Low-dose Cyclosporine Therapy Research Articles

Low-dose Cyclosporine Therapy in the Treatment of Birdshot Retinochoroidopathy

Birdshot retinochoroidopathy is an uncommon uveitic syndrome of presumed autoimmune etiology. Therapy with systemic and periocular steroids is of inconsistent efficacy, attendant with numerous potential long-term side effects. Steroid-sparing strategies with more specific agents such as cyclosporine (Cyclosporin A, CSA) have been suggested as the first line treatment for this disease. The records of 19 patients (35 eyes) with the clinical diagnosis of birdshot retinochoroidopathy were examined. Age at onset ranged from 33 to 69 years (mean, 46.1 years) in nine men and ten women. The median follow-up from disease onset was 36 months. Eight patients were treated with low-dose (2.5-5 mg/kg daily) CSA alone, six required the addition of azathioprine (1.5-2 mg/kg daily), and six received no systemic immunosuppressive therapy. HLA-A29 was positive in 94% (16 of 17) of patients tested. Vitreous inflammation was controlled in 23 (88.5%) treated eyes, with fewer bouts of recurrent inflammation, and a corresponding improvement or stabilization of visual acuity in 20 (83.3%) eyes. In contrast, intraocular inflammation never was controlled fully in untreated eyes, and visual acuity decreased in six (54.5%) eyes by an average of 2.5 Snellen lines. Nephrotoxic side effects of low-dose CSA therapy were not observed, but hypertension developed in two patients. Although the definitive strategy for the management of birdshot retinochoroidopathy is unknown, control of intraocular inflammation with a favorable visual outcome, together with a lack of demonstrable CSA-associated nephrotoxicity and secondary side effects in these patients with birdshot retinochoroidopathy indicate that vision preservation is possible with low-dose CSA alone or in combination with other steroid-sparing immunosuppressive agents as an alternative to the long-term use of corticosteroids.

Acute reversible central nervous system toxicity associated with low-dose oral cyclosporine therapy

Cyc1osporine isan immunosuppressant drug that has been used to prevent rejection of transplanted organs for more than a decade. More recently, cyc1osporine has been used inthe treatment ofcutaneousdiseases suchaspyodermagangrenosum (PG)1-7 that have been unresponsive to other therapies. We describe the occurrence of acute, reversible central nervous system (eNS) toxicity in a patient treated with low-dose oral cyclosporine for PG.

Urinary Acidification Response to Furosemide Administration in Patients on Low-Dose Cyclosporine Therapy

The response of urinary acidification parameters and electrolytes to furosemide administration was prospectively studied in 9 psoriatic patients treated with a low-dose cyclosporine A schedule (initial dose: 5 mg/kg body weight) before beginning cyclosporine A, after 3 months on cyclosporine A and 1 month after cyclosporine A withdrawal. The test was also performed in 29 psoriatic patients after 3 months on 5 mg/kg body weight cyclosporine A treatment. There were no significant differences between before and after cyclosporine A treatment regarding furosemide-induced changes in urinary volume, sodium or potassium excretion. Contrarily, the post-furosemide urinary pH decrease and ammonium and titrable acid increase were significantly lower in cyclosporine-A-treated patients. Five of the 29 studied patients showed abnormal furosemide tests (17%). These patients had lower total serum CO2, urea and creatinine but similar serum potassium and fractional potassium excretion. We conclude that some patients treated with low-dose cyclosporine A therapy develop an abnormal tubular distal response to furosemide administration, suggesting an alteration in the H(+)-ATPase pump or a voltage-dependent mechanism.

Cyclosporin in the treatment of psoriasis

The purpose of this study was to evaluate the efficacy of a low-dose cyclosporin therapy in psoriasis. In the multicentre study, carried out in Korea, 52 patients with moderate to severe psoriasis were treated with an initial dose of 2.5 mg/kg per day cyclosporin for 18 weeks. In 44 patients the dose was increased gradually up to 5 mg/kg per day according to the therapeutic response. Treatment success, defined as a reduction in PASI score by at least 66%, was achieved in 76.9% of patients. PASI scores reduced significantly from 20.0 to 5.4. Changes in systolic and diastolic blood pressure were not statistically significant. A 30% increase in serum creatinine in comparison with baseline was observed in five patients (9.6%) by the 18th week, but none of the patients showed an increase beyond the normal range. The overall assessments of efficacy and tolerability by both the investigators and the patients were mostly ‘good’ or ‘very good’. Our regimen of low-dose cyclosporin therapy (2.5 mg/kg per day initial...

Sustained renal function loss in psoriasis patients after withdrawal of low-dose cyclosporin therapy

Eight patients with psoriasis received low-dose cyclosporin (CyA) treatment for an average period of 12 months (range 4-16 months). There was great variability in minimal effective CyA dose. In 50% of the patients long-term treatment was limited by dose reductions necessitated by side-effects. A considerable impairment of renal function during CyA therapy was found. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured with 125I-iothalamate and 131I-hippuran, respectively. Both at the end of the active treatment period (GFR-CyA and ERPF-CyA), and 4 months after withdrawal of CyA (GFR-4mo and ERPF-4mo), there was sustained renal impairment: GFR-BL = 97 (64-117), GFR-CyA reduction 17.8% (2.2-31.9%) [P < 0.02], GFR-4mo reduction = 9.8% (5.5-21.5%) ml/min/1.73 m2 (P < 0.05 vs. BL); ERPF-BL = 401 (232-607), ERPF-CyA reduction = 10.1% (7.4-27.3%) [P < 0.05], ERPF-4mo reduction = 13.5% (3.0-32.9%) ml/min/1.73 m2 (P < 0.02). Further studies of the effects on renal function during, and after, long-term therapy of psoriasis with low-dose CyA are warranted.

Renal function and blood pressure in patients receiving long-term, low-dose cyclosporine therapy for idiopathic autoimmune uveitis.

To determine the renal side effects of long-term, low-dose cyclosporine therapy (initial dose, 5 mg/kg body weight per day) in patients with autoimmune idiopathic uvetis. Cohort study with at least 2 years of follow-up. A teaching hospital in Paris, France (Hôpital Pitié-Salpétrière). Sixteen patients with idiopathic autoimmune uveitis who were normotensive and had normal renal function before treatment. Cyclosporine was administered orally for at least 2 years at an initial dosage of 5 mg/kg body weight per day. After 2 years of treatment, the serum creatinine level increased by 35 +/- 5 mumol/L (0.40 +/- 0.06 mg/dL) (95% CI, 25 to 46 mumol/L, [73 +/- 4 to 108 +/- 4 mumol/L]). Creatinine clearance decreased significantly from 120 +/- 5 mL/min to 75 +/- 4 mL/min. Glomerular filtration rate decreased from 116 +/- 8 mL/min to 75 +/- 3 mL/min, and effective renal plasma flow decreased from 455 +/- 24 mL/min to 338 +/- 30 mL/min (P less than 0.05). Cyclosporine induced a significant increase in serum uric acid, total cholesterol, and serum potassium levels. Blood pressure was normal in all patients before treatment; 81% (95% CI, 64% to 98%) of these patients developed hypertension after 24 months of treatment. Blood pressure was controlled with a single drug in all but two patients. In patients with healthy native kidneys, long-term cyclosporine therapy, even at a low dose (5 mg/kg per day), is nephrotoxic and is associated with a high incidence of hypertension.

Low-dose cyclosporin therapy of ocular inflammation: Preliminary report of a long-term follow-up study

Cyclosporin A (CsA) is an effective therapy for severe intraocular inflammation but nephrotoxicity and hypertension are major side effects even in low dose in combination with oral corticosteroids and clinical studies on the long-term effects of low-dose CsA therapy outside the field of organ transplantation are lacking. This multicentre, open, longitudinal study has been established to evaluate the long-term efficacy and side effects of low-dose CsA therapy (initial dose less than or equal to 5 mg/kg/day, with a maximum dose of 7 mg/kg/day, and total treatment duration greater than 3 months) in severe ocular inflammation where conventional therapy had failed to control the disease or caused intolerable side effects. Visual response to treatment, clinical signs and symptoms of side effects, biochemical and haematological parameters have been recorded at 3-monthly intervals since January 1987 and will continue until December 1993. Data for 74 patients (age 35.5 +/- 16.6 years) and 293 follow up visits are presented in this preliminary report. [table: see text] Other side effects include (% of all visits): hypertrichosis (4.2), headache (2.8), cramps (1.8), arthropathy (1.8), paraesthesiae (1.8), abdominal pain (1.5), weakness (1.5), dyspepsia (1.4), nausea (1.4), others (4).

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

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

Use of cyclosporin in the management of steroid dependent non-necrotising scleritis.

Many patients with non-necrotising scleritis can be treated adequately with non-steroidal anti-inflammatory drugs or steroids. But, as many of them are young, treatment may present problems if they require high doses of steroids to control the scleral inflammation and then relapse when the dosage is reduced. Five such patients were treated with a combination of steroids and low-dose cyclosporin therapy, and in all cases the scleritis remained under control on a much lower dose of steroids than when steroids were used alone. Cyclosporin is therefore a useful drug in the management of younger patients dependent on high-dose steroids to control their scleral inflammation.

Immunohistologic evaluation of the effect of cyclosporine treatment on the lichen planus immune infiltrate

We have investigated immunohistologically the cutaneous immune infiltrate in the lesions of five patients with severe, extensive lichen planus of recent onset before and after 15 days of oral, low-dose cyclosporine therapy (3 mg/kg/day). Before therapy, we observed an abnormal bandlike cellular infiltrate localized in the papillary dermis, composed mostly of CD3+ cells, with a prevalence of CD4+ cells. Infiltrating lymphocytes showed markers of activation (HLA-DR antigens and interleukin 2 receptor), and there were many Langerhans (CD1+) cells in the dermal infiltrate. After 15 days of cyclosporine therapy, we observed a dramatic decrease in the total number of T cells and a corresponding decrease in interleukin 2 receptor-positive activated CD25+ cells and in antigen-presenting cells (CD1+ and CD14b+). These changes were concurrent with clinical improvement. Our results are compatible with the hypothesis that the inhibition of CD4 T cells by cyclosporine might explain the drug's therapeutic action and that the interaction between antigen-presenting cells and CD4 T cells is important in the pathogenesis of lichen planus.

Combined anti-interleukin-2 receptor and low-dose cyclosporine therapy in experimental autoimmune uveoretinitis

The effect of combination treatment with anti-interleukin-2 (IL-2)-receptor monoclonal antibody (ART18) and cyclosporine A (CsA) on the effector stage of experimental autoimmune uveoretinitis (EAU) was examined. Efferent-stage EAU was induced in Lewis rats by adoptive transfer of a T-helper cell line specific to retinal soluble antigen (SAg). Rats were treated with ART18 (0.5 mg/kg/day), low dose CsA (1.5 mg/kg/day), or a combination of both. The results were compared to groups treated with high dose CsA (10 mg/kg/day) and to sham-treated animals, with respect to clinical and histological EAU, lymphocyte proliferative responses to SAg, and the ability to transfer EAU to secondary recipients. Ten-day combination therapy with ART18 and low-dose CsA was more effective than high-dose CsA and almost completely suppressed EAU development. ART18 as sole therapy was partially effective, and was better than low dose CsA as sole therapy. Splenocytes of protected animals did not transfer EAU to secondary recipients, while splenocytes of sham-treated controls did, suggesting that the number of uveitogenic lymphocytes in the treated host was reduced by the therapy. In contrast, this therapy was completely ineffective against EAU induced by active immunization. The possible reasons for this discrepancy between the two respective models of EAU are discussed.

THE SURVIVAL AND NATURE OF THE IMMUNE RESPONSE TO SOFT-TISSUE AND COMPOSITE-TISSUE ALLOGRAFTS IN RATS TREATED WITH LOW-DOSE CYCLOSPORINE

We studied a variety of soft-tissue and composite-tissue allografts (CTA) in a histoincompatible rat model to determine the outcome and the nature of the immunologic responses to these tissues using continuous low-dose cyclosporine (CsA) therapy. Brown-Norway (RT1n) rats served as donors of soft tissue and CTA to Lewis (RT1l) rat recipients given low-dose CsA immunosuppressive therapy by gavage. Nine groups were studied. Three control groups were not treated with CsA: group 1, skin grafts alone; group 2, skin flaps alone; and group 3, skin grafts and delayed vessel allotransplants. Six groups were treated with CsA: group 4, skin grafts alone; group 5, skin flaps alone; group 6, skin grafts and delayed vessel allotransplants; group 7, aortas alone; group 8, muscle flaps alone; and group 9, bone grafts alone. Isografts were performed in all groups as technical controls. The appearance posttransplant of donor-directed cytotoxic antibodies was determined in recipient serum using a complement-mediated cytotoxicity assay and was compared to control and pretransplant sera. In the absence of CsA therapy, recipients in groups 1, 2, and 3 rejected their allografts early (8.5-9.4 days) and developed profound antidonor cytotoxic antibody activity posttransplant by day 7. Groups 4, 5, 6, 7, and 9 had prolonged graft survival in the presence of low-dose CsA, despite the presence of antidonor antibody activity. By contrast, group 8 (muscle flaps) were all uniformly rejected in the presence of profound recipient cytotoxic antidonor antibody activity. These results suggest that long-term soft-tissue and CTA survival can be achieved in histoincompatible rat recipients using continuous low-dose CsA immunosuppressive therapy despite the presence of cytotoxic antidonor antibodies.

Skin color reflectance measurements for objective quantification of erythema in human beings

but possibly both, squamous cell carcinomas occurred during immunosuppression by cyclosporine, which facilitated the development of malignancies in skin previously exposed to UVB, PUVA, and perhaps arsenic compounds. Although it has not been entirely excluded that cyc1osporine's efficacy in treatment of psoriasis is due to an action independent ofimmunosuppression,3 webelieve that our case demonstrates that low-dose cyclosporine therapy alone is immunosuppressive enough to facilitate the development ofmalignancies in predisposed skin. Cyclosporine should therefore be withdrawn after the development of squamous cell carcinoma and should not be given to patients with a history of such a lesion. We suggest that previous treatments, such as arseniccompounds; UVB, and PUVA, with modalities predisposing to the development ofmalignancies may prove to be contraindications to the use of low-dose cyclosporine alone as therapy for psoriasis.

Cyclosporine in the Treatment of Psoriatic Arthritis

The short-term efficacy of cyclosporine in the treatment of six patients with moderately severe to severe psoriatic arthritis was evaluated in an open study. Patients received oral cyclosporine (6 mg/kg/d) for eight weeks. In all patients, significant improvement of psoriasis was noted within two to four weeks. At the end of therapy, rheumatologic assessment revealed the following trends in disease activity: a decrease in the number of tender joints, joint tenderness index, duration of morning stiffness, and an increase in grip strength. There was a decrease in the number of swollen joints, joint swelling index, and the time taken to walk 50 ft. Overall disease activity significantly improved as assessed independently by the patient and physician. For psoriasis and psoriatic arthritis, disease activity worsened toward baseline within four weeks of discontinuation of therapy. Short-term, low-dose cyclosporine therapy may be effective in treating psoriasis and psoriatic arthritis.

Effect of cyclosporine on immunologically mediated diabetes in nonobese diabetic mice.

Spontaneous diabetes in NOD mice has an immunologically mediated cause and is a T cell-dependent process. When diabetic NOD mice are grafted with cultured BALB/c islet tissue, the islet graft is destroyed by disease recurrence in the graft. Disease recurrence is a CD4 T cell-dependent process as determined by in vivo administration of anti-CD4 or anti-CD8 monoclonal antibody prior to the grafting of islet tissue. Cyclosporine functions in the early sequence of T cell activation by regulating the production of messenger RNA for lymphokines synthesis. Cyclosporine does not inhibit the synthesis of lymphokine once the lymphokine message is present in the cell. Thus, we might expect cyclosporine to be relatively inefficient as an agent for the regulation of disease recurrence following transplantation to actively diabetic recipients, and we would expect cyclosporine to be more effective when administered before the onset of the disease. Low-dose cyclosporine treatment can prevent development of the disease when the drug is administered before the onset of disease. Data presented here show that cyclosporine is ineffective in controlling disease recurrence in the islet graft transplanted to actively diabetic animals. Also, when we eliminate CD4 T cells from the diseased animals and graft islet tissue prior to the administration of cyclosporine, we are unable to maintain a graft with low-dose cyclosporine therapy. This result leads us to conclude that, although anti-CD4 treatment controls the expression of the disease process and allows the survival and function of the islet graft, this treatment does not return diseased animals to the prediabetic condition in which the development of diabetes can be controlled by low-dose cyclosporine therapy.

Low-dose cyclosporine therapy combined with standard immunosuppression in pediatric renal transplantation

A new immunosuppressive regimen combining anti-lymphocyte globulin, azathioprine, prednisone, and low doses of cyclosporine was used in 28 children aged 9 months to 17 years (mean 5.8 years) who received primary renal allografts between July 1, 1984, and September 25, 1986. After a mean follow-up of 17.3 months, the patient and graft survival is 100% (18 of 18) for mismatched related kidneys, and 90% (nine of 10) for cadaver kidneys. The single graft failure was the result of a death from technical complications. Serum creatinine concentration after transplantation ranged from 0.3 to 1.7 mg/dL (mean 0.85 mg/dL). The probability of a rejection episode in the first year was 45% and 60% for mismatched-related and cadaver kidneys, respectively. Cyclosporine nephrotoxicity was recognized in only one (3.7%) of 27 children, and was rapidly reversed after cyclosporine was discontinued. An initial group of nine children was weaned from cyclosporine therapy 6 to 12 months after transplantation, but two (22%) had rejection episodes. Our preliminary experience suggests that the use of a quadruple immunosuppressive regimen for both living related and cadaver renal transplants in children is associated with an improved graft function rate and a low incidence of complications.