Low-dose Cyclosporine Therapy Research Articles

Adverse effects of low-dose systemic cyclosporine therapy in high-risk penetrating keratoplasty.

The purpose of this study was to investigate the adverse effects of low-dose oral cyclosporine (CsA) therapy following high-risk corneal transplantation. The medical records from 88 subjects who had undergone high-risk penetrating keratoplasties and had been administered oral CsA were retrospectively analyzed. High risk was defined as a history of graft rejection, three or more quadrants of vascularization, or the presence or history of intraocular inflammation. An initial CsA dose of 3-5 mg/kg per day was given for 3-7 days, followed by 2.5-3.5 mg/kg per day for approximately 1 month. The concentration of CsA was maintained at the target trough level of 120-150 ng/ml for at least 6 months or until serious complications developed. The relationship between the cumulative dose and duration of CsA administration and the adverse systemic effects, including the frequency of herpes keratitis, was evaluated. The incidence of herpes keratitis in the study subjects was compared with the incidence in 185 patients who had not received CsA therapy following penetrating keratoplasty. The mean survival time of the grafts was 33.6 months. Adverse effects occurred in 81.8 % of subjects. Hypertension, elevated liver enzyme levels, elevated serum creatinine level, and decreased absolute neutrophil count (ANC) were observed in 14.8, 6.8, 5.7, and 5.7 % of subjects, respectively. Simvastatin-induced rhabdomyolysis also developed in one case. Some patients exhibited minor complications, with gastrointestinal problems and hypertrichosis recorded in 5.7 and 3.4 % of subjects, respectively. Hypertension and hepatotoxicity most frequently occurred after 4 to 8 weeks of medication, while ANC decrease and nephrotoxicity generally developed after 24 weeks of treatment, with incidence related to the cumulative dose. Herpes keratitis occurred more frequently (31.8 %) in the CsA-treated subjects than in subjects that did not receive CsA therapy (p = 0.005). Most of the adverse effects were reversed after discontinuation of CsA therapy. The results of this study suggest that low-dose oral CsA therapy may induce various adverse effects, the most common of which are herpes keratitis and hypertension.

Calcineurin inhibitors in chronic urticaria

The purpose of the review is to review the pathophysiology, available data, and our current recommendations for calcineurin inhibitor (cyclosporine and tacrolimus) treatment in antihistamine refractory chronic idiopathic urticaria (CIU) patients. Low-dose cyclosporine (<5 mg/kg per day) may have unique immunological modulating properties beyond mast cell and basophil stabilization in CIU. Starting CIU treatment with very low cyclosporine dosages (1 mg/kg per day) and titrating based on response and side-effects may decrease adverse events while preserving efficacy. In cyclosporine responsive patients failing cyclosporine taper, case series data support the safety and efficacy of long-term (5-10 years), very low dose (1-2 mg/kg per day) cyclosporine treatment with appropriate clinical monitoring. For CIU patients refractory to antihistamines, low-dose cyclosporine therapy (<3 mg/kg per day) with appropriate laboratory monitoring provides an alternative with an acceptable side-effect profile. Long-term (>12 months) moderate-dose (2.5-5 mg/kg per day) cyclosporine treatment may cause longitudinal increases in serum creatinine. However, decreasing or stopping cyclosporine dosing reverses measured nephrotoxicity in the vast majority of patients, and some patients with careful monitoring can tolerate very low-dose cyclosporine (<2 mg/kg per day) for longer periods. Tacrolimus is an alternative to cyclosporine with a slightly different adverse effect profile. Minimal data are available on its use in chronic urticaria.

Specificity of Histological Markers of Long-Term CNI Nephrotoxicity in Kidney-Transplant Recipients Under Low-Dose Cyclosporine Therapy

The specificity of chronic histological lesions induced by calcineurin inhibitors (CNI) is often questioned, but few studies have directly compared long-term lesions in renal-transplant patients who received this treatment and those who did not. We therefore conducted a retrospective study of 141 kidney-transplant recipients treated with (n = 48) or without (n = 93) cyclosporine (CsA) to compare the histological lesions observed at 3-month, 24-month and 10-year protocol biopsies. All of the chronic elementary lesions (glomerulosclerosis, interstitial fibrosis, tubular atrophy, arteriolar hyalinosis, fibrointimal thickening) progressed in frequency and severity in both groups, although significantly more in the CsA group. Ten-year biopsy results showed that 92% of patients in the CsA-treated group and 65% in the control group had arteriolar hyalinosis lesions. When we focused on muscular arteriolar hyaline deposits more specific to CsA arteriolopathy, we observed these lesions in 68% of CsA patients and 28% of patients who had never received CsA. CsA was not the sole factor involved in the development of arteriolar hyalinosis and was independently associated with an increased risk of graft loss. In summary, we observed that histological lesions commonly attributed to CsA nephrotoxicity were not sufficiently specific to definitively diagnose CNI nephrotoxicity.

成人頻回再発型微小変化群に対するCyclosporin(CsA)少量併用療法の有効性

Low-dose cyclosporin(CsA) therapy combined with prednisolone was performed in 10 adult patients with frequently relapsing minimal change nephrotic syndrome(MCNS). Oral CsA was administered at the dose of 1-3 mg/kg/day(50-150 mg/day) in combination with preceding prednisolone(32.5 +/- 13.1 mg/day). The whole blood traugh concentration of CsA was maintained at the level of 50-100 ng/ml (ranging in 35-160 ng/ml, mean: 68.0 +/- 42.8 ng/ml), and the therapy was continued for 31.7 +/- 12.7 months. The urinary protein excretion, serum total protein, albumin and total cholesterol significantly improved after treatment. The serum creatinine increased slightly at 3-6 months after treatment, but decreased to within the normal range thereafter. The frequency of relapse and the ratio of the complete remission period to the total observed period were compared between the pre-treatment period(36.6 +/- 42.5 months) and post-treatment period(31.7 +/- 12.7 months). The frequency of relapse was significantly decreased after CsA treatment(2.3 +/- 1.5 times/year-->0.7 +/- 0.7 times/year, p = 0.02). The ratio of the complete remission period to the total observed period was increased significantly after CsA therapy(61.7 +/- 24.3%-->88.6 +/- 14.5%, p = 0.01). Thus, the low dose cyclosporin(CsA) therapy combined with prednisolone was an effective treatment for adult MCNS patients who relapsed frequently under conventional prednisolone therapy.

Safety of Low-Dose Cyclosporine Therapy Before Transplantation in Kidney Allograft Recipients

Graft dysfunction immediately posttransplantation can vary from subtle slowing of the expected decrease in creatinine concentration to frank oliguria requiring dialysis therapy for days to weeks. Risk factors for slow and delayed graft function include prolonged preservation, older donor age, and high plasma renin activity in the recipient. Cyclosporine (CsA) nephrotoxicity is another cause of early kidney allograft dysfunction. To evaluate early kidney allograft function in patients who received low-dose CsA therapy for 48 hours before transplant surgery for comparison with that in recipients who received CsA therapy after improvement in allograft function. In a case-control comparative study, 66 kidney recipients were divided into 2 groups on the basis of time of initiation of CsA therapy. In group 1, patients received CsA, 100 mg twice a day, for 48 hours before surgery, and in group 2, patients received CsA therapy after surgery when allograft function had improved (serum creatinine concentration <or=3 mg/dL). Other immunosuppression medications were the same in both groups. Statistical analysis was performed to compare kidney allograft function in the first month posttransplantation. In group 1 vs group 2, at day 1 posttransplantation, mean (SD) blood urea concentration was 73.72 (31.00) mg/dL vs 87.52 (29.82) mg/dL, serum creatinine concentration was 5.11 (1.83) mg/dL vs 6.42 (3.64) mg/dL, and urine volume in 24 hours was 11,052 (4290) mL vs 9629 (45.30) mL. At the end of the study, blood urea concentration was 49.61 (12.18) mg/dL vs 69.11 (33.76) mg/dL, serum creatinine concentration was 1.22 (0.28) mg/dL vs 1.47 (0.79) mg/dL, and urine volume in 24 hours was 3202 (986) mL vs 3095 (726) mL. No significant difference was noted between the 2 groups for age, sex, and immunosuppression medications. Low-dose CsA therapy before transplant surgery preserves early allograft function without deleterious effects.

Weight loss improves the response of obese patients with moderate-to-severe chronic plaque psoriasis to low-dose cyclosporine therapy: a randomized, controlled, investigator-blinded clinical trial

Background:Chronic plaque psoriasis is frequently associated with obesity. The effect of a hypoenergetic diet on psoriasis has not been investigated. Objective:The objective was to investigate whether moderate weight loss (ie, 5–10% of body weight) increases the therapeutic response to a low dose of cyclosporine in obese patients with moderate-to-severe chronic plaque psoriasis. Design:A 24-wk randomized, controlled, investigator-blinded clinical trial was conducted in 61 patients. The efficacy of 2.5 mg · kg−1d−1 cyclosporine combined with a low-calorie diet (intervention group) was compared with cyclosporine alone (control group) in obese patients [body mass index (in kg/m2) > 30] with moderate-to-severe psoriasis. The primary endpoint was an improvement from baseline of ≥75% in the Psoriasis Area and Severity Index (PASI 75 response) at week 24. Results:At week 24, the mean (± SD) reduction in body weight was 7.0% ± 3.5 in the intervention group and was 0.2% ± 0.9 in the control group (P < 0.001). The PASI 75 response was achieved by 20 of 30 patients (66.7%) treated with cyclosporine plus a low-calorie diet and by 9 of 31 (29.0%) patients treated with cyclosporine alone (P < 0.001). Four patients (13.3%) from the intervention group and 14 (45.1%) from the control group withdrew prematurely from the study (P < 0.001). Conclusions:Obese patients with moderate-to-severe psoriasis increase their response to low-dose cyclosporine if a calorie-controlled diet is included in the treatment regimen. Lifestyle modifications, including a low-calorie diet, may supplement the pharmacologic treatment of obese psoriasis patients. This trial was registered at clinicaltrials.gov as NCT00512187.

Is single-daily low-dose cyclosporine therapy really effective in children with idiopathic frequent-relapsing nephrotic syndrome?

A recent study on renal transplant patients has shown that a single dose of cyclosporine (CsA) has added the advantage of decreasing dosages and adverse effects, while maintaining graft function. However, the efficacy of this regimen in children with idiopathic frequent-relapsing nephrotic syndrome (NS) remains controversial. 20 children with steroid-dependent NS or CsA-dependent NS (18 with minimal change disease, MCD and 2 with focal segmental glomerulosclerosis, FSGS) were enrolled in this prospective study. CsA was commenced at 1.5 â 2 mg/kg, given as a single daily dose before breakfast, and the dose was adjusted to reach 2 hours post-dose CsA levels (C2) of 600 - 800 ng/ml. In 9 out of 18 patients with MCD, treatment with single-daily CsA for a median of 13 months (range 7 - 21) resulted in a reduction of mean minimum prednisolone (PSL) dose from 1.1 A+/- 0.55 to 0.04 A+/- 0.09 mg/kg on alternate days (p < 0.01), and the median relapse rate from 1.3 (1.1 - 2.5) to 0 (0 - 0.2) episodes/6 months (p < 0.01). Of them, PSL could be weaned off in 7 patients (4 of 6 with steroid-dependent NS, only 3 of 14 with CsA-dependent NS) without relapse of NS while on this therapy. However, 11 out of 20 were considered to have treatment failure: 1 with steroid-dependent NS and 10 with CsA-dependent NS. In 2 patients having FSGS, this method showed no beneficial effects. In 18 patients with MCD, relapse free ratio on single-daily CsA therapy was significantly higher in patients whose average C2 levels were greater than 700 ng/ml (p < 0.05). Our experience demonstrates that single-daily low-dose CsA therapy maintaining C2 levels greater than 700 ng/ml may be effective in children with steroid-dependent NS or MCD, with no relapse. In contrast, the usefulness of this regimen in children with CsA-dependent NS appears to be limited.

Clinical usefulness and patient satisfaction for treatment with low‐dose cyclosporin administration in patients with moderate psoriasis vulgaris

The Japanese guidelines for psoriasis therapy with cyclosporin microemulsion preconcentrate (CyA MEPC) has been revised, and the clinical application of CyA MEPC is being expanded to include mild to moderate psoriasis. In this study, we aimed to confirm the clinical efficiency of low-dose cyclosporin therapy in patients with moderate psoriasis vulgaris. After informed consent was obtained, 19 patients with psoriasis vulgaris were enrolled in this study. Each patient basically administrated CyA MEPC, 2.5 mg/kg/day, orally over 12 weeks. When the psoriasis area and severity index (PASI) score showed a 75% reduction from the initial value, the dosage of CyA MEPC was reduced to 1.5 mg/kg/day and added a topical application of active vitamin D3 ointment. We interviewed the patients as to their satisfaction for the usefulness and cost of the treatment. All patients obtained improvement within 12 weeks. In 10 patients whose PASI score reduced over 75%, we could reduce CyA MEPC dosage. No adverse effects were noted in any patients during the treatment. It is of note that the cost for 1.5 mg/kg/day administration of CyA MEPC was accepted by all the patients. In conclusion, this preliminary study suggests that the CyA MEPC is effective, safe and would provide patients with acceptable costs.

Split-Liver Transplantation in a Child with Liver Failure Based on Chronic Graft-Versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation from the Same Donor.

We report a case of a 6-year-old boy who developed chronic graft-versus-host-disease (GVHD) of the liver, the intestines and the skin following allogeneic hematopoietic stem cell transplantation.The boy received allogeneic hematopoietic stem cell transplantation by the age of two years because of early recurrence of acute lypmphoblastic leukemia. The chimerism analysis showed complete chimerism. In the following year he developed GVHD despite adequate immunosuppressive therapy. Liver biopsy showed liver-GVHD resulting in liver cirrhosis by the age of five years.Liver transplantation was performed with a split liver segment from the same unrelated donor as of the stem cells. Immunosuppressive therapy consisted of low dose steroids and low dose cyclosporine. The postoperative course was uneventful. Graft function was excellent and we performed protocol biopsies seven days and three weeks after transplantation which did not show any signs of rejection or GVHD.To our knowledge this is the first report on a liver transplantation following allogeneic hematopoietic stem cell transplantation from the same unrelated donor.In the latest liver biopsy three months after liver transplantation slight signs of GVHD could not be ruled out completely so that the low dose cyclosporine therapy is still continued.Further biopsies will show if the immunosuppressive therapy can be discontinued.

Type 2 Pseudohypoaldosteronism: New Insights Into Renal Potassium, Sodium, and Chloride Handling

Type 2 Pseudohypoaldosteronism: New Insights Into Renal Potassium, Sodium, and Chloride Handling

Comparison of Sequential Protocol using Basiliximab versus Antithymocyte Globulin with High-Dose Mycophenolate Mofetil in Recipients of a Kidney Graft from an Expanded-Criteria Donor

This retrospective pilot study investigated use of high-dose mycophenolate mofetil with biological induction and sequential introduction of low-dose cyclosporine in recipients of expanded criteria donor (ECD) kidneys. Fifty-four patients received mycophenolate mofetil 3 g/day for 45 days, cyclosporine 4 mg/kg/day, prednisolone, and rabbit antithymocyte globulin (rATG, n=14) or basiliximab (n=40). Acute rejection incidence was 11.3% (7.1% with rATG, 12.6% with basiliximab). Delayed graft function was observed in 31 patients (54%). At one year, measured glomerular filtration rate was 54+/-4 ml/min, with no significant differences between induction therapies. Thirty patients (55%) required > or =1 MMF dose reduction within month 1 due to adverse events (gastrointestinal symptoms, 67%; leucopenia 33%). Leucopenia was more frequent with rATG, while gastrointestinal symptoms were more frequent with basiliximab. Cytomegalovirus replication occurred in three patients (23%) with rATG and 3 (8%) with basiliximab. In conclusion, high-dose MMF, corticosteroids, delayed low-dose cyclosporine and induction therapy offers an excellent risk-to-benefit ratio in patients receiving an ECD allograft.

P089 IL-6, IL-11, OSM and LIF spontaneous releases are increased in supernatants of biopsies from lesional skin of psoriatic patients

Background: High-dose cyclosporine therapy significantly alleviates psoriasis within 2 to 4 weeks but is associated with a high rate of side effects. Reports are conflicting on the frequency and promptness of relapse after discontinuation of cyclosporine therapy.Objective: Our purpose was to compare the efficacy and safety of low-dose cyclosporine with that of etretinate and the stability of remission after replacing cyclosporine therapy with topical anthralin during tapering of cyclosporine.Methods: In a multicenter study 210 patients with moderate to severe chronic plaque-type psoriasis were randomly assigned to treatment with cyclosporine or etretinate. The initial dosages were 2.5 mg/kg/day for cyclosporine and 0.5 mg/kg/day for etretinate, which could be individually adjusted to 5.0 and 0.75 mg/kg/day, respectively. After a treatment phase of 10 weeks (phase 1) patients receiving cyclosporine were again randomly assigned to a group in which cyclosporine was replaced by topical dithranol (anthralin), or to another group in which the drug was tapered during the next 12 weeks (phase 2). All patients treated with etretinate discontinued therapy after 10 weeks and used topical dithranol.Results: Mean Psoriasis Area and Severity Index decreased by 71% in the cyclosporine group and by 47% in the etretinate group during phase 1. After 10 weeks of treatment 47% of the patients treated with cyclosporine and 10% of those treated with etretinate showed a reduction of more than 80% in skin involvement. Sixty-four percent of the cyclosporine group and 48% of the etretinate group did not require an increase in the initial dosage, resulting in a mean daily dose of 3.0 and 0.53 mg/kg, respectively. There was significant alleviation of nail involvement and joint complaints in both groups. In phase 2 the increase in mean Psoriasis Area and Severity Index and the incidence of relapse were significantly higher in patients in whom cyclosporine was discontinued and replaced by dithranol than in patients in whom cyclosporine was tapered or who were pretreated with etretinate. During treatment four patients from the cyclosporine group and three patients of the etretinate group discontinued the study because of side effects.Conclusion: Low-dose short-term cyclosporine therapy for psoriasis is, in comparison with etretinate, highly effective and well tolerated. Individually adjusted cyclosporine therapy allows the majority of patients to continue the low dosage of 2.5 mg/kg/day and still achieve a good clinical response. Remission can be better preserved by tapering the drug than by discontinuing treatment abruptly.

Renal biopsy findings in long-term cyclosporin treatment of psoriasis

Renal biopsies were performed in 30 psoriatics during long-term low-dose cyclosporin (CsA) therapy (range 2.5-6 mg/kg per day) of from 6 months to 8 years. The study included pretreatment biopsies in 25 of the patients. After 2 years all biopsies shared features consistent with CsA nephropathy despite completely normal pretreatment morphology in 17 of the 25 patients. The severity of the findings which consisted of arteriolar hyalinosis, focal interstitial fibrosis and sclerotic glomeruli increased with length of therapy. Mild renal lesions were seen during the first 2 years. After 4 years all but one had arteriolar hyalinosis, with interstitial fibrosis pronounced in five and moderate in six of 11 patients. At the same time glomerular sclerosis had become significant. A decrease in glomerular filtration rate (GFR) correlated with severity of structural lesions. The data from our study together with experiences from cardiac-transplanted patients treated with CsA indicate that patients with psoriasis after 2 years therapy with CsA should be rotated to other treatments or be followed carefully by GFR and sequential renal biopsies.

Cyclosporine as maintenance therapy in patients with severe psoriasis

Low-dose cyclosporine therapy for severe plaque psoriasis is effective. Most side effects can be controlled by patient monitoring, with appropriate dose adjustment or pharmacologic intervention, or both, if indicated. Prevention or reversibility of laboratory and chemical abnormalities may be achieved by discontinuation of therapy after the induction of clearing. However, relapse occurs rapidly on discontinuation. Maintenance therapy with cyclosporine after induction has not been fully evaluated. Our purpose was to compare a regimen of 3.0 mg/kg per day of oral cyclosporine with placebo in maintaining remission or improvement in patients with psoriasis. After a 16-week unblinded induction phase in which 181 patients received cyclosporine, 5.0 mg/kg per day (an increase up to 6.0 mg/kg per day and a decrease to 3.0 mg/kg per day were allowed, if required, to achieve efficacy or tolerability, respectively), those patients showing a 70% decrease or more in involved body surface area (BSA) entered the 24-week maintenance phase and were randomly assigned to either placebo, cyclosporine, 1.5 mg/kg per day, or cyclosporine, 3.0 mg/kg per day. Patients were considered to have had a relapse when BSA returned to 50% or more of the prestudy baseline value. Clinical efficacy, adverse effects, and laboratory values were monitored regularly throughout both study phases. During induction, cyclosporine at approximately 5.0 mg/kg per day produced a reduction in BSA of 70% or more in 86% of the patients. During maintenance, the median time to relapse was 6 weeks in both the placebo and cyclosporine 1.5 mg/kg per day groups, but was longer than the 24-week maintenance period in the 3.0 mg/kg per day group (p < 0.001 vs placebo). By the end of the maintenance period, 42% of the patients in the 3.0 mg/kg per day cyclosporine group had a relapse compared with 84% in the placebo group. Changes in laboratory values associated with the higher induction dosage generally exhibited partial or complete return toward mean prestudy baseline values during the maintenance phase, with the greatest degree of normalization in the placebo group. Cyclosporine, 3.0 mg/kg per day, adequately and safely maintained 58% of patients with psoriasis for a 6-month period after clearing of their psoriasis with doses of approximately 5.0 mg/kg per day.

Long-term low-dose cyclosporine therapy for severe psoriasis: Effects on renal function and structure

Background: The effectiveness of cyclosporine in the treatment of severe psoriasis is well known. Objective: We evaluated the efficacy and toxicity of systemic cyclosporine in patients with severe psoriasis, observing short-term (12 weeks) and long-term (3 to 5 years) effects. Methods: To further elucidate efficacy and safety, 42 patients with severe psoriasis were treated initially with cyclosporine 5 to 6 mg/kg per day for 12 weeks. A subset of 14 patients continued maintenance treatment for 3.5 years to study the long-term effects of cyclosporine on renal function and structure. Renal biopsies were performed after 2.5 years and 3.5 years of treatment. Renal histologic findings were correlated with renal function. Results: By weeks 8 and 12, 64% (n = 27) and 86% ( n = 36) of patients, respectively, were rated clear or almost clear of the psoriasis. However, a subpopulation of 15 patients did not respond to 5 mg/kg daily but improved when the dose was increased to 6 mg/kg daily. Clearance or near clearance was achieved in 67% of this subpopulation after 4 weeks. For the 29 patients whose glomerular filtration rate (GFR) was measured, mean GFR fell by 7% from baseline to week 4 ( p < 0.05). This change was reversible when dosage was reduced by 1 mg/kg per day in each of these patients. Patients older than 45 years of age experienced significant elevation of mean diastolic blood pressure and had reduced GFR and increased serum creatinine. After 2.5 years, of the 14 patients who continued maintenance treatment, two had biopsy specimens that showed moderate interstitial fibrosis and tubular atrophy. The remainder showed only minimal to mild structural damage. After 3.5 years of cyclosporine treatment, repeat renal biopsy specimens revealed slight increases in structural changes in nine subjects. These changes correlated with increasing age and drug-induced hypertension. Conclusion: We conclude that 5 mg/kg of cyclosporine daily is usually an effective initial dose for psoriasis. Patients who do not respond will often benefit from elevation of the dose to 6 mg/kg daily. Older patients experience cyclosporine-induced hypertension and changes in renal function and structure more frequently than do younger patients.

Changes in T-cell phenotype and adhesion molecules expression in psoriatic lesions after low-dose cyclosporin therapy.

Cyclosporin is a very effective treatment for severe psoriasis, but its exact mechanism of action in this disease is not completely understood. It has been hypothesized that the drug could act through the inhibition of the expression of certain cell adhesion molecules on the keratinocytes prior to the reduction in the number of epidermal inflammatory cells. Several studies have focused on ICAM-1 changes on keratinocytes and endothelial cells after cyclosporin treatment in psoriatic patients but their results have been somewhat contradictory. We examined changes in T-cell markers and adhesion molecules among keratinocytes, endothelial and inflammatory cells after low-dose cyclosporin treatment for severe psoriasis. We performed a histological and immunohistochemical study on psoriatic skin among 10 patients (7 males and 3 females; mean age 37 years) treated with low-dose (2.5 mg/kg/day) cyclosporin, prior to therapy, after 1 month, and after 3 months of treatment. The mean PASI (Psoriasis Area and Severity Index) before treatment was 23 +/- 4, 13 +/- 7 after the first month of therapy, and 8 +/- 2 at the end of the third month of therapy. Pretherapy samples showed a moderate to severe inflammatory infiltrate mainly due to T-lymphocytes expressing a T-cell memory (UCHL-1) and helper/inducer (CD4) phenotype. Most of these cells also expressed HLA-DR and LFA-1 and ICAM-1 antigens. After the treatment, an overall reduction in the degree of epidermal hyperplasia was seen (p = 0.01). The severity of the infiltrate was clearly reduced (p = 0.05), but no significant changes in the phenotype profile were observed. Although slightly reduced, endothelial ICAM-1 expression persisted after cyclosporin therapy. Keratinocyte ICAM-1 expression was uniformly and significantly reduced after 1 month and 3 months of therapy (p = 0.01). These results support the hypothesis that cyclosporin interferes with the expression of keratinocyte adhesion molecules in patients with psoriasis. Servitje O, Bordas X, Serón D, Vidaller A, Moreno A, Curcó N, Sais G, Peyrí J. Changes in T-cell phenotype and adhesion molecules expression in psoriatic lesions after low-dose cyclosporin therapy.

Low-dose cyclosporine in the treatment of patients with psoriasis: experience in Hong Kong

An open-label, uncontrolled, 24-week study was conducted in Hong Kong to determine the most effective regimen and the efficacy, tolerability, and side effects of low-dose cyclosporine therapy in the treatment of patients with psoriasis. Thirty patients were treated with a dosage of 2.5 to 5 mg/kg per day for 16 weeks. At each of the follow-up visits, the modified Psoriasis Area and Severity Index score, blood pressure, and serum creatinine and potassium levels were measured. At the end of 16 weeks of treatment, 77% (23) of the patients had ⩾50% improvement, and 43% (13) had ⩾75% improvement. The mean established dosage was 3 mg/kg per day. The improvement reached a plateau around week 12. Only 7% (2) of the patients had elevated serum creatinine levels (>30% of baseline). Thus low-dose cyclosporine was effective and relatively safe for short-term treatment of patients with severe and refractory psoriasis. However, the relapse rate was high (47%) after cessation of treatment.

Experimental graft coronary artery disease in a murine heterotopic cardiac transplant model.

The development of immunosuppressive therapy has brought about a remarkable decrease in the risk of acute cardiac allograft rejection; however, the major cause of patient death or retransplantation after the first postoperative year is coronary artery disease (CAD) in the graft. The pathogenesis and management of CAD are still not clearly established. To make an animal model of CAD, we performed primary vascularized heterotopic cardiac transplantation using mice. Inbred strains, sharing major histocompatibility antigens but differing in minor antigens, were selected. DBA/2 mice (H-2d) served as donors and B10.D2 mice (H-2d) as recipients. Viability of the cardiac grafts was assessed by abdominal palpation. Eight of twelve cardiac allografts (67%) survived for 10 weeks after operation without any immunosuppressive therapy. Allografts rejected within 4 weeks showed acute rejection histologically, whereas allografts surviving more than 4 weeks displayed intimal hyperplasia in the coronary arteries, together with interstitial and perivascular fibrosis. The severity of intimal thickening in the graft coronary artery was then assessed by point counting. In allografts surviving for 70 days, intima comprised approximately 42% of the graft arterial wall, whereas in DBA/2 and B10.D2 syngeneic grafts, it comprised approximately 13%. A significant difference in percentage was observed between the intima area of allografts and that of syngrafts (P < .01, ANOVA). Long-term oral administration of cyclosporine at a dose of 40 mg/kg per day decreased the intima area to 34% (P < .05 versus nontreated allografts, ANOVA); however, this dose did not affect the incidence of arterial lesions. The histopathological features of DBA/2 allografts surviving for 10 weeks in B10.D2 recipient mice mimicked those in human CAD. Using this animal model, the beneficial effect of low-dose cyclosporine therapy on CAD was demonstrated, although this effect seemed to be limited. This DBA/2-B10.D2 mouse heterotypic cardiac transplant model provides valuable results for future studies of the disease.

Low-dose short-term cyclosporine versus etretinate in psoriasis: Improvement of skin, nail, and joint involvement

Background: High-dose cyclosporine therapy significantly alleviates psoriasis within 2 to 4 weeks but is associated with a high rate of side effects. Reports are conflicting on the frequency and promptness of relapse after discontinuation of cyclosporine therapy. Objective: Our purpose was to compare the efficacy and safety of low-dose cyclosporine with that of etretinate and the stability of remission after replacing cyclosporine therapy with topical anthralin during tapering of cyclosporine. Methods: In a multicenter study 210 patients with moderate to severe chronic plaque-type psoriasis were randomly assigned to treatment with cyclosporine or etretinate. The initial dosages were 2.5 mg/kg/day for cyclosporine and 0.5 mg/kg/day for etretinate, which could be individually adjusted to 5.0 and 0.75 mg/kg/day, respectively. After a treatment phase of 10 weeks (phase 1) patients receiving cyclosporine were again randomly assigned to a group in which cyclosporine was replaced by topical dithranol (anthralin), or to another group in which the drug was tapered during the next 12 weeks (phase 2). All patients treated with etretinate discontinued therapy after 10 weeks and used topical dithranol. Results: Mean Psoriasis Area and Severity Index decreased by 71% in the cyclosporine group and by 47% in the etretinate group during phase 1. After 10 weeks of treatment 47% of the patients treated with cyclosporine and 10% of those treated with etretinate showed a reduction of more than 80% in skin involvement. Sixty-four percent of the cyclosporine group and 48% of the etretinate group did not require an increase in the initial dosage, resulting in a mean daily dose of 3.0 and 0.53 mg/kg, respectively. There was significant alleviation of nail involvement and joint complaints in both groups. In phase 2 the increase in mean Psoriasis Area and Severity Index and the incidence of relapse were significantly higher in patients in whom cyclosporine was discontinued and replaced by dithranol than in patients in whom cyclosporine was tapered or who were pretreated with etretinate. During treatment four patients from the cyclosporine group and three patients of the etretinate group discontinued the study because of side effects. Conclusion: Low-dose short-term cyclosporine therapy for psoriasis is, in comparison with etretinate, highly effective and well tolerated. Individually adjusted cyclosporine therapy allows the majority of patients to continue the low dosage of 2.5 mg/kg/day and still achieve a good clinical response. Remission can be better preserved by tapering the drug than by discontinuing treatment abruptly.

Low-dose cyclosporine therapy in triple-drug immunosuppression for heart transplant recipients

The toxicity of long-term immunosuppressive therapy has become a major concern in long-term follow-up of heart transplant recipients. In this respect the quality of renal function is undoubtedly linked to cyclosporin A (CsA) drug levels. In cardiac transplantation, specific CsA trough levels have historically been maintained between 250 and 350 μg/L in many centers without direct evidence for the necessity of such high levels while using triple-drug intmunosuppression. This retrospective analysis compares the incidence of acute and chronic graft rejection as well as overall mortality between groups of patients with high (250 to 350 μg/L) and low (150 to 250 μg/L) specific CsA trough levels. A total of 332 patients who underwent heart transplantation between October 1985 and October 1992 with a minimum follow-up of 30 days were included in this study (46 women and 276 men; aged, 44± 12 years; mean follow-up, 1,122 ± 777 days). Standard triple-drug immunosuppression included firstyear specific CsA target trough levels of 250 to 300 μg/L. Patients were grouped according to their average creatinine level in the first postoperative year (group I, 1;30 μmol/L, n = 234; group II, 3≥130 μmol/L, n = 98). The overall 5-year survival excluding the early 30-day mortality was 92% (group I, 216/232) and 91% (group II, 89/98) with 75% of the mortality due to chronic rejection. The rate of rejection for the entire follow-up period was similar in both groups (first yean group I, 3.2 ± 2.6 rejection/patient/year; group II, 3.6± 2.7 rejection/ patient/year; p = not significant). The CsA levels were significantly lower in group II patients (CsA level: group 1,240± 58 μg/L versus group II, 197± 51 μg/L; p < 0.05). The results show that in patients with preoperatively or perioperatively compromised renal function specific CsA levels can be lowered safely to less than 200 μg/L without an increased risk for acute or chronic graft rejection. This reduction often is associated with preservation or even improvement of renal function.