看一点儿，贴一点儿，留个记录，大家分享。借用第一篇文献的副标题，给自己的帖子命名：我们在半路上，更远的路在前方。

Long-term Treatment for Severe PsoriasisWe’re Halfway There, With a Long Way to GoARCH DERMATOL/VOL 143 (NO. 9), SEP 2007OVER THE LAST 30 YEARS, THE LANDMARKPUVA [psoralen–UV-A] Follow-upStudy has demonstrated the importanceof clinical epidemiology researchin making informed treatment decisionsfor patients with psoriasis. When PUVA was firstintroduced, psoriasis was widely believed to be an epidermalcell proliferation disorder, and there were few systemictreatment options available at that time.1 Thirty yearslater, psoriasis is believed to be an immunologic disorder,and more new systemic therapies have been approvedto treat it in the last 4 years than in the previous30 years combined.2-8 Our objective criterion regardingwhich patients have severe psoriasis and therefore are candidatesfor systemic therapy has also evolved during thisperiod, declining from 20% to 30% body surface area(BSA) in the 1970s to 1990s to 5% more recently.9,10 Withthe increasing recognition of the impact of psoriasis onhealth-related quality of life and the advent of novel therapiestargeting its immunopathogenesis, the treatment ofpsoriasis is undergoing a revolution. As patients with psoriasisare increasingly being treated with systemic agentson a long-term basis, the PUVA study provides an importantreminder of the challenge involved in makingclinical decisions based on a scientific understanding ofthe disease’s natural history and the robust long-termsafety and efficacy data of its treatments.

First, the PUVA experience exemplifies the critical importanceof long-term studies to fully define the risks andbenefits of a novel treatment. In 1974, years before theimportance of PUVA in targeting T cells and dendriticcells was recognized, this treatment was first shown tobe effective for severe psoriasis in 21 patients who hadat least 50% BSA involvement.1,11 The use of PUVA fortreating very severe psoriasis was a major development,as all patients in the trial achieved complete clearanceand reported adverse effects were minimal. In 1977, a largemulticenter clinical trial involving more than 1300 patientswho received more than 45 000 treatments demonstratedthat only 3% of patients failed to achieve clearancewith this regimen and that adverse effects due toPUVA therapy were uncommon, temporary, and generallymild.12 Although PUVA therapy was considered anexperimental technique, with limited long-term safetydata, it was widely used in the United States, with an estimated35 000 patients being treated in 1978 alone.13 In1979, the first observations of cutaneous carcinoma werereported in the cohort; however, it was not clear if PUVAtherapy was responsible for the excess number of skincancers, as affected patients had a history of treatmentwith ionizing radiation or a history of skin cancer.13 In1984, about 2 years after being approved by the Food andDrug Administration, PUVA was definitively linked toan excess risk of squamous cell carcinoma when the cohorthad an average follow-up of 5.7 years.14 In 1997, whenthe median follow-up of patients reached 19 years, PUVAuse was associated with an increased risk of melanoma,a finding that remains controversial.15

Although it took 10 years to clearly demonstrate therisk of squamous cell carcinoma from PUVA therapy andeven longer to detect a potential association with melanoma,the PUVA study represents a success in definingthe long-term safety of a systemic psoriasis treatment. Currently,the most robust safety data for psoriasis treatmentsare derived predominantly from randomized controlledclinical trials. However, these trials are generallyof short duration, measured in weeks to months, whereaspsoriasis is a lifelong disease that requires several decadesof treatment for control.16 Although clinical trialsare well suited to define the efficacy of an agent, they areparticularly prone to miss the effects of drugs that aredelayed and/or uncommon (eg, cancer, cardiovascular disease,and serious infections).17 The current drug approvalprocess leaves us with wide gaps in our knowledgeof treatment safety, which is particularly problematicwhen the therapy is to be used in large populations ofpatients on a long-term basis.18 In particular, existing safetydata of systemic therapies for severe psoriasis are limitedin the duration of drug exposure and in the numberof patients who are receiving follow-up. Therefore, thepotential risks associated with truly long-term treatmentof psoriasis remain to be further defined for seriousend points such as malignancy.19

The current PUVA Follow-up Study, as analyzed byNijsten et al,20 also provides unique data regarding theeffectiveness of long-term treatment of severe psoriasis.During the follow-up of 815 patients who underwent 2378skin examinations from 1985 to 2005, approximately 50%of such examinations demonstrated that patients had mildto no skin disease. Moreover, Nijsten and coauthors notethat the likelihood that the extent of psoriasis will changemore than 1 physician global assessment level over 1 yearand over 10 years is relatively small. These observationssuggest that our treatment approach is about 50% effectiveover the long term, given that the average BSA of patientswho initially entered the multicenter PUVA trialSee also page 1113(REPRINTED) ARCH DERMATOL/VOL 143 (NO. 9), SEP 2007 WWW.ARCHDERMATOL.COM1191©2007 American Medical Association. All rights reserved.Downloaded from www.archdermatol.com at University of Pennsylvania, on September 17, 2007was 33%. Based on the ecological design used for thePUVA study, in which treatment use and psoriasis severitywere not linked at the individual level, it is unclearif these patients had mild or no psoriasis becauseof the natural history of psoriasis or because of the useof psoriasis treatments. The natural history and determinantsof psoriasis remission and flare remain poorlyunderstood as reviewed by Nijsten and colleagues. Thisstudy therefore underscores the need for further prospectiveepidemiological investigations to determine thetrue rate and determinants of spontaneous psoriasis improvementand flare, as well as how psoriasis may leadto other disease states that are associated with chronicTH1 inflammation, such as psoriatic arthritis, metabolicdisease, atherosclerosis, and myocardial infarction.21-24Such information would better inform patients about thenatural history of their psoriasis, would improve clinicaltrial designs and the interpretation of safety data, andwould allow clinicians and patients to make more informeddecisions about long-term vs intermittent therapy.

Dermatologists and patients have scant data to makehead-to-head comparisons of systemic therapies, and ourgeneral assumptions about which treatments are most safe,efficacious, and cost-effective based on short-term trialdata may not be valid when the end point is more clinicallyrelevant (eg, long-term effectiveness). The burdenof treatment success and failure over the patient’s lifetimeis eloquently described by John Updike,29 whowrote,“ . . . when I am at last too ill for all of these demandingand perilous palliatives, the psoriasis like a smolderingfire in damp peat will break out and spread triumphantly;in my dying I will become hideous, I willbecome what I am.”

Over the last 30 years, tremendous progress has beenmade in our knowledge of the pathogenesis of psoriasisand in the development of systemic therapies to treat thisdisease. This progress has been well documented by themore than 20 000 medical publications related to psoriasissince PUVA was introduced. Despite this progress,we still have major gaps in our basic knowledge of thenatural history of psoriasis, and a large percentage of patientswith extensive psoriasis will continue to suffer fromthe burden of this disease for decades.Correspondence: Dr Gelfand, Department of Dermatologyand Center for Clinical Epidemiology and Biostatistics,University of Pennsylvania, 3600 Spruce St, 2 MaloneyBldg, Philadelphia, PA 19104 ([email protected]).Financial Disclosure: Dr Gelfand has been a consultantfor Genentech, Centocor, Amgen Inc, Wyeth, Warner-Chilcott, Novartis, Signum, Follica, and Therakos andhas received honoraria fromCMEConsultants and EmeritusEducational Sciences as well as grants from Biogenidec,AMGEN, Astellas, Centocor, and Longport Inc. Heis also on the Medical Advisory Board for the NationalPsoriasis Foundation and on the Clinical Guidelines Committeefor the American Academy of Dermatology.Funding/Support: Dr Gelfand is supported by grantK23AR051125 from the National Institute of Arthritis andMusculoskeletal and Skin Diseases.Role of the Sponsor: The sponsor had no role in this editorial.Additional Contributions: John R. Stanley, MD, andDaniel Roling, MD, provided helpful feedback on earlydrafts of this manuscript.

Guys with Physical&emotional stress can worsen psoriasis....reallyyyyyyyyyy...environmental factors r important!