Cyclosporine Treatment Research Articles

A study to assess the efficacy of topical cyclosporine A 0.05% in the management of dry eye with meibomiam gland dysfunction

: Dry eye is a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface. It is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface. Meibomian Gland Dysfunction (MGD) is an abnormality of the meibomian gland that blocks the secretion of lipids. Without sufficient lipid production, tears evaporate quickly causing Dry Eye.MGD is associated with multiple pathological mechanisms including inflammation, microbial factors and lipid deficiencies. Topical Cyclosporine A (CsA) 0.05% is a calcineurin inhibitor that reduces inflammation by specifically inhibiting T‑cell activity, which reduces ocular surface inflammation and improves tear film dynamics. This was a prospective observational study done on 100 patients at the Department of Ophthalmology Basaveshwar teaching and general hospital, on patients of dry eyes due to meibomian gland dysfunction. Patients who were diagnosed with dry eyes due to meibomian gland dysfunction were invited to take part in the study. Patients were divided randomly into two groups of 50 patients each. This study, was explained in detail to them. An informed consent was obtained. Patients fulfilling the inclusion criteria were listed.All OSDI scores (symptom intensity, frequency and aggravation) revealed decreasing patterns throughout the observation period in both the groups. In single analysis, the cyclosporine A 0.05% group showed a significant improvement for each score at 3 months (p < 0.01, p = 0.01, p = 0.02, respectively). The mean TBUT after treatment in the group A (cyclosporine A group) increased to 12.36± 3.58(p<0.001) seconds, and in the group B (Control group) the TBUT score increased to 11.01±3.06 seconds. After 3 Months, there was statistically significant improvement in the mean Schirmer’s scores in both the treatment groups, however improvement was significantly greater in Cyclosporine A group. Prior to the treatment in group A (Cyclosporine A) mean Lissamine staining score was 2.73±0.15 and post treatment it reduced to 1.32±0.15 which was statistically significant (P<0.001). In group B (Control group) score before treatment was 2.46±0.15 and after treatment it reduced to 2.39±0.27 (p=0.11), not much difference was seen. : Findings from our study showed that there were significant improvements in the dry eye conditions due to defect in meibomian gland by treatment of topical Cyclosporine A 0.05% and sodium hyaluronate 0.1%.

How challenging can it be to treat Behçet uveitis?

A 20-year-old male Behçet uveitis (BU) patient presented with visual acuities (VAs) of hand movement in OD and counting fingers at 1 m in OS following treatment with corticosteroid monotherapy elsewhere. He had active intraocular inflammation OU along with macular hole and retinal detachment in OS. Infliximab (IFX) was started and vitreoretinal surgery was performed. He had infusion reaction with IFX, hepatotoxicity and depression with interferon, and resistance to adalimumab and tocilizumab therapies. Cytomegalovirus retinitis developed in OD following intravitreal dexamethasone implant and endophthalmitis developed in OS. At the 33rd month of follow-up, the patient was in clinical remission; however, there was persistent angiographic inflammation under certolizumab pegol, cyclosporine, mycophenolate mofetil, and low-dose prednisolone treatment. The left eye was phthisical and VA was 0.4 in OD. Immunomodulatory treatment is given based on the severity of inflammation in BU and needs to be closely monitored for efficacy and adverse effects.

Evidence for Early Cyclosporine Treatment for Hunner Lesion Interstitial Cystitis

(Abstracted from Female Pelvic Med Reconstr Surg 2021; doi: 10.1097/SPV.0000000000001108) Hunner lesion interstitial cystitis (HLIC) is a form of interstitial cystitis/bladder pain syndrome (IC/BPS), occurring in 5%–57% of patients. HLIC is diagnosed by the presence of Hunner lesions on cystoscopy.

Systemic Treatment of Immune-Mediated Keratoconjunctivitis Sicca with Allogeneic Stem Cells Improves the Schirmer Tear Test Score in a Canine Spontaneous Model of Disease.

Keratoconjunctivitis sicca (KCS) is characterized by ocular discomfort, conjunctival hyperaemia, and corneal scarring, causing reduced aqueous tear production that can be measured using the standard Schirmer tear test (STT). Canine adipose tissue-derived MSCs (cATMSCs) have been proposed as treatment due to their anti-inflammatory effect, by releasing cytokines and immunomodulatory soluble factors. Purpose: The aim of this study was to evaluate the effect of the systemic administration of cATMSCs on tear production in dogs with immune-mediated KCS, compared to classical Cyclosporine A (CsA) treatment. Methods: Twenty-eight client-owned dogs with spontaneous KCS were allocated in the experimental group (n = 14, treated with systemic cATMSCs or control group (n = 14, treated with CsA). SST values increased significantly at days 15 (p = 0.002), 45 (p = 0.042) and 180 (p = 0.005) with no observed side-effects in the experimental group. Eyes with an initial STT value of 11–14 mm/min maintained significant improvement at day 180, needing only artificial tears as treatment. Eyes with an initial STT value <11 mm/min needed cyclosporin treatment at day 45, so follow-up was stopped. Control animals treated with CsA did not improve their STT at day 180. Results and Conclusions: Systemic allogeneic cATMSCs application appeared to be a feasible and effective therapy with positive outcome in dogs with initial STT between 11–14 mm/min, with a significant improvement in tear production. The STT increment was maintained for at least 180 days, without needing additional medication, thus suggesting it could constitute an alternative therapy to classical immunosuppressive treatments.

Newer Treatment Modalities in Urticaria

Wheals (hives), angioedema, or both are symptoms of urticaria, a chronic clinical disorder. Urticaria has a complicated pathogenesis, as well as a large disease burden, a negative effect on health-care expenditures and quality of living. Urticaria could also be a chronic condition that affects up to 1% of the general population at some stage in their lives and can drastically impair quality life. The use of second-generation, non-sedating antihistamines has replaced antihistamines to use as the first-line therapy. However, urticaria can be difficult to manage in some cases; in these cases, alternate treatment approaches must be considered. This article reviews antihistamines, leukotriene antagonists, anti-inflammatory drugs, biologicals, subcutaneous autologous serum therapy, doxepin, cyclosporine ,tranexamic acid and other newer treatment modalities.

Stevens-Johnson syndrome and toxic epidermal necrolysis: a systematic review and meta-analysis.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare and severe skin and mucosal reactions that are associated with high mortality. Despite the severity, an evidence-based treatment protocol for SJS/TEN is still lacking. In this systematic review and meta-analysis, the PubMed database was searched using the following terms: [Stevens-Johnson syndrome] OR [toxic epidermal necrolysis] AND [therapy] OR [treatment] over a 20-year period (1999-2019) in the German and English language. All clinical studies reporting on the treatment of SJS/TEN were included, and epidemiological and diagnostic aspects of treatment were analysed. A meta-analysis was conducted on all comparative clinical studies that met the inclusion criteria. A total of 88 studies met the inclusion criteria, reporting outcomes in 2647 patients. Treatment was either supportive or used systemic corticosteroid, intravenous immunoglobulin, plasmapheresis, cyclosporine, thalidomide or cyclophosphamide therapy. The meta-analysis included 16 (18%) studies, reporting outcomes in 976 (37%) patients. Systemic glucocorticoids showed a survival benefit for SJS/TEN patients in all analyses compared with other forms of treatment. Cyclosporine treatment also showed promising results, despite being used in a small cohort of patients. No beneficial effects on mortality could be demonstrated for intravenous immunoglobulins. Glucocorticoids and cyclosporine may be tentatively recommended as the most promising immunomodulatory therapies for SJS/TEN, but these results should be investigated in future prospective controlled trials.

A Retrospective Review of Calcineurin Inhibitors’ Impact on Cytomegalovirus Infections in Lung Transplant Recipients

Immunosuppressive therapy reduces the risk for allograft rejection but leaves recipients susceptible to infections. Cytomegalovirus (CMV) is one of the most frequent causes for infection after transplantation and increases the risk for allograft rejection. As lung transplant recipients (LTRs) need to be under immunosuppression for life, they are a vulnerable group. To determine the potential association between the development of CMV infection and the calcineurin inhibitor (CNI) blood levels within previous 90 days, a retrospective review of LTRs was performed. Data from recipients who underwent a lung transplantation (LTx) at our center from January 2011 to December 2018 were collected. The studied recipients, after case/control matching, included 128 CMV-infection cases. The median time from the transplant to the first positive CMV viral load was 291.5 days. In our study, more patients were treated with tacrolimus (91.9%) than with cyclosporine (8.1%). Drug blood levels at selected timepoints showed no statistically significant difference between cases and controls. However, we found that CMV infection was more frequent in the donor-seropositive/recipient-seronegative group, interstitial lung disease (ILD) recipients, LTRs who underwent basiliximab induction, cyclosporine treated recipients, and LTRs with lymphopenia (at the time of CMV infection and 90 days before). In this review of LTRs, no association between the CNI blood level and CMV infection was seen, although other immunity-related factors were found to be influencing, i.e., basiliximab induction, cyclosporine treatment, and lymphopenia.

Effect of Cyclosporine on Cytokine Production in Elective Coronary Artery Bypass Grafting: A Sub-Analysis of the CiPRICS (Cyclosporine to Protect Renal Function in Cardiac Surgery) Study

The augmented inflammatory response to cardiac surgery is a recognized cause of postoperative acute kidney injury. The present study aimed to investigate the effects of preoperative cyclosporine treatment on cytokine production and delineate factors associated with postoperative kidney impairment. A randomized, double-blind, placebo-controlled, single-center study. At a tertiary care, university hospital. Patients eligible for elective coronary artery bypass grafting surgery; 67 patients were enrolled. Patients were randomized to receive 2.5 mg/kg cyclosporine or placebo before surgery. Cytokine levels were measured after the induction of anesthesia and 4 hours after the end of cardiopulmonary bypass. Tissue-aggressive (interleukin [IL]-1β, macrophage inflammatory protein [MIP]-1β, granulocyte colony-stimulating factor [G-CSF], IL-6, IL-8, IL-17, MCP-1), as well tissue-lenient (IL-4) cytokines, were significantly elevated in response to surgery. Changes in cytokine levels were not affected by cyclosporine pretreatment. Elective coronary artery bypass grafting surgery with cardiopulmonary bypass triggers cytokine activation. This activation was not impacted by preoperative cyclosporine treatment.

Acquired Aplastic Anemia Patients Using Single Agent Cyclosporine a, in Resource Poor Setting

Abstract: Aplastic Anemia (AA) is a syndrome characterized by peripheral blood pancytopenia and bone marrow hypo-cellularity. Acquired AA is considered to have an underlying autoimmune etiology. Hematopoietic stem cell transplantation (HSCT) still remains the treatment of choice for AA patients. However, due to cost restrictions, cyclosporine A has been tried in resource poor setting as a single agent.Aim: The aim of this study is to observe the single agent Cyclosporine treatment response in AA patients.Materials and Methods: The following study is a retrospective study. Patients diagnosed for the first time between January 2010 and December 2020, aged 14 years old and up, treated with cyclosporine A and supportive therapy, were included in this study. Statistical analysis for this study was performed using SPSS.All subjects were started on 5mg/kg per day of cyclosporine. The patients were divided into three groups according to the IAASG classification criteria (Non severe AA, Severe AA and Very severe AA). Another subgroup analysis related to sex (females to males) and age was performed, classifying the patients into three subgroups (14-29; 30-59; 60+ years old).Overall Survival (OS) was evaluated using Kaplan-Meier method with Log-Rank test. Overall survival (OS) was defined as the duration from the first day of treatment to all-cause death. T-test and Chi-square test were used for categorical and continuous parameters analysis. P value lower than 0.05 was considered statistically significant.Results: A total of 35 patients were diagnosed as Acquired Aplastic Anemia between 2010-2020. The median age at diagnosis was 51 years old. The incidence of Aplastic Anemia in Albania is 1.35 per million inhabitants. 5 patients (19.2%) developed complete response. NSAA showed the best treatment response (38.5%). The relation between the treatment response at the end of the first year of cyclosporine treatment and the 5-year survival was statistically significant, Pearsons' correlation coefficient 0.441 (P=0.035).The estimated mean survival time of AA patients in our study is 68.6 months. When compared the survival to the severity, the SAA group showed a better OS (53 months) (P=0.081). The 5-year cumulative survival of the patients resulted 71.9%. VSAA group had the worst estimated survival (45.5%). The youngest age group showed the worst 5-year survival on cyclosporine alone (33.3%) (P=0.016). The subgroup analysis between males and females resulted in women having a slightly better survival than men, 59 and 58 months respectively (P=0.276). Those patients who failed the treatment with cyclosporine alone at the end of the first year, showed the worse 5-year survival (50%).Conclusions: This study emphasizes once again the importance of the IAASG classification on AA patients' prognosis and treatment outcome. The youngest patients should be considered for HSCT rather than be treated on cyclosporine alone. Treatment on cyclosporine alone and supportive therapy is a reasonable option for older patients in poor resource countries as Albania.Abbreviations: AA- Aplastic Anemia, NSAA- Non severe aplastic anemia, SAA- Severe aplastic anemia, VSAA- Very severe aplastic anemia, HSCT- Hematopoietic stem cell transplantation, IAASG-International Aplastic Anemia Study Group, SPSS-Statistical Package for the Social Sciences. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Efficacy and Safety of Cyclosporine Treatment in Autoimmune Cytopenias: The Experience of Two Italian Reference Centers

▪Background: Autoimmune cytopenias (immune thrombocytopenia ITP, autoimmune hemolytic anemia AIHA, and chronic idiopathic neutropenia CIN) are a heterogeneous group of disorders characterized by the presence of autoantibodies directed against platelets (PLT), erythrocytes, and neutrophils (ANC). Frontline steroids are the mainstay of treatment, although most patients relapse and require 2 nd line therapies which slightly differ according to disease subtype. Rituximab is mainly effective in AIHA, although only a fraction of cases would experience long-term relapse-free. Splenectomy may be contraindicated due to age and risk of thrombotic and infectious complications and thrombopoietin-receptor agonists (TPO-RA), effective in more than 70% of ITP patients, may result in great PLT fluctuations and increased bone marrow reticulin fibrosis.Cyclosporine (CyA) is an immunosuppressant used for over 30 years in the post-transplant setting and in the treatment of aplastic anemia. It is a manageable oral drug with known toxicities and its plasma concentrations may be monitored to optimize treatment. However, few data exist about its efficacy in autoimmune cytopenias either used as single drug or in combination with other treatments.Aim: The aim of this study was to evaluate the efficacy and safety of CyA in a cohort of patients with ITP, AIHA, and CIN, followed at two reference hematology centers in Milan, Italy.Methods: Medical charts of consecutive patients treated with CyA 3-5 mg/ kg day in the last 20 years were evaluated. Responses were assessed at 3, 6 and 12 months, and divided into partial (PR, for Hb> 10 g/dL; PLT> 30x 109/L and ANC> 0.8 x 109/L) and complete (CR, for Hb> 12 g/dL; PLT> 100x109/L; ANC>1 x 109/L). Adverse events were recorded according to CTCAE criteria.Results: 41 patients, 27 ITP (66%), 11 AIHA (27%) and 3 CIN (7%), were included, 16 men (39%) and 25 women (61%), with a median age of 60 year (21-81). The median time from diagnosis to CyA start was of 10 years (5-15), with a median of 3 (1-8) previous therapy lines. Most patients were receiving concomitant treatment including steroids (N=13), IVIG (3), or TPO-RA (14). Reasons to start CyA included no response to previous treatments (N=27), platelets fluctuations (N=5) or bone marrow fibrosis (N=5) on TPO-RA, and contraindication for splenectomy (N=4). Median duration of CyA therapy was 5 years (1-9) and 34 patients (83%) responded: 34% CR, 44% PR at month+3; 39% CR and 39% PR at month+6; and 26%CR and 43%PR at month+12 (Figure 1). Specifically, median PLTs increased by 32 x10^9/L at month+3, by 121 x10^9/L at month+6, and by 43 x10^9/L at month+12. Median Hb improved by 0.5 g/dL at month+3, by 1 g/dL at month+6, and by 2,6 g/dL at month +12. Median ANC augmented by 0.7 x10^9/L at month +3, by 1.7 x10^9/L at month +6, and by 0.07 x10^9/L at month +12. Importantly, 9 patients could stop steroids, and 10 subjects discontinued or tapered TPO-RA (5 each). Better responses were observed in ITP patients with baseline bone marrow hypocellularity (p = 0.01), absence of reticulin fibrosis (p=0.02), and in those not previously splenectomized (p=0.04). Among AIHA cases, those with IgG+C direct antiglobulin test positivity showed higher percentage of non-response (67 versus 22% in IgG+). Adverse events were mainly G1-2, occurring in 52% of patients, and included asthenia, dyspnea, myalgia, nausea, vomiting, diarrhea and abdominal pain, epistaxis, petechiae and an Escherichia Coli cystitis. Three patients on concomitant long-term steroids developed a G3 event (1 pulmonary embolism, 1 Aspergillus lung infection and 1 bronchitis), and 1 died for Pneumocystis jirovecii pneumonia.Conclusion: Cyclosporine was effective in about 80% of highly pretreated patients and allowed tapering/discontinuation of concomitant treatments in 63% of cases. Responses were higher in those with ITP, and hypocellular bone marrow without reticulin fibrosis. The occurrence of infectious episodes, including a fatal pneumonia, warrants careful surveillance in this heavily pretreated patient population. [Display omitted] DisclosuresFattizzo: Kira: Speakers Bureau; Alexion: Speakers Bureau; Novartis: Speakers Bureau; Momenta: Honoraria, Speakers Bureau; Annexon: Consultancy; Apellis: Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Bianchi: Agios pharmaceutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Barcellini: Agios: Honoraria, Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Alexion Pharmaceuticals: Honoraria.

M271 SEVERE EOSINOPHILIC CYSTITIS CONTROLLED WITH BENRALIZUMAB

Eosinophilic Cystitis (EoC) is a rare disorder of the bladder resulting in lower abdominal pain, hematuria and dysuria. Standard treatment of antihistamines, leukotriene antagonists, NSAID's, cyclosporine, hydroxyurea and intravesicular corticosteroids is not always effective. Benralizumab is a monoclonal antibody directed against the IL-5 receptor, reducing eosinophil production and survival. Unlike other antagonists of IL-5, it is very effective in tissue depletion of eosinophils. It has previously been shown to be effective in EoC.

Cyclosporine Treatment in Cats with Presumed Chronic Pancreatitis-A Retrospective Study.

Simple SummaryChronic pancreatitis (CP) is a common disease in middle-aged to older cats. Cyclosporine, an immunosuppressive drug, has been suggested as an alternative treatment when other drugs that suppress inflammation are ineffective or unsuitable. However, no published studies have investigated its efficacy in cats with CP. The aim of this retrospective study was to evaluate the efficacy of cyclosporine as a treatment for pancreatitis in cats with presumed CP. All cats had a history and clinical signs suggestive of CP and blood samples showed abnormally high concentrations of feline pancreas-specific lipase (Spec fPL) on at least two occasions. This is common in CP. All cats were treated with cyclosporine for at least three weeks. Nineteen cats, aged 6.9–17.5 years, were included. Daily treatment with cyclosporine resulted in an improvement of serum Spec fPL concentrations which indicates that the pancreatic inflammation likely had improved. The study has several limitations, including different treatment durations and doses, lack of biopsies to confirm CP and the treatment effect was not compared with an untreated control group. Despite the limitations, our results suggest that cyclosporine treatment decreases serum Spec fPL concentrations and may be effective in the management of feline chronic pancreatitis.Chronic pancreatitis (CP) is a common disease in middle-aged to older cats. Cyclosporine has been suggested as an alternative treatment when other immunosuppressive treatments are insufficient or contraindicated. However, no published studies have investigated its efficacy on feline CP. The aim of this retrospective study was to evaluate the efficacy of cyclosporine on supranormal serum feline pancreas-specific lipase (Spec fPL) concentrations in cats with presumed CP. Inclusion criteria were history and clinical signs suggestive of CP, serum Spec fPL concentrations above 5.3 μg/L (reference range 0–3.5 μg/L, equivocal range 3.6–5.3 μg/L) on at least two occasions and treatment with cyclosporine for at least three weeks. Serum Spec fPL was analyzed at Idexx Laboratories, Kornwestheim, Germany. Nineteen cats, aged 6.9–17.5 years (median 11.6), were included. No pancreatic biopsies were available. Median (range) serum Spec fPL concentration was 14.2 μg/L (6.1–43.3) at baseline and 6.7 μg/L (0.9–23.6) at follow-up. Cyclosporine treatment (5.0–7.9 mg/kg orally SID) was associated with a significant reduction in serum Spec fPL concentrations (p < 0.001) at follow-up after 23–206 days (median 35). Body weight decreased significantly between inclusion and follow-up (p = 0.013). Significant improvement of clinical signs could not be measured (p = 0.781). This study has several limitations, including unstandardized treatment length and dose, no control group and lack of pancreatic biopsies. Despite the limitations, our results suggest that cyclosporine treatment reduces supranormal serum Spec fPL concentrations in cats with presumed CP.

Apremilast improves endothelial glycocalyx and microvascular perfusion: a possible protective mechanism against COVID-19

Abstract Background/Introduction The phosphodiesterase 4 inhibitor apremilast is an approved treatment option for psoriasis. Purpose We aimed to investigate the effects of apremilast on endothelial glycocalyx, vascular and left ventricular (LV) myocardial function in psoriasis. Methods Ninety patients with psoriasis were randomized to receive apremilast (n=30), anti-tumor necrosis factor-a (etanercept, n=30), or cyclosporine treatment (n=30). At baseline and 4 months post-treatment, we measured: (1)Perfused boundary region (PBR) of the sublingual microvessels with a diameter 5–25μm using a dedicated camera (Sidestream Dark Field imaging, Microscan, Glycocheck). Increased PBR indicates reduced glycocalyx thickness. Perfused microvascular density (PMD), an index of microvascular perfusion, was also measured. (2)Pulse wave velocity (PWV - Complior; ALAM Medical) and central systolic blood pressure (cSBP), and (3)LV global longitudinal strain (GLS) and percent difference between peak twisting and untwisting at mitral valve opening (%dpTw-UtwMVO) using speckle-tracking echocardiography. Results Compared with baseline, PBR20–25 decreased only after apremilast treatment (−13% at 4 months, P&amp;lt;0.05) whereas no statistically significant changes in PBR20–25 were observed after etanercept or cyclosporine. Compared with etanercept and cyclosporine, apremilast resulted in a greater increase of PMD (+12% versus +3% versus +3%) and in a higher reduction of PWV (−10% versus −3% versus +8%) and cSBP (−8% versus −2% versus +7%) at 4 months. Apremilast showed a greater increase of GLS (+12% versus +5% versus +2%) and %dpTw-UtwMVO (+15% versus +3% versus +3%) than etanercept and cyclosporine (P&amp;lt;0.05 for all comparisons). Changes of PBR and PMD post-apremilast treatment correlated with a concomitant reduction of PWV and cSBP (P&amp;lt;0.05). Conclusions In psoriasis, apremilast confers a greater improvement of endothelial glycocalyx, microvascular perfusion and LV myocardial function compared with etanercept or cyclosporine treatment. Apremilast restores glycocalyx integrity and thus reduces vascular permeability to pro-inflammatory molecules. This may explain the beneficial effects of apremilast on COVID-19. Funding Acknowledgement Type of funding sources: None.

199 The molecular signature of Eosinophilic Cellulitis correlates with the efficacy of baricitinib in a refractory patient

Eosinophilic cellulitis (EC) is a rare skin disorder characterized by fixed pruritic urticarial plaques and a dermal eosinophilic infiltrate. Pathogenesis is unclear and current paradigm stands for an IL-5 mediated delayed type hypersensitivity. However, numerous patients are resistant to standard corticosteroids, dapsone or cyclosporine treatments. To better characterize the inflammatory pathways involved in EC, we retrospectively analyzed skin samples from 12 EC patients and 5 healthy controls, using RT-qPCR and phospho-STAT (pSTAT) immunostaining. We next explored the clinical and molecular response in one refractory patient treated with the new JAK1/JAK2 inhibitor, baricitinib. A significant increase of mRNA transcripts related to specific markers of type 2 inflammation (IL-13 and IL-3R, but not IL-5) and eosinophil recruitment (CCL17, CCL18 and CCL26) was found in lesional skin of EC patients compared to controls. We also observed that almost all EC samples were strongly positive for pSTAT-5 and, at a lesser degree, for pSTAT-1. Comparatively, pSTAT-3 staining was negative. As pSTAT-1 and -5 are classically associated with JAK1/2 activation, we then treated one refractory EC patient with baricitinib at 4mg/day. Strikingly, skin lesions completely resolved in one month. The up-regulation of type 2 inflammation markers, notably IL-13 and IL-3, were also completely normalized in the healed skin following baricitinib treatment. Our results therefore highlight that a unique type 2 inflammation typifies acute lesions of EC, associated with an IL-13 and IL-3 signature. They also suggest that JAK1/JAK2 inhibition could be a promising strategy to treat refractory patients.

Evidence for Early Cyclosporine Treatment for Hunner Lesion Interstitial Cystitis.

The objective of this study was to evaluate our experience using cyclosporine A (CyA) in the treatment of Hunner lesion interstitial cystitis (HLIC). Retrospective chart review was performed on patients with HLIC treated with CyA from August 2012 to September 2019. Demographic and clinical variables, number of interstitial cystitis therapies, frequency, nocturia, and bladder pain visual analog scores before and after CyA treatment were collected, as well as the Global Response Assessment (GRA) and the Interstitial Cystitis Symptom Index and Interstitial Cystitis Problem Index. CyA responders were defined as those with moderately or markedly improved GRA scores. A total of 51 patients with HLIC treated with CyA were identified. Mean follow-up was 3 years (0.36-6.8 years). Seventy-six percent (28 of 37) were female; mean age was 68 years (51-84 years). Before CyA treatment, an average of 8 previous therapies were tried and patients reported an average of 8 of 10 bladder pain. Daytime frequency was 11-20 times per day, and nocturia was 7 times per night. Per the GRA, 84% (31 of 37) were considered CyA responders. Posttherapy Interstitial Cystitis Symptom Index and Interstitial Cystitis Problem Index scores were lower in responders compared with nonresponders (8.9 ± 5.7 vs 21.3 ± 7.0, P = 0.001). Bladder pain, number of hydrodistentions/fulgurations, nocturia, and daytime frequency improved significantly after CyA treatment. The cyclosporine A response rate was 84%, with most of these patients reporting marked improvement. Bladder pain, daytime frequency, and nocturia were significantly improved after CyA treatment, and the number of interventions after CyA treatment decreased. Cyclosporine A should be considered earlier than fifth-line therapy in HLIC.

A randomized clinical trial of topical dexamethasone vs. cyclosporine treatment for oral lichen planus.

Background Oral lichen planus (OLP) is a common, frequently symptomatic, immune-mediated disease. Various treatments have been used for symptomatic OLP, including corticosteroids and immunosuppressants administered topically or systemically. The aim of this study was to compare the effectiveness of topical dexamethasone vs. topical cyclosporine in treatment of symptomatic OLP.Material and Methods Thirty-two patients with biopsy-proven symptomatic OLP were randomly assigned to two therapeutic groups: dexamethasone 2mg/5ml or cyclosporine 100mg/ml, both administered topically in a swish and spit method three times a day for 4 weeks. The patients were followed up for a total of 6 months. Assessed parameters included clinical scoring (according to Thongprasom’s scale, 0-5), pain (VAS scale, 0-10), dysphagia and speech difficulties (none, mild or severe). Possible side effects, including fungal overgrowth, were also recorded.Results At the end of the 4-week treatment period, both dexamethasone and cyclosporine showed a statistically significant improvement in clinical scoring (p<0.025 and p=0.034, respectively), which was better with dexamethasone (p=0.001). In addition, both dexamethasone and cyclosporine induced statistical significant improvement in pain and dysphagia (and speech difficulties for dexamethasone), without significant differences between the two groups. Regarding side effects, patients in the dexamethasone group developed candidiasis more frequently compared to cyclosporine (p=0.031).At the end of the 6-month follow-up period, the difference in response between the two groups was not statistically significant. Interestingly, a trend for further improvement compared with the end of the 4-week treatment period was noticed only for patients treated with cyclosporine.Conclusions Despite the small number of enrolled patients, topical cyclosporine treatment induces a significant clinical improvement in symptomatic OLP patients, which, compared to topical dexamethasone, appears to be less pronounced during initial administration, but capable to induce further improvement after discontinuation with a satisfactory long-term remission in the absence of significant side effects. This study may contribute to a better understanding of the differences in effectiveness of OLP topical treatments and guide future larger scale clinical trials. Key words:Oral lichen planus, topical treatment, dexamethasone, cyclosporine.

Impact of the COVID-19 pandemic in patients with systemic lupus erythematosus throughout one year

Little is known about the impact of coronavirus disease 2019 (COVID-19) pandemic to the care of patients with systemic lupus erythematosus (SLE) in the long-term. By crossing population data with the results of a web-based survey focused on the timeframes January–April and May–December 2020, we found that among 334/518 responders, 28 had COVID-19 in 2020. Seventeen cases occurred in May–December, in parallel with trends in the general population and loosening of containment policy strength. Age > 40 years (p = 0.026), prednisone escalation (p = 0.008) and infected relatives (p < 0.001) were most significantly associated with COVID-19. Weaker associations were found with asthma, lymphadenopathy and azathioprine or cyclosporine treatment. Only 31% of patients with infected relatives developed COVID-19. Healthcare service disruptions were not associated with rising hospitalisations. Vaccination prospects were generally welcomed. Our data suggest that COVID-19 has a moderate impact on patients with SLE, which might be significantly modulated by public health policies, including vaccination.

Successful treatment of corticosteroid-dependent drug reaction with eosinophilia and systemic symptoms with cyclosporine

BackgroundDrug reaction with eosinophilia and systemic symptoms (DRESS) is an intractable drug hypersensitivity disease with high mortality. The current standard treatment requires high-dose and long-term systemic corticosteroids, which may lead to adverse effects and intolerability of patients. ObjectiveTo evaluate the efficacy and safety of cyclosporine in patients with corticosteroid-dependent DRESS or intolerance to systemic corticosteroids. MethodsA retrospective review of 8 patients with corticosteroid-dependent DRESS who were treated with cyclosporine as an alternative treatment owing to suboptimal response to regular doses of systemic corticosteroids for at least 3 weeks, flare-ups when tapering corticosteroids, or experiencing intolerable adverse effects of corticosteroids. ResultsIn all 8 patients (4 women and 4 men; age range, 15-75 years), either intractable skin eruptions, persistent eosinophilia, or elevated liver function was noted after at least 3 weeks of treatment with systemic corticosteroids. The patients had marked cutaneous improvement and normalization of liver function and eosinophil count after adding cyclosporine, and the systemic corticosteroid treatment was smoothly tapered down. The mean dosage of cyclosporine was 1.68 ± 0.73 mg/kg/d, and the mean duration of cyclosporine treatment was 76.13 ± 35.64 days. Their serum eosinophil counts, serum alanine aminotransferase levels, and serum thymus and activation-regulated chemokine levels were all elevated at baseline and then significantly decreased during the recovery stage after cyclosporine therapy (P < .05). No adverse events were reported after adding cyclosporine. ConclusionCyclosporine is an effective and safe therapeutic alternative as a steroid-sparing agent for corticosteroid-dependent DRESS. Further prospective randomized controlled studies are required to confirm these preliminary results.

Identification of differently expressed mRNAs by peripheral blood mononuclear cells in Vogt-Koyanagi-Harada disease

Vogt-Koyanagi-Harada disease (VKH) is a rare autoimmune disease characterized by diffuse and bilateral uveitis, alopecia, tinnitus, hearing loss, vitiligo and headache. The transcriptional expression pattern of peripheral blood mononuclear cells (PBMC) in VKH remains largely unknown. In this study, mRNA sequencing was conducted in PBMC from VKH patients with active uveitis before treatment (n = 7), the same patients after prednisone combined with cyclosporine treatment (n = 7) and healthy control subjects strictly matched with gender and age (n = 7). We found 118 differentially expressed genes (DEGs) between VKH patients and healthy control subjects, and 21 DEGs between VKH patients before and after treatment. TRIB1 was selected as a potential biomarker to monitor the development of VKH according to the mRNA sequencing. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed to predict the possible biological functions and signaling pathways of DEGs. Neutrophil degranulation, peptidase regulator activity, secretory granule membrane, cellular response to peptide, growth factor binding and cell projection membrane were enriched as GO annotations of DEGs. Arachidonic acid metabolism and mitogen-activated protein kinase (MAPK) signaling pathway were potential signaling pathways involved in pathogenesis and drug response of VKH. A protein–protein interaction (PPI) network was constructed by STRING, and colony stimulating factor 1 receptor (CSF1R) was identified as the hubgene of all DEGs by Cytoscape. The cell type presumed to contribute to the aberrant expression of DEGs was analyzed with the use of publicly available single-cell sequencing data of PBMC from a healthy donor and single-cell sequencing dataset of monocytes from VKH patients. Our findings may help to decipher the underlying cellular and molecular pathogenesis of VKH and may lead novel therapeutic applications.

Quantities and Functions of NK Cells in Severe Aplastic Anemia

IntroductionSevere aplastic anemia (SAA) is an autoimmune disease characterized by bone marrow failure. Natural killer (NK) cells are a key component in the innate immunity and adaptive immune. Our team have previously investigated the quantity and primary functions of NK in SAA. Here, we tend to present the extensive study on the roles NK has played in SAA.MethodsWe successively collected patients with untreated SAA, SAA response to immunosuppressive therapy (SAA-CR+PR), and healthy controls (HC) as research participants. Quantities of circulating NK and their subsets (CD56bright NK and CD56dim NK) were identified, the expressions of surface receptors,intracelluar protein and intracellular cytokines were analyzed by flow cytometry (FCM). Plasmatic IL-2 and IL-12 levels were measured by ELISA. NK cells were cultured with K562 cells. The apoptotic rate of K562 was measured to detect killing functions of NK. NK cells were co-cultured with CD4+ T , CD8+ T and myeloid Dendritic Cells (mDCs) from SAA. Quantities of Th1, Th2, Th17 and Treg, expressions of perforin and Granzyme B in CD8+ T cells and expressions of CD80 and CD86 on mDCs were analyzed by FCM. The mRNA expressions of T-bet, GATA3, RORγt and FOXP3 were measured by qRT-PCR. Proliferation rates of CD8+ T cells and mDC were detected by CCK-8. PeripheralNK cells were sorted and cultured with rhIL-2 and rhIL-12. The supernatants were detected for the cytokines produced by NK. The cytokines and their upstream signal molecules were analyzed by qRT-PCR and Western Blot. Finally, we investigated the quantities and the surface receptors of NK using the mouse model of lymphocyte infusion-induced bone marrow failure to confirm their functions.ResultsThe percentages of NK/lymphocytes and CD56brightNK/NK in SAA were significantly lower than in HC. The absolute number of NK cells in SAA was positively correlated with PLT, absolute number of Reticular cells (Ret) and percentage of Ret (p <0.01). NK cells in SAA expressed higher levels of NKp46, CD158a and perforin compared with those in HC. The percentage of DNAM-1+ NK was higher than that in HC (p=0.007). After PMA stimulation, NK cells in SAA produced lower level of IFN-γ and higher level of IL-10 and TGF-β compared with those in HC. The plasmatic levels of IL-2 and IL-12 in SAA were higher than in SAA-CR+PR and HC. The apoptotic rate of K562 cells when co-cultured with NK cells (1:1) was significantly higher than in HC.IL-2stimulatedNK cells from SAA expressed higher percentage of CD107a+ than from HC (p=0.017) when co-cultured with autologous activated CD4+T cells. After co-cultured with NK cells from SAA, the ratio of Th1/Th2 and Th17/Treg was decreased. The expressions of perforin and Granzyme B in CD8+ T cells were higher when co-cultured with NK from HC than in non-coculture group. The cell inhibition rate of mDCs when co-cultured with NK from SAA was higher than from HC. The expression of CD80 on mDCs when co-cultured with NK from HC was up-regulated.NK cells from SAA secreted lower level of IFN-γ, expressed lower levels of IFN-γ and STAT4 mRNA and phosphorylated STAT4. NK cells from SAA secreted higher levels of IL-10 and TGF-β, expressed higher levels of IL-10, TGF-β and p38 mRNA and phosphorylated p38. Bone marrow failure mouse model showed the quantities of NK cells weredecreased, the expression of NKG2A on NK was elevated. After the treatment of Cyclosporin A (CsA), the quantities NK cells recovered, the expression of NKG2D was elevated while NKG2A was not changed.ConclusionsInsufficient amount of NK cells was shown in SAA patients. The lower quantity of NK cells the patients had,the more severe the disease was. NK cells in SAA were functionally activated and exhibited strong killing abilities. NK cells in SAA produced less Type Ⅰ cytokines and more Type Ⅱ cytokines. Plasmatic levels of IL-2 and IL-12 were elevated in SAA. NK cells from SAA mediated in the differentiation of CD4+ T cells by influencing the balance of Th1/Th2 and Th17/Treg. NK cells from SAA might be able to down-regulate the cytotoxicity activity of CD8+ T cells and the expressions of co-stimulatory molecules on mDCs. The cell signal pathway JAK-STAT4-IFN-γ in NK cells from SAA was down-regulated while pathway p38 MAPK-IL10/TGF-β was up-regulated. Bone marrow failure mouse model suggested the impairment of both quantities and activating status of NK. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.