Knud Kragballe

Methotrexate induced liver cirrhosis Studies including serial liver biopsies during continued treatment

Seven hundred and sixty‐four liver biopsies were performed in 328 psoriatics on treatment with methotrexate or being considered for systemic treatment either with methotrexate or with psoralens and long‐wave ultraviolet light. The diagnosis of cirrhosis was established histologically in twenty‐one patients. Two patients had cirrhosis in their premethotrexate biopsy and were not given methotrexate. The remainder all showed no signs of cirrhosis or fibrosis in their premethotrexate biopsy. The difference between the methotrexate treated psoriatics and the premethotrexate group was highly significant. Among thirty‐nine patients treated for more than 5 years, ten developed cirrhosis (25.6%). Almost all patients were on a divided dose intermittent oral dosage schedule. The cumulative dose of methotrexate, when cirrhosis was first found, ranged from 590 to 8105 mg, with an average dosage of 2200 mg. Other factors contributing to cirrhosis in this study seem to be previous treatment with arsenic, a previous intake of alcohol, and lowered renal function.

Efficacy and safety of a new combination of calcipotriol and betamethasone dipropionate (once or twice daily) compared to calcipotriol (twice daily) in the treatment of psoriasis vulgaris: a randomized, double-blind, vehicle-controlled clinical trial

Summary  Background Calcipotriol and betamethasone dipropionate are both widely used, effective treatments for psoriasis. Vitamin D analogues and topical corticosteroids have different mechanisms of action in the treatment of psoriasis. A new vehicle has been developed in order to contain both calcipotriol (50 µg g−1) and betamethasone dipropionate (0·5 mg g−1) in an ointment form. By using calcipotriol and a corticosteroid together, greater efficacy may be achieved than by using either compound alone.

Comparative effects of calcipotriol solution (50 μg/ml) and betamethasone 17-valerate solution (1 mg/ml) in the treatment of scalp psoriasis

The efficacy, tolerability and safety of calcipotriol solution and betamethasone 17‐valerate solution were compared in a multicentre, prospective, randomized, double‐blind, parallel group study. Four hundred and seventy‐four patients with scalp psoriasis were recruited from six European countries and Canada. Following a 2‐week washout period, either calcipotriol solution (50 μg/ml) or betamethasone 17‐valerate solution (1 mg/ml) was applied twice daily for 4 weeks. After this time, patients who required no further active treatment were observed for relapse. Retreatment with calcipotriol was offered to those patients who relapsed, and who were originally in the calcipotriol‐treated group.

Heterogeneous distribution of lipoxygenase products in psoriatic skin lesions

SummarySeveral biologically active lipoxygenase products or arachidonic acid (AA) have been demonstrated in psoriatic skin lesions. The purpose of the present study was to determine the amounts of the different lipoxygenase products simultaneously in psoriatic skin. Slices of psoriatic skin were obtained at different levels with a keratome. Extracted lipids were identified by high performance liquid chromatography, UV-absorption spectrum, radioimmunoassay, and chemokinesis. Leukotriene B4 (LTB4), and 12- and 15-hydroxy-eicosatetraenoic acid (HETE) were detected in most psoriatic lesions. However, there was a remarkable variation from lesion to lesion. The biopsy specimens contained: 276.2±126.0 pg/g wet tissue of LTB4, 3,130.0±2,898.0 ng/g wet tissue of 12-HETE, and 3,633.0±1,692.0 ng/g wet tissue of 15-HETE. No correlation was found between the levels of the different lipoxygenase products. The content of each of the identified lipoxygenase products was higher in the superficial part of the biopsy specimen consisting of approximately two-thirds of the epidermis plus papillary dermis than in the lower part consisting of approximately one-third of the epidermis plus some reticular dermis. Also, there was a great variation from one anatomical region to another within the same patient. Because these lipoxygenase products possess different biological activities, the variation in their occurrence may be important for understanding their potential role in psoriasis. To determine which lipoxygenase products may be of pathogenic importance, analysis of early psoriatic lesions is warranted.

Morphologic renal changes during cyclosporine treatment of psoriasis: Studies on pretreatment and posttreatment kidney biopsy specimens

BACKGROUND Because of concern about long-term renal toxicity from low-dose cyclosporine therapy, we studied kidney biopsy specimens in psoriasis patients treated with this drug. OBJECTIVE The purpose of the study was to investigate whether any morphologic changes appear after approximately 1 year of treatment. METHODS Pretreatment and posttreatment renal biopsy specimens were performed in 12 psoriasis patients treated with cyclosporine in dosages from 1.8 to 6 mg/kg/day for 6 to 18 months. RESULTS The study disclosed a slight but significant increase in interstitial fibrous tissue, which negatively correlated with creatinine clearance. The findings were similar to those described in patients receiving higher dosages of cyclosporine. CONCLUSION The clinical relevance of these so-far minor changes is unknown and does not exclude the use of cyclosporine in severe psoriasis; however, they should be taken into consideration in so-called low-dose therapy.

Lysophosphatidylcholine: a chemoattractant to human T lymphocytes.

Various cell stimuli act through activation of phospholipase A2 resulting in the release of arachidonic acid, the precursor of eicosanoids, from the sn-2 position of cell membrane phospholipids. A byproduct of phospholipase A2 activity is the lysophospholipids which have been found to potentiate T-lymphocyte activation. The purpose of the present study was to determine whether the various lysophospholipids modulate the migration of peripheral normal human T lymphocytes in vitro. It was found that lysophosphatidylcholine (lysoPC) induced T-lymphocyte migration in the concentration range 10−7 to 10−4M with a maximum at 10−6M (mean chemotactic index, 2.06). The migration was due to chemotaxis rather than chemokinesis. In contrast, lysophosphatidylethanolamine (lysoPE) and lysophosphatidylinositol (lysoPI) did not exhibit chemotactic properties towards T lymphocytes. Further studies showed that the length of the fatty acids in the sn-1 position as well as the presence of double bonds modulated the chemotactic ability. The lysoPC compound with the highest chemotactic activity was lysoPC;1-palmitoyl (C=16∶0). The results demonstrated that lysoPC, a phospholipase A2-generated hydrolysis product of phosphatidylcholine, induced T-lymphocyte chemotaxis in vitro. Because phosphatidylcholine is the major phospholipid in the epidermis, the activation of phospholipase A2 may result in the release of lysoPC in concentrations capable of inducing migration of T lymphocytes into the epidermis.

Supplementation with evening primrose oil in atopic dermatitis: Effect on fatty acids in neutrophils and epidermis

We investigated the effect of oral supplementation with evening primrose oil, containing 72% linoleic acid (18∶2n−6) and 10% γ-linolenic acid (18∶3n−6), on the epidermal and neutrophil phospholipid fatty acid composition in 15 patients with atopic dermatitis (AD). Three different dose levels, 4, 8 and 12 capsules per day containing 0.5 g oil, were given to three groups of patients. The only n−6 fatty acid showing a significant (p<0.05) dose-related increase was dihomo-γ-linolenic acid (20∶3n−6) in neutrophil phospholipids. The highest dose increased dihomo-γ-linolenic acid by 45% in neutrophil phospholipids, by 46% in lesion-free epidermal phosphatidylcholine, and by 15% in lesion-free epidermal phosphatidylethanolamine. In both lesional and lesion-free epidermis, supplementation resulted in a rise in the ratio between n−6 and monounsaturated fatty acids, reaching significance (p<0.05) in lesional epidermis. This study shows that moderate and favorable fatty acid changes can be obtained in the epidermis of AD patients, when given 6 g per day of oil rich in n−6 fatty acids. The abnormal lipid and fatty acid pattern of the atopic epidermis may be involved in the pathogenesis of the disease, and should therefore be the target for future therapeutic approaches with fatty acid supplements.

Histiocytosis X--an immune deficiency disease? Studies on antibody-dependent monocyte-mediated cytotoxicity.

Six children with histiocytosis X, all in clinical remission, were investigated for antibody‐dependent cytotoxicity mediated by monocytes and neutrophils. Monocytes demonstrated a reduced cytotoxicity and a normal Fc receptor activity. ludged by light microscopy the monocytes were normal. Preincubation with the patients serum did not influence the cytotoxicity of normal monocytes. Neutrophils from patients with histiocytosis X showed a normal cytotoxic activity. We postulate a functional defect of the mononuclear phagocyte system in histiocytosis X.

Colchicine in generalized pustular psoriasis: Clinical response and antibody-dependent cytotoxicity by monocytes and neutrophils

SummaryFour patients with generalized pustular psoriasis were treated with oral colchicine in an open study. Three of the four patients went into total remission within two weeks while receiving colchicine. The monocyte- and neutrophil function was assessed by studying antibody-dependent cytotoxicity. Increased values observed before treatment decreased during treatment. The patient who responded poorest clinically also showed less changes in monocyte- and neutrophil antibody-dependent cytotoxicity.

Safety and efficacy of combined high-dose treatment with calcipotriol ointment and solution in patients with psoriasis.

Background: In the vast majority of psoriatic patients, psoriatic lesions are localised on the body as well as on the scalp. Therefore, safety data on the combined use of calcipotriol in lotion and calcipotriol in ointment are needed. Objective: This study investigated the effect of high-dose treatment with a combination of calcipotriol ointment and scalp solution on calcium metabolism, indices of bone turnover and PASI in patients with extensive psoriasis. Methods: Following a 2-week wash-out period, 88 patients were randomised to 4 weeks of treatment with either calcipotriol ointment/scalp solution (80–100 g/week and 30–50 ml/week, respectively; n = 41) or with a dithranol/tar regimen (n = 47). Patients were seen at weeks 1, 2 and 4 during treatment and 1 week following cessation of treatment. Results: No significant differences at the end of treatment were found between the 2 groups with respect to 24-hour urinary excretion of calcium (expressed as calcium/creatinine ratio), phosphate or pyridinoline, serum concentrations of calcium (albumin corrected), creatinine, phosphate, parathyroid hormone, 25-hydroxyvitamin D3, 1,25-dihydroxyvitamin D3, osteocalcin, alkaline phosphatase (total and bone-specific iso-enzymes) or 1-collagen telopeptide. At the end of treatment, the psoriasis area and severity index had decreased by 57.4% in the calcipotriol group and by 36.1% in the dithranol/tar group (p = 0.004). Investigators’ and patients’ assessments of overall efficacy also favoured treatment with calcipotriol (p < 0.001). Conclusion: The combined use of calcipotriol ointment/scalp solution did not affect the indices of calcium metabolism or bone turnover and was significantly more effective than dithranol/tar in reducing disease severity and extent in patients with extensive psoriasis.