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Copyright of Journal of Zhejiang University: Science B is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Objective. To assess the long-term safety and effectiveness of tacrolimus as maintenance therapy in patients with lupus nephritis (LN) receiving treatment in real-world clinical settings in Japan. Methods. An open-label, noncomparative, observational, prospective postmarketing surveillance study was conducted in 1395 patients with LN receiving maintenance treatment with tacrolimus at 278 medical institutions across Japan over a period of 10 years. Tacrolimus continuation rate and cumulative incidence of adverse drug reactions (ADRs), relapse, progression to renal failure, and progression to dialysis were calculated using Kaplan-Meier analysis. Results. Safety data were available for 1355 patients, almost half (49.3%) of whom remained on tacrolimus for the full 10 years of follow-up. A significant reduction in mean (SD) daily oral corticosteroid dose was observed from 16.0 (9.7) mg/day at 4 weeks after initiation of tacrolimus treatment to 7.2 (4.4) mg/day at year 10 (P < 0.001). The most frequently reported serious ADRs were infections (reported for 131 [9.7%] patients). Except for infections, no marked increase in the incidence of any other ADRs was seen over time, including renal impairment, malignant tumors, and cardiac dysfunction. Renal function was generally well maintained over the 10 years of follow-up. At year 10, cumulative rates of relapse, renal failure, and dialysis were 44.5%, 12.2%, and 4.5%, respectively. Conclusion. Tacrolimus was effective and generally well tolerated as maintenance therapy for LN in a large cohort of patients in Japan followed for 10 years, almost half of whom remained on therapy for the entire duration of follow-up. (ClinicalTrials.gov: NCT01410747). [ABSTRACT FROM AUTHOR]

Aim: This study aimed to systematically compare the efficacy of various immunosuppressive agents in treating pediatric frequently relapsing or steroiddependent nephrotic syndrome (FRSDNS). Methods: We conducted systematic searches of PubMed, Embase, the Cochrane Library, and the Web of Science up to May 23, 2023. Outcome measures included relapses within 1 year, mean cumulative exposure to corticosteroids, patients with treatment failure at 1 year, relapse-free survival during 1 year, and adverse events. The quality of the included studies was evaluated using the modified Jadad scale, the Methodological Index for Non-Randomized Studies (MINORS), and the modified Newcastle-Ottawa Scale (NOS). Results: Rituximab was found to be the most likely (92.44%) to be associated with the fewest relapses within 1 year and was also most likely (99.99%) to result in the lowest mean cumulative exposure to corticosteroids. Rituximab had the highest likelihood (45.98%) of being associated with the smallest number of patients experiencing treatment failure at 1 year. CsA was most likely (57.93%) to achieve the highest relapse-free survival during 1 year, followed by tacrolimus (26.47%) and rituximab (30.48%). Rituximab showed no association with serious side effects and had comparable adverse effects to ofatumumab and tacrolimus. Conclusion: Rituximab may be the most favorable immunosuppressive agent for treating pediatric FRSDNS. Nephrologists should consider this drug, along with their clinical experience, patient characteristics, and cost considerations, when choosing a treatment approach. [ABSTRACT FROM AUTHOR]

The use of live attenuated vaccines in patients with immunosuppressive agents is contraindicated in package inserts and guidelines in Japan and other countries. However, patients receiving immunosuppressants have a high risk of infectious disease becoming severe, and the necessity to prevent infectious disease is high. To date, 2,091 vaccinations have been reported in 25 reports of live attenuated vaccines in people receiving immunosuppressants. Twenty-three patients (1.1%) became infected with the virus strain used in the vaccine, which was varicella virus in 21 patients. No reports have described life-threatening complications. A prospective study at the National Center for Child Health and Development conducted under certain immunological conditions (CD4 cell count ≥ 500/mm3, stimulation index of lymphocyte blast transformation by phytohemagglutinin (PHA) ≥ 101.6, serum immunoglobulin G ≥ 300 mg/dL) confirmed the serological effectiveness and safety. The evidence suggests that live attenuated vaccines can be used even in combination with immunosuppressants. Further evidence must be gathered and immunological criteria investigated to determine the conditions for safe use. Depending on the results of these investigations, the wording in package inserts and guidelines may need to be revised. [ABSTRACT FROM AUTHOR]

Introduction: Kidney transplant recipients are at an increased risk of fractures, and targeted preventive strategies are needed. Therefore, in this retrospective cohort study, we investigated a large population-based cohort to identify the transplant recipient-specific risk factors for fractures in Taiwanese kidney transplant recipients. Methods: We conducted a retrospective cohort study using the National Health Insurance Research Database. Patients who underwent renal transplantation between 2003 and 2015 were identified and followed until December 31, 2015, to observe the development of fractures. Variables associated with the development of post-transplant fractures were identified by calculating hazard ratios in a Cox regression model. Results: 5,309 renal transplant recipients were identified, of whom 553 (10.4%) were diagnosed with post-transplant fractures. Independent predictors of post-transplant fractures included an age at transplant ≥65 years (p < 0.001), female sex (p < 0.001), fractures within 3 years prior to transplantation (p < 0.001), and diabetes mellitus (p < 0.001). In addition, daily prednisolone doses >2.9–5.3 mg/day (p < 0.001), >5.3–8.7 mg/day (p < 0.001), and >8.7 mg/day (p < 0.001) were also independent predictors of post-transplant fractures. Conversely, the use of peritoneal dialysis before renal transplantation (p = 0.021), hypertension (p = 0.005), and the use of tacrolimus (p < 0.001), azathioprine (p = 0.006), mycophenolate mofetil/mycophenolic acid (p = 0.002), mTOR inhibitors (p = 0.004), and calcium supplements (p = 0.009) were inversely correlated with post-transplant fractures. Conclusion: We recommend minimizing daily glucocorticoids as early and as far as possible in conjunction with immunosuppressive regimens such as tacrolimus, azathioprine, mycophenolate mofetil/mycophenolic acid, mTOR inhibitors, and calcium supplements, especially in older female recipients and in recipients with diabetes and a history of prior fractures. [ABSTRACT FROM AUTHOR]

AimThis study aimed to systematically compare the efficacy of various immunosuppressive agents in treating pediatric frequently relapsing or steroid-dependent nephrotic syndrome (FRSDNS).MethodsWe conducted systematic searches of PubMed, Embase, the Cochrane Library, and the Web of Science up to May 23, 2023. Outcome measures included relapses within 1 year, mean cumulative exposure to corticosteroids, patients with treatment failure at 1 year, relapse-free survival during 1 year, and adverse events. The quality of the included studies was evaluated using the modified Jadad scale, the Methodological Index for Non-Randomized Studies (MINORS), and the modified Newcastle-Ottawa Scale (NOS).ResultsRituximab was found to be the most likely (92.44%) to be associated with the fewest relapses within 1 year and was also most likely (99.99%) to result in the lowest mean cumulative exposure to corticosteroids. Rituximab had the highest likelihood (45.98%) of being associated with the smallest number of patients experiencing treatment failure at 1 year. CsA was most likely (57.93%) to achieve the highest relapse-free survival during 1 year, followed by tacrolimus (26.47%) and rituximab (30.48%). Rituximab showed no association with serious side effects and had comparable adverse effects to ofatumumab and tacrolimus.ConclusionRituximab may be the most favorable immunosuppressive agent for treating pediatric FRSDNS. Nephrologists should consider this drug, along with their clinical experience, patient characteristics, and cost considerations, when choosing a treatment approach.

Thrombotic thrombocytopenic purpura (TTP) can cause serious morbidity and mortality, and differentiating between this disease and systemic lupus erythematosus (SLE) can prove challenging. Although rare, TTP accompanied by SLE is linked to several complications and a higher mortality rate. Herein, we report a case of a 16-year-old boy who presented with systemic symptoms, such as petechiae, and was diagnosed with acquired TTP following a laboratory test. Steroid treatment was initiated and a diagnosis of SLE was reached after the symptoms had improved. Treatment with low-dose prednisone in addition to hydroxychloroquine was continued. The patient did not develop renal failure or neurologic deficit. No specific symptoms were observed after treatment and during the follow-up period. Early treatment of SLE is crucial, but it is difficult to reach an early diagnosis because the symptoms are similar to those of TTP. In the current study, an early diagnosis of TTP led to prompt treatment, thereby avoiding the fatal symptoms that could be caused by SLE.

• About 40% of women with systemic vasculitis were treated by immunosuppressive drugs during pregnancy. • The number of patients treated with non-recommended immunosuppressant during pregnancy gradually decreased before pregnancy. • Proportion of systemic vasculitis flare did not increase significantly during pregnancy. Systemic vasculitis (SV) rarely affects women of childbearing age and only small series have been reported to date in pregnant patients. The discovery of an unplanned pregnancy can be an urgent cause for modifying treatments. This study aimed to describe immunosuppressive drugs use before, during and after pregnancy in women with SV. We conducted a cohort study using the French nationwide claims database. We included all women with SV being pregnant between 2013 and 2018. Exposure of interest was defined as exposure to oral systemic or injectable immunosuppressive drug identified using out-hospital reimbursement data and in-hospital reimbursement for expensive drugs. Of 3,246,454 pregnancies, 649 pregnancies were observed in 606 women with SV. Immunosuppressant and glucocorticoids use decreased before pregnancy and then increased after pregnancy (48.4%, 40.7%, 50.4%, respectively before, during, after). Prevalence of glucocorticoids use was broadly stable during pregnancy from 27.9% to 27.6% and 23.7% in the 1st, 2nd and 3rd trimesters, respectively, with a daily dose of about 5 mg. The number of patients treated with non-recommended immunosuppressant during pregnancy gradually decreased before pregnancy and then increased after delivery, whereas proportion of systemic vasculitis flare, estimated from the glucocorticoids daily dose, did not increase significantly during pregnancy. Immunosuppressants and glucocorticoids use decreased before pregnancy and remained stable throughout, suggesting a vasculitis control during this period. Our findings support the importance of pre-conceptional consultations to review medications, and switch not-recommended and teratogenic medications to drugs considered being safe during pregnancy. [ABSTRACT FROM AUTHOR]

Objective: The calcineurin inhibitor tacrolimus has been approved in Japan for the treatment of interstitial pneumonia (IP) in patients with polymyositis (PM) and dermatomyositis (DM). Postmarketing surveillance was initiated to examine long-term outcomes of immunosuppressive regimens containing tacrolimus in real-world settings.Methods: Observational, prospective, postmarketing surveillance is ongoing in 179 patients with PM/DM-associated IP initiating treatment with tacrolimus. We report interim findings after 2 years of follow-up. Cumulative overall survival was assessed using Kaplan-Meier analysis. Potential prognostic factors for mortality were assessed by univariate Cox proportional hazards analysis.Results: A total of 170 patients were included in this analysis. At the time of starting treatment with tacrolimus, almost all patients were receiving corticosteroids (98.8%), and cyclophosphamide was additionally used in 42 patients (24.7%). Forty-nine patients (28.8%) discontinued tacrolimus during follow-up, mainly due to loss to follow-up, patient death, and adverse events. Mean (SD) oral corticosteroid dose decreased from 32.4 (21.6) mg/day at baseline to 7.6 (4.2) mg/day at 2 years. Overall survival at 2 years was 90.3%; corresponding progression-free survival was 62.5%. Factors found to be associated with all-cause mortality included diagnosis of clinically amyopathic DM (hazard ratio [HR] 9.04, 95% CI 1.18-69.51 vs PM), ferritin level 500 to < 1500 ng/mL (HR 8.61, 95% CI 2.51-29.45 vs < 500 ng/mL), and presence of antimelanoma differentiation-associated gene 5 antibodies (HR 8.16, 95% CI 1.03-64.47 vs absence).Conclusion: Immunosuppressive regimens containing tacrolimus appear useful for the management of IP in patients with PM/DM. [ClinicalTrials.gov: NCT02159651]. [ABSTRACT FROM AUTHOR]

Abstract Background Henoch-Schönlein purpura (HSP), also called IgA vasculitis, is a systemic vasculitis characterized by deposits of immunoglobulin A in blood vessels. Renal impairment of these patients is the main determinant of prognosis. The optimal treatment of HSP nephritis (HSPN) in children remains controversial, but many clinicians administer an immunosuppressive agent with a corticosteroid. A previous study reported that leflunomide (LEF) with a corticosteroid was effective for adult patients with HSPN and nephrotic proteinuria. However, data on this treatment in pediatric patients is limited. Methods We described our experience at a single center on the use of LEF in 5 pediatric patients who had IgA vasculitis with proteinuria that was nearly 50 mg/kg (nephrotic range) and remained high despite administration of intravenous steroid, and biopsy-proven nephritis. All patients had class II to IIIb lesions based on the International Study of Kidney Disease in Children (ISKDC). Results We successfully treated all 5 children who had IgA vasculitis with nephritis using LEF with a corticosteroid. Four patients achieved a complete remission of proteinuria, and 1 patient had significantly reduced proteinuria. The children received LEF for 6 months to 12 months, and none of them had severe adverse events. Conclusions To our knowledge, this is the first case series to report successful treatment of pediatric HSPN with LEF in combination with a corticosteroid.

Immune abnormality involves in various diseases, such as infection, allergic diseases, autoimmune diseases, as well as transplantation. Several signal pathways have been demonstrated to play a central role in the immune response, including JAK/STAT, NF-κB, PI3K/AKT-mTOR, MAPK, and Keap1/Nrf2/ARE pathway, in which multiple targets have been used to develop immunosuppressive agents. In recent years, varieties of immunosuppressive agents have been approved for clinical use, such as the JAK inhibitor tofacitinib and the mTOR inhibitor everolimus, which have shown good therapeutic effects. Additionally, many immunosuppressive agents are still in clinical trials or preclinical studies. In this review, we classified the immunosuppressive agents according to the immunopharmacological mechanisms, and summarized the phase of immunosuppressive agents. [ABSTRACT FROM AUTHOR]

Immune abnormality involves in various diseases, such as infection, allergic diseases, autoimmune diseases, as well as transplantation. Several signal pathways have been demonstrated to play a central role in the immune response, including JAK/STAT, NF-κB, PI3K/AKT-mTOR, MAPK, and Keap1/Nrf2/ARE pathway, in which multiple targets have been used to develop immunosuppressive agents. In recent years, varieties of immunosuppressive agents have been approved for clinical use, such as the JAK inhibitor tofacitinib and the mTOR inhibitor everolimus, which have shown good therapeutic effects. Additionally, many immunosuppressive agents are still in clinical trials or preclinical studies. In this review, we classified the immunosuppressive agents according to the immunopharmacological mechanisms, and summarized the phase of immunosuppressive agents.

Nephrotic syndrome (NS) may occur after or concomitantly with malignancy. The use of immunosuppressive approaches in patients with cancer and NS is controversial, especially when the association between the pathologies is unclear. The aim of this study was to report the case of a patient with metastatic melanoma who developed NS and to examine the association between NS and neoplasia. A 56‐year‐old woman diagnosed with right hallux melanoma, removed by marginal resection with no sign of metastasis, developed NS after 6 months without the detection of another associated disease. The histological diagnosis was focal and segmental glomerulosclerosis (FSGS). The patient was older than most patients with FSGS and was treated with immunosuppressive agents (prednisone and cyclosporine) concomitantly with melanoma treatment. Nephrotic syndrome was the first manifestation of metastatic melanoma recurrence in this patient. Proteinuria was controlled adequately after immunosuppression and melanoma treatment. Although NS has been associated with cancer, laboratory and histological markers correlating it with melanoma are needed. [ABSTRACT FROM AUTHOR]

Objective: To study the clinical features and treatment of immunosuppressive-related Kaposi sarcoma in mainland China. Methods: Literature articles on immunosuppressive-related Kaposi sarcoma in the Chinese mainland from 1995 to 2020 were searched through CNKI, Wangfang, Weipu and Pubmed databases and systematically analyzed. Results: A total of 42 patients from 40 cases report were included in the review. The mean age was 47.4 years and the male-to-female ratio was 3.67 ∶1. Compared with other patients, a higher incidence of immunosuppressive-related Kaposi sarcoma was reported in patients with renal transplant and patients treated with one or more immunosuppressants/ glucocorticoids. Most cases developed the immunosuppressive-related kaposi sarcoma within 2~3 months or 1~2 years after treatment with immunosuppressive drugs. The lesions were frequently reported in cutaneous, especially in the lower limbs, and less frequently in lymph nodes and visceral organs. The most common treatments for immunosuppressive-related Kaposi sarcoma included discontinuing of immunosuppressive drugs, reducing the amount of immunosuppressive drugs, replacing immunosuppressive drugs/glucocorticoids with other drugs or combined all these therapy. Conclusion: Our results indicate that long-term use of immunosuppressive agents or glucocorticoids can increase the occurrence of the immunosuppressive-related Kaposi sarcoma, and discontinuing or reducing these immunosuppressive drugs with other drugs can improve the prognosis of these patients.

Abstract Nephrotic syndrome (NS) may occur after or concomitantly with malignancy. The use of immunosuppressive approaches in patients with cancer and NS is controversial, especially when the association between the pathologies is unclear. The aim of this study was to report the case of a patient with metastatic melanoma who developed NS and to examine the association between NS and neoplasia. A 56‐year‐old woman diagnosed with right hallux melanoma, removed by marginal resection with no sign of metastasis, developed NS after 6 months without the detection of another associated disease. The histological diagnosis was focal and segmental glomerulosclerosis (FSGS). The patient was older than most patients with FSGS and was treated with immunosuppressive agents (prednisone and cyclosporine) concomitantly with melanoma treatment. Nephrotic syndrome was the first manifestation of metastatic melanoma recurrence in this patient. Proteinuria was controlled adequately after immunosuppression and melanoma treatment. Although NS has been associated with cancer, laboratory and histological markers correlating it with melanoma are needed.

Effective control of severe immune-related adverse events, including cytokine release syndrome (CRS), is essential for the success of immunotherapy. We present a case of a granulocyte colony-stimulating factor–producing pleomorphic lung carcinoma treated with nivolumab plus ipilimumab which developed CRS and severe immune-related pneumonitis. The effect of immunotherapy was heterogeneous; gastric metastasis was eliminated, but the pulmonary lesion had primary resistance. Steroid and tocilizumab were successful in controlling CRS, but additional infliximab was necessary to control pneumonitis. To control immune-related adverse events, it is important to choose immunosuppressive agents to the specific target organ and inflammatory cells.

Background : Graft survival rate of kidney transplantation recipients improves after induction therapy. However, there is no conclusive evidence on which regimen is superior for deceased donor kidney transplantation (DDKT). This study aims at discussing effective induction therapy in DDKT. Methods : Between 2003 and 2016, 395 DDKT recipients were divided into three groups following induction therapy. Recipients of the basiliximab group (n=184) received basiliximab (20 mg/kg) on days 0 and 4. Recipients of the low-dose rabbit anti-thymocyte globulin (rATG) group (n=113) received rATG (1.5 mg/kg) on days 0, 1, and 2, while those of the high-dose rATG group (n=98) received it for more than 4 days. We retrospectively reviewed and analyzed the clinical outcomes and adverse effects of induction therapy.Results : Compared to other groups, the low-dose rATG group donors were older (P

Tacrolimus is an immunosuppressive drug widely used in organ or tissue transplantation. Furthermore, its anti-inflammatory effects are employed in treatments for psoriasis, uveitis, and vernal keratoconjunctivitis. According to the structural characteristics of tacrolimus, different transformations can be occurred on the drug and produces degradation products. Thus, stability and stress tests have a key role in the quality of tacrolimus with a narrow therapeutic index. Up to now, different studies have been developed for the study of tacrolimus stability under different conditions, and the degradation products were detected by different analytical instruments. Therefore, in the current study, available studies about tacrolimus degradation were collected and categorized into five main parts including acidic hydrolysis, alkaline hydrolysis, thermal, oxidative, and photolytic for better survey. The known degradation products with their chemical structures were also discussed in this study. Moreover, the analytical methods that are applied for drug characterization during stability tests were explained.

Objective: To assess the long-term safety and effectiveness of tacrolimus as maintenance therapy in patients with lupus nephritis (LN) receiving treatment in real-world clinical settings in Japan., Methods: An open-label, noncomparative, observational, prospective postmarketing surveillance study was conducted in 1395 patients with LN receiving maintenance treatment with tacrolimus at 278 medical institutions across Japan over a period of 10 years. Tacrolimus continuation rate and cumulative incidence of adverse drug reactions (ADRs), relapse, progression to renal failure, and progression to dialysis were calculated using Kaplan-Meier analysis., Results: Safety data were available for 1355 patients, almost half (49.3%) of whom remained on tacrolimus for the full 10 years of follow-up. A significant reduction in mean (SD) daily oral corticosteroid dose was observed from 16.0 (9.7) mg/day at 4 weeks after initiation of tacrolimus treatment to 7.2 (4.4) mg/day at year 10 ( P < 0.001). The most frequently reported serious ADRs were infections (reported for 131 [9.7%] patients). Except for infections, no marked increase in the incidence of any other ADRs was seen over time, including renal impairment, malignant tumors, and cardiac dysfunction. Renal function was generally well maintained over the 10 years of follow-up. At year 10, cumulative rates of relapse, renal failure, and dialysis were 44.5%, 12.2%, and 4.5%, respectively., Conclusion: Tacrolimus was effective and generally well tolerated as maintenance therapy for LN in a large cohort of patients in Japan followed for 10 years, almost half of whom remained on therapy for the entire duration of follow-up. (ClinicalTrials.gov: NCT01410747)., (Copyright © 2024 by the Journal of Rheumatology.)

Background: Henoch-Schönlein purpura (HSP), also called IgA vasculitis, is a systemic vasculitis characterized by deposits of immunoglobulin A in blood vessels. Renal impairment of these patients is the main determinant of prognosis. The optimal treatment of HSP nephritis (HSPN) in children remains controversial, but many clinicians administer an immunosuppressive agent with a corticosteroid. A previous study reported that leflunomide (LEF) with a corticosteroid was effective for adult patients with HSPN and nephrotic proteinuria. However, data on this treatment in pediatric patients is limited.Methods: We described our experience at a single center on the use of LEF in 5 pediatric patients who had IgA vasculitis with proteinuria that was nearly 50 mg/kg (nephrotic range) and remained high despite administration of intravenous steroid, and biopsy-proven nephritis. All patients had class II to IIIb lesions based on the International Study of Kidney Disease in Children (ISKDC).Results: We successfully treated all 5 children who had IgA vasculitis with nephritis using LEF with a corticosteroid. Four patients achieved a complete remission of proteinuria, and 1 patient had significantly reduced proteinuria. The children received LEF for 6 months to 12 months, and none of them had severe adverse events.Conclusions: To our knowledge, this is the first case series to report successful treatment of pediatric HSPN with LEF in combination with a corticosteroid. [ABSTRACT FROM AUTHOR]

Background and aim: Ustekinumab (UST), a fully humanized monoclonal antibody against the p40 subunit of interleukin‐12/23, is effective for the treatment of Crohn's disease (CD). The benefit of concomitant use of an immunomodulator (IM) with UST, however, is unclear. This study aimed to provide a systematic review and meta‐analysis comparing the efficacy and safety of concomitant use of an IM with UST as an induction therapy for CD patients. Methods: A systematic literature search was performed using PubMed/MEDLINE, the Cochrane Library, and the Japana Centra Revuo Medicina from inception to October 31, 2019. The main outcome measure was achievement of clinical efficacy (remission, response, and clinical benefit) at 6–12 weeks. The quality of the included studies was assessed using the risk of bias in non‐randomized studies of interventions (ROBINS‐I) tools. The fixed‐effects model was used to calculate the pooled odds ratios. Results: From 189 yielded articles, six including a total of 1507 patients were considered in this meta‐analysis. Concomitant use of an IM with UST was significantly effective than UST monotherapy as an induction therapy (pooled odds ratio in the fixed‐effects model: 1.35, 95% confidence interval [1.06–1.71], P = 0.015). The heterogeneity among studies was low (I2 = 2.6%). No statistical comparisons of the occurrence of adverse events between UST monotherapy and concomitant use of an IM with UST were performed. Conclusion: The efficacy of concomitant use of an IM with UST as an induction therapy for CD was significantly superior to that of monotherapy with UST. [ABSTRACT FROM AUTHOR]

Copyright of Chinese Journal of Contemporary Pediatrics is the property of Xiangya Medical Periodical Press and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Objective: To assess the long-term safety and effectiveness of tacrolimus for treating lupus nephritis (LN) in the real-world clinical setting.Methods: This is an ongoing, open-label, noncomparative, observational, postmarketing surveillance study conducted across 275 sites in Japan. Registered patients with LN were followed for 10 years. Here we report data relating to 5 years of tacrolimus maintenance therapy at the interim data cutoff in August 2016.Results: Of 1395 registered patients, 1355 received tacrolimus maintenance therapy for LN and provided safety data. The most common serious adverse drug reactions (ADR) included pneumonia (1.1%), herpes zoster (1.0%), cellulitis (1.0%), and diabetes mellitus (1.0%). ADR occurred mainly within the first 28 weeks of tacrolimus treatment, and no marked increase was observed during the follow-up period. Subgroup analyses suggested that risk factors for commonly observed ADR associated with tacrolimus included inpatient management, LN disease severity, increasing age, abnormal renal or hepatic function, and comorbid or previous disease. The cumulative rate of progression to renal failure (based on the attending physician's assessment) was 0.8% at Year 1 and 6.6% at Year 5. Cumulative relapse rates were 7.8% and 30.6%, respectively. Urine protein:creatinine ratio, serum anti-dsDNA antibody levels, complement C3 levels, and steroid-sparing effects were all significantly improved from 4 weeks after tacrolimus treatment initiation (P < 0.001) and were sustained over 5 years.Conclusion: Long-term tacrolimus maintenance treatment over 5 years in the real-world clinical setting was well tolerated and effective in a large population of patients with LN (www.ClinicalTrials.gov: NCT01410747). [ABSTRACT FROM AUTHOR]

BackgroundMicroparticles (MPs) are vesicular structures that derive from multiple cellular sources. MPs play important roles in intercellular communication, regulation of cell signaling or initiation of enzymatic processes. While MPs were characterized in Systemic Sclerosis (SSc) patients, their contribution to SSc pathogenesis remains unknown. Our aim was to investigate the potential role of MPs in SSc pathophysiology and their impact on tissue fibrosis.MethodsNinety-six SSc patients and 37 sex-matched healthy donors (HD) were enrolled in this study in order to quantify and phenotype their plasmatic MPs by flow cytometry. The ability of MPs purified from SSc patients and HD controls to modulate fibroblast’s extra-cellular matrix genes expression was evaluated in vitro by reverse transcriptase quantitative polymerase chain reaction.ResultsSSc patients exhibited a higher concentration of circulatory MPs compared to HD. This difference was exacerbated when we only considered patients that were not treated with methotrexate or targeted disease-modifying antirheumatic drugs. Total circulatory MPs were associated to interstitial lung disease, lung fibrosis and diminished lung functional capacity, but also to vascular involvement such as active digital ulcers. Finally, contrary to HD MPs, MPs from SSc patients stimulated the production of extracellular matrix by fibroblast, demonstrating their profibrotic potential.ConclusionsIn this study, we provide evidence for a direct profibrotic role of MPs from SSc patients, underpinned by strong clinical associations in a large cohort of patients.

Background: Defining the optimal dosage of the immunosuppressive or duration of anti-infective agents is a challenge in solid organ transplant (SOT) recipients. We aimed to systematically review the literature regarding the use of T cell mediated immune functional assays (IFAs) for adjustment of the immunosuppressive or anti-infective agents in SOT recipients.Methods: We systematically searched PubMed, Scopus, EMBASE, Web of Science (WOS), Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov to find human interventional studies or study protocols that used either in-house or commercially available IFAs for adjustment of the immunosuppressive or anti-infective agents in SOT recipients.Results: We included six clinical trials and six study protocols. Four out of the six clinical trials used interferon-γ release assays for cytomegalovirus (IGRA-CMV), and five out of the six registered study protocols planned to use IGRA-CMV for adjustment of anti-CMV antiviral (Valganciclovir) prophylaxis or preemptive therapy in SOT recipients. Primary or secondary anti-CMV prophylaxes were discontinued in SOT recipients who had positive IGRA-CMV results without an increase in the rate of CMV infection or reactivation. Among other IFAs, one clinical trial used interferon-γ release assays for tuberculosis (IGRA-TB), and one study used ImmuKnow for adjustment of the duration and dosage of isoniazid and tacrolimus, respectively.Conclusion: Our systematic review supports a promising role for the IGRA-CMVs for adjustment of the duration of anti-CMV antiviral prophylaxis in SOT recipients. There are limited data to support the use of IFAs other than IGRA-CMVs for adjustment of immunosuppressive or anti-infective agents. Further multicenter randomized clinical trials using IFAs other than IGRA-CMVs may help in personalized immunosuppressive or prophylactic anti-infective therapy in SOT recipients.

Background: Premature ovarian insufficiency (POI) is extremely rare in the early stage of undifferentiated connective tissue disease. Patients with POI find it difficult to achieve successful pregnancy and delivery., Case Presentation: A 27-year-old female visited an outpatient department for premature ovarian insufficiency (POI) and infertility. She had regular menstrual periods since she was 14 years old and had no history of systemic disease. Laboratory tests showed low estrogen (15 ng/L, range 19.6-144.2 ng/L), elevated follicle-stimulating hormone (34 U/L), low anti-Mullerian hormone (0.1 μg/L), normal prolactin (11.48 ng/mL), and thyroid stimulating hormone (TSH) levels (0.97 mU/L). She demonstrated smaller bilateral ovarian volume and positivity to antinuclear and antiphospholipid antibodies. After the failure of conventional drug therapy and in vitro fertilization, the patient became pregnant naturally after treatment with glucocorticoids., Conclusion: Immunosuppression could help improve ovarian function and pregnancy outcomes in POI patients, but the therapeutic mechanisms are not clear and should be elucidated with more clinical studies., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Organ transplantation remains the gold standard therapeutic option for patients with end-stage organ failure. However, there have been few improvements in the management of post-transplant immunosuppression. As the long-term use of immunosuppressive agents (ISAs) may result in off-target systemic toxicity and complications, minimizing the ISA dosage while preserving the pharmacological efficacy could be a promising solution to address these challenges. Here, we present the design and application of self-assembled prodrug nanoparticles based on chemically derived mycophenolate mofetil, which further provide a hydrophobic core to noncovalently encapsulate additional ISAs such as tacrolimus. The resulting immunosuppressant cocktail nanoparticles are further refined by PEGylation with amphiphilic polymers to form colloidally stable self-assembled immunosuppressant cocktails (SAICs) that are suitable for preclinical studies. In a rat model of allogeneic orthotopic liver transplantation (OLT), administration of SAICs markedly extends graft/recipient survival, retards weight loss and attenuates allograft damage. Furthermore, SAICs significantly abolish intragraft inflammatory cell infiltration and proinflammatory cytokine profiles as well as improve liver graft function. This study demonstrates the superiority of SAICs over traditional ISAs in the treatment of allograft rejection and may support the emerging application of the SAIC platform in clinical settings. Unlabelled Image • PUFAylation of immunosuppressive agents (ISAs) enabled self-assembly of the prodrugs into injectable nanoparticles. • Self-assembled immunosuppressant cocktails (SAICs) were established for target-oriented nanodelivery of ISAs. • Esterase-catalyzed drug activation and release of active metabolite were studied. • SAICs substantially prolonged allogeneic orthotopic liver transplant survival relative to free ISA combination. • Low-dose SAICs were effective therapies against allograft rejection. [ABSTRACT FROM AUTHOR]

Background: Microparticles (MPs) are vesicular structures that derive from multiple cellular sources. MPs play important roles in intercellular communication, regulation of cell signaling or initiation of enzymatic processes. While MPs were characterized in Systemic Sclerosis (SSc) patients, their contribution to SSc pathogenesis remains unknown. Our aim was to investigate the potential role of MPs in SSc pathophysiology and their impact on tissue fibrosis. Methods: Ninety-six SSc patients and 37 sex-matched healthy donors (HD) were enrolled in this study in order to quantify and phenotype their plasmatic MPs by flow cytometry. The ability of MPs purified from SSc patients and HD controls to modulate fibroblast's extra-cellular matrix genes expression was evaluated in vitro by reverse transcriptase quantitative polymerase chain reaction. Results: SSc patients exhibited a higher concentration of circulatory MPs compared to HD. This difference was exacerbated when we only considered patients that were not treated with methotrexate or targeted disease-modifying antirheumatic drugs. Total circulatory MPs were associated to interstitial lung disease, lung fibrosis and diminished lung functional capacity, but also to vascular involvement such as active digital ulcers. Finally, contrary to HD MPs, MPs from SSc patients stimulated the production of extracellular matrix by fibroblast, demonstrating their profibrotic potential. Conclusions: In this study, we provide evidence for a direct profibrotic role of MPs from SSc patients, underpinned by strong clinical associations in a large cohort of patients. [ABSTRACT FROM AUTHOR]

Background: Defining the optimal dosage of the immunosuppressive or duration of anti-infective agents is a challenge in solid organ transplant (SOT) recipients. We aimed to systematically review the literature regarding the use of T cell mediated immune functional assays (IFAs) for adjustment of the immunosuppressive or anti-infective agents in SOT recipients. Methods: We systematically searched PubMed, Scopus, EMBASE, Web of Science (WOS), Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov to find human interventional studies or study protocols that used either in-house or commercially available IFAs for adjustment of the immunosuppressive or anti-infective agents in SOT recipients. Results: We included six clinical trials and six study protocols. Four out of the six clinical trials used interferon-γ release assays for cytomegalovirus (IGRA-CMV), and five out of the six registered study protocols planned to use IGRA-CMV for adjustment of anti-CMV antiviral (Valganciclovir) prophylaxis or preemptive therapy in SOT recipients. Primary or secondary anti-CMV prophylaxes were discontinued in SOT recipients who had positive IGRA-CMV results without an increase in the rate of CMV infection or reactivation. Among other IFAs, one clinical trial used interferon-γ release assays for tuberculosis (IGRA-TB), and one study used ImmuKnow for adjustment of the duration and dosage of isoniazid and tacrolimus, respectively. Conclusion: Our systematic review supports a promising role for the IGRA-CMVs for adjustment of the duration of anti-CMV antiviral prophylaxis in SOT recipients. There are limited data to support the use of IFAs other than IGRA-CMVs for adjustment of immunosuppressive or anti-infective agents. Further multicenter randomized clinical trials using IFAs other than IGRA-CMVs may help in personalized immunosuppressive or prophylactic anti-infective therapy in SOT recipients. [ABSTRACT FROM AUTHOR]

Background The utility of the Columbia classification (Col-class) for focal segmental glomerulosclerosis (FSGS) has not yet been fully proven. Methods We extracted 201 FSGS patients from 10 nephrology centers in Japan and investigated the difference of a composite renal endpoint, defined as doubling of serum creatinine and/or development of end-stage renal disease, in pathological variants. Sensitivity analysis was used to prove the utility of the Col-class to predict renal outcomes. Additionally, the renal protective effects of steroids and/or immunosuppression (steroid/IS) were investigated in patients stratified according to the Col-class. Results The patients were classified into the following variants: not otherwise specified [NOS; n  = 121 (60.1%)], perihilar [ n  = 31 (15.4%)], cellular [ n  = 19 (9.5%)], tip [ n  = 17 (8.5%)] and collapsing [ n  = 13 (6.5%)]. No tip variant patients reached the renal endpoint. The renal outcome in the collapsing variant was significantly poorer than that in the NOS [hazard ratio (HR) 3.71; P = 0.005]. In the sensitivity analysis, the area under the receiver operating characteristic curve for the renal endpoint was increased by adding Col-class to a model including common risk factors (P = 0.021). In a subgroup treated without steroid/IS, the outcome in the cellular variant was worse than that in the NOS (HR 5.10; P =   0.040) but the difference was not observed in the subgroup with steroid/IS (HR 0.54; P =   0.539). Conclusions The Col-class is useful to predict renal prognosis in Japanese patients with FSGS. In addition to good prognosis in the tip variant and poor in the collapsing variant, good clinical course in the cellular variant treated with steroid/IS was suggested. [ABSTRACT FROM AUTHOR]

Current immunosuppressive agents for organ transplantation are not ideal because of their strong toxicity and adverse effects. Hence, there is an urgent need to develop novel immunosuppressive agents. The compound N, N′‐dicyclohexyl‐N‐arachidonic acylurea (DCAAA) is a novel highly unsaturated fatty acid from the traditional Chinese medicinal plant Radix Isatidis. In this study, we systematically investigated the toxicity, immunosuppressive effect and mechanisms underlying the activity of DCAAA. The toxicity tests showed that DCAAA treatment did not lead to red blood cell hemolysis and did not affect the liver and kidney functions in mice. The lymphocyte transformation test showed that DCAAA treatment inhibited lymphocyte proliferation in a dose‐dependent manner. An in vivo cardiac allotransplantation experiment showed that DCAAA treatment could suppress the immune rejection and significantly prolong the survival of cardiac allografts in recipient mice by reducing the proportion of CD4+ T cells in the spleen and grafts, concentration of interferon‐γ in the supernatant and serum and infiltration of inflammatory cells into the grafts. Moreover, a combination treatment with DCAAA and tacrolimus had a synergistic effect in preventing acute rejection of heart transplants. In vitro molecular biology experiments showed that DCAAA treatment inhibited activation of the T‐cell receptor‐mediated phosphoinostide 3‐kinase‐protein kinase B pathway, thereby arresting cell cycle transition from the G1 to the S phase, and inhibiting lymphocyte proliferation. Overall, our study reveals a novel, low‐toxicity immunosuppressive agent that has the potential to reduce the toxic side effects of existing immunosuppressive agents when used in combination with them. [ABSTRACT FROM AUTHOR]

Vogt-Koyanagi-Harada(VKH)syndrome is an autoimmune disease attacking against pigmented cells, resulting in blindness and usually affecting multiple organs including ears, meninges, hair and skin. Correct diagnosis and immediate treatment in the early stage is vital to visual prognosis. Currently, corticosteroids is first-line drug. In addition, VKH patients refractory to corticosteroids can choose other treatment such as immunosuppressive agents and biological agents.

Renal transplantation has become the sole most preferred therapy modality for end-stage renal disease patients. The growing tendency for renal transplants, and prolonged survival of renal recipients, have resulted in a certain number of post-transplant colorectal cancer patients. Antitumor pharmacotherapy in these patients is a dilemma. Substantial impediments such as carcinogenesis of immunosuppressive drugs (ISDs), drug interaction between ISDs and anticancer drugs, and toxicity of anticancer drugs exist. However, experience of antitumor pharmacotherapy in these patients is limited, and the potential risks and benefits have not been reviewed systematically. This review evaluates the potential impediments, summarizes current experience, and provides potential antitumor strategies, including adjuvant, palliative, and subsequent regimens. Moreover, special pharmaceutical care, such as ISDs therapeutic drug monitoring, metabolic enzymes genotype, and drug interaction, are also highlighted. [ABSTRACT FROM AUTHOR]

Objective: Mycophenolate (MPA) and cyclosporin A (CsA) are two immunosuppressive agents currently used for the treatment of autoimmune diseases. However, reports regarding their effects on inflammation and lipid handling are controversial. Here, we compare the effect of these two drugs on the expression of proteins involved in cholesterol handling and lipid accumulation in a macrophage cell system utilizing M0, M1 and M2 human macrophages and in murine bone marrow-derived macrophages (BMDM). Methods: Differentiated M0, M1 and M2 subsets of THP-1 human macrophages were subjected to various concentrations of either MPA or CsA. Expression of proteins involved in reverse cholesterol transport (ABCA1 and 27-hydroxylase) and scavenger receptors, responsible for uptake of modified lipids (CD36, ScR-A1, CXCL16 and LOX-1), were evaluated by real-time PCR and confirmed with Western blot. DiI-oxidized LDL internalization assay was used to assess foam cell formation. The influence of MPA was also evaluated in BMDM obtained from atherosclerosis-prone transgenic mice, ApoE−/− and ApoE−/−Fas−/−. Results: In M0 macrophages, MPA increased expression of ABCA1 and CXCL16 in a concentration-dependent manner. In M1 THP-1 macrophages, MPA caused a significant increase of 27-hydroxylase mRNA and CD36 and SR-A1 receptor mRNAs. Exposure of M2 macrophages to MPA also stimulated expression of 27-hydroxylase, while downregulating all evaluated scavenger receptors. In contrast, CsA had no impact on cholesterol efflux in M0 and M1 macrophages, but significantly augmented expression of ABCA1 and 27-hydroxylase in M2 macrophages. CsA significantly increased expression of the LOX1 receptor in naïve macrophages, downregulated expression of CD36 and SR-A1 in the M1 subpopulation and upregulated expression of all evaluated scavenger receptors. However, CsA enhanced foam cell transformation in M0 and M2 macrophages, while MPA had no effect on foam cell formation unless used at a high concentration in the M2 subtype. Conclusions: Our results clearly underline the importance of further evaluation of the effects of these drugs when used in atherosclerosis-prone patients with autoimmune or renal disease. [ABSTRACT FROM AUTHOR]

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Purpose: The purpose of this study was to identify the risk factors for everolimus discontinuation in kidney transplant recipients converted to everolimus with calcineurin inhibitor (CNI) minimization at a late post-transplant stage. Materials and Methods: An observational retrospective cohort study was conducted on a total of 38 recipients of kidney transplantation at our institution from June 2012 to March 2015 who were converted from antimetabolites to everolimus at a late post-transplant stage and followed for 1 year. We divided the patients into two groups to evaluate the factors affecting everolimus discontinuation after conversion: everolimus continuation group (n = 23), patients in whom everolimus maintained, and everolimus discontinuation group (n = 15), patients in whom everolimus were stopped within 1 year after conversion. Results: Age at conversion was significantly older in the everolimus discontinuation group compared to the everolimus continuation group (57.9 ± 12.0 years in the everolimus discontinuation group vs 45.7 ± 11.2 years in the everolimus continuous group; P = .0062). Multivariate cox proportional hazard regression analysis revealed that age at conversion significantly correlated with everolimus discontinuation (P = .012). Receiver operating characteristic curve of age at conversion showed that the cut-off value was 55 years old for the everolimus discontinuation group [area under curve 0.804, 95% confidence interval (0.654-0.954), sensitivity 86.7%, specificity 65.2%]. Conclusion: Our results indicated that late conversion to everolimus with CNI minimization in elderly recipients older than 55 years of age may be associated with more frequent adverse events and discontinuations. [ABSTRACT FROM AUTHOR]

The patient was a 16-year-old boy who was diagnosed with Crohn's disease at 13 years of age, who was treated with mesalazine, azathioprine, and infliximab. Concurrently, the patient developed small freckle-like pigmented spots on sun-exposed areas, which gradually increased in number. At 14 and 16 years of age, a blue-gray macule and a nodule appeared on his face, respectively. A histopathological examination revealed that the macule had only postinflammatory pigmentation, while the nodule was basal cell carcinoma. The sensitivity to UV-killing by colony formation of the patient's cells was normal but was enhanced by caffeine treatment. In addition, a pathologic mutation in the POLH gene was identified and a diagnosis of xeroderma pigmentosum variant (XP-V) was established. XP-V is a cutaneous type of XP that is commonly diagnosed from middle age after the induction of skin cancer on sun-exposed areas. Our patient had a genetically sensitive background (XP-V), and we considered that immunosuppressive agents for Crohn's disease may have enhanced the photocarcinogenesis at a young age. This finding implies that we should be careful about a skin cancer production and that protection from UV may be essential when pediatric patients with a genetic background of UV sensitivity take immunosuppressive agents. [ABSTRACT FROM AUTHOR]

Background: Treatment of steroid-resistant nephrotic syndrome (SRNS) remains a huge challenge in pediatric patients. Immunosuppressive agents including cyclosporine A (CsA), tacrolimus (TAC) and mycophenolate mofetil (MMF) are recommended for the management of children with SRNS. The aim of this study was to compare the efficacy of CsA, TAC and MMF in children with SRNS and provide guidance for clinical practice. Methods: This is a retrospective analysis of the records of 70 children with SRNS recruited from a children hospital over a period of seven years. They were treated with CsA, TAC and MMF as initial immunosuppressive therapy in addition to steroids. Complete or partial remission was considered a good response. Results: Five (41.7%) of 12 children who were on CsA therapy achieved remission at 6 months and 5 (41.7%) at 12 months. Nine (19.1%) of 47 patients treated with TAC achieved remission at 6 months, 20 (42.6%) at 12 months and 6 (12.8%) within or over 24 months. The remission achieved at 6 months and 12 months was 4 (36.4%) and 2 (18.2%) respectively in MMF group. The relapse rates in children who had achieved remission were 30.0%, 45.7% and 50.0% in CsA, TAC and MMF group respectively. Conclusions: Based on similar baseline characteristics, CsA and TAC as initial therapy for SRNS have a better remission and relapse rates whereas MMF shows a rapid remission effect. [ABSTRACT FROM AUTHOR]

High-risk corneal transplantation immunological rejection is a primary factor affecting the success or failure of the corneal transplantation. As a result, application of immunosuppressive agent in high-risk corneal transplantation rejection reaction occupies an irreplaceable position. However, many local and systemic adverse reactions appeared in the process of application. In order to improve the achievement ratio of the corneal transplantation, experts and scholars at home and abroad have obtained remarkable achievements in dosage form, route of administration and drug combination; meanwhile, a considerable progress was also made in genetic engineering. This paper is a review of prevention and treatment on high-risk corneal graft rejection reaction.