The Risk of Malignancy Associated With Psoriasis
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Researchers: David Margolis, MD, PhD; Warren Bilker, PhD; Sean Hennessy, PharmD, MSCE; Carmela Vittorio, MD; Jill Santanna, MS; Brian L. Strom, MD, MPH
Arch Dermatol. 2001;137:778-783.
Objective To measure the incidence of cancer in patients with psoriasis, stratified by the severity of their disease.
Design A cohort study.
Setting Administrative claims records obtained from Medicaid programs in 3 US states.
Participants All individuals in the claims database who qualified for 1 of the 5 following groups: severe psoriasis as defined by treatment with systemic medication, less severe psoriasis, severe eczema, history of organ transplantation, and hypertension.
Main Outcome Measure A diagnosis of cancer.
Results Individuals with severe psoriasis were more likely to develop a malignancy than those with hypertension (risk ratio, 1.78; 95% confidence interval [CI], 1.32-2.40).The risk of malignancy in the severe psoriasis group approaches that in patients with organ transplants (risk ratio, 2.12; 95% CI, 1.80-2.50). Most of these cancers were nonmelanoma skin cancers and lymphoproliferative malignancies. Those with less severe psoriasis were only slightly more likely to develop a new malignancy than those with hypertension (risk ratio, 1.13; 95% CI, 1.03-1.25).
Conclusions Patients with psoriasis are at an increased risk of developing a malignancy compared with patients with hypertension. The increased risk is greatest for those with severe disease (ie, patients with psoriasis treated with systemic agents) and minimal (if an increased risk at all) for those with less severe disease compared with thosein the hypertension group. The increased risk is mainly for lymphoproliferative cancers and nonmelanoma skin cancers.
INTRODUCTION
PSORIASIS AFFECTS about 1% to 2% of the US population and varies in severity, clinical type, and response to therapy.1-2 First clinical presentation most commonly occurs in young adulthood, and psoriasis could last a lifetime.1-2 Although psoriasis has seldom been linked directly to mortality, it can cause severe morbidity and psychological distress.1 Most patients with psoriasis are treated with topical agents, which are believed to have few systemic adverse effects. However, patients with severe disease are often treated with potent systemic agents, some of which have been associated with increasing an individual's risk of developing a malignancy.1-4 Infact, some previous studies have shown that patients with psoriasis have an increased risk of developing a malignancy.5-12 However, these studies primarily investigated hospitalized individuals with psoriasis or those who had received psoralen with UV-A light treatment (PUVA), which has been well proven to increase the risk ofmalignancy.11-14
Because malignancy in the general population is relatively rare and most patients with psoriasis are treated as outpatients, it can be very difficult to accurately measure the risk of malignancy inpatients with psoriasis. Therefore, the goal of our study was to measure the incidence of cancer in patients with psoriasis, stratified by the severity of their disease.
POPULATION AND PERSON-TIME
Using a large US administrative database we designed a retrospective cohort study. Our database included data on participants in the Medicaid programs of 3 large states from July 1992 to March 1996. One state was located in the mid Atlantic region, 1 in the midwestern region, and 1 in the southern region of the United States. Compared with the general population, Medicaid participants are more likely to be women, ethnic minorities, and children.15 All individuals included in our analytic data set were 20 years or older and had International Classification of Diseases Ninth Revision, Clinical Modification (ICD-9-CM) diagnostic code(s) consistent with a disease study group.
STUDY GROUPS
Individuals were classified into 1 of 5 study groups based on ICD-9-CM codes from medical claims and, when appropriate, National Drug Codes for specific medications used to treat these illnesses. Study groups were made up of individuals with (1) severe psoriasis as defined by a diagnosis of psoriasis and treatment with 1 or more systemic therapeutic agents (ie, psoralen, methotrexate, cyclosporin, etretinate, 6-thioguanine, hydroxyurea, tacrolimus, azathioprine, or acitretin); (2) less severe psoriasis as defined by a diagnosis of psoriasis and no treatment withany systemic agent; (3) severe eczema as defined by a diagnosis of eczema on at least 4 occasions in a 12-month period; (4) heart, kidney, or liver transplants and treatment with immunosuppressive agents; and (5) essential hypertension. When patients qualified for both the psoriasis group and another group, they were only classified as having psoriasis. The hypertension group was selected as our reference group because the cancer risk among hypertensive individuals is not expected to be substantially different from the risk in the general population. A true comparison group without disease was not studied because (1) surveillance for cancer may be less in those who do not regularly see a physician and (2) in Medicaid databases there is difficulty distinguishing whether the absence of claims indicates absence of disease or loss of eligibility.15 We estimated the risk of malignancy in patients with severe eczema to ensure that at least 1 ofour comparison groups had as frequent skin examinations as those with severe psoriasis. Finally, we selected the organ transplant group to try to estimate the risk of malignancy associated withthe use of immunosuppressive agents. Disease codes and drug codes are available from the corresponding author (D.J.M.) on request.
DEFINITION OF OUTCOME
The primary outcome of our study was the first occurrence of a claim that included a diagnosis of any cancer. This diagnosis must have occurred at least 6 months after the patient was classified into their study group. A cancer-free window was selected because we believe that previously diagnosed cancers would most likely be recorded within the first 6 months of available claims.
Cancer diagnoses were also based on ICD-9-CM codes. We qualitatively reviewed the full administrative records of a sample of patients with cancer codes to confirm that these individuals received care consistent with their cancer diagnosis (eg, a patient with lymphoma codes had multiple office visits and received appropriate therapy). Finally, in a subanalysis we altered theoutcome definition such that all patients with a malignancy must have had at least 2 claims for the malignancy on different days within a 60-day window. These risk ratios were identical to those reported in the "Results" section (data not shown).
In addition we examined a priori 2 broad classes of malignancy: lymphoproliferative malignancies and nonmelanoma skin cancers. Only for the analysis of nonmelanoma skin cancers were theICD-9-CM codes for skin neoplasm of uncertain behavior included as part of the outcome definition because these cancers might have been treated before a definitive histologic diagnosis was made.
ANALYSIS
For each study group, incidence density for the onset of any malignancy was calculated with exact 95% Poisson confidence intervals (CIs). An incidence density is a measure of diseaseincidence that is corrected for unequal person-time. Incidence density was calculated by dividing the number of cancer cases (eg, malignancy in an individual with psoriasis) by the total person-time of follow-up (ie, person-years) of the study group. To calculate person-time, once a patient was classified into a study group we defined the starting point as the patient's first medical claim and the stopping point as the patient's last medical or pharmacy claim or the diagnosis of a malignancy.
Poisson regression was used to estimate unadjusted incidence density ratios and 95% CIs for the development of malignancy by comparing each study group with the hypertension group.Incidence density ratio is interpreted similarly to relative risk but takes into account unequal follow-up time. Finally, multivariate Poisson regression was used to adjust the rates for potentialconfounding by age, sex, and state of residence as well as to test for state by diagnosis effect modification.16 All statistical analyses were performed using SAS statistical software (SASInstitute Inc, Cary, NC).
We evaluated 259,808 individuals. Owing to the large size of our database, we were able to observe 1101 individuals with severe psoriasis and 16 519 individuals with less severe psoriasis for an average of more than 2 years (Table 1). About 6.2% of the patients in our Medicaid database who had psoriasis were classified in the severe group. Most of the individuals with severe psoriasis had received either methotrexate or etretinate therapy (Table 2). It should be noted that 17.7% of the individuals with severe psoriasis received therapy with more than 1 of these medications during the follow-up period. In contrast, 1.5% of the patients with severe eczema receivedtherapy with 1 or more of the severe psoriasis medications. For all subjects combined, the malignancy rate ratio (RR) was somewhat greater in the mid-Atlantic state compared with the other 2 states (1.19; 95% CI, 1.03-1.45), and increased with the age of the subject (eg, the risk ratio for the older-than-80-years age group was 4.09 [95% CI, 3.67-4.57] compared with the 20- to 29-year-old age group) (Table 3). The incidence density for the development of malignancy varied among our study groups, with those with severe eczema being the least likely to develop a malignancy and those with severe psoriasis being the most likely to develop a malignancy (Table 1).
table 1
tablw 2
table 3
Table 4 gives the univariate and multivariate incidence ratios for malignancy with the hypertension groups as the reference group. Generally, the unadjusted and adjusted risk ratios varied by more than 15%, indicating that the univariate estimates were confounded by measured patient characteristics. Adjustment measures included state of residence, age in 10-year strata, and sex(Table 4). In our study, age and sex primarily caused confounding. Compared with the hypertension group (our reference group), individuals with severe psoriasis (those receiving therapy withsystemic agents) and transplant patients were more likely to develop a malignancy (adjusted RR, 1.78 [95% CI, 1.32-2.40] and 2.12 [95% CI, 1.80-2.50], respectively). Individuals with less severe psoriasis may have had a slightly increased risk of developing cancer compared with our reference group (adjusted RR, 1.13; 95% CI, 1.03-1.25).
table 4
In addition, we looked in greater detail at 2 types of malignancies: lymphomas and nonmelanoma skin cancers. Generally, for all subjects lymphoma risk was greater in men than in women (RR, 1.59; 95% CI, 1.35-1.88) and was more common in the 60- to 69-year-old age group (RR, 1.50; 95% CI, 1.02-2.22) than in the 20- to 29-year-old age group. Skin cancer risk was greater inmen than in women (RR, 1.39; 95% CI, 1.22-1.58) and also with increasing age. For example, the greatest risk was in the older-than-80-years age group (RR, 17.49; 95 % CI, 10.41-29.38) compared with the 20- to 29-year-old age group. The risk of skin cancer was related to state of residence and was greatest in the southern state (RR, 2.11; 95% CI, 1.54-2.90) compared withthe mid-Atlantic state.
The incidence RRs for both lymphoma and nonmelanoma skin cancer were also greater in the 2 psoriasis groups than in the hypertension group and much greater in the severe psoriasis group than in the less severe psoriasis group (Table 5 and Table 6). The elevated risk ratio for the severe psoriasis group was similar to that for the organ transplant group. The elevated risk in theless severe psoriasis group was similar to that in the severe eczema group. Finally, most of the increased cancer risk for the severe psoriasis group and the less severe psoriasis group was because of the incidence of lymphoma or skin cancer among these groups (Table 7).
In our study we compared the risk of malignancy for individuals with psoriasis of varying severity, severe eczema, and organ transplants with the risk in individuals with hypertension. We did this to compare the rates of malignancy in our study groups with a group of individuals from the same population (ie, all individuals in our study are part of the US Medicaid population) and specifically avoid ascertainment bias and control at least partially for socioeconomic status. We believe that the hypertension group is likely to reflect the true population rate of developing amalignancy in our Medicaid population. An alternative reference group would have been data from the Surveillance, Epidemiology and End Results (SEER) program. However, we believe that acontrol group made up of Medicaid recipients is more appropriate because socioeconomic factors and other social factors are related to the risk of malignancy and would differ between SEER dataand Medicaid enrollees. In our study there is no reason to expect that these sociodemographic factors differ between those with hypertension and those with psoriasis. In addition, we estimatedthe risk of developing a malignancy in patients with organ transplants to obtain a benchmark for rates that are likely to be associated with the use of immunosuppressive medications, many ofwhich are used or might be used in the future to treat psoriasis. Finally, we estimated the risk of malignancy in patients with severe eczema to ensure that at least 1 of our comparison groups had frequent skin examinations and thereby had a similar opportunity to have skin cancers diagnosed as those with psoriasis. There is no known disease-related reason that patients with severe eczema should be inherently at higher risk than those with hypertension for developing skin cancer. However, a few patients (1.1%) in the severe eczema group received either therapies similar to those in our severe psoriasis group or UV light therapy that has been advocated for the treatment of eczema and might increase skin cancer risk.
Previous studies have evaluated the risk of patients with psoriasis for developing a malignancy. This topic has been of interest for several reasons but especially because psoriasis is a life-longdisease and several of the therapies used to treat it (such as those that we used to define disease severity) are potentially carcinogenic.5-8 Many of the studies that evaluated the risk ofmalignancy in individuals with psoriasis compared the individuals with psoriasis who required hospitalization with population-based cancer registries and demonstrated that individuals with psoriasis are at an increased risk of developing a malignancy compared with the population at large.10
For example, a recent study by Hannuksela-Svahn et al9 using the Finnish Hospital Discharge Register and the Finnish Cancer Registry demonstrated that individuals with psoriasis were about30% more likely to develop a malignancy than others in the Finnish population. They also demonstrated that many of these malignancies were skin cancers and lymphomas. However, to be considered as having psoriasis in their study, the patient must have been discharged from the hospital with a diagnosis of psoriasis. No information is available in their study on individuals withless severe psoriasis. In a study from Denmark that found similar results, the authors estimated that while 2% to 3% of the entire population has psoriasis, only 4% of those individuals requiredhospitalization.17
Finally, several reports have been published using data from the PUVA Follow-up Study that has shown that individuals with psoriasis who have had long-term exposure to PUVA are at anincreased risk of developing a malignancy.11-14 These longitudinal series of studies concentrate on a cohort of patients who received PUVA therapy in multiple centers across the United Statesin 1985. Again, no information is available on individuals with less severe psoriasis. In addition, rates of malignancies in the PUVA group are often compared with US population rates. This comparison may potentially be biased by factors such as the socioeconomic factors for receiving Medicaid.
There are several potential limitations to our study. Primarily because of the time frame studied, very few individuals with psoriasis received treatment with cyclosporine, which was not approved by the Food and Drug Administration for the treatment of severe psoriasis until 1997. This is especially important because there is a general concern that patients being treated with this medication may be at risk for developing a malignancy.2, 4, 18-20 Our study cannot differentiate between the 2 most obvious causes for the increased risk of cancer in the severe psoriasis group, namely, the severity of psoriasis necessitating treatment with systemic agents or the use of systemic agents alone. In addition, we could not determine how long an individual needs to be exposed to a systemic agent before their risk increases. Although the average observation period for an individual with psoriasis in our study was about 2 years, many of these individualsprobably had been receiving therapy with these agents previously.
Although our study was very large, we did not have sufficient statistical power to determine if one agent is more likely to increase the risk of cancer than another agent. However, with therecent advent of sequential or rotational therapy (the practice of using an agent for short periods and then rotating to a second agent), differentiating cancer risk for a single agent may beeven more difficult.21 There were undoubtedly some patients classified as having less severe psoriasis who, prior to our study time window, might have had severe psoriasis. The error was probably small, but it could have led us to overestimate the risk of malignancy in both the severe group and the less severe group. Finally, while we required a person to have a disease ofinterest for at least 6 months prior to the diagnosis of cancer, it is still possible that a cancer diagnosis was not incident to the onset or treatment of psoriasis (eg, the cancer diagnosis might have predated the psoriasis diagnosis). A recent study that validated a coding scheme for determining if a patient had breast cancer in the US Medicare system noted that some of the cases that were thought to be incident were actually cases of recurrent disease.22 However, there is no reason to believe that the error in diagnosing a prior malignancy should be different in our maincomparison group (hypertension) and psoriasis group. Therefore, the potential bias would be nondifferential and at worst might result in our underestimating the true increased risk in the severe psoriasis group.
One critical limitation to our study and any administrative database study is estimating the validity of the ICD-9-CM coding schemes to determine study groups and patient outcomes. We didqualitatively demonstrate that subjects in our study groups and subjects with cancer diagnoses received care consistent with their ICD-9-CM codes (eg, a patient with lymphoma receivedappropriate chemotherapy). We also repeated our analysis, requiring at least 2 different claims for the same malignancy at least 60 days apart. Using our coding scheme, it would be much lesslikely that the outcome was due to a coding error. The results of our analyses were the same. However, the gold standard is to verify ICD-9-CM coding schemes by reviewing patient charts.Because of concerns surrounding patient confidentiality in the Medicaid benefits system, we were not able to verify that an individual had severe psoriasis when placed in our severe psoriasisgroup or truly ascertain that a patient with a code for lymphoma truly had lymphoma. We could only adjust our findings for variables coded in the databases. It is possible that the effect estimates could change if these unmeasured confounders (such as cigarette use, alcohol use, occupational exposures, etc) were measured.
In summary, our study adds to the growing body of literature showing that patients with severe psoriasis are at an increased risk of developing a malignancy, especially nonmelanoma skincancers and lymphoma in our study. As has been frequently addressed concerning the use of PUVA, the potential risk of developing cancer must be weighed against the benefit of thetherapy.7, 23-24 We do not know if the risk of malignancy will diminish with the advent of rotational use of systemic agents. However, it should be noted that about 17% of our patients with severe psoriasis received more than 1 systemic agent. Finally, because our database included patients seen on an outpatient basis, we were able to estimate the risk of malignancy in patientswith less severe psoriasis. This group may be at a slight overall increased risk of developing a malignancy compared with individuals with hypertension, specifically for developing nonmelanomacancers of the skin and lymphoma. The risk is similar to the risk seen in patients with severe eczema.
AUTHOR INFORMATION
A cooperative effort of the Clinical Epidemiology Unit of the Istituto Dermopatico dell' Immacolata–Istituto di Ricovero e Cura a Carattere Scientifico (IDI-IRCCS) and theArchives of Dermatology.
Accepted for publication March 19, 2001.
Our study was supported by an unrestricted research grant from Novartis Pharmaceuticals Corporation, East Hanover, NJ, to the trustees of the University of Pennsylvania, Philadelphia.
We would like to thank Sandy Masiak for her secretarial assistance.
Corresponding author: David J. Margolis, MD, Department of Dermatology, Biostatistics & Epidemiology, University of Pennsylvania School of Medicine, 423 Guardian Dr, Room 815, Blockley Hall,Philadelphia, PA 19104 This e-mail address is being protected from spambots. You need JavaScript enabled to view it.
From the Departments of Biostatistics and Epidemiology, Center for Clinical Epidemiology and Biostatistics (Drs Margolis, Bilker, and Strom, Mr Hennessy, and Ms Santanna) and Dermatology (Drs Margolis and Vittorio), University of Pennsylvania School of Medicine, Philadelphia.
REFERENCES
1. van de Kerkhof PCM. Textbook of Psoriasis. Oxford, England: Blackwell Science Ltd; 1999.
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2. Stern RS. Psoriasis. Lancet. 1997;350:349-353. FULL TEXT | WEB OF SCIENCE | PUBMED
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3. Ashcroft DM, Li Wan PA, Griffiths CE. Therapeutic strategies for psoriasis. J Clin Pharm Ther. 2000;25:1-10. FULL TEXT | WEB OF SCIENCE | PUBMED
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4. Bardolph E, Ashton R. Psoriasis: a review of present and future management. Nurs Stand. 1998;12:43-47.
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5. Peritz AE, Gasparro FP. Psoriasis, PUVA, and skin cancer—molecular epidemiology: the curious question of T
A transversions. J Investig Dermatol Symp Proc. 1999;4:11-16. WEB OF SCIENCE |PUBMED
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6. Morison WL, Baughman RD, Day RM, et al. Consensus workshop on the toxic effects of long-term PUVA therapy. Arch Dermatol. 1998;134:595-598. FREE FULL TEXT
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7. Lindelof B. Risk of melanoma with psoralen/ultraviolet A therapy for psoriasis: do the known risks now outweigh the benefits? Drug Saf. 1999;20:289-297. FULL TEXT | WEB OF SCIENCE | PUBMED
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8. Murphy GM. Skin cancer in patients with psoriasis-many intertwined risk factors. Br J Dermatol. 1999;141:1001-1002. FULL TEXT | WEB OF SCIENCE | PUBMED
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9. Hannuksela-Svahn A, Pukkala E, Laara E, Poikolainen K, Karvonen J. Psoriasis, its treatment, and cancer in a cohort of Finnish patients. J Invest Dermatol. 2000;114:587-590. FULL TEXT | WEBOF SCIENCE | PUBMED
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10. Pasker-de Jong PC, Wielink G, van der Valk PG, van der Wilt GJ. Treatment with UV-B for psoriasis and nonmelanoma skin cancer: a systematic review of the literature. Arch Dermatol.1999;135:834-840. FREE FULL TEXT
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11. Stern RS, Vakeva LH. Noncutaneous malignant tumors in the PUVA Follow-up Study: 1975-1996. J Invest Dermatol. 1997;108:897-900. FULL TEXT | WEB OF SCIENCE | PUBMED
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12. Stern RS, Nichols KT, Vakeva LH. Malignant melanoma in patients treated for psoriasis with methoxsalen (psoralen) and ultraviolet-A radiation (PUVA): the PUVA Follow-up Study. N Engl J Med. 1997;336:1041-1045. FULL TEXT | WEB OF SCIENCE | PUBMED
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13. Stern RS, Liebman EJ, Vakeva L. Oral psoralen and ultraviolet A light (PUVA) treatment of psoriasis and persistent risk of nonmelanoma skin cancer: PUVA Follow-up Study. J Natl CancerInst. 1998;90:1278-1284. FREE FULL TEXT
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14. Stern RS, Lunder EJ. Risk of squamous cell carcinoma and methoxsalen (psoralen) and UV-A radiation (PUVA): a meta-analysis. Arch Dermatol. 1998;134:1582-1585. FREE FULL TEXT
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15. Carson JL, Strom BL. Medicaid databases. In: Strom BL, ed. Pharmacoepidemiology. Chichester, England: Wiley Europe Ltd; 1994:199-216.
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16. Long JS. Count outcomes: regression models for counts. In: Long JS, ed. Regression Models for Categorical and Limited Dependent Variables. Thousand Oaks, Calif: Sage Publications; 1997:217-249.
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17. Frentz G, Olsen JH. Malignant tumours and psoriasis: a follow-up study. Br J Dermatol. 1999;140:237-242. FULL TEXT | WEB OF SCIENCE | PUBMED
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18. Paquet P, Pierard GE. Breast and lung cancers in two cyclosporin-A–treated psoriatic women. Dermatology. 1998;196:450-452. FULL TEXT | WEB OF SCIENCE | PUBMED
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19. Zackheim HS. Cyclosporine-associated lymphoma. J Am Acad Dermatol. 1999;40:1015-1016.
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20. Paul C, Hornig F. Risk of malignancy associated with cyclosporin use in psoriasis. Dermatology. 1999;198:320-321. FULL TEXT | WEB OF SCIENCE | PUBMED
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21. Koo J. Sequential therapy of psoriasis: introducing a new therapeutic paradigm for better clinical results. Curr Probl Dermatol. November 1995:1-8.
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22. Freeman JL, Zhang D, Freeman DH, Goodwin JS. An approach to identifying incident breast cancer cases using Medicare claims data. J Clin Epidemiol. 2000;53:605-614. FULL TEXT | WEB OFSCIENCE | PUBMED
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23. Lindelof B, Sigurgeirsson B, Tegner E, et al. PUVA and cancer risk: the Swedish follow-up study. Br J Dermatol. 1999;141:108-112. FULL TEXT | WEB OF SCIENCE | PUBMED
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24. Wolff K. Should PUVA be abandoned? N Engl J Med. 1997;336:1090-1091. FULL TEXT | WEB OF SCIENCE | PUBMED
Lymphoma Risk in Psoriasis: Results of the PUVA Follow-up Study
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Researcher: Robert S. Stern, MD
Arch Dermatol. 2006;142:1132-1135.
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 (
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 thegeneral population.
INTRODUCTION
With the advent of new treatments for psoriasis that may increase the risk of lymphoma, determining the innate risk of lymphoma in patients with psoriasis has become important both for clinical decision making and to ensure the robust evaluation of the risks of newer therapies. Most studies1-15 suggest that the risk of lymphoma inpatients with psoriasis is comparable to that in the general population. However, 3 recent studies16-18 suggested an increased risk of lymphoma in persons with psoriasis.
The PUVA [psoralen–UV-A] Follow-up Study provides a unique resource to establish the incidence of lymphoma among persons with moderate to severe psoriasis, both overall and in subgroups defined by their exposures to established treatments for psoriasis. This cohort study of 1380 persons first treated from 1975 through 1976 nowincludes nearly 30 000 person-years of follow-up of individuals with moderate to severe psoriasis whose major health events and use of treatments for psoriasis have been prospectively documented during a 30-year period. Determining the risk of lymphoma was an original primary end point for the study. Our data suggest that the innate risk of lymphoma among persons with moderate to severe psoriasis is unlikely to differ substantially from that in the general population.
The PUVA Follow-up Study is a multicenter prospective cohort study. Its methods have been previously detailed.1, 19 This study was approved by the Committee for ClinicalInvestigation of the Beth Israel Deaconess Medical Center. From 1975 through 1976, patients who had enrolled in a therapeutic study of PUVA were asked if they wished to be followed up long term to determine the safety and efficiency of PUVA. Of the 1450 patients participating in the clinical trial, 1380 (95%) enrolled in the long-termprospective study. In addition to baseline information collected from 1975 through 1976, during the subsequent 30 years, these patients were interviewed 22 times. Datacollection for this study ended in 2005. Any patient who reported a serious health event, such as lymphoma, was asked to provide permission for us to obtain medical records that pertained to this event. In addition, we used the National Death Index to ascertain cause of death among individuals who were lost to follow-up.20
The questionnaires administered at entry (1975-1976) and the 22 follow-up interviews administered during the subsequent 30 years included structured questions designed to determine exposureto systemic therapies for psoriasis and to PUVA and UV-B. On the basis of these data, for each calendar year we calculated the extent of exposure to methotrexate, UV-B, and PUVA. As in prioranalyses, we defined high-dose exposure to methotrexate as 36 or more months of use and high-dose exposure to UV-B as at least 300 treatments.19
STATISTICAL ANALYSIS
We calculated the expected numbers of lymphoma cases based on data from the Surveillance Epidemiology and End Results (SEER) program of the National Cancer Institute.21 We used age- andsex-specific rates applicable to each year of follow-up. To calculate the expected number of lymphoma cases for 2003, 2004, and 2005, we used SEER incidence data for 2002, the most recentyear available at the time of analysis (June 2005).
We compared the characteristics of cases to other cohort patients still being followed up (and alive) at the mean year at onset of lymphoma. For categorical variables, we used the 
2 test todetermine statistical significance with Yates correction when appropriate. For continuous variables, we used the t test. We compared observed and expected number of tumors to calculate theincidence rate ratios (IRRs) and used the Poisson distribution to calculate the 95% confidence intervals (CIs). We compared observed and expected numbers of lymphoma cases for the cohort asa whole and for cohort subgroups as defined by demographic and exposure characteristics.
In calculating expected numbers of tumors based on age-, sex-, and year-specific incidence data from SEER, our analyses were standardized for age, sex, and calendar year. Our multivariatemodels were Poisson regression models and included all exposures and attributes that were related to lymphoma with P
.20 in the univariate analyses. We also tested for possible interactionsamong exposures that were related to lymphoma risk with P.20 in the univariate analysis using 2-way interaction terms. In addition, we performed analyses for each significantly associatedexposure that were stratified according to level of exposure to other factors that were also significantly associated with lymphoma risk in the univariate analysis.
RESULTS
Of the 1380 patients originally enrolled in the study (1975-1976), at the time of the 22nd and final follow-up interviews (2003-2005), we successfully interviewed 526 (83%) of the 636 who were still alive and participating in the study. As detailed in Table 1, the attrition rate, except because of death, was low until after 1995.
Table 1. Follow-up Status, by Decade, of 1380 Patients Enrolled From 1975 Through 1976
In 28 554 person-years of prospective follow-up, we detected 16 persons with lymphoma, of which 14 had non-Hodgkin lymphoma and 2 had Hodgkin disease. We did not include cutaneous T-celllymphoma. Of the 16 incident lymphomas, 13 were ascertained through our normal follow-up procedures and 3 from our search of the National Death Index database. Compared with our lastreport, which spanned 1975 through 1996, the incidence of lymphoma was significantly higher from 1997 through 2005 than in prior years (1975-1996) (IRR, 4.38; 95% CI, 1.60-12.06).
Table 2 compares the characteristics of the cases at the time of detection of lymphoma (mean year of detection, 1995) and the 848 other cohort patients still alive and being followed up in1995. Patients with lymphoma were significantly older. Except for a significantly higher proportion of patients with high-dose exposure to methotrexate but not PUVA or UV-B, those who developed lymphoma and other active cohort members had similar characteristics and exposures.
Table 2. Demographic Characteristics and Treatment Exposures of Lymphoma Cases and Other Cohort Members
Table 3 provides the univariate and multivariate analysis results of associations of various patient exposures and attributes with lymphoma risk. The incidence of lymphoma was significantlyhigher after 1996 compared with that for the cohort from 1975 through 1996 (Table 3) and for those who had used methotrexate for at least 36 months (Table 3). There was an apparentinteraction between the follow-up year and level of exposure to methotrexate. Beginning in 1997, persons who had used methotrexate for at least 36 months had a risk of lymphoma that was more than 7 times that of cohort members earlier in the study and with less exposure to methotrexate (IRR, 7.77; 95% CI, 2.83-21.39).
Table 3. Univariate and Multivariate Estimates of IRR for Lymphoma Among Persons With Psoriasis, Adjusted for Age and Sex, Based on SEERIncidence Rates*
In the univariate analysis, more than 300 UV-B treatments were significantly associated with lymphoma risk, but this association was no longer significant in the multivariate analysis (Table 3).Because UV-B use and methotrexate exposure were associated, we performed an analysis of the relationship between level of UV-B exposure and lymphoma risk limited to patients with less than 3 years of exposure to methotrexate (ie, low-dose exposure). Patients with high-dose exposure to UV-B but lacking high-dose exposure to methotrexate had no increased risk of lymphoma (IRR,1.02; 95% CI, 0.21-5.04). Level of exposure to PUVA and having had ionizing radiation therapy for psoriasis were not significantly associated with increased lymphoma risk (Tables 2 and 3). Afterwe adjusted for level of exposure to methotrexate, risk of lymphoma in patients with 400 or more PUVA treatments was nearly identical to that of patients with fewer than 200 PUVA treatments (IRR, 1.12; 95% CI, 0.23-5.38). The frequency of exposure to oral retinoids, cyclosporine, and biologics (all <2.5% of person-years of follow-up) was too low to assess the relationship betweenthese substances and lymphoma.
Patients without high levels of exposure to methotrexate had a lymphoma risk comparable to that based on SEER data (8 observed, 9.40 expected; IRR, 0.85; 95% CI, 0.37-1.67). In contrast, weobserved 8 lymphoma cases in those with exposure to high levels of methotrexate (8 observed, 2.14 expected; IRR, 3.74; 95% CI, 1.61-7.36).
After nearly 30 000 person-years of prospective study of the PUVA cohort, the risk of lymphoma observed in cohort members who lacked substantial exposures to methotrexate was nearly identical to that in the general population. In persons with high levels of exposure to methotrexate, a significant increase in lymphoma risk was noted. Level of exposure to PUVA was not associated with lymphoma risk. Risk in the cohort was higher in later years, which may reflect either greater exposure tocarcinogenic therapies with the passage of time or that only in later years of the study had a sufficiently long period elapsed for the effect of such exposures to be manifested.
In the univariate analysis, high levels of UV-B were significantly associated with lymphoma risk. However, the results of both the multivariate model and a stratifiedanalysis did not demonstrate any significant relationship between UV-B and lymphoma risk. Population-based studies also indicate that sunlight does not appear to be a risk factor for lymphoma.22 These results suggest that high levels of exposure to UV-B are more likely to be a marker of greater exposure to other agents that increase lymphoma risk than a true risk factor. When patients with exposure to systemic psoriasis therapies are excluded, most other studies2-3,5-6,8-10,12-14,17 of patients with psoriasis found that the risk of lymphoma is not significantly different in patients with psoriasis than in the general population. Particularly noteworthy is the large case-control study of non-Hodgkin lymphoma in women that found the odds of lymphomaamong patients with psoriasis to be nearly identical to that among persons without this disease.15
Unlike Epstein-Barr virus–related lymphoma, which usually occurs soon after exposure to immunosuppressive treatments and is related to degree of immunosuppression, our data suggest that long-term and even intermittent exposure at more modest doses of some psoriasis therapies may, after many years, increase lymphoma risk.
Others have noted that a higher likelihood of greater exposure to treatments used for more severe psoriasis is also associated with increased risk of lymphoma. In a Medicaid population, Margoliset al17 noted that those with psoriasis who had used systemic therapies had a risk of lymphoma that was almost twice that of Medicaid enrollees with psoriasis who had no record of using thesetreatments. Paul et al14 noted that the risk of melanoma was more than 3-fold higher among patients with psoriasis exposed to 2 years of low-dose, often intermittent cyclosporine treatmentcompared with other cohort members also treated with cyclosporine but for shorter periods. A Finnish study16 of patients hospitalized for psoriasis an average of 2.5 times during 10 years observed a modest and significant increase in lymphoma risk. However, similarly designed studies in Sweden and Denmark did not detect any significant increase in lymphoma among persons hospitalized for psoriasis.5, 13, 19
Within the spectrum of patients with moderate to severe disease, those with more severe psoriasis are more likely to have greater exposure to systemic therapies. Therefore, we cannot excludethe possibility that the association we observed with high levels of exposure to methotrexate reflects a higher innate risk among those with more severe disease rather than risk related to greater exposure to certain psoriasis therapies. Within the spectrum of moderate to severe psoriasis, the lack of a significant relationship between extent of exposure to PUVA and lymphomarisk, as well as the lack of association of UV-B to lymphoma risk, in both multivariate and stratified analyses argues against increased severity of psoriasis.
Our study has both strengths and weaknesses. Among its strengths are its prospective nature, documentation of exposures, long-term follow-up (nearly 30 years), and high follow-up rates. Still,we detected 3 of 16 lymphoma cases through the National Death Index. This illustrates the difficulty of complete ascertainment of fatal outcomes in a prospective study that uses interviews as its primary basis for data collection.
Because of limited exposure to systemic treatments such as cyclosporine and the biologics, our study lacked the power to assess the risk of lymphoma associated with systemic agents other than PUVA and methotrexate. Furthermore, the higher incidence of lymphoma noted since 1996 suggests that there may be a long latency between causative exposure and the detection ofcancer. Clearly, if we are to exclude a substantial increase in risk of lymphoma in association with newer systemic therapies for psoriasis, long-term studies with sufficiently large study groups,including substantial numbers of patients exposed to high doses of the agents of interest, will be required. High long-term participation rates are needed for a robust analysis, a goal not achievedin the industry-sponsored study of cyclosporine.14
Our findings are potentially important for evaluating the results of long-term safety studies of systemic agents, particularly some biologic modifiers that both mechanistically and on the basis ofspontaneous reports have been linked to a higher risk of lymphoma.23-24 Our data and those of other studies suggest an elevated incidence of lymphoma in persons with psoriasis receiving methotrexate and cyclosporine.14 However, our data and those of other studies suggest that it is unlikely that persons with moderate to severe psoriasis have a higher innate risk of lymphoma.
AUTHOR INFORMATION
Correspondence: Robert S. Stern, MD, Department of Dermatology, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Room GZ-522, Boston, MA 02215 This e-mail address is being protected from spambots. You need JavaScript enabled to view it. .
Accepted for Publication: March 2, 2006.
Financial Disclosure: Dr Stern is a consultant to Nucryst Pharmaceuticals Corp.
Funding/Support: This study was funded in part by contract N01-AR-0-2246 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health.
Acknowledgment: Since its inception in 1975, more than 100 dermatologists and nurses have collected data for the PUVA Follow-up Study. Without their skilled work, this study would not have been possible. The 16 original centers that enrolled patients in the study are Stanford University School of Medicine, University of California Medical School, Baylor College of Medicine, Washington Hospital Center, University of Michigan Medical School, Columbia University College of Physicians and Surgeons, Mayo Graduate School of Medicine, University of Miami, Mount Sinai Medical Center, Temple University School of Medicine, Beth Israel Deaconess Medical Center, Dartmouth Medical School, Yale University School of Medicine, Duke University Medical Center, University of Pennsylvania Hospitals, and Massachusetts General Hospital. In addition, Jane Unaeze, MD, helped with use of the SEER data.
Author Affiliation: Departments of Dermatology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Mass.
REFERENCES
1. Stern RS, Lange R. Cardiovascular disease, cancer, and cause of death in patients with psoriasis. J Invest Dermatol. 1988;91:197-201. FULL TEXT | WEB OF SCIENCE |PUBMED
2. Lindelof B, Eklund G, Liden S, Stern RS. The prevalence of malignant tumors in patients with psoriasis. J Am Acad Dermatol. 1990;22:1056-1060. WEB OF SCIENCE | PUBMED
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3. Bhate SM, Sharpe GR, Marks JM, Shuster S, Ross WM. Prevalence of skin and other cancers in patients with psoriasis. Clin Exp Dermatol. 1993;18:401-404. FULL TEXT | WEB OF SCIENCE | PUBMED
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4. Doody MM, Linet M, Glass A, et al. Leukemia, lymphoma, and multiple myeloma following selected medical conditions. Cancer Causes Control. 1992;3:449-456. FULL TEXT | WEB OF SCIENCE |PUBMED
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5. Olsen JH, Moller H, Frentz G. Malignant tumors in patients with psoriasis. J Am Acad Dermatol. 1992;27:716-722. WEB OF SCIENCE | PUBMED
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6. Stern RS, Fitzgerald E, Ellis CN, Lowe N, Goldfarb MT, Baughman RD. The safety of etretinate as long-term therapy for psoriasis: results of the etretinate follow-up study. J Am Acad Dermatol. 1995;33:44-52. FULL TEXT | WEB OF SCIENCE | PUBMED
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7. Hannuksela A, Pukkala E, Hannuksela M, Karvonen J. Cancer incidence among Finnish patients with psoriasis treated with trioxsalen bath PUVA. J Am Acad Dermatol. 1996;35:685-689. FULL TEXT | WEB OF SCIENCE | PUBMED
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8. Stern RS, Vakeva LH. Noncutaneous malignant tumors in the PUVA follow-up study: 1975-1996. J Invest Dermatol. 1997;108:897-900. FULL TEXT | WEB OF SCIENCE | PUBMED
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9. Frentz G, Olsen JH. Malignant tumors and psoriasis: a follow-up study. Br J Dermatol. 1999;140:237-242. FULL TEXT | WEB OF SCIENCE | PUBMED
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10. Frentz G, Olsen JH, Avrach WW. Malignant tumors and psoriasis: climatotherapy at the Dead Sea. Br J Dermatol. 1999;141:1088-1091. FULL TEXT | WEB OF SCIENCE | PUBMED
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11. Lindelof B, Sigurgeirsson B, Tegner E, et al. PUVA and cancer risk: the Swedish follow-up study. Br J Dermatol. 1999;141:108-112. FULL TEXT | WEB OF SCIENCE | PUBMED
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12. Tavani A, La Vecchia C, Franceschi S, Serraino D, Carbone A. Medical history and risk of Hodgkin's and non-Hodgkin's lymphomas. Eur J Cancer Prev. 2000;9:59-64. FULL TEXT | WEB OF SCIENCE| PUBMED
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13. Boffetta P, Gridley G, Lindelof B. Cancer risk in a population-based cohort of patients hospitalized for psoriasis in Sweden. J Invest Dermatol. 2001;117:1531-1537. FULL TEXT | WEB OF SCIENCE| PUBMED
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14. Paul C, Ho V, McGeown C, et al. Risk of malignancies in psoriasis patients treated with cyclosporine: a 5 y cohort study. J Invest Dermatol. 2002;118:211-216. FULL TEXT | WEB OF SCIENCE |PUBMED
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15. Zhang Y, Holford T, Leaderer B, et al. Prior medical conditions and medication use and risk of non-Hodgkin lymphoma in Connecticut United States women. Cancer Causes Control.2004;15:419-428. FULL TEXT | WEB OF SCIENCE | PUBMED
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16. Hannuksela-Svahn A, Pukkala E, Laara E, Poikolainen K, Karvonen J. Psoriasis, its treatment, and cancer in a cohort of Finnish patients. J Invest Dermatol. 2000;114:587-590. FULL TEXT |WEB OF SCIENCE | PUBMED
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17. Margolis D, Bilker W, Hennessy S, Vittorio C, Santanna J, Strom BL. The risk of malignancy associated with psoriasis. Arch Dermatol. 2001;137:778-783. FREE FULL TEXT
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18. Gelfand JM, Berlin J, Van VA, Margolis DJ. Lymphoma rates are low but increased in patients with psoriasis: results from a population-based cohort study in the United Kingdom. Arch Dermatol. 2003;139:1425-1429. FREE FULL TEXT
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19. Stern RS, Laird N, Melski J, Parrish JA, Fitzpatrick TB, Bleich HL. Cutaneous squamous-cell carcinoma in patients treated with PUVA. N Engl J Med. 1984;310:1156-1161. WEB OF SCIENCE |PUBMED
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20. Division of Vital Statistics. National Death Index. Hyattsville, Md: National Center for Health Statistics; 2005.
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21. US Department of Health and Human Services. Public Health Service, National Institutes of Health, National Cancer Institute, Cancer Statistics Branch. Surveillance, Epidemiology, and End Results: SEER Cancer Incidence Public Use Database 1973-2002. Bethesda, Md: US Dept of Health and Human Services; 2005.
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22. Smedby KE, Hjalgrim H, Melbye M, et al. Ultraviolet radiation exposure and risk of malignant lymphomas. J Natl Cancer Inst. 2005;97:199-209. FREE FULL TEXT
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24. Remicade. In: Thomson Physicians' Desk Reference. Stamford, Conn: Thomson Healthcare; 2005:1117-1122.
Safety and Efficacy of ABT-874, a Fully Human Interleukin 12/23 Monoclonal Antibody, in the Treatment of Moderate to Severe Chronic Plaque Psoriasis - Results of a Randomized, Placebo-Controlled, Phase 2 Trial
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Researchers; Alexa B. Kimball, MD, MPH; Kenneth B. Gordon, MD; Richard G. Langley, MD; Alan Menter, MD; Elliot K. Chartash, MD; Joaquin Valdes, MD; for the ABT-874 Psoriasis Study Investigators
Arch Dermatol. 2008;144(2):200-207.
ABSTRACT
Objective To investigate the efficacy and safety of ABT-874, an interleukin 12/23 monoclonal antibody, in psoriasis.
Design Phase 2, 12-week, multicenter, randomized, double-blind, placebo-controlled trial.
Setting Outpatient dermatology clinics.
Patients One hundred eighty patients with clinically stable moderate to severe chronic plaque psoriasis.
Interventions Patients were randomized in groups of 30 to receive 1 of 6 treatments with ABT-874 provided as a subcutaneous injection: one 200-mg dose at week 0; 100 mg every other week for 12 weeks; 200 mg weekly for 4 weeks; 200 mg every other week for 12 weeks; 200 mg weekly for 12 weeks; or placebo.
Main Outcome Measure At least a 75% reduction in the Psoriasis Area and Severity Index.
Results The percentage of patients achieving a 75% reduction in the Psoriasis Area and Severity Index at week 12 was statistically significantly greater in all of the ABT-874 treatment groups than in the placebo group (200 mg once, 63% [19 of 30]; 100 mg every other week for 12 weeks, 93% [28 of 30]; 200 mg weekly for 4 weeks, 90% [27 of 30]; 200 mg every other week for 12 weeks, 93% [28 of 30]; 200 mg weekly for 12 weeks, 90% [27 of 30]; placebo, 3% [1 of 30]; P < .001). Treatment with ABT-874 was well tolerated. The most common adverse event was injection-site reaction, and the most common infectious adverse events were nasopharyngitis and upper respiratory tract infection. There were no serious infectious adverse events.
Conclusions ABT-874, an interleukin 12/23 monoclonal antibody, was highly effective and well tolerated in the treatment of psoriasis. Longer-term studies are required to confirm these findings.
Trial Registration clinicaltrials.gov Identifier: NCT00292396
INTRODUCTION
Psoriasis is a common T-cell mediated systemic inflammatory disease affecting approximately 2% of adults, although the global and racial prevalence varies widely.1-3 Psoriasis has a major effect on quality of life4-6 and is associated with a number of psychological and psychosocial problems.7-8 Although traditional systemic therapies for the treatment of psoriasis are effective, their long-term use is frequently limited because of adverse effects.9-10 In addition, many patients with psoriasis are dissatisfied with traditional therapies,1, 11 and a substantial number of patients with moderate to severe disease are not receiving systemic therapy; thus, there is a clear need for therapies that are safer, easier to use, cost-effective, and able to be prescribed on a long-term basis.
Interleukin 12 (IL-12) and the related cytokine IL-23 are members of the IL-12 superfamily of cytokines that share a common p40 subunit.12 These cytokines are central mediators of adaptive immune function.12 Both cytokines contribute to the development of the type 1 T-helper cell (TH1) immune response in psoriasis, but each has a unique role.13-15 Interleukin 12 primarily stimulates differentiation of TH1 cells and subsequent secretion of interferon-, whereas IL-23 preferentially stimulates differentiation of naive T cells into effector T-helper cells (TH17) that secrete IL-17, a proinflammatory mediator.13, 16-17 Cytokines downstream of IL-23 and IL-17, specifically IL-22, may be a central determinant in not only the inflammation but also the cutaneous changes in psoriasis. The overexpression of IL-12 p40 and IL-23 p40 messenger RNA in psoriatic skin lesions and the recent identification of common variants in 2 genes (IL-12B [OMIM 161561] and IL-23R [OMIM 607562] that are associated with a greater risk for psoriasis in white individuals of European descent suggest that inhibition of IL-12 and IL-23 with a neutralizing antibody to the IL-12/23 p40 subunit protein may offer an effective therapeutic approach for the treatment of psoriasis.15, 18-21
Recent phase 1 and 2 studies have suggested that targeting IL-12/23 p40 with monoclonal antibody therapy may be efficacious in psoriasis.22-23 The objective of the current trial was to demonstrate the efficacy and safety of a range of doses of a human IL-12/23 monoclonal antibody (ABT-874) compared with placebo in the treatment of patients with clinically stable moderate to severe chronic plaque psoriasis.24
METHODS
STUDY DESIGN
This was a 12-week, multicenter, randomized, double-blind, phase 2, placebo-controlled trial that was conducted at 24 North American centers, 16 in the United States and 8 in Canada. ABT-874 (Abbott Laboratories, Abbott Park, Illinois) is a recombinant, exclusively human-sequence, IgG1 monoclonal antibody with genetically engineered complementarity-determining regions that have high affinity for the IL-12/23 p40 subunit protein. Study medication or matching placebo was provided as a subcutaneous solution for injection. Patients were randomized in a 1:1:1:1:1:1 ratio in groups of 30 to receive 1 of 6 treatments with ABT-874: one 200-mg dose at week 0 (200 mg x 1); 100 mg every other week (EOW) for 12 weeks; 200 mg weekly for 4 weeks (200 mg x 4); 200 mg EOW for 12 weeks; 200 mg weekly for 12 weeks; or placebo. After week 12, all patients who achieved at least a 75% reduction in Psoriasis Area and Severity Index (PASI 75) response continued into a 36-week blinded observation/retreatment phase. The results of this latter portion of the study will be reported later, once data become available.
STUDY APPROVAL
The study protocol was approved by an independent ethics committee or institutional review board at each of the study sites. The study was conducted in accordance with International Committee on Harmonisation, Good Clinical Practice, and Food and Drug Administration guidelines for clinical trials and the ethical principles that have their origin in the Declaration of Helsinki. Each investigator ensured that the study complied with local laws and customs. Each patient provided written informed consent (a statement about agents available for their condition by prescription outside the clinical trial was included) before any study-related procedures were initiated.
PATIENTS
Inclusion Criteria
Eligible patients were 18 years or older with a clinical diagnosis of psoriasis for at least 6 months (determined by patient interview and confirmation of diagnosis through physical examination by the investigator), stable plaque psoriasis for at least 2 months before screening and at baseline visits as determined by subject interview, moderate to severe plaque psoriasis defined by involvement of 10% or more body surface area at the baseline visit, a PASI score of 12 or higher at the baseline visit, and a physician's global assessment (PGA) of at least moderate disease at the baseline visit.
Exclusion Criteria
Patients were ineligible if they had previous exposure to systemic or biologic antiIL-12 therapy; had nonplaque psoriasis; or were unable to discontinue topical psoriasis therapies at least 2 weeks before, UV-B light phototherapy at least 2 weeks before, psoralenUV light phototherapy at least 4 weeks before, systemic therapies at least 4 weeks before, and biologic therapies at least 12 weeks before the baseline visit. Also excluded were patients who required intake of oral or injectable corticosteroids during the study (inhaled corticosteroids for stable medical conditions were allowed); had an exacerbation of asthma requiring hospitalization in the 10 years before screening; or had a poorly controlled medical condition, such as uncontrolled diabetes with documented history of recurrent infections, unstable ischemic heart disease, congestive heart failure, recent cerebrovascular accidents, and any other condition that in the opinion of the investigator would put the patient at risk by participation in the study. Patients who had an infection or risk factors for severe infection, had a history of malignant neoplasms other than successfully treated basal cell carcinoma (patients with a history of squamous cell carcinoma were excluded) or cervical carcinoma in situ, or had a history of major immunologic reaction (eg, serum sickness or anaphylactoid reaction) to an IgG-containing agent (eg, intravenous immune globulin, a fusion protein, or monoclonal antibody) were also excluded. The following baseline laboratory values were also exclusion criteria: hemoglobin less than 10 g/dL in women or less than 12 g/dL in men; white blood cell count less than 3000/µL; platelet count less than 100 000/µL; serum aspartate aminotransferase or alanine aminotransferase greater than or equal to 1.5 times the upper limit of normal; serum total bilirubin of 1.5 mg/dL or more; or serum creatinine of 1.6 mg/dL or more. (To convert hemoglobin to grams per liter, multiply by 10; to convert bilirubin to micromoles per liter, multiply by 17.104; and to convert creatinine to micromoles per liter, multiply by 88.4.)
Patients were allowed to continue treatment with medicated shampoos that did not contain corticosteroids, bland (without - or -hydroxy acids) emollients, or class VI or VII low-potency topical corticosteroids on their palms, soles, face, inframammary area, or groin area during the course of the study. Application of these topical psoriasis therapies was disallowed within 24 hours of a study visit. Vaccination with a live viral agent was not allowed within 1 month before dosing with study drug, during the study, or for 1 month after the last dose of study drug was administered.
Occurrence of any of the following clinically significant abnormal laboratory results led to immediate withdrawal of a patient from the study: aspartate aminotransferase or alanine aminotransferase level more than 5 times the upper limit of normal; serum total bilirubin level more than 3 times the upper limit of normal; serum creatinine level more than 3 times the upper limit of normal; creatine phosphokinase more than 5 times the upper limit of normal; hemoglobin level less than 8 g/dL; white blood cell count less than x 109 2000/µL; or platelet count less than 75 x 103/µL. (To convert white blood cell count to x 109 per liter, multiply by 0.001; to convert platelet count to x 109 per liter, multiply by 1.)
EFFICACY ASSESSMENTS
The primary efficacy end point was the percentage of patients achieving at least PASI 75 response at week 12. The PASI is a measure of the severity of psoriatic lesions (in terms of erythema, induration, and desquamation) and the extent of body surface area involvement. The PASI score ranges from 0 (no psoriasis) to 72 (severe disease).25 Other efficacy measures included the percentage of patients who achieved at least a PASI 75 response at weeks 1, 2, 4, and 8; the percentage of patients who achieved at least a PASI 50 or PASI 90 response at weeks 1, 2, 4, 8, and 12; and the percentage of patients who attained a PGA of "clear" or "minimal" at week 12 and at weeks 1, 2, 4, and 8. The PGA measures the severity of disease on a 6-point scale, which ranges from 0 (no disease, or clear) to 5 (very severe).26
SAFETY ASSESSMENTS
Adverse events (AEs), laboratory data, and vital signs were assessed throughout the study. Patients were closely monitored for signs of infection, malignancy, and immunologic reaction. Treatment-emergent AEs were defined as events that occurred between week 0 and the earlier of 45 days after the last nonmissing study drug dose or 1 day before the first retreatment dose (for patients continuing on to the 36-week trial).
STATISTICAL ANALYSIS
With the assumption that 15% of the patients in the placebo group would achieve a PASI 75 response at week 12, the study designers determined that a sample size of 26 in each dosage group would be adequate to detect at least a 45% difference from a treated group by means of the Fisher exact test with 90% power at a 2-sided significance level of .05 (nQuery Advisor 4.0; Statistical Solutions, Saugus, Massachusetts). The study was designed to enroll approximately 180 patients, with 30 patients in each group.
The intention-to-treat population included all patients who were randomly assigned at week 0 and received at least 1 injection of study drug; this population was used for the efficacy analyses. All tests were performed at = .05. Nonresponder imputation was used in the efficacy analyses; any patient with a missing PASI or PGA score at a visit was considered a nonresponder at that visit. To assess the effect of the missing data, a sensitivity analysis of week 12 data was completed by the last-observation-carried-forward method. The statistical comparisons of the treatment difference in PASI 75 response were conducted in the following sequential order to adjust for multiplicity: 200 mg weekly vs placebo, 200 mg EOW vs placebo, 100 mg EOW vs placebo, 200 mg x 4 vs placebo, and 200 mg x 1 vs placebo. The treatment difference between each ABT-874 treatment group and the placebo group for mean percentage change in PASI score was assessed by means of analysis of variance, with baseline PASI score and treatment group as factors. The safety analyses were conducted with the use of the safety population, which included all patients who received at least 1 injection of study drug.
RESULTS
PATIENTS
A total of 180 patients were enrolled and randomly assigned to 1 of the 6 treatment groups (Figure 1). The first randomized visit occurred on November 21, 2005, and the last week 12 visit was on June 23, 2006. Most of the patients (77% of placebo-treated patients and 98% of all ABT-874 treatment group patients) completed the 12-week portion of the study.
Patients were well balanced across treatment groups with respect to demographic characteristics and disease activity (Table 1). Patients were predominantly male (74.4%) and white (92.2%). Mean body surface area involvement was 25% and mean PASI score was 18.8. Of the 180 patients, 52 (28.9%) had a history of psoriatic arthritis.
EFFICACY
The percentage of patients achieving the primary end point of PASI 75 response at week 12 was statistically significantly greater (P < .001) in all of the ABT-874 treatment groups than in the placebo group (Table 2). The PASI 75 responses in all ABT-874 treatment groups were similar, with the exception of the 200 mg x 1 treatment group (Figure 2). Percentage of patients with 75% or more improvement in the Psoriasis Area and Severity Index. By week 8, with the exception of the 200 mg x 1 group, the percentage of patients who had 75% or more improvement was statistically significantly greater (P < .001) in each ABT-874 treatment group for each comparison with placebo. EOW indicates every other week.
A subgroup analysis by demographics (sex, age, race, and weight), baseline disease characteristics (history of psoriatic arthritis, body surface area, and PASI score), and baseline therapy for psoriasis within 12 months of receiving study treatment (systemic biologic and nonbiologic, topical, and phototherapy) demonstrated consistent results for ABT-874treated patients within the various subgroups at week 12 (data not shown).
Most of the patients in the ABT-874 dosage groups attained at least a PASI 50 response by week 12 (P < .001 for each difference compared with placebo). The percentage of patients achieving at least a PASI 90 response at week 12 was statistically significantly greater (P < .001) in all but 1 (200 mg x 1) of the ABT-874 treatment groups when compared with placebo. By week 12, significantly more (P < .001) patients in all ABT-874 treatment groups had attained a "clear" or "minimal" PGA rating than patients in the placebo group (Table 2).
The mean percentage improvement in PASI scores from baseline increased over time for all ABT-874 treatment groups (Figure 3) and were statistically significantly greater for each ABT-874 treatment group compared with placebo at each time point (P < .001, except for the 100 mg EOW group at week 1, P = .02).
SAFETY
Therapy with ABT-874 was generally well tolerated (Table 3). Of the 150 patients treated with ABT-874, 1 (0.7%) discontinued the study owing to a localized skin discoloration; 2 (7%) of the 30 patients treated with placebo discontinued the study, 1 for psoriatic arthropathy and 1 for ovarian cancer. Two of 180 patients (1.1%) experienced serious AEs; 1 placebo-treated patient was diagnosed as having ovarian cancer on day 37, and 1 ABT-874–treated patient (200 mg x 1) was diagnosed as having costal chondritis on day 10. No patients experienced myocardial or cerebral infarctions, there were no opportunistic or other serious infections, and there were no deaths.
Patients receiving any dose of ABT-874 were significantly (P = .03) more likely than patients receiving placebo to experience an AE at least possibly related to study drug (ABT-874, 36.0% [54 of 150]; placebo, 10% [3 of 30]; Table 3); most of these AEs were related to the injection site (injection-site reaction, erythema, pruritus, or irritation).
Most AEs were mild: mild AEs occurred in 46.0% (69 of 150) of ABT-874–treated patients and 30% (9 of 30) of placebo-treated patients. The most common AE was injection-site reaction, occurring in 16.7% (25 of 150) of patients treated with any dose of ABT-874 (no reported injection-site reactions for placebo-treated patients; P = .03; Table 4). There were no statistically significant differences between the incidences of other AEs in the ABT-874–treated patients compared with placebo-treated patients. The next most frequently reported AEs were nasopharyngitis and upper respiratory tract infection.
Infectious AEs were reported by 32.8% (59 of 180) of all patients (placebo, 23.3% [7 of 30]; all ABT-874–treated patients, 34.7% [52 of 150]). The most common infectious AEs reported for any ABT-874 treatment group were nasopharyngitis (12.0% [18 of 150]), upper respiratory tract infection (10.7% [16 of 150]), and bronchitis and viral infection (both 2.7% [4 of 150]). On the basis of the Cochran-Armitage trend test, there was no statistically significant trend for more infectious AEs occurring in patients treated with the higher dosages of ABT-874 compared with placebo-treated patients (P = .08). No serious infectious AEs or opportunistic infections (including tuberculosis) were reported.
Two patients reported malignant neoplasms during the study. One placebo-treated patient was diagnosed as having ovarian cancer, which was ongoing as of day 129. One ABT-874–treated patient (200 mg x 4) was diagnosed as having a nonmelanoma skin cancer (squamous cell carcinoma) that was removed on day 133.
There were no clinically significant changes in hematologic measures, blood chemistry (including blood glucose concentrations), or vital signs compared with placebo.
COMMENT
This phase 2, multicenter, randomized, double-blind, placebo-controlled trial demonstrated statistically and clinically significant efficacy of ABT-874 in the treatment of moderate to severe chronic plaque psoriasis. Most of the patients (90%) in the ABT-874 multiple-dose groups achieved a PASI 75 or greater response by week 12, compared with 3% of placebo-treated patients. Even in the group that received a single 200-mg dose of ABT-874, 63% of patients had achieved at least a PASI 75 response by week 12. In addition, almost 100% of patients treated with ABT-874 reached a PASI 50 or greater response, an end point considered to be a clinically significant improvement,27 by week 12. The results for other secondary end points, such as PASI 90 and a PGA of clear or minimal, were consistent with and supported the primary efficacy analysis.
Response to ABT-874 was rapid. Statistically significant separation between placebo- and ABT-874treated patients occurred as early as week 1 for the mean percentage improvement in PASI scores. Improvement was sustained for the 12-week duration of the trial, even for patients in the ABT-874 200 mg x 1 and 200 mg x 4 dosage groups.
These data corroborate earlier studies of IL-12/23 as a potential target for the treatment of plaque psoriasis. In a phase 1 trial of 18 patients with moderate to severe psoriasis,22 a single dose of human monoclonal IL-12/23 p40 antibody (CNTO-1275) resulted in a dosage-dependent improvement in PASI score. These findings were confirmed in a double-blind, placebo-controlled, phase 2 trial that demonstrated dose-dependent improvements in PASI and PGA scores for patients with moderate to severe plaque psoriasis.23 On the basis of a review of the medical literature and clinical trial registries, we believe that the current study is the only other phase 2 trial that has been reported for patients with moderate to severe psoriasis receiving the new class of human monoclonal IL-12/23 p40 antibodies. The demonstrated efficacy of ABT-874 and CNTO-1275 confirms that IL-12/23 p40 cytokines are likely to be important therapeutic targets for the treatment of psoriasis. Mechanistically, the 2 monoclonal antibodies are similar, but CNTO-1275 is a fully human IgG1, k antibody generated in human immunoglobulin transgenic mice and ABT-874 is a fully human IgG1, l antibody isolated from a human antibody phage display library and optimized in collaboration with Cambridge Antibody Technology Inc (Cambridge, England). Our findings are similar to the results of the CNTO-1275 trial. The efficacy of currently available targeted biologic therapies for the treatment of moderate to severe plaque psoriasis, including tumor necrosis factor antagonists (adalimumab, etanercept, and infliximab),28-30 alefacept (which selectively targets memory-effector T cells),31 and efalizumab (an anti-CD11a monoclonal antibody),32 show variable response (ie, PASI 75 response rates ranging from 21% to 80%) in clinical trials. Although the results for all ABT-874 dosage groups presented herein appear to compare favorably, the current study included small sample sizes for each dosage group and lacked an active comparator.
Treatment with ABT-874 was well tolerated, and most AEs were mild. Although ABT-874treated patients were significantly more likely to experience an AE at least possibly related to study drug, most of these were injection-siterelated AEs (injection-site reaction, erythema, pruritus, or irritation). There was no apparent association between an increased dose of ABT-874 and an increased incidence of AEs, although further study with larger sample sizes is warranted to further explore the possibility of a dose-related association.
Immunologic-related events are of particular interest for patients receiving antiIL-12/23 antibodies. The most frequently reported infectious AEs were nasopharyngitis, upper respiratory tract infection, bronchitis, and viral infection. There were no serious infectious AEs reported for the duration of this trial. Of the 2 malignant neoplasms diagnosed during the study, ovarian cancer was diagnosed in a placebo-treated patient and nonmelanoma skin cancer was diagnosed in an ABT-874treated patient. Future long-term studies and surveillance are required to evaluate the rates of rare but serious AEs.
This 12-week, placebo-controlled, multiple-dose clinical study demonstrates the statistically and clinically significant benefit of ABT-874 for the treatment of patients with moderate to severe chronic plaque psoriasis, with a good tolerability profile. Sample sizes in this phase 2 study are too small to permit reliable conclusions about efficacy and safety differences for the different dosages used. In addition, the trial was not of sufficient duration or statistically powered to detect differences in the occurrence of uncommon but serious AEs. These results underscore a pivotal role for IL-12/23 in a population of patients with psoriasis. Additional studies of ABT-874 are required to determine the optimal dosing regimen for sustained safety and efficacy in the treatment of patients with psoriasis.
AUTHOR INFORMATION
Correspondence: Alexa B. Kimball, MD, MPH, Clinical Unit for Research Trials in Skin (CURTIS), Massachusetts General and Brigham and Women's Hospitals, Harvard Medical School, 50 Staniford St, No. 246, Boston, MA 02114 ( This e-mail address is being protected from spambots. You need JavaScript enabled to view it. ).
Accepted for Publication: July 11, 2007.
Author Contributions: Dr Kimball had full access to all of the data and takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors served on the steering committee for the ABT-874 psoriasis study and were involved in the design of the study, enrollment of patients, interpretation of data, review of the manuscript, and the decision to submit the manuscript for publication. Study concept and design: Kimball, Gordon, Langley, Chartash, and Valdes. Acquisition of data: Kimball, Gordon, Langley, Menter, and Chartash. Analysis and interpretation of data: Kimball, Langley, Chartash, and Valdes. Drafting of the manuscript: Chartash. Critical revision of the manuscript for important intellectual content: Kimball, Gordon, Langley, Menter, Chartash, and Valdes. Statistical analysis: Kimball. Obtained funding: Chartash. Administrative, technical, and material support: Gordon, Langley, and Chartash. Study supervision: Menter, Chartash, and Valdes.
ABT-874 Psoriasis Study Investigators: Diane R. Baker, MD, Lake Oswego, Oregon; Chantal Bolduc, MD, Montreal, Quebec, Canada; Ellen H. Frankel, MD, Johnston, Rhode Island; Scott A. Fretzin, MD, Indianapolis, Indiana; Bernard S. Goffe, MD, Seattle, Washington; Kenneth B. Gordon, MD, Evanston, Illinois; Aditya K. Gupta, MD, London, Ontario, Canada; Tiffani K. Hamilton, MD, Alpharetta, Georgia; Michael P. Heffernan, MD, St Louis, Missouri; Alexa B. Kimball, MD, Boston, Massachusetts; James M. Krell, MD, Birmingham, Alabama; Gerald G. Krueger, MD, Salt Lake City, Utah; Richard G. Langley, MD, Halifax, Nova Scotia, Canada; Craig L. Leonardi, MD, St Louis; Catherine Maari, MD, Laval, Quebec, Canada; Robert T. Matheson, MD, Portland, Oregon; Alan Menter, MD, Dallas, Texas; Kim A. Papp, MD, Waterloo, Ontario, Canada; David M. Pariser, MD, Norfolk, Virginia; Yves P. Poulin, MD, Sainte-Foy, Quebec, Canada; Les A. Rosoph, MD, North Bay, Ontario, Canada; Pranav B. Sheth, MD, Cincinnati, Ohio; Stacy R. Smith, MD, San Diego, California; Darryl P. Toth, MD, Windsor, Ontario, Canada; Stephen K. Tyring, MD, Houston, Texas.
Financial Disclosure: Dr Kimball is or has been an investigator, speaker, and consultant for Amgen, Centocor, Abbott Laboratories, Biogen Idec, and Genentech. Dr Gordon has received honoraria and research support and has served as a consultant for Abbott Laboratories, Amgen, and Centocor. Dr Langley has served on the Scientific Advisory Board and been an investigator for Abbott Laboratories, Amgen, Astellas Pharma Inc, Boehringer Ingelheim, Centocor, and Genentech, and has received lecture fees from Abbott Laboratories, Amgen/Wyeth, Astellas Pharma Inc, Genentech, and Novartis. Dr Menter has received research support and lecture honoraria from Abbott Laboratories, Amgen, Biogen Idec, Centocor, Genentech, and Wyeth. Drs Chartash and Valdes are employees of Abbott Laboratories and hold stock and stock options in Abbott Laboratories.
Funding/Support: Abbott Laboratories funded this study and participated in the study design, data collection, data management, data analysis, data interpretation, and manuscript preparation.
Previous Presentations: This study was presented in part as oral and poster presentations at the 68th Annual Meeting of the Society for Investigative Dermatology; May 11, 2007; Los Angeles, California; as an oral presentation at the 21st World Congress of Dermatology; October 5, 2007; Buenos Aires, Argentina; and as an e-poster presentation at Academy 2007, the Summer Meeting of the American Academy of Dermatology; August 2-4, 2007; New York, New York.
Additional Contributions: Jianhau Zhong, PhD, of Abbott Laboratories, performed the statistical analysis. Jennifer Alexander, MS, MBA, of JK Associates Inc assisted in the drafting of the manuscript.
Author Affiliations: Clinical Unit for Research Trials in Skin (CURTIS), Massachusetts General and Brigham and Women's Hospitals, Harvard Medical School, Boston, Massachusetts (Dr Kimball); Division of Dermatology, Evanston Northwestern Healthcare, Evanston, Illinois (Dr Gordon); Division of Dermatology, Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada (Dr Langley); Division of Dermatology, Department of Internal Medicine, Baylor Research Institute, Dallas, Texas (Dr Menter); Immunoscience, New Products, New Discovery, Abbott Laboratories, Parsippany, New Jersey (Dr Chartash); and Immunology Development, Abbott Laboratories, Abbott Park, Illinois (Dr Valdes).
REFERENCES
1. Stern RS, Nijsten T, Feldman SR, Margolis DJ, Rolstad T. Psoriasis is common, carries a substantial burden even when not extensive, and is associated with widespread treatment dissatisfaction. J Investig Dermatol Symp Proc. 2004;9(2):136-139.
2. Davidson A, Diamond B. Autoimmune diseases. N Engl J Med. 2001;345(5):340-350. FULL TEXT | WEB OF SCIENCE | PUBMED
3. Langley RGB, Krueger GG, Griffiths CEM. Psoriasis: epidemiology, clinical features, and quality of life. Ann Rheum Dis. 2005;64(suppl 2):ii18-ii23.
4. de Korte J, Sprangers MA, Mombers FM, Bos JD. Quality of life in patients with psoriasis: a systematic literature review. J Investig Dermatol Symp Proc. 2004;9(2):140-147.
5. Krueger G, Koo J, Lebwohl M, Menter A, Stern RS, Rolstad T. The impact of psoriasis on quality of life: results of a 1998 National Psoriasis Foundation patient-membership survey. Arch Dermatol. 2001;137(3):280-284.
6. Finlay AY, Coles EC. The effect of severe psoriasis on the quality of life of 369 patients. Br J Dermatol. 1995;132(2):236-244.
7. Kimball AB, Jacobson C, Weiss S, Vreeland MG, Wu Y. The psychosocial burden of psoriasis. Am J Clin Dermatol. 2005;6(6):383-392.
8. Russo PA, Ilchef R, Cooper AJ. Psychiatric morbidity in psoriasis: a review. Australas J Dermatol. 2004;45(3):155-159.
9. Lebwohl M, Ali S. Treatment of psoriasis, part 1: topical therapy and phototherapy. J Am Acad Dermatol. 2001;45(4):487-498.
10. Lebwohl M, Ali S. Treatment of psoriasis, part 2: systemic therapies. J Am Acad Dermatol. 2001;45(5):649-661.
11. Finlay AY, Ortonne JP. Patient satisfaction with psoriasis therapies: an update and introduction to biologic therapy. J Cutan Med Surg. 2004;8(5):310-320.
12. Anderson EJR, McGrath MA, Thalhamer T, McInnes IB. Interleukin-12 to interleukin "infinity": the rationale for future therapeutic cytokine targeting. Springer Semin Immunopathol. 2006;27(4):425-442.
13. Rosmarin D, Strober BE. The potential of interleukin 12 inhibition in the treatment of psoriasis. J Drugs Dermatol. 2005;4(3):318-325.
14. Hong K, Chu A, Ludviksson BR, Berg EL, Ehrhardt RO. IL-12, independently of IFN-gamma, plays a crucial role in the pathogenesis of a murine psoriasis-like skin disorder. J Immunol. 1999;162(12):7480-7491.
15. Yawalkar N, Karlen S, Hunger R, Brand CU, Braathen LR. Expression of interleukin-12 is increased in psoriatic skin. J Invest Dermatol. 1998;111(6):1053-1057.
16. Harrington LE, Hatton RD, Mangan PR; et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distin
17. Park H, Li Z, Yang XO; et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol. 2005;6(11):1133-1141.
18. Lee E, Trepiccchio WL, Oestreicher JL; et al. Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris. J Exp Med. 2004;199(1):125-130.
19. Shaker OG, Moustafa W, Essmat S, Abdel-Halim M, El-Komy M. The role of interleukin-12 in the pathogenesis of psoriasis. Clin Biochem. 2006;39(2):119-125.
20. Piskin G, Sylva-Steenland RMR, Bos JD, Teunissen MBM. In vitro and in situ expression of IL-23 by keratinocytes in healthy skin and psoriasis lesions: enhanced expression in psoriatic skin. J Immunol. 2006;176(3):1908-1915.
21. Cargill M, Schrodi SJ, Chang M; et al. A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am J Hum Genet. 2007;80(2):273-290.
22. Kauffman CL, Aria N, Toichi E; et al. A phase I study evaluating the safety, pharmacokinetics, and clinical response of a human IL-12 p40 antibody in subjects with plaque psoriasis. J Invest Dermatol. 2004;123(6):1037-1044.
23. Krueger GG, Langley RG, Leonardi C; et al. A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis. N Engl J Med. 2007;356(6):580-592.
24. Kimball AB, Gordon KB, Valdes JM. Safety and efficacy of the fully human IL-12/23 monoclonal antibody, ABT-874, in the treatment of moderate to severe plaque psoriasis: results from a phase II trial [abstract 321]. J Invest Dermatol. 2007;127(suppl 1):S54.
25. Fredriksson T, Pettersson U. Severe psoriasis: oral therapy with a new retinoid. Dermatologica. 1978;157(4):238-244.
26. Ko H-S. Clinical trial design in psoriasis. Paper presented at: 49th Meeting of the Dermatologic and Ophthalmologic Advisory Committee; March 20, 1998; Bethesda, MD.
27. Carlin CS, Feldman SR, Krueger JG, Menter A, Krueger GG. A 50% reduction in the Psoriasis Area and Severity Index (PASI 50) is a clinically significant important endpoint in the assessment of psoriasis. J Am Acad Dermatol. 2004;50(6):859-866.
28. Gottlieb AB, Matheson RT, Lowe N; et al. A randomized trial of etanercept as monotherapy for psoriasis. Arch Dermatol. 2003;139(12):1627-1632.
29. Reich K, Nestle FO, Papp K; et al, EXPRESS Study Investigators. Infliximab induction and maintenance therapy for moderate-to-severe psoriasis: a phase III, multicentre, double-blind trial. Lancet. 2005;366(9494):1367-1374.
30. Gordon KB, Langley RG, Leonardi C; et al. Clinical response to adalimumab treatment in patients with moderate to severe psoriasis: double-blind, randomized controlled trial and open-label extension study. J Am Acad Dermatol. 2006;55(4):598-606.
31. Lebwohl M, Christophers E, Langley R, Ortonne JP, Roberts J, Griffiths CE, Alefacept Clinical Study Group. An international, randomized, double-blind, placebo-controlled phase 3 trial of intramuscular alefacept in patients with chronic plaque psoriasis. Arch Dermatol. 2003;139(6):719-727.
32. Menter A, Gordon K, Carey W; et al. Efficacy and safety observed during 24 weeks of efalizumab therapy in patients with moderate to severe plaque psoriasis. Arch Dermatol. 2005;141(1):31-38
Psoriasis in childhood and adolescence
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Researchers: Ricardo RomitiI; Luciana Maragno II; Marcelo Arnone III; Maria Denise Fonseca Takahashi IV
I Assistant Physician. Department of Dermatology, Hospital das Clinicas, Universidade de Sao Paulo (USP)
- Sao Paulo (SP), Brazil
II Resident Physician. Department of Dermatology, Hospital das Clinicas, Universidade de Sao Paulo (USP)
- Sao Paulo (SP), Brazil
III Assistant Physician. Department of Dermatology, Hospital das Clinicas, Universidade de Sao Paulo (USP)
- Sao Paulo (SP), Brazil
IV Assistant Physician. Department of Dermatology, Hospital das Clinicas, Universidade de Sao Paulo (USP)
- Sao Paulo (SP), Brazil
ABSTRACT
Psoriasis is a chronic, immunologically mediated, recurrent and universal inflammatory disorder. Approximately one third of adults refer onset before 16 years of age. The sooner the onset, the worse is the prognosis. In children, lesions may be physically disfiguring, leading to psychological impairment and evident loss of quality of life. Systemic therapy used in psoriasis, as well as phototherapy, has limited use in children due to accumulative effects of drugs, low acceptance, and risk of teratogenicity. In this section, we discuss the main clinical aspects of psoriasis in childhood and adolescence, differential diagnosis, therapeutic options, and prognosis.
INTRODUCTION
Psoriasis vulgaris represents a rare dermatosis in childhood and corresponds to about 4% of all dermatosis observed in patients below the age of 16 years 1. Psoriasis that starts in childhood has high family incidence. The most common type presented in infants is characterized by well-delimited erythematous plaques involving the genitals, gluteal and peri-umbilical region, which tends to be persistent and resistant to treatment Facial affection is rare. As time goes by, new erythematous-squamous plaques show up, affecting primarily the trunk and the limbs.
Childhood psoriasis variants include peri-ungual affection with different levels of onycodystrophy present, as well as forms restricted to the scalp. Guttate psoriasis is rarely observed in children below the age of 5 years.
Treatment basically depends on severity, association with articular affections, presence of co-morbidities, patient age, previous therapies and adverse events. To present, there is no authorized systemic treatment for psoriasis in childhood approved by the Food and Drug Administration (FDA). In Brazil, acitretin and cyclosporine have indication for pediatric use in severe cases of psoriasis. As to methotrexate, the package insert does not include indication to children with psoriasis, but it refers to its use in the symptomatic control of recalcitrant, severe and disabling psoriasis, especially in cases that do not response well to other approaches.
HISTORY
The first historical report on psoriasis was made by Celsus (25AC-DC45). Hippocrates (460-375AC) described lesions similar to psoriasis that he classified as "squamous eruptions" and named them lopoi (from lepo, desquamation). Galenus (DC 133-200) created the word psoriasis, from Greek, psora, pruritus. However, palpebral affection associated with other psoriasiform lesions, as well as the presence of desquamation and pruritus in the original description of Galenus, suggest the hypothesis that his report referred in fact to seborrheic eczema.
In the end of 18th century, psoriasis and Hansen's disease were classified together and patients were treated based on the same prejudice and marginalization by the society. Willian, in the beginning of 19th century, made a careful and precise characterization of psoriasis and described all its different clinical variants. Only in 1841, psoriasis was definitely separated from Hansen's disease by Ferdinand von Hebra.
EPIDEMIOLOGY
Even though psoriasis is seldom reported in children, the real prevalence in this age range is unknown 2. It is estimated that between 25 and 45% of the cases of psoriasis may start their course before the age of 16 years and about 2% of them before the age of 2 years 3. It may in some exceptional occasions be congenital or nevoid 4. Even though in the past there was greater prevalence of psoriasis in girls, but current studies indicate that both genders are equally affected, similarly to adults .5,6
The risk of developing psoriasis is greater when one of the parents is affected. Among the patients who develop psoriasis in childhood, 49% have first degree relatives with the disease, whereas in patients who have the onset at adult age, this figure is 37%. Studies with twins have shown agreement between monozygotic twins of up to 75% 6.
ETIOPATHOGENESIS
Despite the advances in the last decade, the cause of psoriasis remains unknown. It is a chronic skin and joint inflammatory disease, immunomediated, with polygenic predisposition, characterized by complex modifications of growth and epidermal differentiation and multiple biochemical, immune and vascular abnormalities, in addition to the unexplained correlation with emotional episodes. In the past, keratonocyte disorder was the etiopathogenic basis of psoriasis; however, currently it is known that it is initially an immune affection mediated by type Th1 response 5,7,8,9,10.
The genetic component involved in the etiology of psoriasis may be evidenced through studies about family incidence, incidence in cases of issues, level of concordance between twins and identify of histocompatibility antigens (HLA). Multiple HLA alleles have been associated with psoriasis, especially HLA-Cw6, HLA-B13, HLA-B17, HLA-B37, HLA-DR7, HLA-B46, HLA-B57, HLA-Cw1 and HLA-DQ9. Recent studies have revealed loci of susceptibility named Psors, located on chromosomes 6p, 17q, 4q, and 1q5,6,11.
Populational studies with monozygotic twins have shown there is a participation of environment factors in the process, among which cutaneous trauma, infections (beta-hemolytic streptococcus, HIV), drugs (lithium, beta-blockers, antimalaric agents and interruption of corticoid therapy - in this case, it may lead to severe generalized pustular psoriasis and erythrodermia), vaccination, psychogenic/ emotional factors, endocrine and metabolic disorders, smoking, alcohol abuse and weather variations 12. There is a possible exacerbation of psoriasis by the use of non-hormonal antiinflammatory drugs, tetracyclines and ACE inhibitors should be considered with care, because despite the high frequency of use of these drugs, there are few reports associating their use with worsening of psoriasis 13.
In pathogenesis, there is acceleration of epidermal germinative cycle, increase in proliferation cells and shortening of the time required for cell renovation on the epidermis, both of the lesion and the normal skin in patients with psoriasis. It is believed that hyperproliferation of keratinocytes is due to increase in amount of epidermal growth factor (EGF), alpha transformation growth (TGF-alpha) and the participation of proinflammatory cytokines (IL-1, IL-6, IFN-gamma), which would operate as mitogenic agents to these cells. Other implied mechanism would be failure of keratinocytes to respond to inhibitory cytokines (IFNµ, TNFa, TGFÃ) produced by CD8 lymphocytes in psoriasis lesions. To guttate psoriasis, there is induced self-immunity by cross-reaction to streptococcus antigens.
CLINICAL ASPECTS
Relative frequency of clinical types of psoriasis and the clinical presentations of the disease differ among adults and children. Plaque psoriasis is the most frequent clinical variant in children and adolescents (34-84%), apart from the form that affects the diaper region (psoriatic diaper rash)5.
Lesions are characterized by papules and well-delimited erythematous plaques of varied sizes and silver desquamation, frequently organized in a symmetric fashion. In childhood, psoriasis may present atypical characteristics, that is, single or few erythematous plaques that are slightly desquamative, affecting uncommon regions such as the face - including periorbital, perioral and nasal regions - many times hindering the correct diagnosis. What is characteristic in childhood psoriasis is follicular affection with variable pruritus, better detected in limb lesions 14,15,16. There may also be alternate forms that mimic pityriasis alba.
Psoriasis lesions frequently affect the scalp, followed by extremities and the trunk. There is frequent symmetric distribution of lesions and absence of pruritus (Figure 5A). Affection of hands, feet, genitals and flexion areas (Figure 5B), including the periumbilical area, is also common among children 6,17.
The congenital form, defined as occurrence of any of the clinical variants of psoriasis at birth or during the first days of life, is extremely rare. It is normally expressed in the forms of plaque psoriasis. Cases of congenital or neonatal erythrodermic psoriasis are rare, severe and demand immediate intervention. Differential diagnosis in these cases include staphylococcal scalded skin syndrome, toxic shock syndrome, candidiasis, congenital ichthyosis, immunodeficiencies, such as Omenn syndrome, metabolic disorders, atopical and seborrheic dermatitis, pityriasis rubra pilaris and generalized mastocytosis 1.
Scalp affection, with presence of white scales, adhered and thickened placed around hair follicles with mild erythema (pseudo-tinea amiantacea) may lead to temporary hair loss or even psoriatic alopecia. There may be single plaque lesion or poorly delimited and desquamative lesions, clinically indistinguishable from seborrheic dermatitis 17, 18.
The characteristic topography in children is affection of diaper area (psoriatic diaper rash), which occurs in children up to the age of two years. Differently from diaper dermatitis (contact dermatitis), lesions have clearer and brighter erythema, well-delimited margins, and involve inguinal folds, with variable pruritus. Classically, these signs and symptoms respond poorly to conventional therapeutic approach to diaper dermatitis. After one or two weeks from onset of diaper erythema, some children develop the classical lesions of psoriasis on the face, scalp, trunk and limbs 17.
Guttate psoriasis is a clinical variant of psoriasis that affects children in frequencies that range from 6.4% to 44% 6. Skin presentation is sudden, normally preceded by streptococcal infection (56 - 85% of the cases),5 of the upper airways. Papular lesions of up to 1cm in diameter are symmetrically displaced all over the body surface, predominantly on the trunk and root of limbs. Guttate psoriasis normally regresses spontaneously within 3 to 4 months. Occasionally, lesions may persist and increase in size, taking the characteristics of plaque psoriasis 19. Within 10 years, between one and two thirds of patients with diagnosis of guttate psoriasis progress to chronic presentation in plaques.
Linear psoriasis, a rare form of psoriasis, is characterized by erythematous-squamous lesions following the lines of Blaschko. It may start in childhood or adult age and affect essentially the trunk or the limbs with variable extension and progression. It should be differentiated from inflammatory linear verrucous epidermal nevus (ILVEN), whose onset is in childhood and affects primarily inguinal-crural and genital regions, following the lines of Blaschko. Pruritus may be intense. Despite the fact that histopathology may evidence psoriasiform dermatitis, the chronicity of the lesion and resistance to any form of therapeutic intervention differentiate it from linear psoriasis 6, 20.
Pustular psoriasis in children is rare. It is characterized by multiple sterile pustules, over erythematous basis. It may be generalized or localized. The generalized form (von Zumbusch) may be triggered in a patient with psoriasis vulgaris by interrupting systemic corticoid, hypocalcemia, infection or local irritants. In general, there is affection of overall status, high temperature and leukocytosis. Eruption is sudden and generalized, but commonly it persists for few weeks, reverting the previous presentation or transforming it into erythrodermic psoriasis.
The localized form comprises three subforms: pustular plaque or annular psoriasis, continuous acrodermatitis of Hallopeau (pustules or pus lakes in fingers and more rarely on the toes, chronic course, no tendency to spontaneous remission), and palmar-plantar pustular (characterized by episodes of sterile pustules comprising palmar and plantar regions, symmetrically distributed and without other manifestations) 19. Rare complications of this form of psoriasis, described in children, are renal failure, cholestatic jaundice, bone lytic lesions, and sterile multifocal osteomyelitis 1. The annular form that is associated with erythematous-desquamative lesions and peripheral pustules seem to be exclusive to children2. This variant may be followed by fever, aseptic osteomyelitis, and lung impairment.
When compared to adults, erythrodermic psoriasis and psoriatic arthritis are less frequent clinical presentations in children.
In erythordermic psoriasis, there is marked, universal edema with variable desquamation. There may be natural progression of the disease, or more frequently, after attempted therapies, interruption of systemic corticoid therapy, or in patients with AIDS. There is clear predominance of erythema over desquamation.
There may be hyper or hypothermia and in long-term cases, there may be reduction of cardiac output and impairment of liver and renal function. The eminent risk of cardiovascular shock and septic shock transform these patients into extremely severe cases, requiring immediate hospitalization and therapeutic intervention associated with support measures.1,16,21
Psoriatic arthritis is characterized as a form of seronegative arthritis found between 5 and 42% of the patients with psoriasis, but it is rare in childhood 22. Conversely, 8 to 20% of the cases of arthritis in childhood are diagnosed as psoriatic arthritis 6. The incidence peak is between 9 and 12 years and girls are slightly more affected than boys (F:M = 3:2) 1. There may be ophthalmic affections associated with psoriatic arthritis in some occasions.
The most frequent form of psoriatic arthritis is asymmetrical mono or oligoarthritis, which affects primarily hand and feet joints. Other less frequent forms present symmetrical, axial impairment and are sometimes disabling. Arthritis may precede (19%) the skin lesion, be concomitant (16%) or appear after skin psoriasis (65%), on average 10 years later. Almost all forms of psoriasis may be concomitant with arthritis; in general, the more severe the cutaneous affection, the higher the prevalence of arthritis. Cutaneous and articular presentations are not related from the standpoint of activity and progression, Psoriatic uveitis, a previous asymptomatic form of uveitis, occurs in 14-17% of the children with juvenile psoriatic arthritis 22,23, 24.
Ungual affections are observed between 10-40% of the children with psoriasis, which may precede the onset of cutaneous lesions and for years they may be the only manifestation of the disease. The level of involvement depends on the location of the psoriatic process in the ungual system, intensity and duration of the progression of the disease. The most frequent aspect is cupuliform depressions, also named ungual pits (thimble-shaped nails), by affection of proximal ungual fold. Onycolysis, subungual hyperkeratosis and "oil spots" are other evidenced affections and correspond to affections of ungual bed. Finally, affection of ungual matrix may lead to onycodystrophy and trachyonychia. These patterns tend to be similar in children and adults.
Acral affection with variable levels of onycodystrophy may be the only manifestation in children. Ungual involvement increases with age, with duration and extension of disease and the presence of psoriatic arthritis 25. To confirm the diagnosis it is necessary to exclude onycomycosis by mycological exam. Bear in mind that they can coexist given that ungual psoriasis increases the likelihood of contamination by dermatophytes 26, 27.
DIAGNOSIS
Diagnosis of psoriasis is mainly clinical. Through methodic curettage of Brocq, we may find the two typical clinical findings of this dermatosis: sign of stratification of scales and sign of bleeding points or Auspitz sign (small points of bleeding when the scale is removed) 18. Woronoff hale or ring (perilesional light zone) is highly characteristic of the disease, but it is rarely observed 19. Isomorphic phenomenon of Köbner manifests the onset of the dermatosis in healthy skin areas after different types of local trauma in patients genetically predisposed and affected by the disease. Psoriasis is characterized by the classical example of Köbner phenomenon, which occurs in 1/3 of the patients with psoriasis. The lesions appear between 10 and 14 days after the trauma. However, the onset of lesions after few days or even years has also been reported. The pathogenesis of this phenomenon remains controversial, focusing mainly on immune and vascular affections.
The phenomenon may be evidenced in 50% of the children with psoriasis, and in 39% of the affected adults. Köbner-positive patients may become Köbner-negative and vice-versa, regardless of any therapeutic strategies used 16, 17.
Another phenomenon that was recently described, named Renbök phenomenon, and also called reverse Köbner, expresses the situation in which any local trauma posed on the psoriatic plaque leads to the disappearance of the lesion and replacement by apparently healthy skin on the site. Classically, Köbner-positive patients do not have Renbök phenomenon, because they seem to be mutually exclusive 20.
There is no specific laboratory exam to diagnose psoriasis 1. Histological presentation is not specific, but it is highly suggestive. The first modifications evidenced are vasodilation and perivascular inflammatory infiltrate. The infiltrate invades the epidermis, in which there is mild spongiosis, invasion of neutrophils and parakeratosis. In a defined lesion there is elongation of regular epithelial cones, with thinning of supra-papillary portion; papillae are enlarged and swollen, showing dilated and tortuous capillaries. In the epidermis, there is parakeratosis, disappearance of granular layer and presence of neutrophil groups (Munro microabscesses). Especially in pustular psoriasis, there may be the presence of cavities containing neutrophils, named spongioform pustules of Kogoj. Inflammatory infiltrate is mild and comprised by mononuclear cells, especially lymphocytes 5, 28. Differential diagnosis to be considered in childhood and adolescence include seborrheic dermatitis, eczemas, superficial mycosis, secondary syphilis, pityriasis rubra pilaris, lichen planus, lupus erythematous, chronic lichenoid pityriasis, ILVEN, enteropathic acrodermatitis, erythrodermic pemphigus foliaceus, drug erythrodermia, Sneddon-Wilkinson sub-corneum pustulosis, generalized acute exanthematic pustulosis and impetigo bullous 16, 19.
TREATMENT
Treatment of psoriasis intends to control the disease and improve quality of life of the patients. To determine the best therapeutic regimen, we should consider gender, age, clinical presentation, disease severity, associated signs and symptoms, co-morbidities, concomitant modification, previous treatment, adverse events and participation of parents or guardians in treatment. Initially we should clarify the patients and parents about the characteristics of the treatment and its course, as well as to guide them about the importance of sun exposure 2. To some patients, psychotherapic follow-up may be necessary 21. For most pediatric patients, psoriasis may be treated with topical medication. Phototherapy is an option to more extensive and refractory cases. Systemic therapy is reserved to more severe and extensive cases that cannot be controlled with topical treatment and/or phototherapy 1, 6, 19. Therefore, specific therapies depend on form and extension of the disease 28-32.
Topical Treatment
As monotherapy or combined regimen, the use of topical medications is normally enough to control mild forms of psoriasis. In the moderate to severe cases, topical treatment, when associated with phototherapy and/or systemic therapy, provides more comfort to patients, speeds up improvement and minimizes pruritus.
Emollients and/or humectants (ammonia lactate, Vaseline, ceramides or mineral oil) and, in hyperkeratosic lesions, keratolytic agents (salicylic acid - 3 to 6%, urea - 5 to 20%), should be included in all therapeutic regimen, be it supportive or alternated with active products, or even in asymptomatic stages. The options for topical use are the following described below.
Topical corticosteroids: they have antiinflammatory actions, anti-proliferative (anti-mitotic), immunosuppresant, vasoconstrictor and anti-pruriginous action. It is the most widely used topical therapy in cases of childhood psoriasis. Efficacy of response to topical corticosteroids range according to its clinical form, and it is high in inverted psoriasis, moderate in body psoriasis, and mild in palmar-plantar and ungual psoriasis.
The location of the psoriasis lesion determines the potency of topical corticosteroids to be used owing to the risk of adverse events. Medium and high potency corticosteroids are indicated in scalp, limb and trunk lesions. Less powerful corticosteroids are indicated in lesions located on the face, periauricular regions, folds and genitals. After clinical improvement, we should try to replace them by low potency corticosteroids to avoid development of atrophy, strias, hypertrichosis and inhibition of hypothalamic-pituitary-adrenal axis, especially in children. Tachyphylaxis, that is, loss of efficacy as a result of continuous use of the medication and the need to use stronger and stronger drugs to control the disease, is a constant factor in this infirmity.
Coal tar (2-10%): the vehicle is Vaseline, cold cream or ointments. When used in isolation, it has moderate action on plaque psoriasis, but when associated with phototherapy, its action is maximized. It may be combined with salicylic acid 2-5% in hyperkeratosic lesions.
It represents a very effective and very low cost therapeutic option. On the scalp, it is used as liquor carbonis detergens (coaltar 20% in alcohol 95o, emulsified with quillaja extract, diluted in creams or emulsions), or as shampoo. Folliculitis is the most frequent adverse event in the use of coaltar. Among the inconveniences of its use, we may include low cosmetic acceptance. There is controversy about the carcinogenic potential of coaltar. Despite in vitro studies and animal models clearly showing its carcinogenic potential, epidemiological studies with coaltar in human beings have not demonstrated increase in incidence of neoplasms in the studied group 33.
Göckerman Method: indicated for disseminated plaque psoriasis, not erythrodermic. It is the association of coaltar with UVB radiation. Coaltar ointment is applied on the patient, and it should remain in place as long as possible. UVB application is made in increasing doses, daily or in alternate days, without removing the ointment. After irradiation, a shower should be taken to remove the scales and reapply the ointment. Total of 20-30 applications until lightening of lesions.
Anthralin (or ditranol): It is believed that its effect is cytostatic, reducing the mitotic activity of psoriatic epidermal cells. It may be used in low concentrations (0.1% to 0.5%) during 24h or in high concentrations (1 to 3%) in applications of only 15 to 30 minutes. Prepared as creams, pastes or ointments. Skin lightening takes place 3 to 4 weeks after application. Irritating substance, it should be avoided in intertriginous areas, close to the eyes and mucosa and on healthy perilesional skin, where there may be erosion and blisters. It stains clothes, tiles and the skin around the lesions. There is practically no risk of systemic toxicity, presenting excellent safety profile in children. It is considered highly effective medication for psoriasis, leading to prolonged periods of remission and no tachyphylaxis 34.
Calcipotriol: analog of vitamin D3 that reduces proliferation and induces differentiation of keratinocytes, in addition to modifying immune response. It is safe and, in monotherapy, it had moderate efficacy to treat mild and moderate episodes of psoriasis in adults. When used in combined regimens or in sequence with topical corticosteroids, they offer prolonged periods of remission, without rebound effect that is induced by corticosteroids in monotherapy. It should be applied at night and washed off in the morning.
Efficacy and safety of calcipotriol in treatment of pediatric patients are not fully defined yet. In different literature reports, calcipotriol ointment has been proved to be effective, well tolerated and safe in children with psoriasis, and local irritation is the most commonly reported adverse effect 35-38. Even though there are no formal guidelines for its use in children, the use of up to 45 g/week/m2 in children does not seem to influence calcium serum levels 36. It may cause skin irritation, especially on the face, where it should be avoided. In addition to pruritus, erythema and ardor, there may be folliculitis and pigmentation abnormalities on the applied sites.
Topical Immunomodulators: pimecrolimus and tacrolimus may be indicated to localized forms on the face, folds and mucosa, because they cause fewer adverse events than corticosteroids and analogs of vitamin D and they have better absorption in these areas. Efficacy is extremely variable. In Brazil, pimecrolimus is indicated in children as of 3 months of life and tracolimus as of 2 years. They should not be used if there are virus, bacterial or fungal infections present 39.
Topical retinoids: The retinoid used in psoriasis patients is tazarotene, available in gel and concentrations at 0.01% and 0.05%. With mild to moderate efficacy, tazarotene is indicated to chronic plaque psoriasis. It is not approved for use in children with psoriasis, but there is indication for its use in acne for children older than 12 years. There are no studies referring to efficacy and safety of its use in children with psoriasis. It may cause irritation, burning sensation and local erythema. It should not be used on folds. It does not cause tachyphylaxis, and current it is not available in Brazil 34.
Phototherapy and Systemic Treatment PUVA, broad band UVB (290-320 nm) and narrow band UVB (311 nm) phototherapy. It is a therapeutic option used in isolation or combined with other therapeutic modalities, either topical or systemic.
The action mechanism of phototherapy is through anti-proliferative, antiinflammatory and immunosuppresant activity. Different forms of psoriasis may be treated with this method, but the best indication is to moderate psoriasis, with predominance of fine plaques. Patients with pustular or erythrodermic psoriasis should not be submitted to phototherapy and even sun exposure, owing to the risk of worsening and vasodilation. In children, treatment should be reserved to those that can understand and accept this therapeutic modality. The necessary frequency for satisfactory treatment is three times a week.
UVB radiation is highly effective also for the treatment of plaque and guttate psoriasis. It is used in isolation or associated with the use of coaltar (Göckerman method). The most common adverse effect is burns, and it has low risk for skin cancer. Contraindications to the method are photosensitivity and melanoma history. Protection glasses should be worn during the exposure. The anti-psoriatic effect is greater when using the 311nm range, which allows less time of exposure to narrow band. Satisfactory outcomes can normally be seen after 8 weeks of treatment.
PUVA method tends to be more effective and quick in inducing improvement when compared to UVB. Associated with 8-MOP systemic, topical or added by sun exposure. Systemic medication should be taken every two hours before light exposure and it has the disadvantage of requiring eye protection for 24 hours. The advocated dose is 20mg below 50Kg of weight, 30mg between 51-65Kg, 40mg between 66-80Kg and 50mg over 80kg. There are no studies showing safety of oral PUVA in children below the age of 8 years, but the method may be used in adolescents 2, 40, 41.
Antibiotics: Even though there are evidences that antibiotic therapy modifies the natural progression of guttate psoriasis triggered by infection, children with this form of the disease and documented streptococcus infection should receive penicillin or erythromycin for seven to 14 days 1.
Methotrexate (amethopterin): Antagonist of folic acid, with which it has structural similarity. It may be administered by oral, intramuscular or intravenous route, and it is essentially excreted by renal route. Bioavailability of the medication reduces with the intake of some foods, especially dairy foods; however, the drug does not have to be taken in fast. Methotrexate should be used in extensive and resistant cases of psoriasis in childhood, or in cases of arthropathic, erythordermic and generalized pustular psoriasis. The used dose for pediatric cases is 0.2-0.4 mg/kg/week, up to the weekly total dose of 12.5 to 20mg. It may be associated with folic acid (1 to 5 mg per os/ day). It has quick action. The youngest child treated with it in the literature was 4 years old and had severe psoriasis since the age of 2 years.
Recently, low doses of methotrexate have been associated with use of biologicals, especially infliximab, based on its inhibitory action in the production of antibodies 42, 43. This association has not been assessed for the pediatric population to present.
Hematological controls and periodical liver and renal function tests are mandatory. Clinically, one of the early signs of intolerance is the onset of aphthoid lesions on the oral mucosa, signaling significant leucopenia. The most frequent adverse effect is gastric intolerance. It has multiple drug interactions, Absolute contraindications are pregnancy and breastfeeding, liver cirrhosis, active liver infection and liver failure 44, 1. Live or attenuated virus vaccine should be avoided.
Acitretin: derived from vitamin A (retinol), it is employed in the dose 0.5 to 1.0 mg/kg/d. Especially indicated in generalized pustular psoriasis, also used in generalized plaque psoriasis, and erythrodermic psoriasis (improvement is expected within 3-4 months from treatment). It represents a systemic therapeutic option most used in children with disseminated and resistant presentations to topical treatment and phototherapy. Adverse effects include mild cheilitis (dose-dependent), epistaxis, conjunctivitis, paronychia, alopecia, pruritus, dyslipidemia and teratogenia (etretinate persists in the body for two years, and it should be contraindicated in childbearing age women). Prolonged therapy with acitretin should be carefully considered in children because there are reports of premature closure of bone epiphysis, tendon and ligaments calcifications and delay in bon growth. Radiological exams should be performed annually. Efficacy of acitretin tends to be moderate and it is high when associated with phototherapy. Clinical response is delayed. Among absolute contraindications are pregnancy and willingness to get pregnant in near future, liver and renal failure and allergy to paraben contained in capsules 46. The use of vaccines to the specific age range is not contraindicated.
Cyclosporine A: acts by inhibiting activated T-CD4 lymphocytes preventing IL-2 release. Even though it has been widely studied in patients with atopical dermatitis, there are no safety and efficacy studies for psoriasis in children. It should be reserved for severe cases, such as erythrodermic psoriasis and in cases rapidly progressive and without response to other therapeutic methods. Cyclosporine dose is 2-5 mg/Kg, daily, for 3-4 months, after which it should be gradually discontinued. Recurrences tend to happen as a result of dose tapering. Adverse effects include nephrotoxicity, hypertension, nausea, paresthesia feelings, gingival hyperplasia, hypertrichosis and increase in risk of neoplasms, but they do not seem to be more frequent in children than in adults with psoriasis. The drug requires renal, hepatic and hematological monitoring every 2-4 weeks. Contraindications to the use of cyclosporine are renal function abnormalities, uncontrolled systemic hypertension, malignancy and breastfeeding. Immunization with live or attenuated virus vaccine should be avoided during the period and between 3-12 months after its completion, depending on the dose 2. Cyclosporine has multiple drug interactions, but it is one of the few treatments for psoriasis that may be used in pregnant women 46.
Immunobiological agents: Immunobiological or simply biological agents represent a group of drugs that interfere in specific and timely manner over the immune system. They act by blocking or stimulating one or more immune response pathways. Despite their high complexity and structural variability, all biological agents represent proteins obtained from modern biotechnology techniques. The goal of these therapeutic agents includes the traffic of lymphocytes in skin microcirculation, antigenic presentation of antigen-presenting cells to lymphocytes and, finally, different cytokines 6,47,48
They are extremely expensive drugs. To present, etanercept is the biological agent most carefully studied to be used in children with psoriasis. It represents the soluble form of totally human tumor necrosis factor (TNF) receptor 49, 50, 51.
The drug was approved for the first time in 1998 for moderate to severe rheumatoid arthritis, and later it was approved for treatment of children and adolescents with juvenile rheumatoid arthritis (1999). In 2004, etanercept was approved to treat moderate to severe plaque psoriasis in adults 52-54.
In a recent study published in the literature, children aged 4 to 17 years with moderate to severe psoriasis responded favorably to the mediation at a dose of 0.8 mg/Kg/week (maximum of 50mg), cutaneous route, within a total of 48 weeks, which included serious adverse events (including pneumonia, gastroenteritis, dehydration and surgical removal of ovarian cyst), which were solved without sequels 55.
The medication is still waiting for approval in Europe and in the USA to be used in children with moderate to severe psoriasis.
PROGNOSIS
Most children present the mild form of psoriasis with favorable response to topical treatment. Even though regression of the picture may be followed by prolonged remission, a chronic and recurrent course is the most common progression. In many cases, there are changes to the psoriasis pattern. Some children get worse as they become older, requiring more aggressive treatments. 56
Patients with guttate psoriasis tend to progress to remission of the disease or even progress to plaque psoriasis 15, 26.
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16. Griffiths CEM, Camp RDR, Barker JNWN. Psoriasis. In: Burns T, Breathnach S, Cox N, Griffiths C. Rooks - Textbook of Dermatology. 7th ed. Oxford: Blackwell Publishing, 2004. p. 35.1- 69.
17. Janniger CK, Schwartz RA, Musumeci ML, Tedeschi A, Mirona B, Micali G. Infantile psoriasis. Cutis. 2005;76:173-7.
18. Sampaio SAP, Rivitti EA. Dermatologia. 3 ed. São Paulo: Artes Médicas; 2007. p. 231- 41.
19. Van der Kerkhof P, Schalkwijk J. Psoriasis. In: Bolognia JL, Jorizzo JL, Rapini RP. Dermatology. 2nd ed. New York: Mosby; 2008.
20. Criado PR, Valente NY, Michalany N, Martins JE, Romiti R, Aoki V, et al. An unusual association between scalp psoriasis and alopecia areata: the Renbök phenomenon. Clin Exp Dermatol. 2007;32:320-1.
21. Lewkowicz D, Gottlieb AB. Pediatric psoriasis and psoriatic arthritis. Dermatol Ther. 2004;17:364- 75.
22. Gladman DD, Brockbank J. Psoriatic arthritis. Expert Opin Investig Drugs. 2000;9:1511-22.
23. Kleinert S, Feuchtenberger M, Kneitz C, Tony HP. Psoriatic arthritis: clinical spectrum and diagnostic procedures. Clin Dermatol. 2007;25:519-23.
24. Robertson DM, Cabral DA, Malleson PN, Petty RE. Juvenile psoriatic arthritis: followup and evaluation of diagnostic criteria. J Rheumatol. 1996;23:166-70.
25. Jiaravuthisan MM, Sasseville D, Vender RB, Murphy F, Muhn CY. Psoriasis of the nail: anatomy, pathology, clinical presentation, and a review of the literature on the therapy. J Am Acad Dermatol. 2007;57:1- 27.
26. Naldi L, Gambini D. The clinical spectrum of psoriasis. Clin Dermatol. 2007;25:510-18.
27. Griffi CEM, Barker JNWN. Pathogenesis and clinical features of psoriasis. Lancet. 2007; 370:263- 71.
28. Murphy M, Kerr P, Grant-Kels JM. The histopathologic spectrum of psoriasis. Clin Dermatol. 2007;25:524-8.
29. Lowes MA, Bowcock AM, Krueger JG. Pathogenesis and therapy of psoriasis. Nature. 2007;445:866-73.
30. Menter A, Griffi CEM. Current and future management of psoriasis. Lancet. 2007;370:273-84.
31. Menter A, Gottlieb A, Feldman SR, Van Voorhees AS, Leonardi CL, Gordon KB, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 1. Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics. J Am Acad Dermatol. 2008;58:826-50.
32. Ceovic R, Pasic A, Lipozencic J, Murat-Susic S, Skerlev M, Husar K, et al. Treatment of childhood psoriasis. Acta Dermatovenerol Croat. 2006;14:261-4.
33. Pion IA, Koenig KL, Lim HW. Is dermatologic usage of coal tar carcinogenic? A review of the literature. Dermatol Surg. 1995;21:227-31.
34. Cordoro KM. Topical therapy for the management of childhood psoriasis: part I. Skin Therapy Lett. 2008;13:1-3.
35. Choi YJ, Hann SK, Chang SN, Park WH. Infantile psoriasis: successful treatment with topical calcipotriol. Pediatr Dermatol. 2000;17:242-4.
36. Darley CR, Cunliffe WJ, Green CM, Hutchinson PE, Klaber MR, Downes N. Safety and efficacy of calcipotriol ointment (Dovonex) in treating children with psoriasis vulgaris. Br J Dermatol. 1996;135:390-3.
37. Oranje AP, Marcoux D, Svensson A, Hutchinson PE, Klaber MR, Downes N. Topical calcipotriol in childhood psoriasis. J Am Acad Dermatol. 1997;36(2 Pt 1):203-8.
38. Travis LB, Silverberg NB. Psoriasis in infancy: therapy with calcipotriene ointment. Cutis. 2001;68:341-4.
39. Cordoro KM. Systemic and light therapies for the management of childhood psoriasis: part II. Skin Therapy Lett. 2008;13:1-3.
40. Wolff K. Side-effects of psoralen photochemotherapy (PUVA). Br J Dermatol. 1990;122 Suppl 36:117-25.
41. MacDonald A, Burden AD. Psoriasis: advances in pathophysiology and management. Postgrad Med J. 2007;83:690-7.
42. Hersh EM, Carbone PP, Wong VG, Freireich EJ.. Inhibition of primary immune response in man by antimetabolites. Cancer Res. 1965;25:1997-2001.
43. Mitchell MS, Wade ME, DeCenti RC, Bertino JR, Calabresi P. Immune suppressive effects of cytosine arabinoside and methotrexate in man. Ann Intern Med. 1969;70:535-47
44. Gladman DD, Mease PJ, Krueger G, Van der Heidje DM, Antoni C, Helliwell PS, et al. Outcome measures in psoriatic arthritis. J Rheumatol. 2005;32:2262-9.
45. Gottlieb A, Korman NJ, Gordon KB, Feldman SR, Lebwohl M, Koo JY, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 2. Psoriatic arthritis: overview and guidelines of care for treatment with an emphasis on the biologics. J Am Acad Dermatol. 2008;58:851-64.
46. Consenso Brasileiro de Psoríase e Guias de Tratamento. Rio de Janeiro: Sociedade Brasileira de Dermatologia; 2006.
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48. Smith CH, Anstey AV, Barker JNWN, Burden AD, Chalmers RJ, Chandler D, et al. British Association of Dermatologists: guidelines for use of biological interventions in psoriasis 2005. Br J Dermatol. 2005;153:486-97.
49. Goffe B, Cather JC. Etanercept: an overview. J Am Acad Dermatol. 2003; 49(Suppl):S105-11.
50. Gottlieb AB. Etanercept for the treatment of psoriasis and psoriatic arthritis. Dermatol Ther. 2004;17:401-8
51. Tan JK, Alphale A, Malaviya R, Sun Y, Gottlieb AB. Mechanisms of action of etanercept in psoriasis. J Investig Dermatol Symp Proc. 2007;12:38-45.
52. Tyring S, Gottlieb A, Papp K. Etanercept and clinical outcomes, fatigue, and depression in psoriasis: double-blind placebo-controlled randomized phase III trial. Lancet. 2006; 367:29-35.
53. Leonardi CL, Powers JL, Matheson RT, Goffe BS, Zitnik R, Wang A, et al. Etanercept as monotherapy in patients with psoriasis. N Engl J Med. 2003;349:2014-22.
54. Wu EQ, Feldman SR, Chen L, Kaltenboeck A, Yu AP, Gupta SR, et al. Utilization pattern of etanercept and its cost implications in moderate to severe psoriasis in a managed care population. Curr Med Res Opin. 2008;24:3493-501. [ Links ]
55. Paller AS, Siegfried EC, Langley RG, Gottlieb AB, Pariser D, Landells I, et al. Etanercept treatment for children and adolescents with plaque psoriasis. N Engl J Med. 2008;358:241-51.
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Ricardo Romiti
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The Genetics of Psoriasis 2001
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ABSTRACT
Accumulating evidence indicates that psoriasis is a multifactorial disorder caused by the concerted action of multiple disease genes in a single individual, triggered by environmental factors. Some of these genes control the severity of multiple diseases by regulating inflammation and immunity (severity genes), whereas others are unique to psoriasis. Various combinations of these genes can occur even within a single family, accounting in large measure for the many clinical manifestations of psoriasis. The disease-causing variants (alleles) of these genes probably arose early in the history of modern humans. As a result, psoriasis disease alleles are common in the general population, have a worldwide distribution, and often share the same ancestral chromosome with neutral alleles at adjacent loci. This phenomenon, called linkage disequilibrium, explains why psoriasis is strongly associated with HLA-Cw6 worldwide, although HLA-Cw6 is unlikely to be the disease allele. Many unaffected individuals carry 1 or more disease alleles, but lack other genetic and/or environmental factors necessary to produce disease. This explains why psoriasis develops in only about 10% of HLA-Cw6positive individuals, and why genome-wide linkage scans for psoriasis and other multifactorial genetic disorders have not been uniformly successful. The Human Genome Project is rapidly generating a catalog of human DNA sequence variations. This resource has already allowed precise linkage disequilibrium mapping of the major histocompatibility complex psoriasis gene to just beyond HLA-C, toward HLA-A. This gene is likely to be identified soon. Further development and use of linkage disequilibrium resources will provide a powerful tool for the identification of the remaining psoriasis genes.
INTRODUCTION
Psoriasis is a chronic, inflammatory, hyperproliferative disease of the skin, scalp, nails, and joints, affecting 1% to 2% of the US population at an estimated cost of more than $3 billion per year.1 It has a variety of clinical presentations, most of which eventuate into erythematous, scaly plaques with or without nail disease and arthritis. At the cellular level, psoriasis is characterized by (1) markedly increased epidermal proliferation and incomplete differentiation; (2) elongation, dilatation, and "leakiness" of the superficial plexus of dermal capillaries; and (3) a mixed inflammatory and immune cell infiltrate of the epidermis and papillary dermis. Psoriasis is found worldwide, although its frequency varies widely among different ethnic groups. Susceptibility to psoriasis is unmistakably heritable, but environmental factors, notably trauma, stress, and infections, are also important determinants of disease onset and severity. While several plausible immune/inflammatory mechanisms have been proposed,2 true molecular insight into the cause of psoriasis is lacking.
This review will address the following 4 points of relevance to clinicians and basic scientists alike: (1) How can we be sure psoriasis is genetic? (2) What do we know about PSORS1 (psoriasis susceptibility 1), the psoriasis gene in the major histocompatibility complex (MHC)? (3) What do we know about psoriasis genes across the rest of the genome? and (4) Do genetic differences explain the many clinical variants of psoriasis?
HOW CAN WE BE SURE PSORIASIS IS GENETIC?
Psoriasis only appears to run in families about a third of the time. Even in those families, it often does not appear to follow simple patterns of dominant or recessive inheritance. (3-5) The simplest way to explain this observation is to assume that disease alleles (ie, alternative forms of a gene at a given locus) encoded by several genes located at several different loci throughout the genome are required for the disease to develop. The model proposed suggests that disease alleles at each of 4 loci on different chromosomes are required for psoriasis to develop, and that only 1 copy of each disease allele is required for the disease to develop (ie, each disease allele acts in a dominant fashion). Although this model is unproven, it is instructive in explaining the low frequency of families with multiple psoriatic members.
Under this model, the chance of psoriasis developing in any given individual would be (1/2) 4 = 1 /16. Thus, families would need to be quite large to observe more than 1 case per family. The fact that familial involvement is observed in one third of cases suggests that the burden of psoriasis genes in the healthy population may be even higher than that shown in Figure 1.
What is the actual evidence of the genetic basis for psoriasis? One of the best indications we have comes from twin studies. Identical twins share all their genes in common, whereas fraternal twins, like siblings, only share half their genes in common. Thus, even if a disorder is caused by many genes, disease should be concordant (present in both) in identical twins more often than in fraternal twins. Psoriasis fulfills this requirement, being concordant about 3 times as often in identical twins as in fraternal twins. Both concordance rates, however, are markedly lower in Australia than in the United States or in Denmark. (6-8) As solar radiation is more intense in Australia than in Denmark and most of the United States, these differences suggest that ambient UV irradiation may be a therapeutic environmental factor in Australia. Twin studies and pedigree studies can be used to calculate heritability (h2), a value used to measure the proportion of variability of a trait that is due to genetic factors. As reviewed previously, (3) various estimates have placed the heritability of psoriasis in the range of 60% to 90%, among the highest of the multifactorial genetic disorders (ie, diseases caused by more than 1 gene plus environmental factors).
Another important measure of the genetic character of psoriasis is the risk ratio. For any set of probands (ie, index case in a family), the risk ratio is defined as the prevalence of a disease in relatives of a given degree of relatedness divided by the prevalence of disease in the general population. (First-degree relatives share half of their genetic material; second-degree relatives, one fourth; etc.) On the basis of a large epidemiological study, Henseler and Christophers (9 )showed that the risk ratio is approximately 10 for first-degree relatives of patients with juvenile-onset psoriasis. This finding is very similar to those of the classic epidemiological studies of Lomholt (11) and Hellgren,(12) as reviewed previously. (3)
This finding has major significance for studies of genetic linkage of psoriasis (ie, the measure of the correlation between transmission of any allele at the marker locus and the disease locus within families). It has been shown that if the risk ratio for first-degree relatives is at least 4, and at least 1 of the loci is of major effect, then a search for the genes by means of genetic linkage techniques is feasible. (13 )
These conditions appear to be met in the case of juvenile-onset psoriasis, if one assumes a strong genetic effect coming from within the MHC. Therefore, a decade ago, we began searching for the psoriasis genes by means of genetic linkage in families, requiring that the proband must have juvenile-onset psoriasis. Our studies indicate that more than 90% of psoriatic relatives of the proband also have juvenile-onset disease. In contrast, only about 75% of psoriatic patients in general fall into the juvenile-onset category.(9-10)
This finding provides additional support for the genetic basis of juvenile-onset psoriasis.
Because of the long-standing and strong evidence of HLA associations in psoriasis, our working hypothesis has been that 1 of the psoriasis genes resides in the MHC, on the short arm of chromosome 6, and that several other psoriasis genes are scattered throughout the human genome. Some of these genes may be general regulators of inflammation and/or immunity, and therefore may be involved in a variety of inflammatory and/or immune diseases in addition to psoriasis. (14) These are termed severity genes. Other genes may make a distinctive contribution to the psoriatic phenotype; these are termed disease-specific genes.
Associations between psoriasis and particular HLA types have been recognized for nearly 30 years.15 Henseler and Christophers9 defined type I psoriasis as having age of onset younger than 40 years, with strong HLA associations. Patients with type II disease were characterized by age of onset 40 years or older, and much weaker HLA associations.9-10 Patients with type I disease showed a much stronger tendency for familial involvement. As shown in Figure 2, the risk ratio for first-degree relatives was approximately 10 for patients with type I psoriasis, but only about 1 to 2 for those with type II psoriasis.
The HLA associations identified in our study of familial psoriasis are very similar to those identified in previous case-control studies of HLA association in psoriasis. (3) In particular, strong associations with HLA-Cw6 and HLA-B57 were found. We know that approximately two thirds of the psoriatic patients in those earlier studies had a family history negative for psoriasis and could be assumed to represent sporadic cases. The similarity of the HLA associations obtained in pedigree and case-control studies implies that so-called sporadic psoriasis must also have a genetic basis. Because no other inflammatory disease manifests such a strong HLA-C association, we suspect that the MHC psoriasis gene is a disease-specific gene.
In northern Europe and the United States, only about two thirds of psoriatic patients carry HLA-Cw6. This figure is even lower in most Oriental populations, where many affected individuals carry HLA-Cw7. In an effort to explain this observation, others have postulated a primary role for alanine at position 73 of the HLA-C protein molecule, which is also found on HLA-Cw7. We have not found such a role for alanine-73 in our study, as shown on the last line of Table 1. We believe that this phenomenon is better explained by the phenomenon of linkage disequilibrium.
Usually, HLA associations are due to linkage disequilibrium between the disease locus and 1 or more HLA loci. Linkage disequilibrium is a measure of the presence of a particular marker allele in apparently unrelated affected individuals. It usually represents a special case of genetic linkage, caused by the founder effect (ie, the occurrence of a disease-predisposing mutation in a distant ancestor). In the case of genetic linkage, different marker alleles are observed to segregate with disease from family to family, usually due to the occurrence of different mutations in the gene in question from family to family.
In contrast, when linkage disequilibrium is present, the same marker allele will segregate through seemingly unrelated pedigrees . This occurs because the disease allele and the marker allele are descended from a single founder, and therefore still reside on the same ancestral chromosome. This phenomenon allows linkage disequilibrium (but not linkage) to be detected in a case-control sample.
As generations pass, the segment of the ancestral chromosome containing the disease mutation becomes shorter and shorter, due to meiotic recombination events occurring in multiple generations. In contrast, genetic linkage is only broken by recombination events occurring within an individual family, which in practice rarely contains more than 3 generations and therefore presents far less opportunity for meiotic recombination. Thus, linkage disequilibrium is a powerful tool for fine mapping of genes, if one can first find the approximate location of the gene by means of genetic linkage.
Since 1997, several groups have presented evidence of genetic linkage between psoriasis and the MHC. (17-19) However, despite strong evidence of HLA association , it initially proved difficult for us to detect convincing, significant linkage to the HLA region in our original genome scan (ie, the technique whereby a collection of polymorphic markers distributed evenly across the genome are tested for genetic linkage with a particular trait). (20)
The MHC region (chromosome 6p21.3) contained one of the most significant linkage signals, but this peak did not reach the criterion lod scoreof 3.3 required for definitive declaration of linkage. (21) (The term lod score refers to the logartihm of the odds ratio, a measure of genetic linkage, where the odds ratio is defined as the likelihood of encountering the observed outcome if the marker and disease are linked, divided by the likelihood of the same outcome if the marker and disease are unlinked.) Moreover, this peak was only observed under a recessive genetic model.
This was surprising, because most psoriatic patients who carry HLA-Cw6 carry only 1 copy of this allele, and inheritance of this locus should therefore be dominant. The explanation for this difficulty in detecting linkage appears to be the presence of numerous unaffected married-in HLA-Cw6 carriers in our pedigrees, creating a situation in which the HLA-linked susceptibility gene is brought in from both sides of the family .
When an affected member of the third generation inherits the susceptibility chromosome from an unaffected married-in family member, the linkage computer program is forced to assume that a recombination event has occurred. As the computer detects more such apparent recombination events, the statistical evidence for linkage diminishes. In subsequent studies, we took this phenomenon into account using the presence of HLA-Cw6 to identify these unaffected carriers. Under these conditions, we were readily able to detect linkage to HLA-C, with a lod score of nearly (10.22 )
The fact that we were able to establish linkage to HLA-C does not mean that HLA-C is itself PSORS1. The HLA region is nearly 3.5 million base pairs long and contains more than 200 genes. Because not all psoriatic patients carry HLA-Cw6, and because not all HLA-Cw6 bearing haplotypes (ie, the set of alleles carried by genes on 1 chromosome of a particular individual) confer equal risk for psoriasis, we suspected that the strong HLA-Cw6 association reflects a causative role for a nearby gene on the same ancestral chromosome.
To address this possibility, we developed a dense microsatellite marker map of the HLA region and used it to more precisely map the psoriasis susceptibility determinant within the HLA region. (23) (Microsatellites are short DNA sequences, usually repeats of C and A, that vary in length from chromosome to chromosome, and can therefore be used to distinguish between maternal and paternal chromosomes). The critical tool for localizing PSORS1 turned out to be ancestral haplotype analysis. In this method, haplotypes are inferred by following the segregation of markers through individual pedigrees, then these haplotypes are clustered to identify ancestral haplotypes shared between families. Numerous ancestral haplotypes were identified and tested for linkage disequilibrium with psoriasis.
The shortest haplotypes that consistently demonstrated linkage disequilibrium shared a 60- to 70-kilobase (kb) interval extending from 30 to approximately 100 kb from HLA-C, toward the telomere (end) of the short arm of chromosome 6.23 The location of this haplotype was in good agreement with the regions of peak linkage disequilibrium identified by 2 other recent studies. (24-25) We have named this 60-kb interval risk haplotype 1 (RH1). Risk haplotype 1 did not contain HLA-Cw6 as a component allele, providing the strongest evidence to date that HLA-Cw6 is not PSORS1. The RH1 region is rich in repetitive sequences, including remnants of 3 different endogenous retroviruses. However, no genes have been identified in RH1 to date. There are several additional genes mapping just telomeric to RH1, including OTF3 (also known as POU5F1), TCF19 (also known as SC1), HCR (also known as PG8), and corneodesmosin (also known as the S gene).
Each of these genes displays strong associations with psoriasis.26-29 However, none of these genes predicts the risk for psoriasis as well as does the presence of RH1.27, (30-35) Therefore, we are continuing to focus on the RH1 region, although it appears to contain no genes. We are determining the DNA sequence across the RH1 region in a set of normal and disease chromosomes. By comparing these sequences, we hope to tease out the critical DNA sequence difference that predisposes to psoriasis.
The MHC psoriasis gene, then, appears not to encode any of the known HLA antigens. Psoriasis therefore differs from several other MHC-linked disorders, including ankylosing spondylitis (AS), (36) Behçet disease,(37) and type 1 diabetes mellitus,(38) in which the best available evidence indicates that the most closely disease-associated HLA alleles are directly responsible for disease susceptibility. The proof of this point awaits the discovery of the disease-predisposing mutation.
WHAT DO WE KNOW ABOUT THE NON-MHC PSORIASIS GENES?
Our studies have shown that RH1 is found in approximately 15% of the general population, and yet the prevalence of psoriasis is only approximately one tenth of this (1.5%). Other studies have repeatedly shown that only about 10% of those carrying HLA-Cw6 ever develop psoriasis. (3) Why is this? Although environmental factors such as streptococcal infection and stress undoubtedly play a role, we believe that this is primarily because of a requirement for additional disease alleles, encoded by different genes in the same person, as envisioned in the model explained above.
Presumably, these genetic and environmental factors are not present in the right combination up to 90% of the time.
There have been numerous reports of non-MHC loci in psoriasis . However, in contrast to the prevailing agreement on the importance of the PSORS1 locus, these additional non-MHC loci have only sometimes been confirmed by other groups, often without overwhelmingly strong evidence. (20, 39, 42) In the field of complex disease genetics, a linkage result found by one group may not be confirmed by others, even if the linkage is real. (47) In addition to PSORS1, at least 2 independent groups have found evidence of linkage of psoriasis to chromosomes 1q, 17q, and 20p and the central area of chromosome (19.17, 20, 40, 45, 48)
These confirmatory findings are not definitive proof of the existence of a gene, but they are nevertheless very encouraging that non-MHC psoriasis genes do exist. We are currently collaborating with 2 other groups looking for psoriasis genes in an effort to learn whether several loci identified by various genome scans represent true positive results.
We believe that the high frequency of disease alleles is one of the main reasons why the non-MHC loci have been difficult to identify and to replicate. If we assume that there are 3 non-MHC disease genes, all of equal frequency, and that these genes interact with PSORS1 in a multiplicative fashion (as might be the case if the products of the various genes acted along a common biochemical pathway), then each one of these non-MHC disease alleles would have to be present in approximately half of the general population! This scenario is depicted in Figure 7.
There are now several multifactorial disorders for which strong evidence implicates a particular gene (or nearby markers in linkage disequilibrium with it). In many of these examples, the prevalence of the disease allele appears to be high.
In androgenetic alopecia, a polymorphism in the androgen receptor gene is found in nearly 100% of young bald men, but also in 77% of old nonbald men. (49) In type 1 diabetes mellitus, nearly 80% of the population carries a particular allele of the interleukin 12 p40 subunit gene that has been strongly implicated as a non-MHC locus in this disease. (50) In 2 other examples (the calpain-10 gene in type 2 diabetes mellitus (51) and the interleukin 3 gene in rheumatoid arthritis (52), the frequency of the disease allele ranges from 20% to 50%.
Thus, high disease allele frequencies appear to be the rule, rather than the exception, in the complex genetic disorders.
Figure 8 is not an exhaustive depiction of all possible consequences of high gene frequency, but it does illustrate how high disease allele frequencies can make linkage harder to demonstrate. Part A depicts a dominant disease allele D being transferred from an affected father to 2 affected siblings. Linkage programs have no problem dealing with this situation. They can also be programmed to handle unaffected carriers (the father in part B) by including a variable telling the computer how often to expect unaffected carriers. However, they are stymied when 1 parent carries 2 copies of the disease allele (part C), or when both parents carry 1 or more copies (part D). In the situation depicted in part C, the computer cannot distinguish between disease alleles D and D', and therefore cannot determine whether either of these alleles is consistently passed along to the affected children. In part D, the affected child inherits the disease allele D' from the unaffected parent, rather than D from the affected parent. Unless the computer is told that the mother in part D is an unaffected carrier, it must (erroneously) conclude that D is not a relevant candidate for the disease gene. It is possible that PSORS1 might be the most readily detectable psoriasis gene by linkage techniques because it has a relatively low population prevalence (approximately 15%), thereby minimizing situations such as those depicted in parts C and D of Figure 8.
Given these difficulties, one might worry that the non-MHC genes might never be detected by tests of genetic linkage. However, the same feature of these genes that makes them hard to detect by tests of linkage (their high prevalence) may make it possible for us to detect them by tests of linkage disequilibrium. We have seen that if multiple genes contribute to disease in any given individual, then each disease allele must be quite prevalent in the population.
On reflection, it becomes clear that the most plausible way that a disease allele can become common is for it to arise as a founder mutation relatively early in the history of modern humans, expanding thereafter as the human population expanded. In fact, many of these so-called disease alleles may actually be beneficial in other contexts, eg, a diabetes gene. One can readily imagine a scenario early in the history of modern humans in which food was scarce. In this setting, it was a good idea to hold on to and store as much glucose as possible, whenever a meal was available. However, in a world of plenty, possession of the same allele could result in diabetes. A founding father of human genetics, the late James Neel, MD, called this the thrifty gene hypothesis. (53 )
As a result of such a founder effect, the same disease allele will be present in apparently unrelated families and individuals. If most of the complex genetic disorders are in fact caused by such founder mutations, then once a likely candidate gene is identified, it will be possible to test for them. Although several different tests of linkage disequilibrium are available, the most straightforward is the case-control study: one simply asks whether a specific gene variant is present more often in cases than in controls. Now that we have a fairly complete listing of some 30 000 genes in hand, courtesy of the Human Genome Project, the task of testing for candidate gene association is somewhat less daunting than it once seemed. However, other genes in the immediate vicinity of the candidate gene are also likely to exhibit strong disease associations, as we have observed for PSORS1 in the MHC. Therefore, some form of functional test will almost certainly be necessary to confirm the biological significance of each genetically detected candidate gene for psoriasis.
DO GENETIC DIFFERENCES EXPLAIN THE MANY CLINICAL VARIANTS OF PSORIASIS?
As dermatologists, we appreciate that guttate psoriasis is usually observed in younger individuals, and may or may not eventuate into chronic plaque psoriasis. From the work of Henseler and Christophers,9 we know that patients in whom psoriasis develops at a young age are more likely to carry HLA-Cw6, (and therefore to carry PSORS1). A recent study from England found that 100% of 29 patients with poststreptococcal guttate psoriasis were positive for HLA-Cw6. (54)
This finding suggests that the PSORS1 gene plays a major role in this form of psoriasis. This finding fits with the predominance of PSORS1 in juvenile-onset psoriasis, together with the fact that poststreptococcal guttate psoriasis is typically observed in younger individuals. In many of these individuals, disease resolves completely, without the evolution of chronic plaque disease. We would speculate that the presence or absence of additional genes may determine the patients in whom chronic plaque psoriasis develops. We have observed anecdotally that the few subjects who carried 2 copies of HLA-Cw6 tended to have severe and recalcitrant psoriasis, suggestive of a gene dosage effect. Similar gene dosage effects may be present for the non-MHC genes, singly or in various combinations.
The spondyloarthropathies can present with psoriasiform skin eruptions, suggesting certain common genetic determinants between these diseases. However, the joint manifestations of both are substantially different. HLA-Cw6 is detected substantially more often than HLA-B27 in psoriatic arthritis, (55) indicating that HLA-B27 is not the major genetic determinant of psoriatic arthritis. As arthritis is a relatively infrequent concomitant of psoriasis, whereas it is a cardinal feature of AS, we would speculate that the primary genes determining psoriatic arthritis lie outside of the HLA region. The chromosome 17q locus is a prime candidate for such a gene, as 2 groups have found that the evidence of linkage to 17q is stronger in families that have joint symptoms or deformities. (39, 42) The same region of chromosome 17q has also been implicated in familial rheumatoid arthritis. (56)
Although this finding does not prove that the same gene is responsible for both conditions, the findings are certainly suggestive.
One of the most interesting findings from our genome scan has been the identification of a candidate locus for psoriasis on chromosome 16q. (20) Although this locus remains to be confirmed, several groups presented evidence suggestive of a chromosome 16q locus at the May 2001 meeting of the International Psoriasis Genetics Committee in Stockholm, Sweden. Eight different genetic studies of Crohn disease, and 1 genetic study of AS have found linkage to the same region of chromosome (16.36 )
The risk for psoriasis in patients with Crohn disease is 7 times that of the general population. (20) The NOD2 gene, located on chromosome 16q, has recently been implicated in Crohn disease. (57 )
Preliminary studies from our laboratories have failed to implicate NOD2 in psoriasis. (58) Nevertheless, this is an exciting development that may accelerate the identification of the 16q psoriasis locus. Another very recent study identified loci for childhood atopic dermatitis on chromosome regions 1q21, 3q21, 17q25, and 20p, (59) all of which have been implicated in psoriasis by at least 1 study.
These chromosome regions are rather broad, and at this point we have no proof that the actual genes involved are the same in these various diseases. However, these findings raise the interesting possibility that certain genes may contribute to more than 1 disease, perhaps by controlling certain aspects of inflammation and immunity. They also illustrate how the many different ways that psoriasis can present in our patients (ie, guttate, pustular, inverse, with or without nail disease, arthritis, or inflammatory bowel disease) may reflect the particular mix of genes for psoriasis, arthritis, and/or gut disease that our patients are unfortunate enough to inherit.
FUTURE PERSPECTIVES
Much work remains to be done. Although there are intriguing clues to disease pathogenesis, eg, the mapping of PSORS1 in HLA, the Crohn disease connection, and the identification of the same candidate loci by multiple groups, none of the responsible genes have yet been identified. Our recent progress in the HLA region suggests that the identification of PSORS1 will occur soon. The characterization and function of PSORS1 and, it is hoped, the non-MHC psoriasis genes will unlock the mystery of psoriasis. These studies should provide appropriate molecular targets for improved drugs to treat the disease and key insights into how emotions, infections, and other environmental factors interact with genes to trigger this common, enigmatic disease.
AUTHOR INFORMATION
This research was supported by awards P30 HG00209-03 and R01 AR4274-01 from the National Institutes of Health, Bethesda, Md (Drs Elder, Nair, and Voorhees); by award DFG-WE 905/1-1 from the Deutsche Forschungsgemeinschaft, Bonn, Germany (Drs Henseler, Jenisch, and Christophers); by the Ann Arbor Veterans Affairs Hospital, Ann Arbor, Mich (Dr Elder); by the National Psoriasis Foundation, Portland, Ore, and by the Babcock Memorial Trust, Ann Arbor. Portions of these studies were conducted at the General Clinical Research Center at the University of Michigan, Ann Arbor, funded by grant M01EE00042 from the National Center for Research Resources, National Institutes of Health.
Our special thanks go to all the study subjects and referring physicians for their participation in these genetic studies of psoriasis during the past decade.
Corresponding author and reprints: James T. Elder, MD, PhD, 3312 CCGC, University of Michigan, 1500 E Medical Center Dr, Ann Arbor, MI 48109-0932 (e-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it. ).
From the Departments of Dermatology (Drs Elder, Nair, Chia, and Voorhees and Mr Stuart) and Radiation Oncology (Dr Elder), University of Michigan, and Department of Dermatology, Ann Arbor Veterans Affairs Hospital (Dr Elder), Ann Arbor, Mich; and the Departments of Dermatology (Drs Henseler and Christophers) and Immunology (Dr Jenisch), Christian-Albrechts University, Kiel, Germany.
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