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Pilot studies with cyclosporin A (CsA, Sandimmun) in more than 100 patients with Crohn's disease have shown that CsA was more efficient in chronic active disease than in acute attacks. The onset of effect was rapid, usually within the first month, but most patients relapsed during the weeks following the interruption of CsA treatment. These findings were confirmed by a placebo-controlled study (parallel groups) in 71 patients, in whom the rate of improvement at 3 months was 61% on CsA and 33% on placebo. Promising results have also been reported after short-term use of intravenous CsA in severe acute ulcerative colitis. Further controlled trials are still ongoing in order to ascertain the efficacy of CsA administered according to the current safety guidelines (dose less than or equal to 5 mg/kg/day) for a period of one year in patients with chronic active Crohn's disease.

Remission from insulin dependency in insulin-treated recent-onset type I (insulin-dependent) diabetic patients can result from a partial recovery of insulin secretion, an improvement in tissue sensitivity to insulin, or both. The same hypothesis must be analyzed when remission occurs in cyclosporin A (CsA)-treated patients. In this study, plasma C-peptide levels were serially measured in the basal state and after stimulation in 219 recent-onset type I diabetic patients; 129 received CsA, and all patients were similarly monitored and insulin treated. The results were analyzed in view of the occurrence of remission. Remission was defined as good metabolic control in the absence of hypoglycemic treatment for greater than or equal to 1 mo. Remission occurred in 44% of the CsA-treated group and lasted for mean +/- SE 10.0 +/- 0.9 mo vs. 21.6% in the non-CsA-treated group with a duration of 4.4 +/- 0.8 mo. Plasma C-peptide levels were initially dramatically lower than normal in both groups in the basal and stimulated states. C-peptide levels increased significantly later, at 3 and 6 mo, in both groups. C-peptide values were proportional to the rates of remission in both groups. In the non-CsA-treated group, C-peptide levels later decreased, and these patients inexorably relapsed to insulin dependency. In contrast, in the CsA-treated group, the initial recovery in insulin secretory capacity was maintained over the 18-24 mo of the study. Furthermore, higher remission rates and longer-lasting remission were obtained in patients who reached higher C-peptide levels at the 3rd mo of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

The aim of this study was to determine which candidates were suitable for immunotherapy among adult insulin dependent diabetic patients of recent onset. A statistical analysis was performed using the results of a multicentre randomized trial of cyclosporine versus placebo after nine months of treatment. When the baseline characteristics of the patients in remission were compared with those not in remission, there was no difference observed either in initial residual beta-cell function (glucagon stimulated C-peptide level), or in immunological markers (T4 and T8 lymphocytes counts, Interleukin 2). The parameters showing the most difference were, in addition to treatment group, the duration of diabetes symptoms and body mass index at inclusion, and the HLA-DR phenotype. This was confirmed using a logistic regression analysis, in which these variables were found to be significantly related to remission. The probability of remission in each individual patient was then calculated using these variables in the mathematical function provided by the logistic model. Ninety eight out of 110 patients were correctly classified using this method. In addition, it must be noted that only subjects adequately treated by cyclosporine were still in complete remission after a one year follow-up. Conversely, it appeared that immunosuppression in subjects having a predicted probability of remission lower than 0.35 using the mathematical function, and being non-DR3, non-DR4 has to be avoided. These results will be useful in optimizing the recruitment of patients in on-going or future trials of immunotherapy in early diabetes.

The efficacy of cyclosporin A (CyA) in severe psoriasis was analysed in 457 adult patients included in five European multicentre dose-finding studies. Initial CyA doses were 1.25 mg/kg/day in 33 patients, 2.5-3 mg/kg/day in 285 and 5 mg/kg/day in 139. After 3 months of treatment, the reduction of the Psoriasis Area and Severity Index (PASI) score was 35 +/- 6% with 1.25 mg/kg/day of CyA, 57 +/- 2% with 2.5 mg or 3 mg/kg/day and 86 +/- 2% with 5 mg/kg/day (P less than 0.001). The rates of success, defined by a PASI score reduction greater than or equal to 75% or a score less than or equal to 8, were 24%, 52% and 88%, respectively. There were no differences in age, initial severity or duration of psoriasis. The improvement was maintained for 9 months or more in the majority of patients receiving continuous CyA therapy.

Cyclosporin A (CyA) trough (pre-dose) levels were measured in whole blood with a radioimmunoassay (RIA) using specific monoclonal antibody in 193 patients receiving CyA for the treatment of psoriasis. These patients received either CyA 2.5 mg/kg/day (n = 134) or 5 mg/kg/day (n = 59). In addition, a subgroup of 94 patients also had CyA trough levels measured using a non-specific polyclonal RIA. Within each CyA dose group, no difference was detected between mean CyA trough levels in relation to success or failure nor to the presence or absence of renal dysfunction with the use of either the specific or non-specific RIA. Based on the experience in transplantation, CyA thresholds of 100 and 200 ng/ml (specific) were selected for the assessment of efficacy and renal dysfunction. The success rate was higher by 10-15% when the CyA level was above, rather than below, 100 ng/ml in both the CyA 2.5 mg and 5 mg/kg/day groups. A slightly increased incidence of renal dysfunction was only found in the 5 mg/kg/day group when the CyA level was above 200 ng/ml. Because of its low predictive value, measurement of the level of CyA was not particularly useful for monitoring patients with psoriasis treated with low-dose CyA.

Serum creatinine and blood pressure were measured in patients who had severe psoriasis and who were treated with cyclosporin A (CyA) in initial doses of 1.25 mg (n = 34), 2.5 or 3 mg (n = 314), or 5 (n = 215) mg/kg/day. Of the 563 patients involved, 201 were treated for more than 3 months, and 100 received CyA continuously for 12 months or more. Sixty-eight additional patients were included as controls and received placebo (n = 42) or etretinate (n = 26). At doses of 2.5 and 5 mg/kg/day, CyA induced slight but significant dose-dependent increases in serum creatinine and blood pressure. Creatinine increases of 50% or more over baseline values were detected in 4% of the patients receiving 2.5 mg/kg/day and in 13% of those receiving 5 mg/kg/day. After an initial rise during the first weeks of treatment, mean creatinine level remained stable over 1 year provided that the CyA dose was reduced whenever creatinine levels increased by 30% or more over baseline. The incidence of hypertension was 10.6% and did not vary whether the CyA dose was 2.5 or 5 mg/kg/day. The first elevated blood pressures were recorded early after starting CyA therapy (median: 1 month). However, 3 months after stopping treatment, the increases in creatinine as well as in blood pressure were reversible and the levels did not significantly differ from baseline values.

Several lines of evidence suggest that phagocyte-mediated oxidative processes are involved in damage to pancreatic islet cells of Type I insulin-dependent diabetes mellitus (IDDM). This hypothesis, however, has not yet been explored at the clinical onset of IDDM. Similarly, the possibility that cyclosporine A (Cy-A) might exert a selective influence on these phagocyte-mediated oxidative reactions has also not yet been investigated as compared to a placebo. The present study tested both hypotheses in 32 patients with recently diagnosed IDDM who were part of the recent French multicenter randomized therapeutic trial of Cy-A. The production of reactive oxygen intermediates (ROI) by circulating polymorphonuclear (PMN) and mononuclear (MN) phagocytes was determined by luminol-dependent chemiluminescence (CL), both directly within microamounts of whole blood and in purified PMN or MN phagocyte suspensions. Lastly, CL production was measured in the absence (resting CL) and the presence of a panel of particular and soluble phagocyte membrane-stimulating agents. We found that on entry into the trial, i.e. within less than 2 months of the clinical onset of IDDM, patients had normal whole blood CL production in the absence of a stimulating agent and upon phagocytic challenge with latex or opsonised zymosan particles. By contrast, whole blood CL responses to soluble stimuli such as phorbol myristate acetate (PMA), concanavalin A (Con-A) and F Met-Leu-Phe (FMLP) were significantly higher than in the control group of 52 normal subjects (P less than 0.01). In purified PMN and MN phagocyte suspensions, both resting and stimulated CL productions were normal, regardless of the type of stimulating agent. After 3 months of treatment, whole blood CL responses to Con-A and FMLP returned to almost normal levels in patients treated with Cy-A (15 cases) but not in those receiving the placebo (17 cases); PMA-induced CL responses were also decreased, but this was found in both groups of patients. In purified phagocyte suspensions we detected no effect of Cy-A on PMN, whereas MN phagocytes from Cy-A-treated patients showed reduced CL responses to FMLP but not to other stimuli. Altogether, these results demonstrate for the first time that the capacity of circulating PMN and MN phagocytes to generate ROI is normal at the clinical onset of IDDM and suggest that circulating substances increase oxidative responses to soluble, but not particulate, stimuli.(ABSTRACT TRUNCATED AT 400 WORDS)

Dose-dependent hypertrichosis is a common dermatological side-effect affecting the majority of patients treated with cyclosporine A (CSA). Previous studies have not demonstrated the influence of CSA on specific sex hormone levels. The aim of this study is to investigate whether CSA increases the activity of 5 alpha-reductase, an enzyme which transforms androgens into dihydrotestosterone in peripheral tissues. The metabolite which best reflects this activity is 5 alpha-androstane-3 alpha,17 beta-diol glucuronide (Adiol G). The study was carried out on 49 insulin-dependent diabetes patients participating in the double-blind "Cyclosporine-Diabète-France" clinical trial, of which 28 were treated with CSA (16 males and 12 females), and 21 received only placebo (10 males and 11 females). All patients underwent extensive clinical and laboratory evaluations prior to and during the present study. In addition to Adiol G, testosterone (T), dehydroepiandrosterone sulfate (DHEA S) and sex hormone-binding globulin (SHBG) were assayed. Levels of Adiol G increased significantly in CSA-treated groups: males, 11.86 +/- 2.58 vs 7.83 +/- 2.30 nmol/l; females, 4.48 +/- 2.70 vs 2.10 +/- 1.22 nmol/l; P less than 0.02 (comparison of means). There were no significant differences in this parameter before and during treatment in either the male or female placebo groups (paired t-test). During the treatment period, T, DHEA S, SHBG and the T/SHBG ratio did not significantly change with respect to their baseline values in any of the groups studied (comparison of means). Comparison (using paired t-test) showed a significant increase of DHEA S in CSA-treated groups: males, delta = 3.08 +/- 3.33 nmol/l, P less than 0.01; females, delta = 0.98 +/- 1.13 nmol/l, P less than 0.05. In conclusion, it is possible that CSA induces hypertrichosis or hirsutism by increasing 5 alpha-reductase activity in peripheral tissues. Nevertheless the role of increased DHEA S as a possible Adiol G precursor cannot be excluded.

Cyclosporin 5-10 mg/kg daily was given for 2-8 months to twelve recently diagnosed type 1 diabetics from a mean of 49 +/- SE 14 days after the start of insulin therapy, which was regulated to give near-normal blood glucose and haemoglobin A1c values. Mean insulin dosage dropped from 46 +/- 5 U/day before cyclosporin treatment to 16 +/- 4 U/day by the 7th month. Four patients had a complete remission and the insulin needs of four more were cut by half. The remaining four did not have remissions. Initial basal and glucagon-stimulated C peptide concentrations were higher in those who went into remission than in those who did not; they rose during cyclosporin treatment in the former but not in the latter. OKT4+ lymphocyte functions were suppressed in all patients and OKT4/OKT8 ratios declined. Anti-beta-cell autoimmunity, as indicated by lymphocyte-induced inhibition of insulin release from mouse islet cells, declined in all patients who went into remission. No consistent trend was observed for anti-islet cell antibodies. In forty-four similar, but non-randomised, recently diagnosed diabetics treated with insulin alone, the incidence of remission was 6%.

In a double-blind trial 122 patients aged 15-40 years with insulin-dependent diabetes of recent onset were randomly assigned to cyclosporin 7.5 mg/kg per day or placebo. At the sixth month 25.4% of the cyclosporin group and 18.6% of the placebo group were in complete remission (not a significant difference). Treatment was continued in those patients with complete or partial remission (insulin requirement less than 0.25 U/kg per day) and 106 patients were followed to nine months, at which stage 24.1% of the original cyclosporin group and 5.8% of the original placebo group were in complete remission (p less than 0.01). For those patients whose whole-blood trough cyclosporin levels in the first three months averaged 300 ng/ml or more, the rates of complete remission at six and nine months were 37.5% and 37%. The rates of partial remission were also higher in the cyclosporin group and at six months the rate of complete or partial remission was 46% in the whole cyclosporin group and 65.6% in those with an average blood level exceeding 300 ng/ml in the first three months, versus 28.8% in the placebo group. The principal side-effect of cyclosporin was a modest and reversible increase in plasma creatinine. These results indicate that cyclosporin promotes the remission of type I diabetes and suggest the need for new controlled protocols aimed at evaluating the length of the effect and selecting the best drug regimen.

Seventy patients aged 15-40 yr with recent-onset insulin-dependent diabetes mellitus (IDDM) were entered into a double-blind trial, in which they were randomly assigned to either cyclosporin (7.5 mg.kg-1.day-1) or to placebo and were monitored for 1 yr for various phenotypic and functional parameters of T-lymphocyte-mediated immunity. Before treatment, the proportions of total T-lymphocytes (CD3+) and helper-inducer T-lymphocytes (CD4+) were normal, whereas significantly decreased values of suppressor/cytotoxic T-lymphocytes (CD8+), as compared with normal controls, were found in 31% of the patients. The interleukin 2 (IL-2)-receptor expression was significantly increased in IDDM patients compared with control subjects, although the single values were low: patients, 2.02 +/- 0.41%; controls, 0.88 +/- 0.25% (means +/- SE). Circulating levels of soluble IL-2 receptor were also significantly increased in IDDM patients compared with controls: patients, 372.3 +/- 25.4 U/ml; controls, 235.5 +/- 29.3 U/ml (means +/- SE). However, no major abnormalities were found in mitogen (phytohemagglutinin)-induced IL-2 production, cell proliferation, or IL-2-receptor expression. After 6 mo of cyclosporin treatment, no major modifications of any of the parameters analyzed were noted, even in patients who had cyclosporin blood trough levels greater than 300 ng/ml, i.e., the threshold value associated with clinical efficacy. One explanation for the absence of a major effect of cyclosporin, in contrast with its demonstrated clinical effectiveness, is the reversibility of its activity. Our results preclude the use of the described tests to reliably monitor IDDM patients undergoing immunosuppressive therapy.

Increasingly, experimental results are underlining the role played by autoimmune mechanisms in the pathogenesis of type I insulin-dependent diabetes mellitus (IDDM). It has appeared logical to attempt to preclude the onset of IDDM by suppressing immune responses, but trials using steroids or azathioprine were unequivocal. Subsequently, a Canadian and a French group performed pilot studies to assay a new immunosuppressive drug, cyclosporine A (CyA) in human diabetes (Stiller et al., 1984; Assan et al., 1985). However, further testing is required to evaluate and confirm its potential benefits and possible risks.

Cyclosporine is an 11 aminoacid cyclic peptide of fungal origin endowed with potent immunosuppressive activity. Unlike the conventional immunosuppressants, cyclosporine does not interfere with DNA metabolism, but it selectively and reversibly inhibits lymphocyte T-helper activation by inhibiting the production of interleukin-2 which plays a role in immune response development. Cyclosporine has little effect on lymphocytes B and does not modify the production of antibodies when it is in progress. The drug is effective in preventing spontaneous or autoantigen-induced auto-immune diseases in animals. The best studied models are experimental allergic encephalomyelitis, uveitis in the rat and spontaneous diabetes of BB rats. However, cyclosporine has no effect on diseases exclusively due to the pathogenic action of antibodies, such as spontaneous thyroiditis of the obese chicken. It is also possible to obtain a curative effect, this type of model being nearer to therapeutic conditions in humans than the previous models.

Thirteen patients with severe steroid-resistant or steroid-dependent forms of systemic lupus erythematosus were treated with cyclosporine (average dose 5 mg/kg/d) for an average period of 12 months. In eight patients the disease activity decreased, as substantiated by the reduction in the amount of steroid required to control the clinical manifestations. Interruption of cyclosporine treatment was associated with relapse or worsening of disease in five subjects. These favorable clinical results occurred in the absence of changes in the levels of antinuclear, anti-double-stranded deoxyribonucleic acid autoantibodies or plasma complement components; plasma IgG concentration increased significantly. Six patients had signs of moderate cyclosporine nephrotoxicity that disappeared when the administration of the drug was discontinued. Hypertension was the most serious side effect observed in eight subjects; in every case it was controlled by antihypertensive medicine. These data indicate that cyclosporine may be beneficial in the treatment of some patients with severe forms of systemic lupus erythematosus.

Anti-beta-cell-specific cell-mediated immunity was studied over a 12-mo period in 65 recently diagnosed diabetic patients randomly receiving either cyclosporin or placebo. Anti-beta-cell cellular immunity was assessed by an in vitro test based on the inhibition of insulin release from cultured rat islet cells by patients' mononuclear cells. This beta-cell-suppressive effect disappeared in cyclosporin A-treated patients within 1 mo and did not reappear during 12 mo of follow-up. Conversely, the suppressive effect persisted unchanged in placebo-treated patients during 12 mo of follow-up. These changes were predictive neither of cyclosporin A-induced remission nor of relapses. Results of the insulin-release inhibition test were not correlated to islet cell autoantibodies or HLA phenotype.

When injected daily into normal young or aging mice, cyclosporin A (CsA) induces a significant stimulation of thymic hormone (thymulin) secretion, as measured by the peripheral level of the hormone and the number of thymulin-producing cells in the thymus. This stimulation is dose dependent and reversible after the end of treatment. Similar findings have been made in primary cultures of human thymic epithelial cells in which CsA increases the percentage of thymulin-producing cells evaluated by immunofluorescence, as well as the amount of hormone released into the supernatants. No effect of CsA is observed on the expression of class II major histocompatibility complex antigens. CsA also increases the proliferation of cultured human thymic epithelial cells, as assessed by bromodeoxyuridine and [3H]thymidine incorporation. The present study strongly suggests that CsA can stimulate the proliferation and endocrine function of thymic epithelial cells. Its action on the immune system is thus not restricted to lymphoid cells and might be partially mediated by its effect on the thymic epithelium.

The effect of cyclosporine was evaluated in a double blind placebo controlled trial in 122 recent onset insulin-dependent diabetics. A significantly higher incidence of complete remissions was observed in patients treated with cyclosporine than in those receiving placebo (respectively 24 and 5.8%). The effect was still more clear-cut in patients having presented the highest cyclosporine blood level (37%). These results which have been obtained with modest toxicity demonstrate that cyclosporine induces remission of insulin-dependent diabetes and prompt to set up new controlled trials to evaluate the duration of the effect obtained and the potential risks of the treatment.

Anti-islet cell and anti-insulin antibody production was studies over a 12-mo period in 82 recently diagnosed diabetics randomly receiving either cyclosporin or placebo. Cyclosporin had only minimal effects on the production of anti-islet cell antibodies whether directed to islet cytoplasmic (immunofluorescence) or membrane (cytotoxicity assay) antigens even in patients undergoing remission. These data suggest that these antibodies do not play a major role in the pathogenesis of the disease particularly since their (irregular) presence is not predictive of the clinical response to cyclosporin. Conversely, cyclosporin completely suppressed the synthesis of antibodies elicited by exogenous insulin irrespective of the insulin doses received, and decreased the autoantibody production against thyroid antigens, indicating that cyclosporin has variable effects on antibody production against various antigens.

The effectiveness of cyclosporin against human auto-immune diseases has been well established in uveitis, rheumatoid arthritis and insulin-dependent diabetes. No firm conclusion can be drawn from trials conducted in other diseases, since the results are discordant or based on an insufficient number of subjects. In view of the side-effects, and notably the risk of nephrotoxicity, of the drug, the blood levels of cyclosporine must be measured and the patient's renal function evaluated at regular intervals. For the time being, these risks reduce the prescription of cyclosporin to the severe forms of autoimmune diseases, i.e. those which resist conventional corticosteroid therapy. Things are different with diabetes, since cyclosporin is the only immunosuppressant which has proved effective in inducing remissions. But whether such remissions can be maintained in the long term remains uncertain, and this type of treatment is still limited to therapeutic trials.