Biomedical subjects
Publications and source records attributed to R J Chalmers.
We report a case of Sweet's syndrome associated with hydralazine. The association of Sweet's syndrome with hydralazine, and with the oral contraceptive, minocycline, and trimethoprim/sulphamethoxazole, has been reported previously. We suggest that a drug aetiology should be sought in cases of Sweet's syndrome.
In a previous study, it was shown that the serum levels of type III procollagen aminoterminal peptide (P3NP) were significantly greater in patients receiving methotrexate (MTX) treatment for psoriasis than in untreated control patients with psoriasis. Although levels were highest in patients with hepatic fibrosis and cirrhosis, serum P3NP concentrations in those patients with normal liver histology on light microscopy were also shown to be significantly higher than in controls. In the present study, liver biopsies from 22 such 'normal' patients were examined by electron microscopy, in order to determine whether P3NP levels correlated with ultrastructurally demonstrable fibrosis. Fibrosis in the perisinusoidal space of Disse was present in as many as 82% of biopsies. Although the prevalence of such fibrosis in psoriasis patients who have not received MTX is unknown, the high prevalence of Disse space fibrosis and of raised P3NP in MTX-treated patients suggests that MTX causes subtle liver damage in a majority of treated patients. However, we were unable to show a statistical correlation between P3NP and the degree of Disse space fibrosis.
One hundred and eighty-two liver biopsies were performed over a 10-year period on patients receiving long-term, low-dose, once weekly oral methotrexate (MTX) for severe psoriasis. Forty-nine patients had two or more biopsies during continued treatment and formed the study population for our analysis. The first and last biopsies were compared to determine progression of any histological abnormalities. Liver biopsies were assessed without knowledge of the MTX dose and allocated to one of five groups according to the severity of the histological abnormalities. These were defined as: (1) normal; (2) steatosis alone; (3) inflammation without fibrosis; (4) fibrosis; and (5) cirrhosis. The mean cumulative dose of MTX at the time of the first biopsy was 2743 mg (range 315-10,024), given over 275 weeks (range 26-738). In the interval between the first and last biopsies, patients received, on average, a further 2362 mg (range 390-7155) over 225 weeks (range 60-460). There was improvement in the histological assessment in 12 patients, no change in 28 patients, and deterioration in nine patients. None developed cirrhosis. Liver biopsy findings prompted discontinuation of MTX in four of the 49 patients on long-term treatment. This has to be weighed against the cost and morbidity of the 124 biopsies performed in these patients. Our results suggest that, with careful follow-up, the risk of development or progression of liver disease in patients receiving long-term, low-dose, once weekly oral MTX for psoriasis is modest, and that the requirement for performing routine liver biopsies in these patients needs to be reconsidered.
The benefits of using cyclosporin in organ transplantation to prevent graft rejection outweigh its potential disadvantages, but with the use of low-dose cyclosporin in relatively healthy individuals, such as those with psoriasis, the risk:benefit ratio is altered. The effects of low-dose cyclosporin (< 5 mg/kg body weight) on liver function and serum lipids and lipoproteins were examined in 40 normolipidaemic, normotensive psoriasis patients with normal renal function. After 3 months of treatment, serum cholesterol and bilirubin concentrations and alkaline phosphatase activity increased significantly (p = 0.001), and glomerular filtration rate (GFR) declined from 107 to 96 ml/min/1.73 m2 (p = 0.05). All these values returned to pretreatment levels 3 months after cessation of cyclosporin. In 15 patients in whom lipoproteins were isolated by ultracentrifugation, there was an increase in plasma low-density lipoprotein (LDL) cholesterol (p = 0.05), but very-low-density lipoprotein cholesterol, high-density lipoprotein (HDL) and HDL2 and HDL3 cholesterol concentrations did not change. The increases in serum bilirubin, alkaline phosphatase activity and LDL cholesterol, seen in individuals with normal baseline liver and renal function, which reverted to baseline following cessation of cyclosporin, suggest that cyclosporin-induced hypercholesterolaemia may be due to either decreased biliary excretion of cholesterol or impaired catabolism of LDL.
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To improve the monitoring of patients on low doses of cyclosporine there is a need for new tests of tubular function. N-1 methylnicotinamide (NMM) is an endogenous organic cation that is secreted by the proximal tubule and its clearance can be measured. In 27 patients with psoriasis, serial measurements of NMN clearance, plasma aldosterone, plasma chloride, bicarbonate, and magnesium were compared with changes in the radionuclide measurement of glomerular filtration rate and renal blood flow before, during, and after a 3-month course of low-dose cyclosporine (< 5 mg/kg/d). N-1 methylnicotinamide clearance decreased significantly with cyclosporine only (2.5 mg/kg/d, n = 10, P < 0.01). Recovery of NMN clearance lagged behind that of glomerular filtration rate and renal blood flow. Serum magnesium decreased significantly on cyclosporine (2.5 mg/kg, n = 10, P < 0.01; 5 mg/kg, n = 9, P < 0.0001). In the whole group, plasma potassium increased significantly (n = 27, P < 0.02) and plasma aldosterone was inappropriately low. Low doses of cyclosporine in psoriasis cause a reduced clearance of NMN, hypomagnesemia, and a variable hyperchloremic acidosis. Nifedipine may alter these biochemical variables without necessarily improving renal hemodynamics. The delayed recovery of NMN clearance in comparison with renal haemodynamic measurements following cyclosporine therapy suggests that this noninvasive test of tubular function may be a marker of persisting cyclosporine nephrotoxicity and that it should be evaluated further.
1. Cyclosporin A, an immunosuppressive drug used to treat psoriasis, stimulates renal synthesis of 1,25-dihydroxyvitamin D in rats. 1,25-Dihydroxyvitamin D can also reduce the activity of psoriasis, and in the present study we have examined the possibility that cyclosporin A mediates some of its actions in psoriasis by renal or extra-renal production of 1,25-dihydroxyvitamin D. 2. Treatment of 12 psoriatic patients with cyclosporin A (5 mg day-1 kg-1) for 3 months significantly improved the psoriasis activity and severity index and reduced glomerular filtration rate, but serum 1,25-dihydroxyvitamin D levels were not changed. However, 1-3 months after stopping cyclosporin A treatment, an increase in the psoriasis activity and severity index score was accompanied by a small, but significant, increase in serum 1,25-dihydroxyvitamin D concentration. Plasma 1,25-dihydroxyvitamin D levels in rats gavaged with cyclosporin A (15 mg day-1 kg-1 for 2 weeks) were significantly increased compared with controls, but a lower dose of cyclosporin A (2.4 mg day-1 kg-1) had no effect. Renal 25-hydroxyvitamin D-24-hydroxylase activity in rat kidney homogenates was not different between control and cyclosporin A-treated rats. Renal 25-hydroxyvitamin D-1 alpha-hydroxylase activity was not detectable in these homogenates. Extra-renal production of 1,25-dihydroxyvitamin D by activated macrophages isolated from the synovial fluid of patients with inflammatory arthritis was reduced after incubation with cyclosporin A (0.1-10 mumol/l) for 30 h or 5 days.(ABSTRACT TRUNCATED AT 250 WORDS)
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It is unclear whether cyclosporin A (CsA) alters the synthesis of 1,25-dihydroxyvitamin D3 [1,25(OH)2D] by the normal human kidney. Serial changes in 1,25(OH)2D, parathyroid hormone (PTH), GFR and renal blood flow were compared in 14 patients with psoriasis who were being treated with less than 5 mg/kg/day of cyclosporin for 3 months. GFR fell significantly although there were no significant changes in serum 1,25(OH)2D, 25-hydroxyvitamin D or PTH. Absolute values for GFR and PTH were negatively correlated (rP = -0.54; p < 0.001) as were the changes in GFR and PTH observed during CsA therapy (rP = -0.73; p < 0.05). The significant fall in serum magnesium was not significantly correlated with changes in PTH. The close relationship between changes in GFR and PTH suggests that a reduction of GFR within the normal range is enough to stimulate production of PTH. CsA does not appear to stimulate the synthesis of 1,25(OH)2D3 in man.
Abnormalities of the renin-angiotensin system after low-dose cyclosporin (5 mg/kg/day or less) have not been adequately defined in patients with normal kidneys. 27 patients with psoriasis were assessed before starting cyclosporin, after three months of cyclosporin (5 mg/kg/day or less) and then finally three months after finishing cyclosporin. On each occasion plasma renin activity (PRA), aldosterone, angiotensin II and atrial natriuretic peptide (ANP) were measured together with total renal blood flow (RBF), GFR and filtration fraction (FF) following an i.v. bolus injection of Tc-99m DTPA. Significant renal hemodynamic toxicity was defined as > 25% fall in RBF or > 20% fall in GFR. Using these criteria we identified 12 patients with hemodynamic toxicity (Group A) and 15 patients whose GFR and RBF did not fall significantly (Group B). In Group A a significant fall in GFR (p < 0.001) and reduction in renal blood flow (p < 0.04) were associated with significant rises in both ambulant and recumbent angiotensin II (p < 0.0005). PRA, aldosterone and ANP did not significantly alter. GFR partially recovered after withdrawal of cyclosporin although RBF remained significantly lower compared to initial values. In Group B there was no significant change in GFR or RBF although there was a reversible fall in FF (p < 0.02). There were no significant differences in angiotensin II, PRA, aldosterone or ANP. Circulating angiotensin II rises in patients who develop cyclosporin nephrotoxicity and may be responsible for mediating the hemodynamic effects.
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AIM: To determine the effects of a three month course of low dose cyclosporin on the expression of epidermal cell adhesion molecules. METHODS: Eighteen patients with psoriasis were treated for 12 weeks with either 2.5 or 5 mg/kg/day of oral cyclosporin. Biopsy specimens taken from skin before, during, and after cyclosporin treatment were stained immunohistochemically for CD 54 (ICAM-1), CD 29 (beta-1 integrins), and CD18 (beta-2 integrins). RESULTS: There was a highly significant (p < 0.01) clinical response after 12 weeks of cyclosporin as assessed by the Psoriasis Area and Severity Index (PASI) score. The staining of CD 29 on keratinocytes of affected and unaffected psoriatic skin was not affected by cyclosporin. Epidermal CD54 was variably expressed in active psoriatic plaques and changed unpredictably after cyclosporin (p = NS). Staining for CD18 on large epidermal dendritic cells was reduced after cyclosporin (p < 0.02). The expression of CD18 by large epidermal dendritic cells during treatment correlated strongly with the PASI score at that time and one month after stopping cyclosporin (p < 0.02). CONCLUSIONS: Persistence of epidermal staining for CD 54 in psoriasis is compatible with a good clinical response to cyclosporin. Residual staining for CD 18 on large epidermal dendritic cells may be a useful marker for early clinical relapse.
Ten patients with psoriasis received a 3-month course of cyclosporin (2.5 mg/kg/day) followed by a 3-month washout period, before commencing a 3-month course of cyclosporin and nifedipine SR 20 mg b.d. Serial haemodynamic and biochemical measurements were performed before, during, and after treatment. Total renal blood flow (RBF) was measured following an intravenous injection of [99mTc]-DTPA based on a renographic analysis of the first-pass effect in the kidneys, and GFR was estimated from the subsequent clearance of this radiotracer. A significant individual change in RBF or GFR was taken as 25% and 20% respectively. Simultaneous assays of the circulating vasoactive mediators renin, aldosterone, angiotensin II, and atrial natriuretic peptide were performed. Two patients withdrew from the study because they could not tolerate nifedipine, leaving eight for complete analysis. The significant reductions in RBF and GFR which occurred on cyclosporin alone (P < 0.05; ANOVA) did not occur with added nifedipine. Four months after this second course, RBF and GFR had recovered. The response to nifedipine was, however, variable and unpredictable. Of the four patients to show a significant decline in GFR on cyclosporin alone, only two showed a significant improvement on the combined therapy. Of the six patients who showed a significant decline in RBF on cyclosporin alone, only four showed benefit from the added nifedipine. Nifedipine suppresses the increase in blood pressure which occurred on cyclosporin alone. The circulating concentration of angiotensin II was significantly less on cyclosporin and nifedipine than on cyclosporin alone (P < 0.05; Student's t test).(ABSTRACT TRUNCATED AT 250 WORDS)
Qualitative and quantitative assessment of integrin expression by dermal nerves was made by an avidin-biotin immunoperoxidase method on snap-frozen biopsies from affected psoriatic skin, and skin from normal control subjects with no history of skin disease. Nerves expressed alpha 1, alpha 2, alpha 3, alpha 6, beta 1 and beta 4 integrin subunits, and perineural sheaths in the mid-dermis also expressed these subunits, with the exception of alpha 2. There were more upper dermal nerve segments expressing alpha 1 integrin compared with other integrins both in controls and in psoriatic skin. The greater number of nerves expressing alpha 1 integrin compared with other integrins may be due to anatomical or functional differences between groups of nerves. There were significantly more nerves expressing alpha 1, alpha 2, alpha 3, alpha 6 and beta 4 integrins in psoriatic skin compared with control skin. This generalized increase may indicate a secondary trophic effect on all nerves rather than a specific increase in one type of nerve. However, the expression of alpha 2 integrin may be significant in the pathogenesis of the psoriatic plaque, in that it was barely detectable in the normal site-matched biopsies, but much greater in psoriatic plaques. The study of the expression of adhesion molecules by neurones in psoriasis offers a new avenue for investigation of the role of neuronal hypertrophy in the initiation and maintenance of psoriatic plaques.
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BACKGROUND AND DESIGN: Although the association between streptococcal infection and guttate psoriasis is well known, to date there has been little information on whether only limited groups and/or serotypes of beta-hemolytic streptococci are involved. One hundred eleven patients with a sudden onset or deterioration of psoriasis were investigated for evidence of streptococcal infection. Of these patients, 34 had acute guttate psoriasis, 30 had a guttate flare of chronic psoriasis, 37 had chronic plaque psoriasis, and 10 had other types of psoriasis. RESULTS: Serologic evidence of recent streptococcal infection was present in 19 (58%) of 33 patients with acute guttate psoriasis compared with seven (26%) of 27 patients with guttate exacerbations of chronic psoriasis. Streptococcus pyogenes was isolated from 19 (17%) of all 111 patients (9 [26%] of 34 with acute guttate psoriasis, four [13%] of 30 with guttate exacerbations of chronic psoriasis, and five [14%] of 37 patients with chronic psoriasis) compared with seven (7%) of 101 of a control population of patients being seen for treatment of viral warts. Other beta-hemolytic streptococci were found with equal frequency in the study and control populations. Thirteen isolates of 10 different streptococcal serotypes were obtained from the 64 patients with guttate psoriasis. These serotypes were similar in distribution and prevalence to those present in the local community. CONCLUSIONS: This study confirms the strong association between prior infection with S pyogenes and guttate psoriasis but suggests that the ability to trigger guttate psoriasis is not serotype specific.