Local radiation and phototherapy are the most cost-effective treatments for stage IA mycosis fungoides: A comparative decision analysis model in the United States.

BACKGROUND: Treatments for early-stage mycosis fungoides (MF) include topical steroids, topical nitrogen mustard, topical bexarotene, narrowband ultraviolet B (NBUVB), psoralen plus ultraviolet A (PUVA), and local radiation. The relative cost-effectiveness of each treatment given the differences in treatment failure, disease progression, and therapy escalation is not established. OBJECTIVE: To compare the cost-effectiveness (CE) of treatment options for stage IA MF. METHODS: A state-transition model was constructed with health states of stage IA to stage IV disease, no MF, and death. Treatment-specific remission and relapse rates were obtained from the literature. Lifetime costs were calculated by accounting for medications, office visits, laboratory monitoring, related procedures, work absences, and travel. RESULTS: The order of CE of the study treatments was determined to be as follows: local radiation, $225,399 for 15.40 life-years (LYs); NBUVB, $344,728 for 15.17 LYs; PUVA, $371,741 for 15.07 LYs; topical corticosteroids, $469,354 for 14.65 LYs; topical nitrogen mustard, $951,662 for 14.29 LYs; and topical bexarotene, 11,892,496 for 13.55 LYs. Sensitivity analyses confirmed the CE rankings. LIMITATIONS: We assumed a constant probability of response, relapse rates, and 3-month treatment intervals. CONCLUSIONS: Local radiation is the most cost-effective treatment for limited local disease, whereas phototherapy (NBUVB or PUVA) is cost-effective for generalized disease. Our findings can serve to inform future studies and recommendations regarding selection of therapy for stage IA MF.

Risk of serious infections, cutaneous bacterial infections, and granulomatous infections in patients with psoriasis treated with anti-tumor necrosis factor agents versus classic therapies: Prospective meta-analysis of Psonet registries.

BACKGROUND: Anti-tumor necrosis factor (TNF) therapy in psoriasis has been associated with an increased risk of serious infections compared with nonbiologic systemic therapies. OBJECTIVE: We sought to quantify the risk of: (1) serious infections (leading to hospitalization, sequelae, or death); and (2) "any infection," bacterial cutaneous infections, and granulomatous infections among patients receiving anti-TNF therapy compared with nonbiologics (acitretin, methotrexate, cyclosporine). METHODS: We used prospective meta-analysis to combine data from the Psocare registry (Italy), Biobadaderm registry (Spain), and Clalit Health Services database (Israel), including 17,739 patients and 23,357.5 person-years of follow-up. RESULTS: For serious infections, age, gender, and Charlson morbidity index adjusted hazard ratio of exposure to anti-TNFs compared with nonbiologics was 0.98 (95% confidence interval 0.80-1.19), for bacterial cutaneous infections it was 1.00 (95% confidence interval 0.62-1.61), and for granulomatous infections it was 1.23 (95% confidence interval 0.82-1.84). Using methotrexate as comparator and comparing first year of exposure with later exposure did not modify the results. For any infectious episode, risks and relative risks were heterogeneous among registries, probably because of different definitions of outcome. LIMITATIONS: There was lack of power to describe risk of single drugs. CONCLUSION: In current clinical practice, treatment with anti-TNF drugs was not associated with a higher risk of serious infections than treatment with nonbiologic systemic therapy.

The risk of squamous cell and basal cell cancer associated with psoralen and ultraviolet A therapy: a 30-year prospective study.

BACKGROUND: By 1977, psoralen and ultraviolet A (PUVA) was established as a highly effective therapy for psoriasis. Because of concerns about potential long-term adverse effects, particularly cancer, the PUVA Follow-Up Study was established to assess long-term risk and benefits of PUVA. OBJECTIVE: We sought to determine the association of certain squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) risk with exposure to PUVA. METHODS: For nearly 30 years, this prospective cohort study of 1380 patients with psoriasis first treated with PUVA in 1975 to 1976 documented exposures and incident events including biopsy-proven skin cancers. RESULTS: From 1975 to 2005, 351 of 1380 (25%) cohort patients developed 2973 biopsy-proven SCC and 330 (24%) developed 1729 BCCs. After adjusting for age, gender, and significant confounders, the risk of developing one or more SCC in a year was strongly associated with total number of PUVA treatments (350-450 vs <50 treatments, incidence rate ratio [IRR] = 6.01, 95% confidence interval [CI] = 4.41-8.20). When all tumors are included this risk is significantly higher (IRR = 20.92, 95% CI = 14.08-31.08). Corresponding risks for BCC were much lower (person counts IRR = 3.09, 95% CI = 2.36-4.06; tumor counts IRR = 2.12, 95% CI = 1.47-3.05). LIMITATIONS: This was an observational prospective study of a cohort with severe psoriasis. An unknown factor associated with higher dose exposure to PUVA in our cohort that was not included in our analysis could account for the observed associations. CONCLUSION: Exposure to more than 350 PUVA treatments greatly increases the risk of SCC. Exposure to fewer than 150 PUVA treatments has, at most, modest effects on SCC risk. Even high-dose exposure to PUVA does not greatly increase BCC risk. The risks of SCC in long-term PUVA-treated patients should be considered in determining the risk of this therapy relative to other treatments for severe psoriasis.

Reduced-Intensity Conditioning Regimens, Prior Chronic Lymphocytic Leukemia, and Graft-Versus-Host Disease Are Associated with Higher Rates of Skin Cancer after Allogeneic Hematopoietic Stem Cell Transplantation.

To assess incidence and risk factors for skin cancer associated with allogeneic hematopoietic stem cell transplantation, we evaluated 1,974 adult allogeneic hematopoietic stem cell transplantation patients from Beth Israel Deaconess Medical Center and Dana-Farber Cancer Institute who received transplants between January 1995 and July 2013 for hematologic malignancy and survived at least 100 days. Median age was 51.1 years, and median follow-up time was 3 years. Overall, 119 patients had 221 skin cancers. The incidences of squamous cell carcinomas (incidence rate ratio = 9.8; 95% confidence interval = 7.7-12.3), basal cell carcinomas (incidence rate ratio = 2.5; 95% confidence interval = 1.9-3.2), and melanoma (standardized incidence ratio = 3.3; 95% confidence interval = 1.7-5.9) were elevated in our cohort. In multivariable models, risk factors for squamous cell carcinomas were increased age (P < 0.0001), chronic lymphocytic leukemia (P = 0.02), and chronic graft-versus-host disease (P = 0.0002). Risk factors for basal cell carcinomas were chronic lymphocytic leukemia (P = 0.003), reduced-intensity conditioning (P = 0.02), acute graft-versus-host disease (P = 0.03), and chronic graft-versus-host disease (P = 0.003). To our knowledge, previously unreported risk factors in this contemporary cohort include prior CLL for squamous cell carcinoma and basal cell carcinoma and reduced-intensity conditioning for basal cell carcinoma. This study also supports chronic graft-versus-host disease as a risk factor for nonmelanoma skin cancer, particularly squamous cell carcinoma.

Investigation into the multidimensional genetic basis of drug-induced Stevens-Johnson syndrome and toxic epidermal necrolysis.

OBJECTIVE: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare severe blistering skin diseases, which are mainly caused by drugs. The two idiosyncratic conditions are distinguished on the basis of the degree of blistering, possibly representing diseases at different ends of the same spectrum. A genetic predisposition has been postulated. METHOD: We have retrospectively identified a heterogeneous group of patients with SJS and TEN (n = 73 cases, 141 matched controls) induced by a number of marketed drugs and evaluated effector candidate genetic predisposition. We have used a multivariate genetic analysis method for the first time to handle the heterogeneity of clinical presentation, drug etiology, ethnicity and gender in these adverse events. RESULTS: Our results show that predisposition varied according to ethnicity. There was a correlation for SJS with HLA-B*44, DRB1*07 and with the MHC ancestral 57.1 haplotype (and its constituents) in subjects who self-reported as Caucasians, which did not differ with gender. The HLA-DRB and -DRQ genetic predisposition to SJS seemed to be distinct from that of TEN, but further work is needed for both conditions to identify the causal variants. No conclusion concerning correlations with different drugs could be made because of small numbers in each drug group. CONCLUSION: This study stresses the importance of accurate clinical phenotyping, exemplifies a novel analysis method to dissect complicated samples and calls for collaborative prospective studies.

Clinical severity of psoriasis in last 20 years of PUVA study.

OBJECTIVE: To assess the severity of psoriasis over time. DESIGN: We analyzed the results of structured dermatologic examinations administered over a 20-year period beginning 10 years after study enrollment. SETTING: The PUVA [psoralen-UV-A] Follow-up Study, which is a prospective cohort study. PATIENTS: The analyses were restricted to 815 patients (83.2% of those eligible) who underwent at least 2 of 4 possible examinations between 1985 and 2005. MAIN OUTCOME MEASURE: A 4-point physician global assessment (PGA). RESULTS: The distribution of the PGA levels in the study group did not change significantly over time, except that in 2005 more patients had no psoriasis compared with patients who underwent examinations in the previous study years (9.6% vs < 5.1%, P < .03). The PGA level changed more than 1 level between examinations in only 14% of patients. Multistate Markov models estimated that patients had a likelihood of about 80% to remain at the same PGA level 1 year later. After 10 years, this likelihood varied between 19% and 53%, depending on the PGA level. Except for patients who were clear of disease at baseline, on average patients had about 1 year without psoriasis over 20 years. On average, individuals with moderate to severe disease remained at these levels for 11 or more years. Conclusion Three decades after a large and diverse group of patients sought a cure for their psoriasis, consistent control of their psoriasis often had not been achieved.

Use of biological agents in patients with moderate to severe psoriasis: a cohort-based perspective.

OBJECTIVE: To compare characteristics of patients enrolled in a long-term multicenter cohort trial who had used biological therapies for treatment of psoriasis with those who had not used these agents. DESIGN: Retrospective analysis of users vs nonusers of biological therapies. SETTING: Database from the PUVA Follow-up Study, a multicenter, 30-year study of patients originally treated with psoralen UV-A (PUVA) for moderate to severe psoriasis. Patients A total of 521 patients who completed the last cycle of follow-up of the PUVA Follow-up Study. MAIN OUTCOME MEASURES: Demographic data, severity data (physician global assessment), type of biological therapy used, patients' opinions about their therapy, and their best treatment. RESULTS: Seventy-four of 521 patients (14%) used biological therapies: 65% etanercept (n = 48), 22% infliximab (n = 16), 11% efalizumab (n = 8), and 8% alefacept (n = 6). Users of biological therapies were younger, had more formal education, and were more likely to have had a greater extent of psoriasis at entry than the other cohort members. In 1998, those who used biological treatments were more likely than other cohort members to have been assessed as having severe psoriasis. In 2004, no significant difference was noted. Users of etanercept considered this agent to be as effective as methotrexate and more effective in clearing their skin and having fewer adverse effects than PUVA or UV-B. The proportion of patients originally enrolled in the 16 centers who had used biological agents varied greatly (0%-33%). CONCLUSION: After short durations of therapy, patients' opinions about biological agents tended to be positive.

Psoralen plus ultraviolet A does not increase the risk of cataracts: a 25-year prospective study.

BACKGROUND: In some animal species, exposure of the unprotected eye to psoralen plus ultraviolet A (PUVA) therapy induces lens opacities. The relevance of these animal findings to human beings is not established. However, some case reports suggest that PUVA in human beings may increase the risk of lens abnormalities. OBJECTIVE: Our aim was to evaluate any possible associations between exposure to PUVA and increased risk of ocular lens abnormalities. METHODS: Since 1977 the PUVA follow-up study has periodically monitored the ocular status of 1237 cohort members with psoriasis using structured eye examinations. In our previous report we presented data results of the first 10 years of prospective study. This report includes data from two additional cycles of eye examinations that span an additional 14 years of follow-up. RESULTS: Based on our data from the last pre-1993 to final eye examination (2004), compared with that observed for the earlier period (first ever to last pre-1993 eye examination), the age-adjusted incidence of cataract did not increase significantly (incidence rate ratio = 1.04, 95% confidence interval = 0.82-1.31). In both the univariate and multivariate analyses increasing exposure to PUVA was not associated with a higher risk of cataract. LIMITATIONS: Our cohort principally enrolled middle-aged or older patients so our data do not permit us to assess the effects of PUVA on the eyes of younger persons. CONCLUSIONS: Increasing exposure to PUVA does not increase cataract risk among persons using eye protection at the rates used in our cohort.

The reduced Impact of Psoriasis Questionnaire has good psychometric properties in Italian patients.

BACKGROUND: A recent refinement study suggested that a Rasch reduced version of the Impact of Psoriasis Questionnaire (IPSO) of 11 items most adequately assessed the psychosocial impact of US psoriasis patients. OBJECTIVE: To test whether the IPSO would also behave well in a different population that varies culturally, demographically, and in disease severity. METHODS: The psychometric properties of the IPSO, using classical test and item response theory (Rasch analysis), were assessed in 805 Italian psoriasis patients. RESULTS: Patients with more severe psoriasis reported significantly higher impact on their HRQOL (p < 0.001) and the IPSO correlated well with the Skindex-29 (r = 0.74) confirming its validity. The response distribution was adequate for all items, except item 9. The Cronbach's alphas were excellent and the high item-rest correlations confirmed its homogeneity. Principal component analysis demonstrated one dominant factor with an eigenvalue of 4.47 (items loading >0.40). Overall, the 11 IPSO items fitted the Rasch model (p = 0.07) and all items demonstrated a logical threshold order. Of the 11 items, 2 items showed significant individual misfit and only 1 item demonstrated significant differential item functioning for age but none for gender or global severity score. CONCLUSION: The 11-item IPSO is a valuable psoriasis-specific HRQOL instrument in different populations.

Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: Associations, Outcomes, and Pathobiology-Thirty Years of Progress but Still Much to Be Done.

Although rare, Stevens-Johnson syndrome and toxic epidermal necrolysis remain among the most devastating of acute conditions involving the skin. In the past 30 years, tremendous progress has been made in understanding the causes and pathobiology of this often life-threatening condition. Su et al demonstrate associations between IL 15 serum levels and the outcome of patients with Stevens-Johnson syndrome and toxic epidermal necrolysis. Their findings provide ideas for further investigations that may help us better understand the role of cytokines in this T-cell mediate disease and provides clues to possible new therapies.

Impact of psoriasis on health-related quality of life decreases over time: an 11-year prospective study.

Although psoriasis typically affects patients for many years, studies quantifying impairment in health-related quality of life (HRQOL) owing to psoriasis over long periods are lacking. This study, which interviewed patients independent of psoriasis care, investigates change in the impact of psoriasis on HRQOL over 11 years and factors associated with change among 484 patients using the Impact of Psoriasis Questionnaire (IPSO). We determined changes in the impact of psoriasis on HRQOL using a psychometrically optimized version of the IPSO. In 1993, the patients were 53+/-11.4 years and 61.8% males. From 1993 to 2004, impact on most social aspects of HRQOL remained stable, but concerns related to physical appearance decreased (e.g., 36-13%, P = 0.001). Over 11 years, the proportion of patients with low overall impact of psoriasis increased significantly (43-53%, P < 0.001). Mean IPSO scores (range 0-22) decreased by one-fifth (5-4, P < 0.001). At follow-up, patients reporting poor health had mean improvement in HRQOL about three times greater than those in good health (P < 0.05). In this large cohort interviewed independent of treatments and psoriasis status, impact of psoriasis on HRQOL decreases over time. For chronic diseases, HRQOL is best measured over time and independently of seeking treatment.

Severe cutaneous reactions to sulfadoxine-pyrimethamine and trimethoprim-sulfamethoxazole in Blantyre District, Malawi.

We estimated the frequency of clinically diagnosed Stevens-Johnson syndrome and toxic epidermal necrolysis associated with sulfadoxine-pyrimethamine (SP) and trimethoprim-sulfamethoxazole (CTX) in Blantyre District, Malawi. Cases were detected by passive surveillance at 22 health centers from March 2001 through September 2002. Denominators were estimated from the Malawi national census for Blantyre District and the frequency of SP and CTX use reported in five household surveys. Crude rates of adverse reactions were estimated to be 1.2 per 100,000 exposures for SP and 1.5 per 100,000 exposures for CTX. Rates were higher in adults (1.7 cases per 100,000 SP exposures and 2.6 cases per 100,000 CTX exposures) and in persons positive for human immunodeficiency virus (4.9 cases per 100,000 SP exposures and 8.4 cases per 100,000 CTX exposures). Infrequent treatment doses with SP are associated with a low risk of an adverse cutaneous reaction, and SP can be recommended for treatment of malaria in areas where P. falciparum is susceptible.

Lymphoma risk in psoriasis: results of the PUVA follow-up study.

OBJECTIVE: To assess the risk of lymphoma in patients with psoriasis. DESIGN: Prospective cohort study that spans 30 years and a systematic review of the literature. SETTING: Sixteen university medical centers. PATIENTS: A total of 1380 patients with psoriasis who were initially treated with psoralen-UV-A (PUVA) from 1975 through 1976 and who underwent periodic interviews and physician examinations irrespective of their use of any treatment. MAIN OUTCOME MEASURE: Incidence of lymphoma relative to that expected in the general US population (original primary end point of the study). RESULTS: The incidence of lymphoma in patients who received PUVA and were not exposed to high levels of methotrexate was comparable to that expected in the general population (incidence rate ratio, 0.85; 95% confidence interval, 0.37-1.67) but was elevated among those exposed to high levels of methotrexate (> or =36 months) (incidence rate ratio, 4.39; 95% confidence interval, 1.59-12.06). CONCLUSION: Unless exposed to high levels of methotrexate, the risk of lymphoma among members of the PUVA Follow-up Study was comparable to that observed in the general population.

High levels of ultraviolet B exposure increase the risk of non-melanoma skin cancer in psoralen and ultraviolet A-treated patients.

Sunlight and psoralen and ultraviolet A (PUVA) are risk factors for the development of squamous cell carcinoma (SCC) and, to a lesser extent, basal cell carcinoma (BCC). Ultraviolet B (UVB) therapy, used for the treatment of psoriasis, might also increase the risk of these tumors. We studied the relation of skin cancer incidence to UVB use among 1380 adult subjects enrolled in a long-term safety trial of PUVA therapy. We used negative binomial regression models to quantify the association between UVB and the development of non-melanoma skin cancer (NMSC), controlling for known confounders. High UVB exposure (> or =300 treatments vs <300 treatments) was associated with a modest but significant increase in SCC (adjusted incidence rate ratio (IRR)=1.37, 95% confidence interval (CI)=1.03-1.83) and BCC (adjusted IRR=1.45, 95% CI=1.07-1.96) risk. Among patients with <100 PUVA treatments, high UVB exposure was significantly associated with the development of SCC (adjusted IRR=2.75, 95% CI=1.11-6.84) and BCC (adjusted IRR=3.00, 95% CI=1.30-6.91) on body sites typically exposed to UVB therapy but not on chronically sun-exposed sites typically covered during therapy. For adults with high UVB exposure levels, UVB confers a modest increase in NMSC risk, much less than that observed with PUVA. Therefore, UVB remains a relatively low-risk treatment for psoriasis.

The psychometric properties of the psoriasis disability index in United States patients.

Although it has had only limited psychometric assessment in one country (the UK), the Psoriasis Disability Index (PDI) is a commonly used measure of the impact of psoriasis on patients. This study's objective was to analyze the psychometric properties of the PDI in 1196 US patients. High Cronbach's alpha coefficients suggested that the PDI's internal consistency is good. The validity of the PDI was tested using a global question on disease burden and self-assessed extent of disease and both appeared to be good predictors of the PDI. Large floor effects and the suboptimal response distribution of most items, however, suggested that the PDI is insensitive to mild functional limitation. Factor analyses indicated that the current PDI subscales are suboptimal. In the Rasch analysis, the PDI and its subscales appeared to measure multiple constructs, making the validity of deriving a single overall score questionable. The frequent presence of differential item functioning related to several patient characteristics confirmed the instrument's multidimensionality. These findings suggest that the PDI is not an optimal measure for use in US study populations. The psychometric properties of instruments designed to measure the impact of psoriasis should be tested in populations in which the instrument is to be applied.