Cyclosporine Group Research Articles

Comparison of postoperative cyclosporine 2.0% versus betamethasone 0.1% eye drops following trabeculectomy: A randomized clinical trial.

To investigate the effect of cyclosporine A 2% eye drop following trabeculectomy on intraocular pressure (IOP) and surgical success compared to postoperative steroid drop. Prospective, randomized clinical trial in an institutional setting. Forty patients with primary open-angle glaucoma and candidates for trabeculectomy were included in this study. Standard fornix-based trabeculectomy augmented with mitomycin C was performed for all patients. None of the included subjects had a history of prior laser or intraocular surgery in that eye. All included subjects were randomly assigned to either postoperative cyclosporine A 2% or betamethasone 0.1% eye drops. IOP measured by applanation tonometer and surgical success rate. Seventy-five potentially eligible POAG patients were seen during the study period, and 40 met the study criteria and were randomly assigned to one of the study groups. Patients in the cyclosporine A 2% group had consistently lower IOP, fewer glaucoma medications, and higher success rates for at least 24 months after surgery (P < 0.0001). Complete success was more frequent in the cyclosporine group. Moreover, the cyclosporine A group had more diffuse and elevated bleb with less vascularity in the first 3 months after surgery (P ≤ 0.01). This was paralleled with fewer dry eye signs and symptoms in the cyclosporine group in the first 3 months (P < 0.03). Postoperative cyclosporine A 2% eye drop can be used instead of steroid drops and is associated with improved surgical success and decreased dry eye manifestations.

Efficacy of Topical Cyclosporine Combined with Punctal Plugs in Treating Dry Eye Disease and Inflammation

Purpose To evaluate the effect of punctal plugs combined with cyclosporine eye drops on dry eye disease (DED) and ocular surface inflammation. Methods In a clinical trial, 73 patients were randomly allocated into three groups: punctal plug group, combination therapy group, and cyclosporine group. At the baseline and four weeks after treatment, the Schirmer I test score, fluorescein tear film break-up time (FBUT), ocular surface staining score and dry eye symptoms were assessed. Tear samples were collected to detect the level of inflammatory factors (interleukins, matrix metalloproteinase 9 (MMP-9) and tumor necrosis factor alpha (TNF-α)). In an animal experiment, a New Zealand rabbit dry eye model was induced. The rabbits were randomly divided into control group, punctal plug group, and combination therapy group (n = 6). Conjunctival goblet cell density, protein level of MMP-9 in conjunctiva and mRNA levels of inflammatory factors in conjunctiva and cornea were measured before and after treatment. Results In combination therapy group of the clinical trial, the following results were observed: significant improvement in Schirmer I test scores and FBUT compared to the cyclosporine group and punctal plug group, respectively; a decrease in the tear levels of IL-6, IL-1, and MMP-9 compared to the punctal plug group; and a decrease in the tear levels of IL-1α, IL-6, and IL-17 compared to the baseline (all p < 0.05). In the animal experiment, rabbits in combination therapy group had a higher goblet cell density (p < 0.01) and lower mRNA levels of IL-16 (p < 0.05), IL-17 (p < 0.05), and MMP-9 (p < 0.01) in conjunctiva and that of MMP-9 (p < 0.01) in cornea compared to punctal plug group. Conclusion Cyclosporine eye drops combined with degradable punctal plugs is a more optimized clinical treatment strategy for DED compared with degradable punctal plugs or cyclosporine eye drops alone, considering the influence of comprehensive clinical efficacy and ocular surface inflammation.

Effect of Early Cyclosporine Treatment on Survival in Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis.

Early cyclosporine administration is a potentially useful treatment in patients with Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN). However, previous studies have reported conflicting results regarding the survival benefits. Therefore, in this study, we evaluated the survival of patients with SJS/TEN according to whether they received early cyclosporine administration. This retrospective cohort study was conducted using a Japanese national administrative claims database. Data on patients admitted to the hospital with SJS/TEN between April 1, 2016, and March 31, 2021, were extracted. Patients with missing data, those discharged within two days of admission, pregnant women, and children aged <16 years were excluded. Patients who received cyclosporine on the day of admission (early cyclosporine group) were compared with those who did not (comparison group). The primary endpoint was in-hospital mortality. Secondary endpoints were 30- and 50-day mortality and length of hospital stay. The effect of early cyclosporine treatment was evaluated after baseline adjustment using doubly robust estimation. Among 3807 enrolled patients (mean age, 65.5 years; 53.8% women), the early cyclosporine and comparison groups included 115 and 3692 patients, respectively. After adjustment, cyclosporine treatment decreased in-hospital mortality by 6.03% (95% confidence interval (CI), 5.27-6.82%), 30-day mortality by 2.94% (95% CI, 2.43-3.50%), and 50-day mortality by 4.38% (95% CI, 3.70-5.04%), but increased the length of hospital stay by 9.45 days (95% CI, 1.00-20.23 days). Early cyclosporine administration can improve the survival of patients with SJS/TEN but is associated with a longer hospital stay.

Water-Free Cyclosporine Ophthalmic Solution vs Vehicle for Dry Eye Disease

Dry eye disease (DED) is a prevalent eye disorder. Cyclosporine is an effective immunomodulator that is widely used in DED; however, due to its highly hydrophobic nature, delivery of cyclosporine to the ocular surface is challenging. To evaluate the efficacy and safety of SHR8028, a water-free cyclosporine ophthalmic solution, 0.1%, compared with vehicle in Chinese participants with DED. This was a multicenter, double-blind, vehicle-controlled, phase 3 randomized clinical trial conducted from March 4, 2021, to July 22, 2022. Adult participants with moderate to severe DED were recruited from 12 hospitals in China. Study data were analyzed April 2, 2022, for the primary analysis. Following a 14-day run-in period with an artificial tear, participants were randomly assigned (1:1) to receive water-free cyclosporine or vehicle (1 eye drop in each eye twice daily). After a 29-day treatment, participants of both groups were given the option to receive water-free cyclosporine for an additional 12 weeks for longer-term safety assessment. The primary end points were changes from baseline in total corneal fluorescein staining (tCFS) using the National Eye Institute scale and in dryness score on a visual analog scale at day 29. A total of 206 participants (mean [SD] age, 47.8 [14.2] years; 185 female [90%]) were enrolled, with 103 each in the cyclosporine group and the vehicle group. At day 29, the cyclosporine group experienced improved tCFS compared with vehicle (change [Δ] = -1.8; 95% CI, -2.7 to -1.0; P < .001), with a tCFS score decrease from baseline of -4.8 in the cyclosporine group and -3.0 in the vehicle group. Dryness score decreased from baseline in both groups (-19.2 vs -15.4; Δ = -3.8; 95% CI, -9.2 to 1.6; P = .17). During the 29-day treatment, treatment-related adverse events were reported in 15 participants (14.6%) in the cyclosporine group and 11 participants (10.7%) in the vehicle group. Results demonstrated superiority of a water-free cyclosporine, 0.1%, eye solution over vehicle in improving tCFS score at day 29 in Chinese participants with DED. However, dryness score (VAS) was not improved at day 29. ClinicalTrials.gov Identifier: NCT05841043.

Possible mechanisms involved in the protective effect of lutein against cyclosporine-induced testicular damage in rats

Oxidative stress and aberrant inflammatory response have important implications in cyclosporin-induced reproductive functions. Previous studies have shown that agents with antioxidant and anti-inflammatory activities might be beneficial in reversing cyclosporin-induced reproductive impairment. Lutein is a naturally occurring compound with antioxidant and anti-inflammatory properties. However, the effect of lutein against cyclosporin-induced reproductive impairment remains in complete. Hence, we investigated the protective effect of lutein, specifically focusing on the role of nuclear factor erythroid 2 related factor-2 (Nrf2)/heme-oxygenase-1 (HO-1)/connexin-43 (Cx-43) upregulation system against cyclosporine-induced reproductive impairment. Six male Wistar rats were allotted into 5 groups and given daily gavage of cyclosporine (40 mg/kg) and/or lutein (30 mg/kg) for four (4) weeks or in combination, respectively. The testicular antioxidant scaffolds: superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH), add to sulfhydryl (T-SH), non-protein sulfhydryl (NP-SH), glutathione reductase (GR), glutathione-S -transferase (GST), glutathione peroxidase (GSH-Px), thiobarbituric acid reactive substances (TBARS), myeloperoxidase (MPO), testicular proinflammatory cytokines, apoptotic related protein, nucleic acids, sialic acid, testicular proton pump ATPase, stress responsive protein, BTB-related protein and total protein levels in the testes were assayed thereafter. Cyclosporin significantly increased NOX-1, TNF-α, IL-1β, MPO, caspase-3 and -9 levels, which were reversed by lutein. Lutein reversed cyclosporin-induced decreases in Nrf2, HO-1, BCL-2, cytochrome C, with corresponding increase in CAT, SOD, GSH, T-SH, NP-SH, GST, GR, GSH-Px, and Cx-43 levels compared to cyclosporin groups. Lutein also abates cyclosporin-induced alterations Na + -K + -ATPase activities. Our findings showed that lutein's protective effect against cyclosporin-induced reproductive impairment might be associated with mechanisms linked to its antioxidant, anti-apoptotic, and anti-inflammatory properties, notably through up-regulation of Nrf2/HO-1/Cx-43 signaling and down-regulation of NOX-1 signaling.

Effects of Cyclosporine and Azacitidine on Some Hematologic and ‎Biochemical Parameters of Benzene-Induced Aplastic Anemia in Rats

Aplastic anemia, marked by deficiencies in hematopoietic stem cells, leads to peripheral blood pancytopenia and hypocellular bone ‎marrow. This study aimed to evaluate the therapeutic efficacy of cyclosporine and azacitidine, administered either alone or in combination, in rats with benzene-induced aplastic ‎anemia, focusing on restoring normal blood cell levels and preventing disease complications. Thirty adult female Wistar rats ‎(Rattus ‎norvegicus)‎ were randomly divided into five groups: negative control (C-, untreated), positive control (C+, induced aplastic anemia with ‎distilled water), cyclosporine-treated (CsA, 5.86 mg/kg), azacitidine-treated (Aza, 5.75 mg/kg), and combination-treated (CsA+Aza, 3.68 ‎mg/kg each). Benzene (1940 mg/kg) was administered orally for fifteen days to induce aplastic anemia. Post a 30-day treatment period, ‎evaluations included differential WBC and reticulocyte counts, serum IL-2 levels, and alkaline phosphatase (ALP) activity. Results ‎showed significant improvements in WBC% and reticulocyte% in all treated groups compared to the C+ group, with the combination-‎treated group showing the highest enhancement. IL-2 levels in the combination group were significantly reduced compared to other ‎treatment groups, aligning closely with the negative control. The ALP activity was significantly higher in both the cyclosporine and ‎azacitidine-treated groups compared to the positive control, with the combination group showing a marked increase over the azacitidine ‎group but no significant difference from the cyclosporine group and negative control.‎ In conclusion, the study demonstrates the potential therapeutic benefits of cyclosporine and azacitidine in treating benzene-induced ‎aplastic anemia in rats. The combination therapy, in particular, showed improved efficacy in all tested parameters, suggesting a potential ‎strategy for dose reduction and toxicity mitigation.

Comparison of the Effects of 0.05% and 0.1% Cyclosporine for Dry Eye Syndrome Patients after Cataract Surgery

Purpose: We compared the effects of 0.05% and 0.1% cyclosporine on dry eye symptoms following cataract surgery.Methods: We retrospectively reviewed the medical records of patients with dry eye syndrome who underwent cataract surgery. The patients were separated into 0.05% and 0.1% cyclosporine groups. Each group had been treated with their routine eye drops for 3 months after cataract surgery. We evaluated dry eye symptoms and signs using the Schirmer test, tear film breakup time (TBUT), corneal and conjunctival staining score, ocular surface disease index (OSDI), and matrix metalloproteinase 9 (MMP-9) testing of the tear film preoperatively and at 2 weeks, 1 month, and 3 months postoperatively. We also compared dry eye symptoms between the groups by dividing all patients according to dry eye severity.Results: The study included 84 eyes (84 patients). The 0.05% cyclosporine group had an increase in the Schirmer test and improved corneal and conjunctival staining scores at 3 months postoperatively. The 0.1% cyclosporine group had improved corneal and conjunctival staining scores at 1 and 3 months postoperatively. The OSDI and MMP-9 results indicated a significant decrease in both groups at 2 weeks, 1 month and 3 months postoperatively. There were no significant differences in the change in dry eye symptoms after cataract surgery between the 0.05% and 0.1% cyclosporine groups. In the patients with level II dry eye syndrome, the 0.05% cyclosporine group showed a significant increase in the Schirmer test compared to the 0.1% cyclosporine group at 3 months postoperatively. The 0.1% cyclosporine group showed a significant improvement in TBUT compared to the 0.05% cyclosporine group at 3 months postoperatively.Conclusions: Both 0.05% and 0.1% cyclosporine are effective treatments for improving dry eye symptoms and ocular surface inflammation after cataract surgery. Both eye drops are considered to have similar effectiveness.

Cyclosporine A therapy in patients with COVID-19 and failure of immunosuppression therapy: a retrospective cohort propensity-score matched analysis

INTRODUCTION: Therapy of COVID-19 patients with progressive lung damage after the use of glucocorticosteroids (GCS) and interleukin-6 inhibitors (IIL-6) has not yet been developed. OBJECTIVE: Assessment of the effectiveness of cyclosporine A in patients with COVID-19 with progression of lung damage and hypoxemic acute respiratory failure, who received therapy with GCS and IIL-6. MATERIALS AND METHODS: A retrospective cohort propensity-score matched analysis (n = 98). Cyclosporine A was prescribed in the first 72–96 hours after IIL-6 administration when the patient's condition worsened. The patients of comparison group corresponded to the study group, but did not receive cyclosporine A therapy. The primary end point was in-hospital mortality. Secondary endpoints — duration of hospitalization, number of patients admitted to the intensive care unit (ICU), need for respiratory support. RESULTS: Mortality was 12 (22) % in the cyclosporine group and 27 (61) % in the comparison group, р = 0.001 (hazard ratio [HR] 2.00 (1.12–3.48), р = 0.018), ICU admission rate 14 (26) % vs 29 (66) %, р = 0.001, respectively. In the cyclosporine group on day 7 CT-4, there were 26 % of patients vs 52 % in the control group, р = 0.014, the need for respiratory support (37 % vs 63.6 %, р = 0.011); saturation 88 % (82–93) vs 80 % (70–86), р = 0.001, respectively. The need for respiratory support at day 11 after IIL-6 increased the likelihood of death (HR 7.10 (2.5–20), р = 0.001). Risk factors for death: age over 57.5 years, body mass index over 30 kg/m2, hemoglobin oxygen saturation below 85.5 % on the day of IIL-6 application. Duration of hospitalization was 18.5 (14–24) days vs 18 (12–24) days, р = 0.778. CONCLUSIONS: Cyclosporine A in addition to GCS and IIL-6 for COVID-19 therapy may reduce mortality, ICU admissions, and respiratory support requirements.

Chronic dehydration induces injury pathways in rats, but does not mimic histopathology of chronic interstitial nephritis in agricultural communities

CINAC-patients present renal proximal tubular cell lysosomal lesions which are also observed in patients experiencing calcineurin inhibitor (CNI) nephrotoxicity, suggesting that CINAC is a toxin-induced nephropathy. An alternative hypothesis advocates chronic dehydration as a major etiological factor for CINAC. Here, we evaluated histological and molecular changes in dehydrated versus toxin exposed rats. Wistar rats were divided in 3 groups. Group 1 (n = 6) had free access to drinking water (control group). Group 2 (n = 8) was water deprived for 10 h per 24 h, 5 days/week and placed in an incubator (37 °C) for 30 min/h during water deprivation. Group 3 (n = 8) underwent daily oral gavage with cyclosporine (40 mg/kg body weight). After 28 days, renal function, histopathology and proteomic signatures were analysed. Cyclosporine-treated rats developed focal regions of atrophic proximal tubules with associated tubulo-interstitial fibrosis. PASM staining revealed enlarged argyrophilic granules in affected proximal tubules, identified as lysosomes by immunofluorescent staining. Electron microscopy confirmed the enlarged and dysmorphic phenotype of the lysosomes. Overall, these kidney lesions resemble those that have been previously documented in farmers with CINAC. Dehydration resulted in none of the above histopathological features. Proteomic analysis revealed that dehydration and cyclosporine both induce injury pathways, yet of a clear distinct nature with a signature of toxicity only for the cyclosporine group. In conclusion, both cyclosporine and dehydration are injurious to the kidney. However, dehydration alone does not result in kidney histopathology as observed in CINAC patients, whereas cyclosporine administration does. The histopathological analogy between CINAC and calcineurin inhibitor nephrotoxicity in rats and humans supports the involvement of an as-yet-unidentified environmental toxin in CINAC etiology.

A single-centre prospective study comparing efficacy and safety of apremilast with cyclosporine in moderate to severe atopic dermatitis.

Apremilast regulates several pro-inflammatory signals involved in atopic dermatitis (AD). A randomized, open-labelled study was conducted at a tertiary care centre in India. Fifty patients with AD of >1 year duration were randomly assigned in a 1:1 ratio to receive either apremilast (30 mg twice daily after initial titration) or cyclosporine (5 mg/kg/day) for 24 weeks, followed by a 12-week follow-up period. Primary outcome was mean percentage change in Eczema Area and Severity Index (EASI) from baseline to week 24. Secondary outcome measures were proportion of patients achieving EASI 75, EASI 90, ≥2-point improvement in Investigator's Global Assessment (IGA), SCORing Atopic Dermatitis (SCORAD) 75 at week 24 and percentage of patients experiencing ≥1 adverse effect (AEs). Mean percentage change in EASI (standard deviation) was -67.79% [22.44] in the apremilast treatment group and -83.06% [21.20] in the cyclosporine treatment group (p < 0.05). At week 24, 52.38% of patients in the apremilast group and 78.26% in the cyclosporine group achieved EASI 75 (p < 0.05); 14.29% in the apremilast group and 52.17% in the cyclosporine group achieved EASI 90 (p < 0.05) and 80.95% in the apremilast group and 82.60% patients achieved ≥2 point reduction in IGA (p > 0.05). 57.14% of patients achieved SCORAD 75 in the apremilast group and 69.56% in the cyclosporine group (p > 0.05). Mean time taken to achieve EASI 75 in the apremilast group was 4.50 ± 4.62 weeks, while it was 3.96 ± 3.43 weeks in the cyclosporine group (p > 0.05). Incidence of AEs was 28.57% in the apremilast group and 21.74%) in the cyclosporine group. Apremilast demonstrated lesser efficacy in comparison to cyclosporine; it has the advantage of a favourable safety profile and requires no laboratory monitoring.

A randomized non-inferiority trial of therapeutic strategy with immunosuppressants versus biologics for Vogt-Koyanagi-Harada disease

Biologics are increasingly used to treat Vogt-Koyanagi-Harada disease, but head-to-head comparisons with conventional immunosuppressants are lacking. Here in this randomized trial (Chinese Clinical Trial Registry, ChiCTR2100043061), we assigned 110 patients (27 early-phase and 83 late-phase) to cyclosporine-based immunosuppressant strategy (N = 56) or adalimumab-based biologic strategy (N = 54), each combined with a modified corticosteroid regimen. The primary outcome is change from baseline in best-corrected visual acuity at week 26. The margin of non-inferiority for cyclosporine is −7 letters. The primary outcome is 11.2 letters (95% CI, 7.5 to 14.9) in the cyclosporine group and 6.3 letters (95% CI, 3.1 to 9.6) in the adalimumab group (difference, 4.9; 95% CI, 0.2 to 9.5; P < 0.001 for non-inferiority). The between-group difference is −0.8 letters (95% CI, −6.1 to 4.5) in early-phase disease and 5.7 letters (95% CI, 0.2 to 11.2) in late-phase. Serious adverse events are reported less frequently in the cyclosporine group than in the adalimumab group (0.70 vs. 1.21 events per patient-year). Here, we report that combined with a non-standard corticosteroid regimen, cyclosporine-based immunosuppressant strategy is non-inferior to adalimumab-based biologic strategy by 26 weeks for visual improvement in a cohort of patients with Vogt-Koyanagi-Harada disease, 75% of whom have a late-phase disease.

Comparison of matrix metallopeptidase-9 expression following cyclosporine and diquafosol treatment in dry eye

Purpose We sought to evaluate the expression of matrix metalloproteinase-9 (MMP-9) in dry eyes treated with 0.05% cyclosporin A and 3.0% diquafosol tetrasodium. Methods One-hundred ninety-five eyes of 195 patients with dry eye were divided into three groups as follows: group 1, cyclosporin group (n = 69); group 2, diquafosol group (n = 59); and group 3, artificial tears eyes (n = 67). All eyes were treated and followed up for three months. Schirmer I Test, corneal staining, tear-film break-up time (TBUT), and tear-film MMP-9 content were measured at three months and compared between groups. The expression of MMP-9 was confirmed using a point-of-care test device (InflammaDry®; RPS Diagnostics, Sarasota, FL, USA) and graded as zero to four points. Results At the third month, MMP-9 expression was lower in group 1 as compared with in groups 2 and 3 (p = 0.020 and 0.006, respectively). The mean MMP-9 grade according to point-of-care testing was also lower in group 1 than in groups 2 or 3 (p = 0.002 and 0.038, respectively). MMP-9 showed a correlation with corneal staining in both groups 1 and 2 (all p < 0.001) and with Schirmer I Test and TBUT in group 1 (p = 0.018 and 0.015, respectively). Conclusions MMP-9 expression and grade were lower after treatment with cyclosporin than after treatment with diquafosol in the dry eye disease. Anti-inflammatory treatment can decrease ocular MMP-9 levels in dry eye disease.

#3776 THE TYPE Ⅱ ANTI-CD20 MONOCLONAL ANTIBODY MIL62 OR CYCLOSPORINE IN CHINESE PRIMARY MEMBRANOUS NEPHROPATHY: PRELIMINARY RESULTS OF A PHASE ⅠB/Ⅱ TRIAL

Abstract Background and Aims Anti-CD20 monoclonal antibody has become one of the first-line therapies for the treatment of moderate and high-risk primary membranous nephropathy (pMN). A novel glycoengineered type Ⅱ anti-CD20 antibody, MIL62 with a nearly completely afucosylated N-glycans in Fc region, has demonstrated superior activity compared with rituximab and obinutuzumab in vitro and in vivo, respectively. To evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of MIL62 in pMN, we conducted a multicenter, randomized, controlled, open-label, phase Ib/Ⅱ study (NCT05398653). Method This study aims to investigated MIL62 or Cyclosporine for the treatment of Chinese pMN. Eligible patients with pMN diagnosed by kidney biopsy, proteinuria of at least 3.5 g per 24 hours received intravenous MIL62 (two infusions, 600 or 1000 mg each, administered 14 days apart; repeated at 6 months) or Cyclosporine (starting at a dose of 3.5 mg per kilogram of body weight per day for 12 months). Patients were followed up for up to 104 weeks. The primary outcome was a composite of complete or partial remission of proteinuria and stable eGFR at 76 weeks. Laboratory variables and safety were also assessed. Results From February 23th, 2022 to December 21th, 2022, 85 patients were randomly enrolled from 19 centers in China, and received at least one dose of MIL62 or Cyclosporine. At the data cut-off date (January 30th, 2023), 60 patients were followed up for at least 12 weeks, 24/40 (60%) patients in the MIL62 group and 7/20 (35%) patients in the Cyclosporine group achieved complete or partial remission; 26 patients were followed up for at least 24 weeks, 11/18 (61.1%) patients in the MIL62 group and 2/8 (25%) patients in the Cyclosporine group achieved partial remission. In the 56 patients who were positive for anti-PLA2R antibodies (≥14RU/mL) at baseline and followed up for at least 12 weeks, 29/38 (76.3%) patients in the MIL62 group achieved immunological remission (PLA2R Abs&amp;lt;14RU/mL), which was superior to the Cyclosporine group where 8/18 (44.4%) patients achieved immunological remission (P&amp;lt; 0.05). The remission to MIL62 in our study was rapid because 61.1% of patients achieved complete or partial remission at 24 weeks compared with the 35% 6-month response rate reported in the Membranous Nephropathy Trial of Rituximab study [1]. Among the 85 safety-evaluable patients, treatment emergent adverse events (TEAEs) occurred in 23/30 (76.7%) patients in the MIL62 600 mg group, 26/30 (86.7%) patients in the MIL62 1000 mg group and 24/25 (96.0%) patients in the Cyclosporine group; treatment-related AEs (TRAEs) occurred in 21/30 (70.0%), 23/30 (76.7%) and 18/25 (72.0%) in the MIL62 600 mg, MIL62 1000 mg and Cyclosporine group respectively; Grade 3 or above TEAEs were observed in 5 (16.7%), 1 (3.3%) and 2 (8.0%) patients in the MIL62 600 mg, MIL62 1000 mg and Cyclosporine group respectively; Serious adverse events (SAEs) occurred in 5 (16.7%), 0 (0.0%) and 2 (8.0%) patients in the MIL62 600 mg, MIL62 1000 mg and Cyclosporine group respectively. Only one patient in the MIL62 600 mg group experienced serious treatment-related thrombocytopenia and has recovered so far; Other SAEs are not related to treatment. B cell depletion occurred within 24 hours after MIL62 infusion and could last for 24 weeks. Conclusion The 12-week immunological remission rate in the MIL62 group was significantly higher than the Cyclosporine group. MIL62 had a manageable safety profile. This phase Ib/II preliminary data warrant further phase III clinical trials of MIL62 in pMN.

Effects of Postoperative Intravenous Cyclosporine Treatment on the Survival and Functional Performance Status of Patients With Glioblastoma: A Randomized, Triple-Blinded, Placebo-Controlled Clinical Trial

Glioblastoma is associated with low median survival time irrespective of maximal treatment. Previous invitro studies have revealed tumor inhibitory effect of cyclosporine A. However, whether the addition of cyclosporine could improve survival among patients with glioblastoma is unknown. This study aimed to determine the impact of postoperation treatment with cyclosporine on the survival and performance status. In this randomized, triple-blinded, placebo-controlled trial, 118 patients with glioblastoma who underwent surgery were treated with standard chemoradiotherapy regimen. Patients were randomized to receive intravenous cyclosporine for 3days postoperatively or placebo during the same period. The primary endpoint was the short-term effect of intravenous cyclosporine on survival and Karnofsky performance scores. Secondary endpoints were chemoradiotherapy toxicity and neuroimaging features. The overall survival (OS) in the cyclosporine (17.03 ± 5.8, 95% confidence interval: 11-17.37months) group was statistically lower than in the placebo (30.53 ± 4.9, 95% confidence interval: 8-32.3months) groups (P=0.049). However, compared to the placebo group, a statistically higher percentage of patients in the cyclosporine group were alive at 12months follow-up. Also, progression-free survival in the cyclosporine group was significantly prolonged than in the placebo group (6.3 ± 4.07months vs. 3.4 ± 2.98months, P < 0.001). In the multivariate analysis, age <50years (P= 0.022) and gross total resection (P= 0.03) were significantly associated with OS. Our study results demonstrated that administering postoperative cyclosporine does not improve OS and functional performance status. Notably, the survival rate was significantly dependent on the patient age and the extent of glioblastoma resection.

EXCELLENT OUTCOMES OF SUBCUTANEOUS PANNICULITIS‐LIKE T‐CELL LYMPHOMA TREATED WITH CYCLOSPORIN‐BASED REGIMEN, A MULTICENTER RETROSPECTIVE STUDY IN THAILAND

Background: Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare form of cytotoxic T-cell lymphoma, characterized by primary cutaneous tissue involvement mimicking inflammatory panniculitis. Treatment for this disease is still under debated between conventional chemotherapy or immunosuppressive agents like cyclosporin and prednisolone. Material and Methods: A multicenter retrospective study was conducted among adult patients who was diagnosed as subcutaneous panniculitis-like T-cell lymphoma from January 2013 to December 2020, in 15 medical centers in Thailand. The patient demographic data, treatment regimens which divided into conventional chemotherapy or immunosuppressive agents, and treatment outcomes were retrieved from the Thai lymphoma registry database. All of aspects were analyzed and compared between the treatment group. Results: A total of 34 patients were reviewed in this cohort. The median age was 30 years (range;16–64) with female predominance (67.6%). The majority of patients was diagnosed as advanced stage of disease as Ann Arbor stage IV (58.8%). All patients presented with skin and subcutaneous involvement while one-fourth of them had extra-cutaneous lesions including liver (14.7%) and bone marrow (11%). B symptom was observed in 64% and elevated LDH level in 70.6% of the patients which represented the high disease burden. However, almost all of our patients were in good performance status (ECOG 1–2). For treatment options, 41% of the patients received conventional chemotherapy, mostly CHOP, while 38% received cyclosporin containing regimens. The overall response rate (ORR) was 64% in chemotherapy group and 76% in cyclosporin group, which was comparable. Precisely 57% and 76% of the patients in conventional chemotherapy and cyclosporin treatment, respectively, had complete remission. Patients with Ann Arbor stage IV were received conventional chemotherapy as first-line treatment for 69%, on the other hand, 31% received cyclosporin-based treatment, which was in complete remission around 60% on both groups. With median follow up time of 35.2 months, the overall survival and progression free survival were not reached in both groups. Conclusions: Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare form of cytotoxic T-cell lymphoma which predominantly affects young female and usually presents with extranodal lesions especially skin and subcutaneous tissues, bone marrow, and liver. Patients were responded well to cyclosporin-based treatment both limited and advanced stages of the disease. Keywords: chemotherapy, cyclosporin, Subcutaneous panniculitis-like T-cell lymphoma Keyword: Cutaneous non-Hodgkin lymphoma No conflicts of interests pertinent to the abstract.

Cyclosporine A induces cardiac remodeling through TGF-β/Smad3/miR-29 signaling pathway and alters gene expression of miR-30b-5p/CaMKIIδ isoforms pathways: alleviating effects of moderate exercise.

Cyclosporine A (CsA)-induced cardiac interstitial fibrosis and cardiac hypertrophy are highly known phenomena; however, the basic mechanisms of CsA cardiotoxicity are unclear. The present study evaluated the role of the Transforming growth factor-beta (TGF-β)/Smad3/miR-29b signaling pathway and CaMKIIδ isoforms gene expression in cardiac remodeling under CsA exposure alone or combined with moderate exercise. A total of 24 male Wistar rats were divided into control, cyclosporine (30mg/kg BW), and cyclosporine-exercise groups. After 42 days of treatment, the findings revealed a significant decline in miR-29 and miR-30b-5p gene expression and an increase in gene expression of Smad3, calcium/calmodulin-dependent protein kinaseIIδ (CaMKIIδ) isoforms, Matrix Metalloproteinases (MMPs), protein expression of TGF-β, heart tissue protein carbonyl and oxidized LDL (Ox-LDL), and plasma LDL and cholesterol levels in the CsA-treated group compared to the control group. The CsA group presented greater histological heart changes such as fibrosis, necrosis, hemorrhage, infiltrated leukocyte, and left ventricular weight/heart weight than the control group. Moreover, combined moderate exercise and CsA relatively improved gene expression changes and histological alternations compared to the CsA group. TGF-β-Smad3-miR-29 and CaMKIIδ isoforms may mainly contribute to the progression of heart fibrosis and hypertrophy due to CsA exposure, providing new insight into the pathogenesis and treatment of CsA-induced side effects on the heart tissue.

Efficacy and Safety of a Water-Free Topical Cyclosporine, 0.1%, Solution for the Treatment of Moderate to Severe Dry Eye Disease

Dry eye disease (DED) is a common public health problem with significant impact on vision-related quality of life and well-being of patients. Medications with rapid onset of action and a good tolerability profile remain an unmet need. To assess efficacy, safety, and tolerability of a water-free cyclosporine ophthalmic solution, 0.1% (CyclASol [Novaliq GmbH]), applied twice daily in DED compared with vehicle. CyclASol for the Treatment of Signs and Symptoms of Dry Eye Disease (ESSENCE-2) was a phase 3, multicenter, randomized, double-masked, vehicle-controlled clinical study conducted from December 5, 2020, to October 8, 2021. Following a 14-day run-in period with an artificial tear administered 2 times per day, eligible participants were randomly assigned 1:1 to the treatment groups. Patients with moderate to severe DED were included in the study. Cyclosporine solution vs vehicle administered 2 times per day for 29 days. The primary end points were changes from baseline in total corneal fluorescein staining (tCFS; 0-15 National Eye Institute scale) and in dryness score (0-100 visual analog scale) at day 29. Conjunctival staining, central corneal fluorescein staining, and tCFS responders were also assessed. A total of 834 study participants were randomly assigned to cyclosporine (423 [50.7%]) or vehicle (411 [49.3%]) groups at 27 sites. Participants had a mean (SD) age of 57.1 (15.8) years, and 609 (73.0%) were female individuals. The majority of participants self-identified in the following race categories: 79 Asian (9.5 %), 108 Black (12.9%), and 635 White (76.1%). Participants treated with cyclosporine solution had greater improvement in tCFS (-4.0 grades) than the vehicle group (-3.6 grades) at day 29 (change [∆] = -0.4; 95% CI, -0.8 to 0; P = .03). The dryness score showed treatment benefits from baseline in both groups: -12.2 points for cyclosporine and -13.6 points for vehicle (∆ = 1.4; 95% CI, -1.8 to 4.6; P = .38). In the cyclosporine group, 293 participants (71.6%) achieved clinically meaningful reductions of 3 grades or higher in tCFS vs 236 (59.7%) in the vehicle group (∆ = 12.6%; 95% CI, 6.0%-19.3%; P < .001). These responders showed greater improvement in symptoms at day 29 including dryness (∆ = -4.6; 95% CI, -8.0 to -1.2; P = .007) and blurred vision (Δ = -3.5; 95% CI, -6.6 to -4.0; P = .03) compared with nonresponders. The ESSENCE-2 trial confirmed that treatment with a water-free cyclosporine solution, 0.1%, results in early therapeutic effects on the ocular surface compared with vehicle. The responder analyses suggest that the effect is clinically meaningful in 71.6% of participants in the cyclosporine group. ClinicalTrials.gov Identifier: NCT04523129.

Effects of Quercetin-3-O-β-D-Glucuronide on Platelet Apoptosis and Activation in Mice with Immune-Mediated Bone Marrow Failure via PI3K/AKT Pathway

To investigate the effect of quercetin-3-O-β-D-glucuronide(QG) on platelet apoptosis and activation in mice with immune-mediated bone marrow failure via PI3K/AKT pathway. An immune-mediated bone marrow failure mice model was established and forty C57BL/6 mice were randomly assigned into 4 groups: normal group, model group,cyclosporine (CsA) group and QG group, with 10 mice in each group.The mice in CsA group were intragastrically administered with 0.027 g/kg CsA daily and the mice in QG group were intragastrically administered with 0.2 g/kg QG daily, while the mice in the normal group and model group were intragastrically administered with normal saline, respectively. After three days of modeling, the mice were euthanized, and the blood was collected through the tail vein. Part of the blood was used for blood routine examination, and the other part was used to prepare washed platelets. Some of the prepared washed platelets were used to detect the expressions of BAX, BAD, caspase-9, phosphatidylserine (PS), platelet activated complex-1 (PAC-1) and P-selectin by flow cytometry; some of washed platelets was used to determine the protein contents of PI3K, p-PI3k, AKT and p-AKT by Western blot; the other part of the washed platelets was used to measure the expressions of PI3K mRNA and AKT mRNA by real-time quantitative PCR (RT-qPCR). In the model group, the absolute platelet count of the mice was significantly decreased, and the levels of BAX, BAD, caspase-9, PS, PAC-1, and P-selectin in the washed platelets were significantly increased, compared to the normal group (P<0.05). At the same time, the expression levels of PI3K, p-PI3K, AKT, p-AKT proteins and PI3K mRNA, AKT mRNA in model group were significantly reduced, compared to the normal group (P<0.05). In the CsA group and QG group, the expression levels of BAX, BAD, caspase-9, PS, PAC-1, and P-selectin in the washed platelets were significantly reduced (P<0.05), while the levels of PI3K, p-PI3K, AKT, p-AKT and PI3K mRNA, AKT mRNA were significantly increased, compared to the model group (P<0.05). QG can reduce platelet apoptosis in mice with immune-mediated bone marrow failure, and activation of some platelets is involved, which may be related to the regulation of PI3K/AKT pathway.

P472 Cyclosporine versus infliximab in patients with Acute Severe Ulcerative Colitis: A single-centre retrospective study

Abstract Background In steroid refractory acute severe ulcerative colitis (ASUC), cyclosporine or infliximab are potential rescue treatments to avoid colectomy. Our objective is to assess the short-term and long-term efficacy and safety of cyclosporine versus infliximab as rescue agents. Methods We performed a retrospective analysis of 121 patients admitted with ASUC to a single gastroenterology centre during 2010-2020. ASUC was defined by the Truelove &amp; Witts criteria. Primary outcome was short-term colectomy-free rate, secondary outcomes were severe adverse events, re-hospitalization or need of treatment with steroids within 2 years due to flare ups and colectomy rate at 2-year follow-up. Results 119 patients initially received intravenous corticosteroids, while 2 patients underwent emergency colectomy on the first day. Sixty-four (53%) were females, median age of all patients was 33 (IQR 27-49) years. 66 (55%) patients responded to intravenous corticosteroids (IVS), while 53 (45%) failed to respond to steroid therapy: 45 (37%) patients received second-line rescue therapy (29 with cyclosporine, 16 with infliximab). Evaluating the short-term efficacy of treatment there was no significant difference between cyclosporine and infliximab: during admission colectomy was performed in 10.3% vs. 12.5% of patients, respectively (p=0.826). In terms of long-term outcomes, the colectomy rate was higher in the infliximab group at 2-year follow-up, although the difference did not reach statistical significance (10.3% vs. 31.2%, p=0.079). The need for oral steroids during follow-up was comparable in both groups (38,5% vs. 50%, p=0.481). Comparing patients who did not undergo colectomy, patients in the infliximab group were more often re-hospitalized due to the need for IVS at 2-year follow-up (7.7% vs. 50%, p=0.002). No severe side effects due to infliximab and cyclosporine were observed. Conclusion In the treatment of steroid refractory ASUC infliximab and cyclosporine were equally effective in short-term period and there was no difference in safety, however cyclosporine treated patients trended to have better long-term outcomes, with significantly rarer re-hospitalization. Additional analysis is needed for other factors that may have contributed to differences in long-term outcomes between the cyclosporine and infliximab groups.

Comparison of cyclosporine and systemic corticosteroid for treating drug reaction with eosinophilia and systemic symptoms syndrome: A retrospective 20-year single-centre study in South Korea.

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a potentially life-threatening hypersensitive disorder. Cyclosporine has been indicated for adverse cutaneous drug eruptions. However, studies evaluating its clinical effectiveness in DRESS syndrome have been rare. This study aimed to evaluate the clinical efficacy of cyclosporine in DRESS syndrome compared to that of systemic corticosteroids. In the cyclosporine group, oral cyclosporine was administered twice a day for a total of 2-3mg/kg/day for 1week, and subsequently reduced to 1-1.5mg/kg/day for extended treatment. In the corticosteroid group, intravenous or oral methylprednisolone was administered at 1-1.5mg/kg/day for 1week, with variable tapering plans. Laboratory changes before and after treatment, hospitalized days, treatment periods, and time to normalization from clinical manifestations in each group were statistically evaluated. Adverse effects of these regimens were observed during the entire treatment period. Eighty patients were enrolled in this retrospective study. The cyclosporine and corticosteroid group had 27 and 53 patients, respectively. Total leucocyte and eosinophil counts, liver enzymes, and C-reactive proteins were significantly decreased after treatment in both groups. There were no statistically significant differences observed in hospitalized days, treatment period, and time to normalization from clinical manifestations between the two groups. The corticosteroid group experienced relatively more adverse effects than the cyclosporine group. Cyclosporine was discovered to be clinically effective in DRESS syndrome and this study suggests that cyclosporine could be a feasible primary therapeutic option for DRESS syndrome.