University of California Davis in United States.
Participants: We examined metabolomic profiles using blood serum samples from 30 patients age and gender matched into three groups: 10 patients with psoriasis, 10 patients with psoriasis and psoriatic arthritis and 10 control participants.
Main outcome(s) and measures(s): Metabolite levels were measured calculating the mean peak intensities from gas chromatography time-of-flight mass spectrometry.
Results: Multivariate analyses of metabolomics profiles revealed altered serum metabolites among the study population. Compared to control patients, psoriasis patients had a higher level of alpha ketoglutaric acid (Pso: 288 ± 88; Control: 209 ± 69; p=0.03), a lower level of asparagine (Pso: 5460 ± 980; Control: 7260 ± 2100; p=0.02), and a lower level of glutamine (Pso: 86000 ± 20000; Control: 111000 ± 27000; p=0.02). Compared to control patients, patients with psoriasis and psoriatic arthritis had increased levels of glucuronic acid (Pso + PsA: 638 ± 250; Control: 347 ± 61; p=0.001). Compared to patients with psoriasis alone, patients with both psoriasis and psoriatic arthritis had a decreased level of alpha ketoglutaric acid (Pso + PsA: 186 ± 80; Pso: 288 ± 88; p=0.02) and an increased level of lignoceric acid (Pso + PsA: 442 ± 280; Pso: 214 ± 64; p=0.02).
Conclusions and relevance: The metabolite differences help elucidate the pathogenesis of psoriasis and psoriatic arthritis and they may provide insights for therapeutic development.
PMCID: PMC4288418  PMID: 25580230
12.  The impact of biologics on health-related quality of life in patients with inflammatory bowel disease 
Inflammatory bowel disease (IBD) is characterized by a chronic relapsing inflammation of the gastrointestinal tract. Adult IBD patients suffer from a disabling disease which greatly affects health-related quality of life (HRQoL). A worse HRQoL in these patients may result in a defensive and ineffective use of medical attention and thus higher medical costs. Because of its chronic nature, IBD may also cause psychological problems in many patients which may also influence HRQoL and care-seeking behavior. An important factor reducing HRQoL is disease activity. Induction of remission and long-term remission are important goals for improving HRQoL. Furthermore, remission is associated with a decreased need for hospitalization and surgery and increased employment, which in turn improve HRQoL. Treatment strategies available for many years are corticosteroids, 5-aminosalicylates and immunnosuppressants, but these treatments did not show significant long-term improvement on HRQoL. The biologics, which induce rapid and sustained remission, may improve HRQoL.
To review and evaluate the current literature on the effect of biologics on HRQoL of IBD patients.
We performed a MEDLINE search and reviewed the effect of different biologics on HRQoL. The following subjects and synonyms of these terms were used: inflammatory bowel disease, Crohn’s disease, ulcerative colitis, quality of life, health-related quality of life, fatigue, different anti-TNF medication, and biologicals/biologics (MESH). Studies included were limited to English-language, adult population, full-text, randomized, double-blind, placebo-controlled in which HRQoL was measured.
Out of 202 identified articles, 8 randomized controlled trials (RCT) met the inclusion criteria. Two RCTs on infliximab showed significant improvement of HRQoL compared to placebo which was sustained over the long term. One RCT on adalimumab showed a significant and sustained improvement of HRQoL compared to placebo. This study showed also significant decrease of fatigue in the adalimumab-treated patients. Three RCTs on certolizumab showed a significant improvement of HRQoL in the intervention group compared to placebo. Two RCTs of natalizumab treatment were found. One study showed significant and sustained improvement compared to placebo, and also scores of HRQoL comparable to that in the general population, but in the other no significant results were found.
The biologics infliximab, adalimumab, certolizumab, and natalizumab demonstrated significant improvement of HRQoL of IBD patients compared with placebo. However, we found differences in improvement of HRQoL between the different biologics.
PMCID: PMC3108643  PMID: 21694833
inflammatory bowel disease; health-related quality of life; health care costs; biologics
13.  Do eating disorders accompany metabolic syndrome in psoriasis patients? Results of a preliminary study 
Metabolic syndrome (MBS) has been reported as a frequent comorbidity in psoriatic patients. The main pathogenesis is considered to be inflammation in this association. MBS has been investigated in eating disorders as well. While psoriasis has some psychiatric comorbidities, the link between psoriasis, MBS, and eating disorders (EDs) is unknown.
The study was designed as a cross-sectional, randomized, and controlled trial. A total of 100 patients with psoriasis were included in the study. Sociodemographic data, clinical subtype of psoriasis, Psoriasis Area and Severity Index (PASI) scores, and associated diseases were registered for each patient. The criteria for diagnosis of MBS developed by the International Diabetes Foundation (IDF) was used. These are central obesity (waist circumference ≥94 cm in men or ≥80 cm in women), plus two of the following: elevated triglycerides (≥150 mg/dL), reduced high-desity lipoprotein cholesterol (>40 mg/dL for men; >50 mg/dL for women), elevated blood pressure (≥130 mmHg systolic or ≥85 mmHg diastolic), and elevated fasting blood glucose (≥100 mg/dL). Additionally, the Eating Attitude Test (EAT), Beck Depression Inventory (BDI), and Beck Anxiety Inventory (BAI), and psychiatric interview were performed for all patients.
There were 45 female and 55 male patients, aged between 18 and 85 years old (median 41.12 ± 16.01). MBS was present in 31% of the patients with psoriasis. There was no correlation between the severity of psoriasis and MBS. EAT scores were ≥30 in 7/100 patients. Four out of 31 patients with MBS (12.9%) had ED and 3/69 patients were without MBS (4.3%). Mean ED scores were compared statistically and the difference was significant (EAT = 17.9 ± 9.558 and 11.5 ± 7.204, P < 0.001).
Defining risk factors leading to comorbidities is important in psoriasis. EDs seem to have an impact on the development of MBS in psoriasis. Establishment and treatment of EDs in patients with psoriasis may prevent the onset of MBS and other comorbidities due to MBS.
PMCID: PMC3173015  PMID: 21931499
obesity; abdominal obesity; binge-eating disorder; anxiety; inflammation
14.  Cancer risk in immune-mediated inflammatory diseases (IMID) 
Molecular Cancer  2013;12:98.
Inflammation and cancer have a profound yet ambiguous relationship. Inflammation - especially chronic inflammation - has protumorigenic effects, but inflammatory cells also mediate an immune response against the tumor and immunosuppression is known to increase the risk for certain tumors.
This article reviews current literature on the role of inflammation in cancer and the cancer risk in immune-mediated inflammatory diseases (IMIDs). We discuss the effect on cancer risk of different drug classes used in the treatment of IMIDs treatment, including biologicals such as tumor necrosis factor (TNF) inhibitors.
Overall cancer incidence and mortality risk are similar to the general population in inflammatory bowel disease (IBD), and slightly increased for rheumatoid arthritis and psoriasis, with risk profiles differing for different tumor types. Increased risk for non-melanoma skin cancer is associated with thiopurine treatment in IBD, with the combination of anti-TNF and methotrexate in rheumatoid arthritis and with PUVA, cyclosporine and anti-TNF treatment in psoriasis. Data on the safety of using biologic or immunosuppressant therapy in IMID patients with a history of cancer are scarce.
This review provides clinicians with a solid background to help them in making decisions about treatment of immune-mediated diseases in patients with a tumor history.
This article is related to another review article in Molecular Cancer:
PMCID: PMC3765952  PMID: 23987103
Antirheumatic agents; Autoimmune diseases; Biological products; Cancer; Inflammation; Tumor necrosis factor
15.  Women, men, and rheumatoid arthritis: analyses of disease activity, disease characteristics, and treatments in the QUEST-RA Study 
Gender as a predictor of outcomes of rheumatoid arthritis (RA) has evoked considerable interest over the decades. Historically, there is no consensus whether RA is worse in females or males. Recent reports suggest that females are less likely than males to achieve remission. Therefore, we aimed to study possible associations of gender and disease activity, disease characteristics, and treatments of RA in a large multinational cross-sectional cohort of patients with RA called Quantitative Standard Monitoring of Patients with RA (QUEST-RA).
The cohort includes clinical and questionnaire data from patients who were seen in usual care, including 6,004 patients at 70 sites in 25 countries as of April 2008. Gender differences were analyzed for American College of Rheumatology Core Data Set measures of disease activity, DAS28 (disease activity score using 28 joint counts), fatigue, the presence of rheumatoid factor, nodules and erosions, and the current use of prednisone, methotrexate, and biologic agents.
Women had poorer scores than men in all Core Data Set measures. The mean values for females and males were swollen joint count-28 (SJC28) of 4.5 versus 3.8, tender joint count-28 of 6.9 versus 5.4, erythrocyte sedimentation rate of 30 versus 26, Health Assessment Questionnaire of 1.1 versus 0.8, visual analog scales for physician global estimate of 3.0 versus 2.5, pain of 4.3 versus 3.6, patient global status of 4.2 versus 3.7, DAS28 of 4.3 versus 3.8, and fatigue of 4.6 versus 3.7 (P < 0.001). However, effect sizes were small-medium and smallest (0.13) for SJC28. Among patients who had no or minimal disease activity (0 to 1) on SJC28, women had statistically significantly higher mean values compared with men in all other disease activity measures (P < 0.001) and met DAS28 remission less often than men. Rheumatoid factor was equally prevalent among genders. Men had nodules more often than women. Women had erosions more often than men, but the statistical significance was marginal. Similar proportions of females and males were taking different therapies.
In this large multinational cohort, RA disease activity measures appear to be worse in women than in men. However, most of the gender differences in RA disease activity may originate from the measures of disease activity rather than from RA disease activity itself.
PMCID: PMC2688237  PMID: 19144159
16.  Psoriasis, psoriatic arthritis and increased risk of incident Crohn’s disease in US women 
Annals of the rheumatic diseases  2012;72(7):1200-1205.
Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), shares clinical and immunological features with psoriasis. Genome-wide association studies have found common susceptibility genes. However, epidemiologic data evaluating the association between psoriasis, psoriatic arthritis and risk of IBD are sparse. We aimed to evaluate the association between psoriasis, psoriatic arthritis and incident CD and UC among women in the USA.
174 476 women were enrolled in the Nurses’ Health Study (NHS) (1996–2008) and NHS II (1991–2007). Lifetime history of physician-diagnosed psoriasis and psoriatic arthritis was confirmed by supplementary questionnaires. Information on CD and UC was obtained by self-reported questionnaires and confirmed by medical record review.
We documented 188 incident cases of CD and 240 incident cases of UC during follow-up. Psoriasis was associated with a significantly increased risk of subsequent CD with a multivariate-adjusted relative risk (RR) of 4.00 (95% CI 1.72 to 9.27) for NHS and 3.76 (1.82 to 7.74) for NHS II. By contrast, we did not observe a significant increase in risk of UC associated with psoriasis. In a pooled analysis of both cohorts, women with psoriasis experienced a significantly increased risk of CD (RR, 3.86, 95% CI 2.23 to 6.67), but not UC (RR, 1.17, 95% CI 0.41 to 3.36). The risk of CD was especially pronounced among psoriatics with concomitant psoriatic arthritis (RR, 6.43, 95% CI 2.04 to 20.32).
Psoriasis with concomitant psoriatic arthritis is associated with an increased risk of incident CD.
PMCID: PMC3547138  PMID: 22941766
17.  Trends in lipid profiles in patients with psoriasis: a population-based analysis 
BMC Dermatology  2012;12:20.
Psoriasis is associated with an atherogenic lipid profile but longitudinal changes in lipids around disease onset are unknown. The purpose of our study is to examine the effect of psoriasis onset on serum lipid profiles.
We compared changes in lipid profiles in a population based incident cohort of 689 patients with psoriasis and 717 non-psoriasis subjects. All lipid measures performed 5 years before and after psoriasis incidence/index date were abstracted. Random-effects models adjusting for age, sex and calendar year were used to examine trends in lipid profiles.
There were significant declines in total cholesterol (TC) and low-density lipoprotein (LDL) levels during the 5 years before and after psoriasis incidence/index date in both the psoriasis and the non-psoriasis cohorts, with a greater decrease noted in the TC levels (p=0.022) and LDL (p=0.054) in the non-psoriasis cohort. High-density lipoprotein (HDL) levels increased significantly both before and after psoriasis incidence date in the psoriasis cohort. Triglyceride (TG) levels were significantly higher (p<0.001), and HDL levels significantly lower (p=0.013) in patients with psoriasis compared to non-psoriasis subjects. There were no differences in prescriptions for lipid lowering drugs between the two cohorts.
Patients with psoriasis had a significant decrease in TC and LDL levels during the 5 years before psoriasis incidence. Higher mean TG and lower mean HDL levels were noted in the 5 years before psoriasis incidence. These changes are unlikely to be caused by lipid lowering treatment alone and require further exploration.
PMCID: PMC3520693  PMID: 23110323
Psoriasis; Lipids; Epidemiology
18.  Rates of new-onset psoriasis in patients with rheumatoid arthritis receiving anti-tumour necrosis factor α therapy: results from the British Society for Rheumatology Biologics Register 
Annals of the Rheumatic Diseases  2008;68(2):209-215.
Anti-tumour necrosis factor (TNF)α treatments improve outcome in severe rheumatoid arthritis (RA) and are efficacious in psoriasis and psoriatic arthritis. However recent case reports describe psoriasis occurring as an adverse event in patients with RA receiving anti-TNFα therapy.
We aimed to determine whether the incidence rate of psoriasis was higher in patients with RA treated with anti-TNFα therapy compared to those treated with traditional disease-modifying antirheumatic drugs (DMARDs). We also compared the incidence rates of psoriasis between the three anti-TNFα drugs licensed for RA.
We studied 9826 anti-TNF-treated and 2880 DMARD-treated patients with severe RA from The British Society for Rheumatology Biologics Register (BSRBR). All patients reported with new onset psoriasis as an adverse event were included in the analysis. Incidence rates of psoriasis were calculated as events/1000 person years and compared using incidence rate ratios (IRR).
In all, 25 incident cases of psoriasis in patients receiving anti-TNFα therapy and none in the comparison cohort were reported between January 2001 and July 2007. The absence of any cases in the comparison cohort precluded a direct comparison; however the crude incidence rate of psoriasis in those treated with anti-TNFα therapy was elevated at 1.04 (95% CI 0.67 to 1.54) per 1000 person years compared to the rate of 0 (upper 97.5% CI 0.71) per 1000 person years in the patients treated with DMARDs. Patients treated with adalimumab had a significantly higher rate of incident psoriasis compared to patients treated with etanercept (IRR 4.6, 95% CI 1.7 to 12.1) and infliximab (IRR 3.5, 95% CI 1.3 to 9.3).
Results from this study suggest that the incidence of psoriasis is increased in patients treated with anti-TNFα therapy. Our findings also suggest that the incidence may be higher in patients treated with adalimumab.
PMCID: PMC2605571  PMID: 18385277
19.  Social support and adaptation to the disease in men and women with psoriasis 
Archives of Dermatological Research  2012;304(6):421-432.
Social support was shown to be an important factor buffering negative effects of stress in a range of clinical populations. Little is known, however, about the role of social support in the population of patients with psoriasis although strong psychosocial stress has been implicated in this disease. The objective of this study was to evaluate the association between social support and selected indices of adaptation to life with the disease, including health-related quality of life, depressive symptoms and acceptance of life with the disease, in a sample of patients with psoriasis. Additionally, gender differences in these relationships were analyzed. One-hundred-four patients with psoriasis completed psychological tests measuring disease-related social support, health-related quality of life, depressive symptoms and acceptance of life with the disease. Psoriasis severity was assessed by Psoriasis Area and Severity Index. The patients reporting higher social support levels had significantly higher quality of life, lower depression levels, and higher acceptance of life with the disease. The strengths of these effects, however, were different in women and men. Higher social support was slightly more closely associated with better acceptance of life with the disease in men than in women. However, higher social support was more closely associated to lower depression and better quality of life in women than in men. Among different types of social support, tangible support was found to be the best predictor for the all adaptation indices. Effects of social support perceived by psoriasis patients on adaptation to the disease may be gender-related and exact pathways of these effects may depend on the type on the dimension of social support and the selected type of adaptation indicator. Tangible support seems the most important type of support contributing to better adaptation in both women and men with psoriasis.
PMCID: PMC3401292  PMID: 22456752
Social support; Quality of life; Psoriasis; Adaptation to disease; Depressive symptoms; Gender differences
20.  Tnfa Signaling Through Tnfr2 Protects Skin Against Oxidative Stress–Induced Inflammation 
PLoS Biology  2014;12(5):e1001855.
A new zebrafish model of skin inflammatory disease explains new-onset and worsening psoriasis and lichen planus in patients receiving anti-TNFα therapy.
TNFα overexpression has been associated with several chronic inflammatory diseases, including psoriasis, lichen planus, rheumatoid arthritis, and inflammatory bowel disease. Paradoxically, numerous studies have reported new-onset psoriasis and lichen planus following TNFα antagonist therapy. Here, we show that genetic inhibition of Tnfa and Tnfr2 in zebrafish results in the mobilization of neutrophils to the skin. Using combinations of fluorescent reporter transgenes, fluorescence microscopy, and flow cytometry, we identified the local production of dual oxidase 1 (Duox1)-derived H2O2 by Tnfa- and Tnfr2-deficient keratinocytes as a trigger for the activation of the master inflammation transcription factor NF-κB, which then promotes the induction of genes encoding pro-inflammatory molecules. In addition, pharmacological inhibition of Duox1 completely abrogated skin inflammation, placing Duox1-derived H2O2 upstream of this positive feedback inflammatory loop. Strikingly, DUOX1 was drastically induced in the skin lesions of psoriasis and lichen planus patients. These results reveal a crucial role for TNFα/TNFR2 axis in the protection of the skin against DUOX1-mediated oxidative stress and could establish new therapeutic targets for skin inflammatory disorders.
Author Summary
Psoriasis and lichen planus are chronic, debilitating skin diseases that affect millions of people worldwide. TNFα is a multifunctional cytokine that mediates acute and chronic inflammation. While TNFα antagonist therapy is used for autoimmune or chronic inflammatory diseases, such as inflammatory bowel disease (IBD), numerous studies have reported new-onset psoriasis and lichen planus following such therapy. We have used the unique advantages of the zebrafish embryo to identify a novel phenotype that mirrors this unexplained and paradoxical onset of psoriasis and lichen planus. We found that depletion of Tnfa or its receptor Tnfr2 caused skin inflammation and hyperproliferation of keratinocytes through the activation of a Duox1/H2O2/NF-κB positive feedback inflammatory loop. Strikingly, DUOX1 was drastically induced in the skin lesions of psoriasis and lichen planus patients, and pharmacological inhibition of Duox1 abrogated skin inflammation, placing Duox1-derived H2O2 upstream of this inflammatory loop. Our results suggest that therapies targeting DUOX1 and H2O2 could provide innovative approaches to the management of skin inflammatory disorders.
PMCID: PMC4011677  PMID: 24802997
21.  Demography, baseline disease characteristics and treatment history of patients with psoriasis enrolled in a multicentre, prospective, disease-based registry (PSOLAR)* 
The British Journal of Dermatology  2014;171(1):137-147.
Psoriasis is associated with several comorbidities and behavioural risk factors.
To evaluate demographic and disease characteristics in patients enrolled in the Psoriasis Longitudinal Assessment and Registry (PSOLAR).
PSOLAR is a global, prospective, longitudinal, disease-based registry that includes a postmarketing commitment to evaluate safety in patients with psoriasis. Enrolled patients had to be receiving, or be eligible to receive, conventional systemic or biological agents. Demographic/disease characteristics, medical histories, lifestyle risk factors and previous treatments are collected at enrolment. Efficacy and safety data are collected every 6 months for 8 years, and data are extracted annually. Selected parameters are evaluated by age quartile using post hoc analyses.
As of 23 August 2012, 11 900 patients were enrolled at 301 sites in North America, Europe and Latin America. Over half of the PSOLAR population (54·7%) is male, with a mean age of 48·6 years and mean body mass index of 30·9 kg m−2 at enrolment. Mean duration of disease at enrolment was 17·5 years, and mean Physician's Global Assessment score was 2·0. Psoriatic arthritis (35·5%) and cardiovascular diseases (38·2%) were highly prevalent. Diabetes mellitus type II was reported in 11·4% of patients. Depression and anxiety were noted in 14·7% and 11·1% of patients, respectively; 79·0% reported any alcohol use and 56·7% reported smoking or a history of smoking. The occurrence of most comorbidities, including cardiovascular disease and risk factors, increased with age.
In the PSOLAR population, multiple and age-appropriate comorbidities are associated with psoriasis and may affect the selection of psoriasis treatments.
What's already known about this topic?
Psoriasis is a complicated disorder, often accompanied by multiple comorbidities.
Demographic and disease characteristics of patients with psoriasis reported from large claims datasets may be affected by misclassification bias or coding errors.
In clinical trials, many patients are excluded owing to strict inclusion criteria.
What does this study add?
Data collected by the Psoriasis Longitudinal Assessment and Registry reveal that the demographics and disease characteristics of patients with psoriasis who are receiving, or are candidates for, systemic therapy in actual clinical care resemble those reported in clinical trials.
Most comorbidities occur more frequently in older patients, who, in turn, may require more comprehensive overall medical care.
PMCID: PMC4232924  PMID: 24684204
22.  Psoriasis and intraocular inflammation. 
Presented in this series were seven men and three women. Ages when seen, ranged from 32 to 68 years (average 54). Psoriasis had begun in childhood in the women and in the late 20's and 30's in the men. Arthritis (ankylosing spondylitis) was present in only one. Their ocular inflammations began from ages 26 to 62 (average 41). The onset of the inflammation was acute iritis in four and in indolent iridocylcitis in six. All but one were bilateral and chronic. The vitreous had heavy debris in nine of the ten patients. The retina was normal in only three. Boggy congestion was present in two with cystoid edema. Patches of edema. fluorescein leaking, depigmentation of both maculae, pars plana exudate, and retinal vessel obliteration to grey-white, shaggy cords was present in at least one of the remaining five patients. Systemic corticosteroid therapy has been used in eight of the ten patients described in this report. Doses no higher than 30 mg of prednisone per day were used to initiate reversal of the inflammatory response. In case 10, knowledge of the sensitivity of the process to steroids led to the successful rapid reversal of a recalcitrant iritis with only 20 mg of prednisone as a first dose and 20 mg per day for less than three weeks. Maintenance corticosteroid therapy ranged from 40 mg of prednisone every other day in case 9, prednisone 12.5 mg one day and 5 mg the next in case 8, to 8 mg of Aristocort or methylprednisolone acetate (M-edrol) daily in cases 1 and 2. In summary, these patients are older, have an indolent onset bilateral uveitis with dense vitreous debris, retinal abnormalites, and are extremely sensitive to systemic corticosteroids. Many of these patients had undergone the series of clinical evaluations known as a "uveitis survey." Many different systemic abnormalities were found and merited treatment which rarely made a difference in their ocular disease, though two improved after infected teeth were treated. Assuming that these ocular diseases were related to psoriasis, one can then challenge the value of anything found by a "uveitis survey." The author uses information gained from such studies to insure that the patient is in the best possible heatlh and then makes clinical correlations such as presented in this paper. The rarity of this combination of ocular inflammations in patients with psoriasis makes it risky to propose that this is a significant association. Arguments that this is a disease entity began with the clinical similarities: older age, indolent onset, vitreous and retinal involvement, and the extreme sensitivity to systemic corticosteroids. None of these patients had psoriatic arthritis and only one had ankylosing spondylitis. The best explanation for the fact that this disorder has not been emphasized in the past would be an attitude of ophthalmologists and physicians that the eye and skin disease were coincident.
PMCID: PMC1311703  PMID: 575684
23.  Obesity and dyslipidemia in patients with psoriasis treated at a dermatologic clinic in Manaus*  
Anais Brasileiros de Dermatologia  2013;88(6):913-916.
Psoriasis is a chronic inflammatory disease of multifactorial etiology, with participation of genetic, autoimmune and environmental factors. Recent studies have demonstrated the role of inflammatory cells and mediators in the pathogenesis of psoriasis, which is now defined as a systemic and autoimmune inflammatory disease that may be associated with other diseases of inflammatory nature.
To evaluate the occurrence of obesity and dyslipidemia in patients with psoriasis treated at a dermatology clinic in Manaus.
We performed a prospective descriptive study to assess the prevalence of obesity and dyslipidemia in patients with psoriasis. Besides the recommended dermatological care, a physical examination was performed to measure weight, height and waist circumference.
We included 72 patients, 44 (61.1%) female and 28 (38.9%) male, with a mean age of 51.0 years ± 15.9 years. As for body mass index (BMI), 16 (22.2%) were overweight and 20 (27.8%) were obese. In the analysis of waist circumference in relation to gender, we found that 79.5% of women surveyed had central obesity, a percentage statistically higher than that observed among men (42.9%) at the 5% level of significance (p = 0.001). Regarding the diagnosis of dyslipidemia, 29 (65.9%) females and 22 (78.6%) males showed alterations in lipid profile.
The occurrence of dyslipidemia and obesity in patients with psoriasis can affect life quality and expectancy, increasing the risk of systemic and metabolic diseases, which makes periodic investigation of these comorbidities in patients with psoriasis mandatory.
PMCID: PMC3900341  PMID: 24474099
Dyslipidemias; Obesity; Psoriasis
24.  An Antibiotic-Responsive Mouse Model of Fulminant Ulcerative Colitis  
PLoS Medicine  2008;5(3):e41.
The constellation of human inflammatory bowel disease (IBD) includes ulcerative colitis and Crohn's disease, which both display a wide spectrum in the severity of pathology. One theory is that multiple genetic hits to the host immune system may contribute to the susceptibility and severity of IBD. However, experimental proof of this concept is still lacking. Several genetic mouse models that each recapitulate some aspects of human IBD have utilized a single gene defect to induce colitis. However, none have produced pathology clearly distinguishable as either ulcerative colitis or Crohn's disease, in part because none of them reproduce the most severe forms of disease that are observed in human patients. This lack of severe IBD models has posed a challenge for research into pathogenic mechanisms and development of new treatments. We hypothesized that multiple genetic hits to the regulatory machinery that normally inhibits immune activation in the intestine would generate more severe, reproducible pathology that would mimic either ulcerative colitis or Crohn's disease.
Methods and Findings
We generated a novel mouse line (dnKO) that possessed defects in both TGFβRII and IL-10R2 signaling. These mice rapidly and reproducibly developed a disease resembling fulminant human ulcerative colitis that was quite distinct from the much longer and more variable course of pathology observed previously in mice possessing only single defects. Pathogenesis was driven by uncontrolled production of proinflammatory cytokines resulting in large part from T cell activation. The disease process could be significantly ameliorated by administration of antibodies against IFNγ and TNFα and was completely inhibited by a combination of broad-spectrum antibiotics.
Here, we develop to our knowledge the first mouse model of fulminant ulcerative colitis by combining multiple genetic hits in immune regulation and demonstrate that the resulting disease is sensitive to both anticytokine therapy and broad-spectrum antibiotics. These findings indicated the IL-10 and TGFβ pathways synergize to inhibit microbially induced production of proinflammatory cytokines, including IFNγ and TNFα, which are known to play a role in the pathogenesis of human ulcerative colitis. Our findings also provide evidence that broad-spectrum antibiotics may have an application in the treatment of patients with ulcerative colitis. This model system will be useful in the future to explore the microbial factors that induce immune activation and characterize how these interactions produce disease.
Paul Allen and colleagues describe the development of a mouse model of fulminant ulcerative colitis with multiple genetic hits in immune regulation which can be moderated by anti-cytokine therapy and broad-spectrum antibiotics.
Editors' Summary
Inflammatory bowel disease (IBD), a group of disorders characterized by inflammation (swelling) of the digestive tract (the tube that runs from the mouth to the anus), affects about 1.4 million people in the US. There are two main types of IBD. In Crohn's disease, which can affect any area of the digestive tract but most commonly involves the lower part of the small intestine (small bowel), all the layers of the intestine become inflamed. In ulcerative colitis, which primarily affects the colon (large bowel) and the rectum (the part of the bowel closest to the anus), only the lining of the bowel becomes inflamed, the cells in this lining die, and sores or ulcers form. Both types of IBD most commonly develop between the ages of 15 and 35 years, often run in families, and carry an increased risk of cancer. Symptoms—usually diarrhea and abdominal cramps—can be mild or severe and the disorder can develop slowly or suddenly. There is no medical cure for IBD, but drugs that modulate the immune system (for example, corticosteroids) can help some people. Some people benefit from treatment with drugs that specifically inhibit “proinflammatory cytokines,” proteins made by the immune system that stimulate inflammation (for example, TNFα and INFγ). When medical therapy fails, surgery to remove the affected part of the bowel may be necessary.
Why Was This Study Done?
Exactly what causes IBD is not clear, but people with IBD seem to have an overactive immune system. The immune system normally protects the body from harmful substances but in IBD it mistakenly recognizes the food substances and “good” bacteria that are normally present in the human gut as foreign and hence reacts against them. As a result, immune system cells accumulate in the lining of the bowel and cause inflammation. Several different pathways usually prevent inappropriate immune activation, so could IBD be caused by alterations in one or several of these immune regulatory pathways? In previous studies, mice with a defect in just one pathway have developed mild intestinal abnormalities but not the problems seen in the most severe forms of IBD. In this study, therefore, the researchers have generated and characterized a new mouse line with defects in two immune regulatory pathways to see whether this might be a better animal model of human IBD.
What Did the Researchers Do and Find?
To make their new mouse line, the researchers mated mice that had a defective TGFβ signaling pathway in their T lymphocytes with mice that had a defective IL-10 signaling pathway. Both these pathways are anti-inflammatory, and mice with defects in either pathway develop mild and variable inflammation of the colon (colitis) by age 3–4 months. By contrast, the doubly defective mice (dnKO mice) failed to thrive, lost weight, and died by 4–6 weeks of age. The colons of 4- to 5-week old dnKO mice were inflamed and ulcerated (some changes were visible in 3-week-old mice) and contained many immune system cells. Mice with a single defective signaling pathway had no gut abnormalities at this age. The dnKO mice, just like people with IBD, had higher than normal blood levels of IFNγ, TNFα, and other proinflammatory cytokines; these raised levels were the result of abnormal lymphocyte activation. Treatment of the dnKO mice with a combination of agents that neutralize IFNγ and TNFα (anti-cytokine therapy) greatly reduced the colitis seen in these mice; neutralization of IFNγ alone had some beneficial effects, but neutralization of TNFα alone had no effect. Finally, early treatment of the dnKO mice with broad-spectrum antibiotics completely inhibited colitis.
What Do These Findings Mean?
These findings suggest that dnKO mice are a good model for fulminant (severe and rapidly progressing) ulcerative colitis and support the idea that IBD involves multiple genetic defects in immune regulation. They also indicate that the IL-10 and the TGFβ signaling pathways normally cooperate to inhibit the inappropriate immune responses to intestinal bacteria seen in IBD. This new mouse model should help researchers unravel what goes wrong in IBD and should also help them develop new treatments for ulcerative colitis. More immediately, these findings suggest that combined anti-cytokine therapy may be a better treatment for ulcerative colitis than single therapy. In addition, they suggest that clinical studies should be started to test whether broad-spectrum antibiotics can ameliorate ulcerative colitis in people.
Additional Information.
Please access these Web sites via the online version of this summary at
The Medline Plus Encyclopedia has pages on Crohn's disease and on ulcerative colitis (in English and Spanish)
Information is available from the UK National Health Service Direct Health Encyclopedia about Crohn's disease and ulcerative colitis
The US National Institute of Diabetes and Digestive and Kidney Diseases provides information on Crohn's disease and ulcerative colitis
Information and support for patients with inflammatory bowel disease and their caregivers is provided by the Crohn's and Colitis Foundation of America and by the UK National Association for Colitis and Crohn's Disease
PMCID: PMC2270287  PMID: 18318596
25.  Disease Progression and Treatment Responses in a Prospective DMARD-naïve Seropositive Early Rheumatoid Arthritis Cohort: Does Gender Matter? 
The Journal of rheumatology  2010;37(12):2475-2485.
To assess gender differences in disease characteristics and treatment responses over time in a DMARD-naïve seropositive early rheumatoid arthritis (RA) cohort.
DMARD-naïve, seropositive early RA (<14 months) patients with polyarticular disease were recruited by the Western Consortium of Practicing Rheumatologists. Each patient was examined at study entry, after 6 and 12 months, and yearly thereafter. Clinical and demographic data were collected. We investigated gender differences in baseline disease characteristics and treatment using Chi-square, Mann-Whitney and t tests. We used generalized estimating equations (GEE) models for repeated measures to examine whether the rate of change of specific disease outcomes during the first 2 years after DMARD initiation were significantly influenced by gender.
At baseline, men (n=67) and women (n=225) had similar disease activity and radiographic damage; men, however, had significantly worse erosion, while women had worse joint space narrowing. Despite similar treatment, women had worse disease progression over the 2-year follow up, as assessed by trends in DAS28ESR4, physician global scores and tender joint counts. In the GEE model, gender was significantly associated with the rate of change of DAS28ESR4 scores (p=0.009), though not being independently associated with disease activity. Self-reported measures (HAQ-DI, patient global scores, fatigue, pain) were worse among women at baseline and throughout the study period. Men were more likely to achieve remission.
At baseline, men and women had similar disease activity and joint damage. Responses to treatment over time were, however, better among men in this pre-biologic era; women had worse progression despite similar treatment.
PMCID: PMC2996473  PMID: 20889597
Rheumatoid arthritis; Gender; Treatment response

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