Quantification of cutaneous sensory nerves and their substance P content in psoriasis.

The aim of the present study was to extend our previous hypothesis that the inflammatory reaction in psoriasis is neurogenic, and that substance P mediates the inflammation. For this purpose, the pattern of neurofilament-positive sensory nerve fibers was studied and the lengths and substance P content of these fibers measured morphometrically in dermal and epidermal compartments of the psoriatic lesion, psoriatic but lesion-free skin, and control skin. The epidermis and dermis of the psoriatic lesions were significantly more densely innervated with neurofilament-positive fibers than either lesion-free psoriatic or control skin. Although substance P is known to be rapidly degraded in tissues, and its actual concentrations in the sections were unknown, there was an increase in substance P containing nerves in the psoriatic lesion, the increase being significant in the epidermal nerve fibers. No significant differences in the measured parameters were obtained between lesion-free psoriatic and control skin. These results indicate that there is an altered pattern of sensory nerves in a psoriatic plaque and that substance P may be an important mediator in the inflammatory processes that contribute either to the initiation or maintenance of a psoriatic lesion.

Reduced epidermal cyclic AMP accumulation following prostaglandin stimulation: Its possible role in the pathophysiology of psoriasis.

Since prostaglandins are known to be one of the modulators of cyclic AMP, a study of the role of prostaglandins and their relation to the regulation of the nucleotide in psoriasis was initiated. Guinea-pig epidermal preparations were incubated with prostaglandins (PGs) in the presence of theophylline. PGE1 increased cyclic AMP levels 3.5-fold whereas a 2-fold increase was seen with PGE2 and PGA1. The increase in cyclic AMP accumulation was linear with increasing concentration of PGE1, from 10(-11) to 10(-5) M. PGE1 significantly increased cyclic AMP in psoriatic epidermis in vitro; however, the stimulation of cyclic AMP accumulation was significantly less in involved epidermis as compared with uninvolved tissue. The specificity of this stimulation, its occurrence at physiologic levels, and the decreased responsiveness of the cyclic AMP system in psoriatic epidermis to PGE1 stimulation suggest that the altered response of epidermis to PGs may be one of the factors in the pathophysiology of psoriasis.

The role of prostaglandin E, cyclic AMP, and cyclic GMP in the proliferation of guinea-pig ear skin stimulated by topical application of vitamin A acid.

Daily treatment of guinea-pig ear skin with topical 0.5% retinoic acid in acetone produced erythematous scaly dermatitis. Histologic sections revealed bandlike thickening of the epidermis on days 2 to 4, psoriasiform acanthosis, papillomatosis and increased mitotic activity on days 5 to 6. Also seen were dilatation of the upper dermal blood vessels and a fibroblastic, histiocytic reaction in the dermis. Prostaglandin E, cyclic AMP, and cyclic GMP levels were increased in the treated skin and thymidine incorporation was enhanced. Cyclic AMP and GMP levels peaked on day 5 simultaneous with maximal epidermal hyperplasia, increased mitotic activity and dermal reaction. Tritiated thymidine uptake peaked on days 4 and 5, and prostaglandin E levels continued to increase up to day 6. Cyclic AMP phosphodiesterase activity of treated skin on day 5 did not appear to be significantly different from control.

Neuropeptides modulate leukotriene B4 mitogenicity toward cultured human keratinocytes.

Neuropeptides released in skin from nerve fibers may interact with endogenous growth factors (or other mitogenic agents) to induce psoriasis lesions characterized by proliferating epidermal keratinocytes. The mitogenic effects of two neuropeptides, substance P (SP) and vasoactive intestinal peptide (VIP), on human adult and newborn keratinocytes were observed in the presence or absence of leukotriene B4 (LTB4) and leukotriene C4 (LTC4). In the presence of SP or VIP, LTB4 (but not LTC4) demonstrated substantial increase in thymidine incorporation into DNA, which was confirmed by cell-growth observations using the hexosaminidase assay. In the absence of either neuropeptide, LTB4 had only marginal effects, especially with adult (but not newborn) keratinocytes. With adult keratinocytes, LTB4 (but not LTC4) demonstrated synergy with both SP and VIP. VIP was mitogenic to keratinocytes at concentrations as low as 10(-12)M and exhibited a different dose-response curve depending on whether adult or newborn keratinocytes were used. The mitogenic effects of SP were abrogated by the SP antagonist spantide and those of VIP by the VIP antagonist [Ac-Tyr1, D-Phe2] growth-hormone-releasing factor (1-29) amide. This study suggests that the mitogenic effects of LTB4, which are elevated in psoriatic lesions, may be enhanced by the presence of neuropeptides, especially VIP. These effects can be reversed by antagonists that may have potential as drugs for the disease.

Epidermal synthesis of prostaglandins and their effect on levels of cyclic adenosine 3', 5'monophosphate.

Extracts of guinea-pig and human skin epidermis were analyzed for prostaglandins PGE1, E2, and F2alpha by radioimmunoassy, and found to contain a total of 62.0 (guinea pig) and 144.7 (human) ng/gm wet weight. the three prostaglandins occurred in approximately equal amounts. Guinea=pig epidermal homogenates converted labeled arachidonic acid to PGE2 and PGF2alpha, the rate of formaiton being 10 and 2.5 pmoles per mg protein in O.K hr, respectively. Conversion in the dermis occurred to a much smaller extent. Homogenates of univolved and involved epidermis from 10 subjects with psoriasis produced PGE2 from arachidonic acid at rates of 6.48 and 2...

Psoriasis. A review of recent advances in treatment.

Current concepts in the treatment of psoriasis are reviewed, including: traditional modalities of dithranol (anthralin), tar, and corticosteroids alone or in combination with other agents; phototherapy and photochemotherapy; experimental studies with the aromatic retinoid etretinate and related analogues; dialysis; and the potential use of hyperthermia. Prudent administration of agents that are known to have serious side effects should be the concern of all clinicians. Many regimens that have beneficial short term results may have the potential for long term sequelae that may not only affect the patient but the offspring as well. Two of the most promising innovative concepts in the therapeutic armamentarium for psoriasis are psoriasis 'day care centres', and prevention and self-care. With the ever-increasing costs of medical care throughout the world, ways and means of reducing costs should be initiated by the clinician when considering a treatment programme. The clinician has the responsibility of determining whether the severity of the disease warrants ambulatory outpatient regimens or hospitalisation. If the patient would benefit from daily attention, then the psoriasis day care centre approach provides an appropriate clinical setting. However, in addition to administering appropriate medication, it is incumbent upon the clinician to educate patients regarding their disease and the triggering factors to prevent exacerbations. 'Disability prevention' means extending the services of clinicians and others to deal systematically with 2 areas involved in disease development; one is recognising the genetic component of psoriasis; the other, environmental triggering factors, e.g. infection, trauma to the skin, low humidity, and stress. Until recently, dermatology has focused on diseases and repairing the damage they cause. Now, the significance of genetic and environmental influences in multifactorial diseases like psoriasis has been realised, as has the importance of educating psoriasis patients to understand their disease and to encourage them to take responsibility for self-care so that the morbidity will be lessened.

Transient acantholytic dermatosis (Grover's disease). A skin disorder related to heat and sweating.

We report seven cases of transient acantholytic dermatosis (Grover's disease) to exemplify a causal association with heat and sweating. The excessive heat and sweating was related to the use of a hot tub, a hot water bottle, a steam bath, an electric blanket, the prolonged wearing of a polyester suit, and postoperative bed confinement.

Generalized pustular psoriasis provoked by propranolol.

An 80-year-old man who had had plaque-type psoriasis for 40 years experienced a rapid onset of generalized pustular psoriasis three days after initiation of propranolol hydrochloride therapy. Trial therapy with propranolol on two occasions resulted in similar episodes. The skin lesions and systemic symptoms resolved after the discontinuation of propranolol therapy and administration of methotrexate sodium. This case study documents propranolol--a beta-blocker--as another causal factor for pustular psoriasis.

Mechlorethamine desensitization in therapy for mycosis fungoides. Topical desensitization to mechlorethamine (nitrogen mustard) contact hypersensitivity.

Five patients with mycosis fungoides who had developed contact dermatitis to a nitrogen mustard, mechlorethamine hydrochloride, even in low concentrations (1 to 5 mg/100 ml), received daily total-body applications of extremely dilute solutions (0.01 to 0.1 mg/100 ml) of mechlorethamine. The concentrations of the drug were approximately doubled weekly if the patient could tolerate it, or they were raised more slowly if the patient could not. Attempts to desensitize one patient were discontinued since he was unable to tolerate a greater concentration than 1.0 mg/100 ml after trying for one year. Another patient was able to tolerate a concentration of 3 mg/100 ml after three months, at which time his skin had completely cleared and treatment was stopped. Three other patients were desensitized during a period of 8 to 13 months to the point of tolerating the full therapeutic concentration used in our clinic (20 mg/100 ml) without experiencing dermatitis or pruritus.

Histocompatibility (HL-A) antigens in psoriasis.

In 101 white psoriatic patients, two histocompatibility (HL-A) specificities were significantly altered from expected values. The levels of W16 and W17 were found to be substantially increased, suggesting that persons with these antigens are at increased risk of having psoriasis. Clinically distinct patient groups were also observed. Antigens W16 or W17 or both were more prevalent in psoriatic patients who had extensive disease involvement, and patients with W17 antigen had an earlier age of onset as compared to patients with W16 antigen. In one family in this study, a linkage between psoriasis and a specific HL-A haplotype was also observed, further supporting the concept that the HL-A system may serve as a marker for genes affecting specific disease susceptibility.

Long-term risks of psoralen and UV-A therapy for psoriasis.

It has been more than eight years since photochemotherapy with methoxsalen and UV-A (psoralen and UV-A [PUVA]) was introduced for the treatment of psoriasis. This treatment remained under investigation until May 1982 because of concerns about possible chronic toxic effects. With recent Food and Drug Administration approval of PUVA therapy for severe psoriasis, strict drug labeling for administration and patient use and continued monitoring of side effects have become essential. The full effects of PUVA in regard to carcinogenicity, prematurely induced aging of the skin, pigmentary changes, immunologic alterations, and ocular side effects are still unknown. A review of the risks of PUVA therapy is presented, with the aim of maintaining a proper perspective for its limited use in treating selected patients.

Treatment of palmoplantar psoriasis with topical methoxsalen plus long-wave ultraviolet light.

Fourteen patients with chronic plaque-type psoriasis involving the palms and soles and 14 patients with palmoplantar vesiculopustular dermatosis, including three cases of localized pustular psoriasis, were treated with topical application of methoxsalen, followed by exposure to long-wave ultraviolet energy (topical PUVA). Approximately two thirds of the patients with palmoplantar plaque-type psoriasis and half of those with vesiculopustular dermatosis responded with considerable improvement, as evidenced by flattening of plaques, decreased scaling and erythema, and decreased vesicle and pustule formation after 15 to 40 treatments. Complete clearing of the treated areas was achieved in five patients with palmoplantar psoriasis, three of whom had the pustular variety. Most patients required continued maintenance therapy with topical PUVA. The condition of the patients with palmoplantar vesiculopustular dermatosis, especially those with severe involvement, was more labile and more difficult to control with PUVA therapy than in those with chronic scaling plaques.

Response of chronic psoriatic plaques to localized heating induced by ultrasound.

Since tumor regression occurs after hyperthermia, this modality was applied to lesions of psoriasis. A relatively uniform temperature and heat distribution within a lesion was induced using an ultrasound transducer operating at 5.265 MHz. Twenty-two chronic psoriatic plaques in nine patients were heated to temperatures ranging from 42 to 45 degrees C for 30-minute periods three time weekly for a total of four to ten treatments. Fifteen lesions (68%) cleared completely within the heated zone, five lesions (23%) responded partially, and two lesions (9%) remained unchanged. Biopsy specimens taken before and during treatment showed reformation of the granular layer as the earliest and most consistent change in responsive lesions. Remissions were temporary, and the lesions usually relapsed within three months. Hyperthermia may be a useful therapeutic and investigative tool for the problem of psoriasis.

Lowered cutaneous and urinary levels of polyamines with clinical improvement in treated psoriasis.

Polyamine metabolism is important in cell proliferation and may play a role in the epidermal cell hyperproliferation of psoriasis. We have determined changes in polyamine levels in skin and urine accompanying clinical improvement in psoriasis following topical therapy. Nine hospitalized patients were examined at the beginning and end of their courses of treatment. Skin biopsy specimens and portions of 24-hour urine collections were analyzed for polyamines with a modified automatic amino acid analyzer. Treatment resulted in lower cutaneous levels of putrescine (by 50%, P less than .05), spermidine (by 24%, P less than .05), and spermine (by 35%, P less than .005), and lower urinary levels of spermidine (by 20%, P less than .025) and spermine (by 35%, P less than .025). These results suggest that in psoriasis, the skin significantly contributes to the levels of spermidine and spermine in systemic fluids. Topical therapy may reduce epidermal cell proliferation in psoriasis by lowering polyamine levels.

Use of recombinant interferon gamma administered intramuscularly for the treatment of psoriasis.

Twenty-three patients with chronic plaque-type psoriasis were treated with intramuscular administration of human recombinant interferon gamma. Patients were treated with doses of 0.01 to 0.25 mg/m2 daily (five out of seven days) for four weeks, or 0.25 mg/m2 three times weekly for one week with escalation to 0.5 mg/m2 for the subsequent seven weeks. Some patients treated with the 0.25-mg/m2 dose showed improvement coincident with their therapy. Although recombinant interferon gamma may have some therapeutic activity in certain patients' psoriasis, the magnitude of this effect is at best small. This result is in contrast to interferon alfa, which has been reported to cause an exacerbation of this disease. Staining of posttreatment biopsy specimens with a monoclonal antibody against HLA-DR antigen using an immunoperoxidase technique demonstrated HLA-DR expression by keratinocytes in some of the patients treated at the higher doses. No obvious correlation was seen between clinical improvement of the psoriasis and intensity or extent of HLA-DR antigen expression by keratinocytes in the skin biopsy specimens.

Persistence of T-cell clones in psoriatic lesions.

BACKGROUND: We previously demonstrated a clonal dominance in the V beta 13.1 messages isolated from the lesional CD8+ T cells of psoriasis vulgaris, which suggested an interaction of V beta 13.1+ CD8+ T cells with skin antigens. OBJECTIVES: To determine whether the clonality observed accurately reflected a clonal population of infiltrating T cells or was skewed by an overabundance of messages from a small number of cells, and to extend our study of V beta gene usage by lesional CD8+ T cells to 9 new patients. DESIGN: Case study. SETTING: Patients were enrolled at the Psoriasis Research Institute in Palo Alto, Calif, and samples were analyzed at The Immune Response Corporation in Carlsbad, Calif. MAIN OUTCOME MEASURES: For the 2 previous patients, skin samples were sorted directly for V beta 13.1+ T cells, for which the T-cell receptors were sequenced. For the 9 new patients, CD8+ T cells were sorted and their T-cell receptor V beta gene usage measured using semiquantitative polymerase chain reaction with V beta-specific primers. RESULTS: The directly sorted V beta 13.1+ T cells exhibited clonal dominance in both patients. The dominant V beta 13.1 clone in each patient was the same as that found in the previous 2 biopsy specimens for which CD8+ T cells were sorted. Additionally, in 8 of the 9 new patients examined, we again found a preferential usage of V beta 3 and/or V beta 13.1 genes by the lesional CD8+ T cells. CONCLUSIONS: The clonality, which was found in the V beta messages of the sorted CD8+ T cells, accurately reflects the dominance of these clones in the infiltrating T cells. Moreover, the persistence in the same patient of the same clone for as long as 15 months and the overrepresentation of V beta 3 and/or V beta 13.1 in lesional CD8+ T cells in the new patients examined support the pathogenic role of T cells bearing these V betas.

Effect of nerve growth factor on endothelial cell biology: proliferation and adherence molecule expression on human dermal microvascular endothelial cells.

In addition to its effect on the central nervous system, nerve growth factor (NGF) appears to play a key role in the initiation and maintenance of inflammation in many organs. NGF degranulates mast cells, recruits inflammatory cellular infiltrates and activates T cells. Extravascular migration of leukocytes is initially controlled by the interaction of cell surface adhesion molecules of leukocytes and endothelial cells. A marked upregulation of NGF in keratinocytes is also observed in conditions characterized by angiogenesis such as psoriasis and wound healing. In this study we investigated the role of NGF in inflammation by studying its effects on endothelial cell proliferation and intracellular adhesion molecule expression by endothelial cells. The effect of NGF on human dermal microvascular endothelial cell (HDMEC) proliferation was measured using the hexosaminidase assay. ICAM-1 expression on HDMEC was measured by ELISA. The function of ICAM-1 was assessed by adherence of peripheral blood mononuclear cells (PBMC) to HDMEC using 51Cr-labeled PBMC. There was a significant increase in proliferation of HDMEC stimulated with NGF as compared to unstimulated HDMEC (P < 0.001). NGF-neutralizing antibody decreased the mitogenic effect of NGF significantly (P < 0.05). NGF also increased ICAM expression on HDMEC as compared to unstimulated HDMEC (P < 0.05). NGF-neutralizing antibody decreased ICAM expression on NGF-stimulated HDMEC (P < 0.05). The percentage of PBMC adherence was higher in NGF-stimulated HDMEC (P < 0.001). Anti-ICAM antibody decreased PBMC adherence. In the study reported here, the role of NGF in two important aspects of inflammation, i.e. angiogenesis and inflammatory cell recruitment at the site of inflammation, was investigated.

Topical treatment of psoriasis with the topoisomerase inhibitors novobiocin and nalidixic acid: a pilot study.

Our studies in human epidermal keratinocytes as a model system have suggested that the antibiotic topoisomerase II inhibitors, novobiocin and nalidixic acid, may be of value for the treatment of hyperproliferative skin disorders. We have therefore conducted a pilot study of the clinical efficacy of these compounds for the treatment of psoriasis. The compounds were administered topically to psoriatic plaques in seven healthy patients over a period of 6 weeks. Nalidixic acid (2%) or novobiocin (2% or 5%) in methylcellulose were applied twice daily under occlusion, and methylcellulose alone was used as a control. In six of the seven patients, one or both compounds effected somewhat greater improvement than in the control within 3 weeks of treatment.

Intraepidermal nerve fiber expression of calcitonin gene-related peptide, vasoactive intestinal peptide and substance P in psoriasis.

In order to evaluate more fully the role of neuropeptides in the pathogenesis of psoriasis, skin biopsies were obtained from 36 patients with psoriasis to identify substance P (SP), vasoactive intestinal peptide (VIP) and calcitonin gene-related peptide (CGRP). Lesional and nonlesional skin was examined from these biopsies and the results compared with those from biopsies taken from patients with a variety of other inflammatory dermatoses, including lichen planus, lichen simplex chronicus, spongiotic dermatitis, and seborrheic dermatitis. Also studied was a series of nine biopsies taken from patients with no known skin disorders. We found an increase in the number of SP-positive nerve fibers within the epidermis in biopsies from lesional skin of psoriasis patients (8.4 nerves per 3-mm biopsy) compared with nonlesional psoriatic skin (2.6 nerves per 3-mm biopsy) and normal skin (2.0 nerves per 3 mm biopsy). Other inflammatory disorders also demonstrated fewer SP-positive nerves than lesional psoriatic skin; lichen planus (0 nerves per 3 mm biopsy) and lichen simplex chronicus (1.3 nerves per 3 mm biopsy). The difference in SP-positive nerve expression between lesional psoriatic skin and the group comprising nonlesional skin, normal skin, lichen planus, and lichen simplex chronicus attained statistical significance (P < 0.013). SP-positive intraepidermal nerve fibers in lesional psoriatic specimens were fewer than in spongiotic dermatitis (17.4 nerves per 3 mm biopsy). There was no significant difference in numbers of VIP- or CGRP-immunopositive intraepidermal nerve fibers between psoriatic skin and the group comprising all other material tested. However, in five patients with psoriasis, there was a marked increase in the expression of intraepidermal CGRP (up to 10.7 nerves per 3-mm biopsy) and VIP (up to 8.3 nerves per 3-mm biopsy) which was not observed in control groups. These findings suggest that neuropeptides SP, CGRP, and VIP play a role in the pathogenesis of psoriasis.

Psoriasis in the tropics. Epidemiologic, genetic, clinical, and therapeutic aspects.

There is a dearth of information on psoriasis in the tropics. Psoriasis occurs more frequently in northern geographic regions than in tropical climates. Its prevalence varies not only within the ethnic groups of a country but from country to country. A review of published studies on the natural history of psoriasis in the tropics is presented in this article.