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Presents a study that concludes that nephropathy is an important potential effect of cyclosporine therapy. How to minimize the risk of its development in patients with autoimmune diseases who are treated with cyclosporine; Characteristics of patients with autoimmune or inflammatory diseases treated with cyclosporine; Incidence and features of cyclosporine-induced nephropathy; Sjogren's syndrome; Behcet's syndrome; More.

Although cyclosporin is effective in immunosuppression following organ transplantation and in the treatment of psoriasis, its use is limited by its side-effects, notably impaired renal function and hypertension. As SDZ IMM 125, a new derivative of the cyclosporin family, showed considerable immunosuppressive activity in experimental studies, with less effect on renal function, it was considered a potential successor to cyclosporin for both indications. In this multicentre, double-blind, placebo-controlled study, the efficacy and tolerability of 40, 100, 200 and 400 mg SDZ IMM 125 daily were studied in 59 patients with psoriasis. Patients were followed for a period of 5 weeks (4 weeks treatment, and 1 week post-treatment observation). A dose-dependent effect of SDZ IMM 125 was observed. A significant correlation was found between the dose of SDZ IMM 125 and changes in the sum of severity scores of three indicator plaques. There was a significant decrease in the body surface area affected by psoriasis in the 400-mg group (P ≤ 0.01), whereas a decrease of the global psoriasis severity was observed in the 200-mg (P ≤ 0.01) and the 400-mg groups (P ≤ 0.001). No serious adverse events occurred during the 4 weeks of treatment. Three patients discontinued treatment because of adverse events (one sore throat, two influenza). Clinical adverse events were similar to those reported with cyclosporin, the most frequent being gastrointestinal disturbances. Estimation of renal function indices showed that increases from baseline values were dose-dependent, and appeared to be similar to those seen with cyclosporin. Changes in liver function tests showed a clearcut dose-dependent increase of some liver enzymes, principally alanine aminotransferase (ALAT). SDZ IMM 125 is effective in clearing psoriasis. However, long-term studies comparing the efficacy and safety of SDZ IMM 125 and cyclosporin must be performed, to determine whether SDZ IMM 125 has a better risk-benefit ratio than cyclosporin. [ABSTRACT FROM AUTHOR]

Cyclosporin A (CyA) trough (pre-dose) levels were measured in whole blood with a radioimmunoassy (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. [ABSTRACT FROM AUTHOR]

Kidney biopsies were obtained from 14 adult patients treated with cyclosporin A (CyA) for psoriasis. These biopsies were compared with those from 16 psoriatic patients of the same age, but who were not receiving treatment with CyA. Patients receiving CyA had a maximum mean dose of 5&middot1 mg/kg/day for a mean duration of 15 months (range 3–37 months). Minimal or slight interstitial fibrosis, tubular atrophy or arteriolopathy were seen in the biopsies of patients receiving CyA as well as in those of the controls. No relevant CyA-related structural alterations of the kidney were detected. [ABSTRACT FROM AUTHOR]

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 1·25mg (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 I 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: I 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. [ABSTRACT FROM AUTHOR]

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 < 0.001). The rates of success, defined by a PASI score reduction ≥75% or a score ≤ 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. [ABSTRACT FROM AUTHOR]

Background: This open-label single-arm exploratory study evaluated the accuracy of the Ingestible Sensor System (ISS), a novel technology for directly assessing the ingestion of oral medications and treatment adherence., Methods: ISS consists of an ingestible event marker (IEM), a microsensor that becomes activated in gastric fluid, and an adhesive personal monitor (APM) that detects IEM activation. In this study, the IEM was combined to enteric-coated mycophenolate sodium (ECMPS). Twenty stable adult kidney transplants received IEM-ECMPS for a mean of 9.2 weeks totaling 1227 cumulative days., Results: Eight patients prematurely discontinued treatment due to ECMPS gastrointestinal symptoms (n=2), skin intolerance to APM (n=2), and insufficient system usability (n=4). Rash or erythema due to APM was reported in 7 (37%) patients, all during the first month of use. No serious or severe adverse events and no rejection episode were reported. IEM detection accuracy was 100% over 34 directly observed ingestions; Taking Adherence was 99.4% over a total of 2824 prescribed IEM-ECMPS ingestions. ISS could detect accurately the ingestion of two IEM-ECMPS capsules taken at the same time (detection rate of 99.3%, n=2376)., Conclusions: ISS is a promising new technology that provides highly reliable measurements of intake and timing of intake of drugs that are combined with the IEM.

Background: Cyclosporin A (CyA) may induce acute nephrotoxicity. The question has been raised of the possible long-term unfavorable course of CyA-induced lesions. Advantage was taken of a large cohort of diabetic patients treated for several months using moderate CyA dosage to evaluate the long-term evolution of renal function in such patients., Methods: Two hundred and eighty five recently diagnosed type 1 diabetic patients having received CyA for a mean of 19.9 months were monitored for 13 years, in parallel with 100 similar patients treated with insulin alone., Results: In the CyA-treated group, a transient increase in creatininemia levels occurred during the first 18 months of treatment associated with a transient increase in renal vascular resistance. Both effects disappeared later on: creatininemia levels then remained normal. Inulin and p-aminohippurate (PAH) clearances remained normal throughout follow-up. Neither permanent renal failure nor progressive deterioration of renal function occurred in either group or in individual patients. A 10 to 12% increase in inulin and PAH clearance was elicited by IV amino acid infusion at 7 to 10 years, a finding consistent with a normal renal functional reserve. Patients with moderate kidney lesions on biopsy at 1 year had normal and stable clearance values at 7 to 13 years. The prevalence of arterial hypertension and retinopathy was lower in the CyA-treated group than in the control group, possibly because of the tighter metabolic control obtained in the CyA group., Conclusion: These results suggest that low-dose CyA treatment combined with thorough monitoring does not result in long-term renal dysfunction., (Copyright 2002 John Wiley & Sons, Ltd.)

Background & Aims: The role of cyclosporine in Crohn's disease is controversial. This study aimed to delineate the long-term effect of cyclosporine in chronic active Crohn's disease., Methods: One hundred eighty-two patients from 33 European centers were included. The patient cohort was stratified at entry into a stratum with low Crohn's Disease Activity Index (CDAI) ( < 200) and high CDAI ( > 200). The low-activity group continued to receive the pretrial steroid dose for 2 months, and the high-activity group received 1 mg.kg-1.day-1 prednisone initially. During months 3 and 4, the dose of steroids was reduced stepwise to 5 mg/day in all patients. Placebo and cyclosporine (5 mg.kg-1.day-1) were administered throughout the 12-month study period. The main parameter of efficacy was the CDAI, and the main end point was the number of patients in remission at month 12., Results: During cyclosporine therapy, 35% (95% confidence interval [95% Cl], 25%-46%) of the patients achieved a full remission (CDAI, < 150) after 4 months compared with 27% (95% Cl, 18%-38%) in the placebo group (P > 0.05). At month 12, only 20% (95% Cl, 12%-31%) vs. 20% (95% Cl, 12%-31%) of the patients had maintained a continuous remission. No major differences between treatment groups were found within each of the two strata., Conclusions: The long-term treatment of chronic active Crohn's disease with cyclosporine plus low-dose steroids does not offer an advantage compared with low-dose steroids alone.

This was an analysis of the renal investigations performed in 248 cyclosporin A (CyA)-treated patients who had recent-onset type I insulin-dependent diabetes mellitus (IDDM) to assess the clinicopathological relationships, risk factors and predictive indices of CyA nephrotoxicity, and renal function observed with different CyA treatment regimens. There were four different protocols, using initial CyA dosages ranging from 7.5 to 10 mg/kg/day, with dose modification according to serum creatinine concentration, which was measured regularly in some patients for up to 9 years after starting treatment. Kidney biopsies were obtained from 125 patients (74 adults and 51 children) who had received only CyA for an average duration of 13 months before biopsy and had no other sources of renal injury at this stage of IDDM. Of these patients, 58% showed normal or minimal changes on biopsy, 26% showed slight abnormalities, and 16% showed medium-grade (grade III nephropathy) abnormalities. Lesion severity was related to the degree of interstitial fibrosis and tubular atrophy which, in turn, was related to the use of high maximum CyA dosages. Patients' age, and excessive CyA dose and blood trough levels were the main risk factors, and serum creatinine increase was the best predictive factor of CyA-induced nephropathy. However, CyA-induced renal dysfunction was essentially reversible on dosage reduction, and morphological changes were not followed by progressive renal insufficiency when CyA doses were low and adjusted according to serum creatinine levels. We conclude that, at present, it is recommended that low-dose CyA in combination with other non-nephrotoxic immunosuppressive strategies be used in patients with IDDM.

In a diabetic liver transplant recipient, immunosuppressed with FK 506, a severe digestive moniliasis required treatment with the antifungal imidazole derivative fluconazole. This was followed by a brisk rise in serum creatinine levels, which returned promptly to baseline when this combination was stopped. Serial measurements of FK 506 concentrations in plasma showed excessive areas under the 24 h time-concentration curve and trough levels during the concomitant intake of imidazole antifungals and FK 506. Eighteen months later, this patient presents with normal renal function. Antifungal imidazole derivatives inhibit the P 450 cytochrome enzyme system and may thus decrease the catabolism of FK 506. Meticulous monitoring of FK 506 trough levels and dosage adaptation are compulsory when concomitant treatment with such a drug is unavoidable. The same is true for cyclosporine in auto-immune diabetic patients receiving cyclosporine A.

An advisory board of nephropathologists with personal experience in the evaluation of biopsies from patients treated with cyclosporin A (CyA) was set up to address the following problems: 1. Definition of CyA nephropathy as seen in patients with autoimmune diseases; 2. Evaluation of the reliability and reproducibility of the diagnostic criteria for the different morphological lesions seen in CyA nephropathy; 3. Classification of the morphological lesions according to their clinical relevance; 4. Estimation of the possible progression of CyA nephropathy with continuous CyA therapy. The most frequent lesions attributable to CyA therapy in patients with autoimmune diseases are tubular atrophy, interstitial fibrosis, and arteriolar hyalinosis. All other lesions are rare. The reproducibility and diagnostic reliability is high for tubular atrophy and interstitial fibrosis, but low for arteriolar lesions even among experienced nephropathologists. The biopsies may be classified according to the severity of tubular atrophy, interstitial fibrosis and arteriolar hyalinosis with regard to their clinical relevance: In group I (within normal limits), CyA therapy can be continued; in group III (moderate-to-severe CyA-related lesions), CyA should be stopped if possible. Among group II biopsies (slight CyA-related abnormalities), no recommendation can be made in the absence of a second biopsy after a further year of CyA therapy. No clear-cut answer can be given concerning the progression of CyA-induced lesions. However, no significant progression has been found in the cases studied to date.

The optimal use of cyclosporin (CsA) in autoimmune diseases aims at achieving the best risk/benefit ratio and ensuring the absence of potentially irreversible adverse effects, particularly with respect to the kidney [corrected]. The experience gained with CsA therapy in more than 3,000 patients with autoimmune diseases is the basis for the current recommendations: the initial dose should be the lowest effective one and not exceed 5 mg/kg/day in non-life-threatening conditions; treatment should be as brief as possible (2-4 months) in cases of inefficacy; once a satisfactory clinical improvement has been achieved, the treatment should be maintained in the long-term using the lowest individually titrated effective dose; the dose of CsA should be decreased when serum creatinine rises by more than 30% above pre-CsA level. Continuous clinical and biological monitoring (especially of blood pressure and serum creatinine) is mandatory as long as CsA is prescribed. When these conditions are fulfilled, CsA may be an effective and safe therapy for selected autoimmune diseases, even in long-term treatment.

Epstein-Barr virus (EBV) serology was serially studied for a period of 18 months in 49 recently diagnosed type I diabetics randomly assigned to receive cyclosporin (CsA) (n = 25) or placebo (n = 24). Additionally, isoelectrofocusing of serum (IEF) was serially performed in 59 CsA- and 38 placebo-treated diabetics, over a 36 month period (687 sera) in order to detect restriction of heterogeneity of circulating immunoglobulins. Patients were continuously treated with CsA at a dose of 7.5-10 mg/day during the first 6 months and a dose not exceeding 5 mg/kg/day, thereafter. Before treatment anti-EBV antibody levels were in the normal range for the whole group. In the placebo group, Epstein-Barr nuclear antigen (EBNA) and viral capsid antigens (VCA) IgG were moderately raised during the first 6 months in comparison with baseline level (0.33 +/- 0.13 and 0.30 +/- 0.18 two-fold dilutions respectively). In contrast, in the CsA group, EBNA and VCA IgG decreased slightly (0.26 +/- 0.16 and 0.26 +/- 0.17 dilutions). Changes between the two groups at 3 and 6 months were significantly different (P less than 0.05), but the difference disappeared subsequently. No significant changes in anti-early antigen (EA) IgG and in EA and VCA IgA were observed. No IEF abnormalities appeared in the CsA group. One CsA-treated patient who was initially EBV seronegative developed normal serological signs of recent EBV infection at 12 months without restriction of immunoglobulin heterogeneity or clinical symptoms of infectious mononucleosis. This study indicates that CsA, at moderate dosage, slightly reduces the titer of pre-existing anti-EBV antibodies but does not alter the response to recent EBV infection. These results do not provide any evidence of clinically latent EBV-induced benign or malignant lymphocyte proliferation.

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.

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.

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.

Determination of the immune lysis of epithelial cells, especially of hepatocytes, in short term culture is dealt with inadequately because of the lack of accuracy inherent in most classical methods of measurement of cell lysis or because of the high spontaneous release of the lytic marker. We have studied different methods of detection of lysis of rat hepatocytes cultured for a short term (24-48 h) at a concentration of 10 000 cells/50 microliters. The determination of aspartate aminotransferase (ASAT) release, measured with a centrifugal analyser parallels lactate dehydrogenase (LDH) release and trypan blue dye staining which are indisputable markers of cell death, but ASAT release is a more sensitive determination. Surprisingly, 51chromium release (1.72%/h) is much higher than ASAT release (0.51%/h) for an experimental period of 24 h. In cell mediated cytotoxicity tests, the ASAT content of lymphocytes, in contrast to that of LDH, is much lower than that of hepatocytes and this makes determination of ASAT release a sensitive marker of cytotoxicity under these conditions.

The authors report the case of a patient with autoimmune hemolytic anemia, due to anti-KJa antibody, and associated with primary hypothyroidism. They discuss the possible relationship between these two conditions and emphasize the particular hematological pattern related to myxoedema.