T-Lymphocyte Dependence of Psoriatric Pathology in Human Psoriatic Skin Grafted to SCID Mice
Background.—Previous research has suggested that T lymphocytes may play a pathogenetic role in psoriasis. A severe combined immunodeficiency (SCID) mouse model of psoriasis was used to assess the ability of T cells to maintain the phenotype of psoriasis lesions.
Methods.—Human skin with psoriasis lesions was transplanted onto SCID mice. The animals were then injected, intradermally or intravenously, with autologous skin cells, which were cultured from either psoriatic skin lesions or peripheral blood. Another group of SCID mice underwent psoriatic skin grafting but not T-cell injection.
Results.—By 10 weeks, skin grafts on control animals no longer had many of the characteristics of psoriasis. Neither were the psoriatic features maintained in animals injected with peripheral blood T cells. However, animals injected with T cells cultured from psoriatic skin did show maintenance of the psoriatic phenotype. This included such features as epider-mal thickness and labeling index; expression of HLA-DR, involucrin, and ICAM-1; and loss of expression of filaggrin. When skin-infiltrating T cells were injected into the skin of normal donors transplanted onto SCID mice, no psoriatic changes developed.
Conclusions.—In this SCID mouse model, T cells derived from psoriatic skin can maintain the phenotype of psoriasis lesions, whereas T cells from the peripheral blood cannot. Thus, psoriasis appears to be mediated by an autoantigen-reactive T cell, which is more frequent in psoriatic lesions. The findings provide direct evidence that psoriasis is mediated by and dependent on T cells.
Changes in Peripheral Blood Lymphocyte Subsets During Cyclosporin Administration in Patients With Psoriasis Vulgaris
Introduction.—T cell defects are thought to play an important causative role in psoriasis vulgaris, but the true pathogenesis of the disease remains unknown. Cyclosporin A (CyA), an immunosuppressive drug, has been used for the treatment of severe psoriasis. Its major pharmacologic action is to inhibit production of cytokines by activated T cells. The effects of CyA treatment on peripheral blood lymphocyte subsets were investigated, including the possible association between clinical improvement and alteration of lymphocyte subsets.
Methods.—The study included 10 patients with active psoriasis vulgaris who were being treated with CyA. Before and after treatment, peripheral blood lymphocyte subsets were analyzed using a fluorescence-activated cell sorter. Two-color stainings with different combinations of monoclonal antibodies were used.
Results.—Pretreatment analyses showed an elevated percentage of CD4+HLA-DR lymphocytes in the patients, compared with normal controls. By the fourth week of treatment, the CD4+-CD8+ ratio increased significantly. This value subsequently returned to a ratio similar to baseline. None of the other cell surface markers studied showed any significant changes during treatment.
Conclusions.—In patients with psoriasis, treatment with CyA does not appear to have any major effect on the peripheral lymphocyte subsets. Instead, this treatment may act preferentially on activated T lymphocytes in the lesional skin. The transient increase in the CD4+-CD8+ ratio observed in this study may reflect activated T lymphocytes moving from the lesional skin into the peripheral blood.
- Boehncke et al. and Wrone-Smith et al. have demonstrated that injection of superantigen-activated leukocytes can induce psoriasis in human skin grafts on SCID mice. These studies, along with the ones summarized here (Abstracts 3-1 and 3-2), support a direct role for activated T cells in the pathogenesis of psoriasis. However, in the previous studies psoriatic changes were induced in nonlesional skin, whereas in the current study the psoriatic phenotype was maintained in lesional skin. These contrasting results raised the question of what is unique about lesional psoriatic T-cells and superantigen-activated leukocytes that favors the development of psoriatic changes. The results obtained by Abe et al. support a critical role for activated T lymphocytes in lesional skin in the generation of the psoriatic process.
Demonstration and Functional Analysis of IL-10 Receptors in Human Epidermal Cells: Decreased Expression in Psoriatic Skin, Down-modulation by IL-8, and Up-regulation by an Antipsoriatic Glucocorticosteroid in Normal Cultured Keratinocytes
Introduction.—The primary histopathologic features of psoriasis, epidermal hyperproliferation and inflammation may be caused by inappro-priate regulation of a set of genes in the epidermal cells. Overexpression of growth factors and proinflammatory cytokines, such as interleukin-8 (IL- 8) and its corresponding receptor have been observed in psoriatic plaques. The loss of inhibitory control mechanisms is also involved in the pathogenesis of psoriasis, as indicated by decreased mRNA levels for the cell cycle inhibitor in lesional skin. Interleukin-10 is a cytokine with negative regulatory functions. It is only under certain conditions that human keratinocytes (KCs) are able to synthesize IL-10. The expression of the IL-10R gene in the skin disease psoriasis was analyzed.
Methods.—Normal human KCs were isolated from healthy donors and cells were cultured. Interleukin-10 binding to the cells was evaluated by flow cytometry. Punch biopsy specimens from involved and uninvolved skin of patients with psoriasis and healthy controls were analyzed for the presence of IL-10 binding activity, IL-10R gene expression, and HLA-DR expression.
Results.—Specific IL-10 binding on normal human epidermal KC was detected. The presence and functionality of IL-10R in epidermal cells and its dramatically diminished expression in acute exanthematic psoriatic epidermis was shown for the first time in this series of in vitro and in situ binding experiments. Findings were substantiated using semiquantitative reverse transcriptase polymerase chain reaction to show reduced expression of the IL-10R gene in psoriatic skin, its down-modulation by the proinflammatory cytokine IL-8, and its pharmacologic induction in cul-tured cells. The biological responsiveness of epidermal cells toward IL-10 was demonstrated by a lower growth rate and inhibition of interferon-7- induced HLA-DR expression.
Conclusion.—These findings present the first evidence for a role of the IL-10R gene in the homeostasis of the epidermis and validate the idea of a loss of negative regulatory peptides as a step in the evolution of psoriasis.
With the discovery of more and more cytokines and interleukins and other inflammatory mediators over the past 2 decades, it has become apparent that the pathogenesis of psoriasis is extremely complex. Elucidation of the molecular mechanisms involved has demonstrated that many of these cytokines, interleukins, and other inflammatory mediators have a co-regulatory function through cellular intermediates (such as kinases), which affect transcription and translation as well. Interleukin-10 is an “inhibitory” cytokine, the down-regulation of which could cause hyperproliferation (a hallmark of psoriasis), it is, therefore, not surprising that Michel et al. have demonstrated decreased expression of IL-10 receptors in psoriatic skin; this phenomenon is negatively modulated by IL-8, but is up-regulated by antipsoriatic glucocorticosteroids.
Association of Psychic Stress With Clinical Severity and Symptoms of Psoriatic Patients
Background.—Previous studies have indicated that patients with psoriasis have worse symptoms when under stress. Furthermore, their biochemical responses to stress have been shown to differ from those of healthy volunteers. The effects of the degree of stress on the severity of the psoriasis was investigated.
Methods.—Patienzs (24 men and 14 women, 23-69 years old) with psoriasis vulgaris underwent 4 self-rating scales to measure psychological distress/general health, psychosomatic reactivity, depression, and life changes. Patients with only 1 positive assessment were classified as the low-stress group (n = 21), whereas those with 2 or more positive test results formed the high-stress group (n = 17). Low and high scorers on each of the 4 assessments were also determined. For all patients, a Psoriasis Area and Severity Index (PASI) was calculated based on the degree of erythema, infiltration, and desquamation of each body region (range 0 to 72 points). Also, a General Severity score was derived based on the PASI score, the activity of the psoriasis during the study, and whether joint symptoms were present.
Findings.—Overall, 42% of patients had a high score on the psychological distress test, 45% had high psychosomatic reactivity, 37% had depression, and 66% had experienced a stressful life event during the past 3 months. Higher scores on all 4 assessments correlated with higher General Severity scores. The PASI scores did not differ significantly between the low-stress and high-stress groups, nor between men and women. When data were analyzed based on individual test scores, high PASI scores correlated significantly with a high psychosomatic score. For men in the low-stress group, a high PASI score correlated significantly with greater psychological distress, psychosomatic reactivity, and depression. For men in the high-stress group, a high PASI score correlated significantly with a higher score on the life changes/life events test. Furthermore, greater psoriasis activity correlated significantly with a higher score on the life changes/life events test for both sexes. The General Severity score correlated significantly with the psychosomatic score for both men and women. The presence of joint symptoms did not correlate with any of the test results, except that women with joint symptoms scored significantly worse on the psychological distress test. Finally, men with active psoriasis had a significantly higher score on the life changes/life events test than men with stable psoriasis.
Conclusions.—All patients had high scores on the psychological distress, psychosomatic reactivity, depression, and life events tests. Many significant correlations were found between high scorers and low scorers on these 4 parameters of stress, indicating that stress is a significant factor for the patient with psoriasis.
- Many patients report that psychic stress exacerbates their psoriasis, and this study supports that belief. Perhaps we should pay more attention to mental well-being in caring for these patients.
Potent Topical Steroid in a Chinese Herbal Cream
Objective.—With the growing popularity of alternative medicine, there is concern over the possible contents of some of the preparations used in treatment. Some of these products may have inherent toxicities, which may be difficult to identify without correct labeling. A very potent topical steroid marketed as a Chinese herbal remedy is reported.
Case Report.—Woman, 53, consulted a dermatologist because of psoriasis. She had been using a topical cream recommended by a Chinese health center. Her psoriasis improved considerably. Liquid chromatography was performed on a sample of the cream, showing that it contained a high concentration of dobetasol pro-pionate. The authors notified the Health Department, which took appropriate action.
Discussion.—A “Chinese herbal cream” proved to contain the potent steroid, clobetasol propionate. Potentially hazardous drugs are being sold at unauthorized outlets by untrained personnel to patients seeking “alter-native” remedies. The clinician should be aware that such illegal products may be available to patients.
- Is this Skin-Cap revisited? The message is clear: always be suspicious of so-called miracle remedies of uncertain constitution.
The Effects of Topical Calcipotriol on Systemic Calcium Homeostasis in Patients With Chronic Plaque Psoriasis
Objective.—Whereas topical calcipotriol is an effective therapy for chronic plaque psoriasis, small increases in urine calcium excretion have been found at the upper limit of the recommended dose (100 g of 50 pg/g ointment per week) and 2 reports document hypercalcemia in patients applying 80-90 g/wk. The mechanism of calcipotrioPs action on systemic calcium homeostasis was elucidated to predict potential adverse effects of long-term treatment in patients with chronic plaque psoriasis.
Methods.—Sixteen patients (7 women), aged 18-83 years, with chronic plaque psoriasis were given a diet containing 1,000 mg/day of calcium for 1 week and treated with calcipotriol (50 pg/g) ointment for 2 weeks. The maximum dose of caicipotriol was 360 g/wk. Severity of psoriasis was assessed with the Psoriasis Area and Severity Index. Bone turnover, routine biochemistry parameters, vitamin D, calcipotriol, and parathyroid hormone were measured. Intestinal absorption was assessed using nonradioactive stable strontium chloride.
Results.—The dose of calcipotriol per kilogram of body weight was significantly correlated with the change in strontium (r = 0.7), demonstrating a dose-dependent increase in intestinal absorption of calcium. There was no effect on bone at any dose. Mean serum calcium increased significantly, from 2.30 to 2.47 mmol/L. Levels of 1,25-dihydroxyvitamin D, increased significantly, from 55.8 to 368.2. However, this likely represents interference by calcipotriol with the assay. 1,25-dihydroxyvitamin D3 levels fell significantly when levels were reassessed using high-pressure liquid chromatography.
Conclusion.—High doses of topical calcipotriol can cause significant toxicity by affecting systemic calcium homeostasis. Increased intestinal calcium absorption and probably also increased intestinal phosphate absorption result, leading to dose-dependent hypercalcemia, hyperphosphatemia, parathyroid suppression, hypercalciuria, and hyperphosphaturia.
Although not the case in the United States, the prescribing information for calcipotriol (calcipotriene) in many European countries warns against using more than 100 g of the 0.005% ointment per week. At recommended doses, hypercalcemia is extremely uncommon; patients with erythrodermic skin and a decreased glomerular filtration rate are at highest risk for developing this complication. The results of this study, in which an effect on calcium homeostasis was demonstrated after short-term, high-dose therapy, are dramatic and should prompt us to warn patients not to use quantities in excess of those recommended. This is especially important in the current era of “pharmacy managed care,” in which patients are urged to procure 3-month supplies of medications used to treat chronic conditions. The lack of effect on bone turnover is hardly reassuring, as the methods used may not have been sensitive enough to detect subtle abnormalities in this short-term study.
Topical Calcipotriol in Childhood Psoriasis
Background.—Calcipotriol is used successfully to treat psoriasis in adults, but data in children are lacking. These authors evaluated the efficacy of calcipotriol in treating psoriasis in children.
Methods.—A 2-week washout period, during which only emollients were used, preceded the study. Then, children 2-14 years old with mild to moderate (less than 30% body involvement), stable psoriasis vulgaris were divided into 2 groups. The test group (n = 43; 22 boys, 21 girls) applied 50 (ig/g calcipotriol ointment twice daily for 8 weeks, and the placebo group (n = 34; 14 boys, 20 girls) applied the ointment vehicle. The experimental ointments were used on all areas except the face, scalp, genitals, or covered areas (e.g., by diapers), because participants used their usual topical medication in these areas. The maximum amount of ointment that an individual could apply was calculated based on the patient’s height and weight relative to body surface area, with the assumption that 30 g covers 0.2 m2 in twice-daily applications during 1 week. Investigators rated the extent and severity of disease according to the Psoriasis Area and Severity Index (PASI), which assesses the redness, thickness, and scaliness of psoriatic lesions. Serum and urine samples were collected regularly to study the hematologic and metabolic effects of the drug, including bone markers of metabolism.
Findings.—By the end of the study, the PASI score was reduced in both the test group (—52%) and the control group (—31%; difference not significant). The test group did have significantly better redness and scaliness scores than the control group, however. Investigators rated calcipotriol significantly superior to placebo, with symptoms cleared or markedly improved in 60% of patients receiving calcipotriol vs. 44% of patients receiving placebo. Patients showed no clear preference for either treatment. Parameters of hematologic, liver function, or kidney function did not differ between the 2 groups, nor were markers of bone formation or resorption higher in the test group. The main side effect, lesional/perilesional irritation, was reported by 7 (16%) of the test group and 8 (24%) of the placebo group.
Conclusions.—When titrated to an appropriate dose based on the child’s height, weight, and body surface area, topical calcipotriol was effective in treating the redness and scaliness of psoriasis in children. However, the overall PASI score and the thickness of lesions did not differ significantly between the patients receiving calcipotriol and those receiving placebo. Overall the investigators rated calcipotriol significantly better than placebo. Thus this drug shows promise in the treatment of mild to moderate, stable psoriasis in children.
- It is reassuring that no important changes in markers of bone metabolism were found in the treated patients. Nevertheless, the package insert warns that “because of the higher ratio of skin surface area to body mass, children are at greater risk than adults of systemic adverse effects when they are treated with topical medication.’’ Of course, this is true for all topical medications, not just calcipotriol (which is more commonly referred to as calcipotriene in the United States).
Comparison of Psoralen-UVB and Psoralen-UVA Photochemotherapy in the Treatment of Psoriasis
Introduction.—For patients with psoriasis, treatment with oral methox-salen followed by ultraviolet A irradiation (PUVA) may be given. Broadband UVA sources—with a fluorescence spectrum of 320-400 nm and a peak emission of 350-360 nm—are usually used for PUVA. Previous reports have described the use of a narrow-band (peak emission at 311 nm) lamp for UVB psoriasis phototherapy. Psoralen-UVB therapy was compared with conventional PUVA for the treatment of plaque-type psoriasis.
Methods.—The randomized trial included 100 patients with plaque type psoriasis. Both groups received oral methoxsalen, 25 mg/m2; median dose was 40 mg. On the first treatment day, minimal phototoxic dose (MPD) testing was performed 2 hours after methoxsalen ingestion. The maximum test dose was 10 J/cm2 with the PUVA lamps and 2 J/cm2 with the narrow-band UVB lamps. Phototherapy was given twice weekly using whole-body exposure units with 40 fluorescent lamps. The starting dose was 2.5 J/cm2 for UVA and 0.6 J/cm2 for UVB. The dose was then increased in steps equal to the predetermined MPD, or a maximum of 6 J/cm2 for UVA or 1.5 J/cm2 for UVB, on the third and fourth treatment days. The dose was then increased each week, starting with 40% for UVA and 10% for UVB. Incremental decreases were made to 10% for UVA and 2.5% for UVB by the sixth week of treatment. The dose was adjusted as needed if erythema developed.
Results.—The 2 groups were similar in terms of skin type and plaque size. Psoriasis cleared in 86% of the UVB group vs. 72% of the UVA group. The corresponding odds ratio for response was 2.16, with little change when logistic regression was used to account for skin type and plaque size. Median number of treatments to achieve clearance was 16.5 for UVA and 15.0 for UVB. Median cumulative dose to achieve clearance was 72.1 and 19.1 J/cm2, respectively. At 3 months’ follow-up of patients who were psoriasis free at the end of treatment, 32% of the UVA group and 40% of the UVB group remained clear, a nonsignificant difference.
Conclusions.—For patients with plaque-type psoriasis, psoralen/narrow-band UVB treatment gives a response similar to that of conventional PUVA. Psoralen-UVB therapy probably works through a direct effect of 311-nm radiation on psoriasis, in addition to the psoralen-mediated photochemical effect. Further study of the mechanism is needed to predict the long-term safety of psoralen-UVB treatment.
Narrowband UV-B Produces Superior Clinical and Histopathological Resolution of Moderate-to-Severe Psoriasis in Patients Compared With Broadband UV-B
Introduction.—A landmark advance in the treatment of psoriasis was introduced by Goeckerman who, in 1925, combined ultraviolet-B (UVB) and topical tar therapy. This treatment has been modified with fluorescent sources, varying dosing regimens and treatment schedules, and the use of different emollients. Treatment protocols using narrowband or 312-nm UVB from fluorescent bulbs can deliver larger amounts of UVB to the skin, and its effectiveness has been found to be superior to conventional broadband UVB treatment. Using clinical and histopathologic measures of efficacy in patients with recalcitrant disease, the response of psoriasis to conventional UVB treatment was compared to that with narrowband UVB treatment.
Methods.—In 22 patients with moderate to severe plaque-type psoriasis, half of the body was exposed to narrowband UVB treatment and the other half to broadband UVB treatment, daily for 4 weeks. Tl-01 fluorescent bulbs were used for narrowband UVB treatment, and conventional bulbs in the same phototherapy cabinet were used for broadband treatment. Narrowband treatment was compared with broadband treatment above the waist and to broadband treatment with tar below the waist, using a paired treatment approach.
Results.—In 86% of paired sites treated with narrowband UVB, clinical resolution of psoriasis was achieved, compared with 73% of treated sites with broadband UVB. In 88% of lesions treated with narrowband UVB, histopathologic resolution of epidermal hyperplasia was achieved, compared with 59% of sites treated with broadband UVB. Narrowband UVB treatment reduced epidermal acanthosis more completely. After narrowband UVB treatment, clinical resolution of psoriatic lesions was more rapid. Complete resolution was achieved in some patients after 2 to 3 weeks of treatment. There was significantly more intense and persistent erythema response to narrowband UVB treatment than to broadband UVB treatment. In histopathologic sections of skin treated with narrowband UVB, after a single 2.0-minimum erythema dose exposure considerably more necrotic keratinocytes were observed.
Conclusion.—In the treatment of psoriasis, narrowband UVB offers a significant therapeutic advantage over broadband UVB, because it results in faster clearing and more complete disease resolution. Treatment should be coupled with obligate minimum erythema dose testing to narrowband UVB and close clinical observation during dose increases.
- An accompanying editorial in the same journal as Coven et al.’s study (Abstract 3-9) discusses the difficulties in establishing optimal maintenance protocols and remission times, as well as the safety of long-term narrowband UVB therapy. Such treatments are more expensive to provide and require greater skill than broadband UVB and PUVA therapy (Abstract 3-8). Nevertheless, reimbursement for narrowband UVB treatment is less than for PUVA, and sources of funding for comparative studies are difficult to obtain. Thus, although narrowband UVB therapy appears to be more effective than broadband UVB for psoriasis, its long-term safety remains uncertain.
Malignant Melanoma in Patients Treated for Psoriasis With Methoxsalen (Psoralen) and Ultraviolet A Radiation (PUVA)
Background.—Although photochemotherapy with oral methoxsalen (psoralen) and ultraviolet A radiation (PUVA) is effective in the treatment of psoriasis, PUVA is thought to increase the risk of squamous cell skin cancer. The occurrence of melanomas among patients undergoing PUVA was investigated.
Methods.—Cases of melanomas among 1,380 patients with psoriasis initially treated with PUVA in 1975 or 1976 were identified prospectively. The extent of exposure to PUVA was documented. The risks of melanoma associated with a long period (15 years or more) since initial treatment and with a large number (250 or more) of treatments were determined in regression analyses.
Findings.—Four malignant melanomas occurred between 1975 and 1990, which is about the same as that occurring in the general population. The relative risk was 1.1. However, 7 malignant melanomas occurred between 1991 and 1996, which yielded a relative risk of 5.4. The risk was also higher among patients receiving 250 PUVA treatments or more than among those receiving fewer treatments; the incidence-rate ratio of 3.1.
Conclusions.—The risk of malignant melanomas increases about 15 years after initial PUVA treatment among patients with psoriasis. This risk was especially increased among patients receiving 250 treatments or more.
- It has long been suspected that PUVA could induce the development of malignant melanoma, and this has been clearly documented by this study. A long latency period (15 years or longer) and a large number of treatments (250 or more) appear to be necessary to induce the tumor. Unfortunately, other than offering words of caution, the authors do not address how this observation might modify their use of PUVA, e.g., limiting patients to less than 250 treatments or not using PUVA in patients with a family history of melanoma or with numerous moles. These questions need to be addressed.
Acitretin Therapy Is Effective for Psoriasis Associated With Human Immunodeficiency Virus Infection
Introduction.—Up to 3% of the world’s population is affected by psoriasis, a chronic inflammatory skin disorder. It has been associated with HIV infection. The disease tends to be more severe if it follows HIV infection and responds poorly to aggressive treatment. Most treatments for classic psoriasis are potentially immunosuppressive and are unacceptable for patients with HIV infection. Acitretin, however, is an effective therapy for psoriasis and does not have immunosuppressive properties. However, its efficacy and safety for treating psoriasis associated with HIV infection has not been investigated.
Methods.—There were 11 patients with psoriasis-associated HIV infection in a 20-week treatment protocol. During the period of observation, each patient received an optimized dose of acitretin. Every 2 weeks, clinical and laboratory assessments were performed.
Results.—Good-to-excellent responses were achieved in 6 of 11 patients (54%) with acitretin monotherapy of HIV-associated psoriasis. Complete clearing was found in 4 patients (36%). No correlation was seen between the therapeutic response and the pretreatment measures of immunosuppression. Acitretin therapy did not exacerbate the parameters of immunosuppression.
Conclusion.—For psoriasis associated with HIV infection, acitretin is a safe and effective treatment. Most patients with psoriasis associated with HIV infection experienced a response of both skin and joint manifestations to acitretin therapy. A dose of 75 mg/day produced optimal results. Immunosuppressive effects do not seem to occur with acitretin. A formal randomized clinical trial should be conducted.
- Most effective treatments for severe psoriasis are immunosuppressive; these include methotrexate, psoralen plus ultraviolet light, and cyclosporine. Oral retinoids have the obvious advantage of not inhibiting the immune response. Acitretin has replaced etretinate as the oral retinoid of choice for psoriasis because of its decreased lipophilicity and shorter biological half- life. Although acitretin is a major metabolite of etretinate, it must be remembered that acitretin can be converted back to etretinate in a reaction enhanced by alcohol intake. This factor should be emphasized to any woman of child-bearing age being considered for acitretin treatment.
Cyclosporine as Maintenance Therapy in Patients With Severe Psoriasis
Objective.—Whereas low-dose cyclosporine has been shown to be effective in treating severe psoriasis, discontinuing treatment to avoid toxicity results in fast, non-dose-dependent relapse. The safety and efficacy of low-dose maintenance therapy with cyclosporine versus placebo was assessed in patients with cyclosporine-induced remission of severe, recalcitrant, plaque-type psoriasis.
Methods.—Cyclosporine (5.0 mg/kg/day with an increase up to 6.0 mg/kg/day or a decrease to 3.0 mg/kg/day allowable) was administered for 16 weeks to 181 patients enrolled at 10 centers in the open-label induction phase to establish efficacy and tolerability. Patients who had achieved at least 70% clearing entered a 24-week, double-blind, placebo-controlled, maintenance phase and were randomly allocated to placebo or cyclosporine at 1.5-3.0 mg/kg/day. Relapse was defined as at least 50% psoriasis- involved body surface. Overall change was rated on a 1 (cleared) to 8 (markedly worsened) scale. Global evaluation was rated on a 1 (totally clear) to 7 (severe) scale. Safety was also assessed.
Results.—After the 16-week induction period, the involved body surface area (BSA) decreased significantly by 81.1%. The median improvement was 70%, and 86% of patients entered the maintenance phase. Significantly more placebo and cyclosporine (1.5 mg/kg/day) patients than cyclosporine (3.0 mg/kg/day) patients relapsed (84% vs. 42%). Median time to relapse was 6 weeks. Adverse events reported by 88% of patients in the induction phase included headache (30%), paresthesia (18%), hirsutism (17%), new-on set hypertension (8.8%). Seven of 9 cyclosporine patients who discontinued treatment did so because of the study drug. Reasons for discontinuation included decreased renal function (n = 5), increased serum creatinine (n = 3), decreased urine creatinine clearance (n = 1), decreased GFR (n = 1), laboratory abnormality (n = 1), and worsening gynecomastia/hypertension (n = 1).
Conclusion.—Cyclosporine at 3.0 mg/kg/day is effective and reasonably safe in the maintenance treatment of severe psoriasis.
- Unquestionably, cyclosporine is quite effective in the control of even severe psoriasis, although discontinuation of the drug invariably leads to relapse. Hypertension and renal toxicity are common side effects and limit its widespread use.’-2 Shupack et al. attempt to identify a dose of cyclosporine that is effective yet safe enough to use as maintenance therapy after an “induction” phase in which cyclosporine is given at a higher dose to achieve control of the disease. Only monotherapy with cyclosporine was allowed. Quite likely, use of a good topical agent along with the systemic drug would enhance the clinical effect; this would allow for lowering of the cyclosporine dose level and thus decrease the incidence of toxic effects.
The Impact of Psoriasis on the Quality of Life of Patients From the 16-Center PUVA Follow-up Cohort
Introduction.—Psoriasis, a chronic skin disease, can be psychosocially debilitating and often requires systemic therapy. A study initiated in 1976 included 1,376 patients taking psoralen plus ultraviolet light (PUVA), and they were observed for about 16 years. Some patients also had ultraviolet B (UVB) phototherapy and methotrexate. In some of these patients, nonmelanoma skin cancers developed. These patients were interviewed to assess the physical, psychological, and social dimensions of their lives.
Methods.—Telephone interviews were conducted and patients complete questionnaires. There were 1,113 surviving patients, who were assessed 16 years later, and responses were obtained from 877. They were asked about the occurrence of new skin cancers, the development of cataracts, the use of other treatments for psoriasis, and the impact that psoriasis had on their quality of life. An assessment of the severity of the psoriasis was also made.
Results.—The mean age of the patients was 56 years, and their quality of life was substantially impacted by psoriasis. Impairment in quality of life was more often reported by women than by men. Increasing age decreased the impact of psoriasis. Those older than 65 years were less likely to have high impact scores when compared with those younger than 40 years. Patients who had recently used UVB phototherapy reported a moderate-to-high relative impact on their total quality of life when compared with those using PUVA or methotrexate.
Conclusion.—The quality of life is substantially affected by psoriasis. Increasing age seems to decrease its impact. The extent to which psoriasis affects quality of life is influenced by the use of specific treatments. Those patients receiving UVB therapy reported psoriasis as having a more adverse effect on their quality of life than those taking PUVA and methotrexate therapy, perhaps as a result of the inconveniences the patient experiences while taking this type of treatment.
- One of the most interesting observations in this study was the apparent correlation between the kind of therapy prescribed and the impact on quality of life. Patients using more inconvenient therapies noted an increased impact on quality of life compared with those prescribed relatively simple regimens. Thus, both the disease and its therapy could have an important impact on the patient’s psychological well-being.
Psoriatic and Seronegative Inflammatory Arthropathy Associated With a Traumatic Onset: 4 Cases and a Review of the Literature
Introduction.—Previous studies have suggested that seronegative arthritis may be triggered by the occurrence of physical injury. However, few of the reported cases include enough information to diagnose psoriatic arthritis, ankylosing spondylitis, or Reiter’s syndrome, or to confirm their association with the preceding injury. In the authors’ experience of 4 cases, there is no proof that the trauma caused the arthritis; however, the association is too obvious to ignore. These 4 cases of traumatic-onset psoriatic and seronegative inflammatory arthropathy were reported, along with a review of the literature.
Patients.—The patients were 3 men and 1 woman, aged 23-40 years. Two fell downstairs, 1 slipped while jumping, and 1 was in a traffic accident, with injuries involving the ankle, wrists, hands, and/or lower back. The injuries were followed by swelling and rapid development of psoriatic arthritis in 3 patients and unilateral spondyloarthropathy in the fourth. Two patients had severe arthritis, requiring methotrexate or naproxen and steroid injections. The other 2 had milder disease, well controlled with meclofenamate.
Discussion.—The proposed link between trauma and arthritis depends on the temporal relationship between the 2, and the fact that arthritis occurs at the site of the injury. One proposed explanation is the Koebner reaction, in which a physical injury leads to joint inflammation in patients predisposed to psoriasis, just as skin trauma can elicit psoriatic lesions. Unfortunately, HLA typing data were not available in these 4 cases.
- The possibility of an arthropathic Koebner reaction has been proposed before. Alternative explanations for the relationship between the trauma and the arthritis include cross-reactivity to a cutaneous bacterial antigen introduced by the trauma or the release of neuropeptides, such as substance P, that can stimulate the synovium. Do I hear a vote for coincidence?
Presence of Psoriasis Does Not Influence the Presentation or Short Term Outcome of Patients With Early Inflammatory Polyarthritis
Background.—Psoriatic arthritis (PsA) is often defined as psoriasis associated with inflammatory arthritis, that is, peripheral arthritis and/or spondylitis, usually occurring in a patient negative for rheumatoid factor (RF). However, a generally accepted definition of PsA is lacking. The effects of psoriasis on the outcome of inflammatory polyarthritis were evaluated. The study also assessed the incidence of inflammatory polyarthritis associated with concurrent psoriasis.
Methods.—The population-based cohort study included 966 patients with early inflammatory polyarthritis who were referred to a regional arthritis registry. Patients with and without psoriasis were identified, and their clinical and demographic characteristics were compared.
Findings.—Examination revealed psoriasis in 5.3% of patients. Of patients with psoriasis, 49% were men, compared with 34% of those without. The rate of seropositivity for RF was 13% among patients with psoriasis, compared with 31 % for those without. There were no significant differences in pattern of joint involvement or in 1-year outcomes. Of patients with psoriasis, 22% had radiologic erosions, compared with 39% of patients without psoriasis. On multivariate analysis, RF appeared to act as a confounding factor in this relationship.
Conclusions.—This study finds few major differences among patients with early inflammatory polyarthritis, with or without concurrent psoriasis. The differences that do exist may be related to the absence of RF in most patients with psoriasis. Disease outcomes are similar in terms of disability, need for second-line drugs, and remission rate. Differences related to the presence or absence of psoriasis may become apparent only as the disease progresses, or psoriasis may trigger some disease that is indistinguishable from rheumatoid arthritis. The rate of psoriasis among patients with early inflammatory polyarthritis appears higher than that of the general population.
- Is psoriatic arthritis simply a variant of rheumatoid arthritis? The current study cannot definitively answer that question, but it does demonstrate that among patients with early inflammatory polyarthritis, there are a few important differences between those with and without psoriasis. Some of these differences may be explained by the presence or absence of rheumatoid factor.