Use Of Calcineurin Inhibitors Research Articles

Analysis of Risk Factors for Developing Tuberculosis in Patients Who Received Prophylactic Latent Tuberculosis Infection Treatment with Experience of Biologic Medications.

Biologic medications have dramatically improved the treatment outcomes of immunological inflammatory diseases, but their immunosuppressive effects put patients at risk for tuberculosis (TB). We investigated the risk factors for developing TB in patients treated for latent tuberculosis infection (LTBI) who also had experience of using biologic medications. At Keio University Hospital, we retrospectively investigated patients treated with anti-mycobacterial drugs before or concurrently with biologic medications from January 2012 to August 2020. Patients in the 'follow-on cases group' who had a positive TB screening test after initiating biologic medications and subsequently started LTBI treatment were excluded. We researched and compared the patient characteristics for TB and non-TB patient groups. Of the 146 eligible patients, 5 (3.4%) developed TB. The incidence rate was 600/100000 person-years. There were no significant differences between TB and non-TB patient groups in the history of TB, interferon-gamma release assay (IGRA), duration of biologic medication therapy, LTBI treatment periods, concomitant use of calcineurin inhibitors or anti-rheumatic drugs. The percentage of patients who received prednisolone at a dose of ≥15 mg for more than 1 month was higher in those who developed TB than in those who did not (40.0 vs. 7.1%, p = 0.054); however, this difference was not statistically significant. Regular monitoring of TB is necessary for long-term concomitant use of high prednisolone doses during and after the administration of biologic medications.

Delayed Initiation of Calcineurin Inhibitor Is Critical for Tolerance Induction By Posttransplant Cyclophosphamide

[Introduction] We have previously shown that T-cell exhaustion of donor alloreactive T cells plays a critical role in tolerance induction after mouse allogeneic hematopoietic cell transplantation (allo-HCT) (Asakura S: JCI 2010). Emerging evidence indicates that T-cell exhaustion is a multistep process, including precursors of exhausted T cells (pTex) with stem cell-like properties, pTex-derived transitory exhausted T cells (transitory-Tex) with potent effector-like functions, and terminally exhausted T cells (terminal-Tex) with the expression of multiple inhibitory receptors and severely impaired functions. We have demonstrated, for the first time, that calcineurin inhibitors (CNIs) inhibit tolerance induction by suppressing the terminal exhaustion of donor T cells while inducing transitory-Tex after allo-HCT in mice (Senjo H: Blood 2023). In contrast, post-transplantation cyclophosphamide (PTCy) efficiently induces tolerance with low incidence of chronic GVHD. In the current study, we evaluated the mechanisms by which PTCy could induce tolerance even with the use of CNIs. [Methods] In mouse haploidentical HCT model,B6D2F1 recipients (H-2 b/d) were lethally irradiated and transplanted with 2 × 10 6 T cells together with T-cell-depleted bone marrow cells from C57BL/6 (H-2 b) donors on day 0. CSP (25 mg/kg) was administered from either day 0 (early-CSP) or day 5 (late-CSP), and PTCy (50 mg/kg) was i.p. injected on day 3 after HCT. In clinical study, peripheral blood mononuclear cells were prospectively collected from patients who underwent PTCy-based haplo-PBSCT at our institutions after approval of institutional review. [Results] We have shown that Ly6C is a specific marker for transitory-Tex in mice (Senjo H: Blood 2023). In mice, early-CSP followed by PTCy (CSP→PTCy) significantly expanded Ly6C +PD-1 +TOX low CD8 + T cells and Ly6C +PD-1 +GZMB + CD4 + T cells on day 14, while late-CSP following PTCy (PTCy→CSP) induced T-cell differentiation towards Ly6C -PD-1 +TOX high terminally exhausted T cells. When CSP→PTCy recipients were injected with anti-PD-L1 monoclonal antibodies, transitory-Tex demonstrated vigorous proliferation, while terminal-Tex did not respond to PD-1 blockade. These findings indicate that CSP administration after PTCy promotes tolerance induction, whereas CSP administered before PTCy inhibits tolerance induction. Next, we explored the specific markers for human transitory-Tex using scRNA-seq of T cells from the patients who underwent PTCy haplo-PBSCT, in which tacrolimus (TAC) was started either from day -1 (early-TAC) or day 5 (late-TAC). UMAP analysis showed that early-TAC expanded cluster 5 (C5) out of six CD8 + clusters (C1-C6) and C8 out of three CD4 + clusters (C7-C9) (Fig.1). C5 highly expressed exhaustion markers such as Tox and Pdcd1, together with effector molecules such as Prf1, Gzmb and Cx3cr1, while C8 was characterized with high expression of Gzmb, indicating that C5 and C8 are the human counterparts of transitory-Tex. Analysis of differentially expressed genes showed that Fcgr3a (CD16A) was selectively expressed in C5, while Gzmb and Cd74 were selectively expressed in C8. These two populations showed robust proliferative responses to TCR stimulation in vitro. ScTCR-seq demonstrated that C5 and C8 clusters showed less TCR diversity compared to other clusters, suggesting that C5 and C8 were enriched with alloreactive donor T cells that clonally expanded post-transplant. FCM confirmed that both CX3CR1 +CD16 + CD8 + T cells and GZMB +CD74 +CD4 + T cells were significantly increased in the early-TAC group compared to the late-TAC group on day 28 (Fig. 2). In the early-TAC group, 2/9 patients developed moderate and severe chronic GVHD, and only 1/9 patient was off-immunosuppressants (Fig 2). In sharp contrasts, in the late-TAC group, no patient developed chronic GVHD, and 7/9 patients were off-immunosuppressants. Importantly, two patients who developed chronic GVHD had a particularly high proportions of CX3CR1 +CD16 +CD8 + and GZMB +CD74 +CD4 + transitory-Tex on day 28 after HCT (Fig.2). [Conclusion] Our study demonstrated that early initiation of CNIs before PTCy induced transitory-Tex and inhibited tolerance induction after PTCy haplo-PBSCT. Administration of CNIs after PTCy is critical for tolerance reduction without chronic GVHD.

Outcomes after RIC and Abatacept-Based Acute and Chronic Gvhd Prophylaxis in Allogeneic Transplantation for Sickle Cell Disease - Can Calcineurin Inhibitor Use be Curtailed?

Introduction: Sickle cell disease (SCD) progression can be curtailed by successful allogeneic transplantation from suitable donors. Allogenic transplantation with reduced intensity immune suppressive conditioning (RIC) from sibling or unrelated donors was considered acceptable with the availability of an Human Leucocyte Antigen (HLA)-matched (8/8 loci) or minimally mismatched (7/8) donor on NCT00920972 and in 2018 the study was modified to include abatacept for acute and chronic graft-versus-host disease (GVHD) prophylaxis based on the incidence of severe chronic GVHD noted (13-38%) and the benefits described with abatacept1-3. An interim review of trial results following the modification of GVHD prophylaxis is presented. Methods: Patients with symptomatic SCD who were <21 years of age were enrolled on appropriate study cohorts based on the level of donor match. Cohort 1 included HLA matched donors and cohort 3 included donors mismatched at 1 of 8 major HLA loci (-A, -B, -C, -DRB1) by high resolution typing. Conditioning included alemtuzumab (distal: day -22 to -19), fludarabine (days -8 to -4) and melphalan (day -3). Thiotepa (day -4) was included for mismatched donors. GVHD prophylaxis included tacrolimus (day -1 and tapered 6-9 months later), methotrexate (days +1, 3 and 6) and abatacept (days -1, +5, 14, 28, 60, 90, 180, 270 and 365)4. Though the half-life of the drug is ~30 days, the interval was adjusted after day 100 to every 90 days to curb allogeneic T cell proliferation following complete elimination of the drug. No previous data exists on this approach. Outcomes tracked were GVHD, mortality and graft rejection (GR) (<25% donor myeloid cells/disease recurrence) Results: Nine related donor transplants (4-18 years, median 9y) and 9 unrelated donor transplants (URD) (7-20 years, median 16y) (5 mismatched) were undertaken consecutively after the addition of abatacept to the standard GVHD regimen. The duration of follow-up ranged from 2-59 months (median 44m). GR was noted in 2 patients. One patient with primary GR subsequently rejected a second graft after myeloablative conditioning. Another patient with secondary GR received a CD34-selected boost post-ATG unsuccessfully but stabilized after a flu/cy/ATG regimen and another CD34-selected boost. The most recent engraftment analysis in 17/18 patients is 98% (range, 46 to 100) for myeloid and 94.5% (range, 56 to 100) for lymphoid lineage cells. No patient developed > grade 2 acute or any chronic GVHD in the MSD group. In the URD group 1 patient each developed >grade 2 aGVHD and extensive cGVHD. Of evaluable patients, one remains on systemic immune suppression therapy >18 months post-transplant. The only mortality noted was after 2 subsequent transplants in the patient with GR. Seventeen patients remain disease free post-transplant. Disease free survival (DFS) is 94%. GVHD-free-DFS is 89%. The incidence of viral reactivation was 65% and 17% before and after day +100 respectively. Immune reconstitution was noted to normalize beyond 6-9 months. Conclusion: Transplant is beneficial in SCD, and an expansion of donor sources can help to increase the number of patients rendered disease-free. GVHD risks preclude consideration of allogeneic transplantation. A GVHD-free cure rate of >88% despite risk factors such as age and HLA-mismatch following RIC and abatacept-based GVHD prophylaxis is encouraging for allogeneic transplantation options for children and adolescents with SCD. Long-term follow-up is in progress.

Safety and Efficacy of Axatilimab at 3 Different Doses in Patients with Chronic Graft-Versus-Host Disease (AGAVE-201)

Background: Chronic graft-versus-host disease (cGVHD) is an immune-mediated complication of allogeneic hematopoietic cell transplant (alloHCT) that affects multiple organs with inflammatory and fibrotic pathology, leading to significant patient burden and mortality. Colony-stimulating factor 1 receptor (CSF-1R)-dependent monocytes and macrophages play a key role in cGVHD inflammation and fibrosis. Axatilimab (SNDX-6352) is an investigational, high-affinity anti-CSF-1R monoclonal antibody that targets monocytes and macrophages. We previously demonstrated the biological and clinical activity of axatilimab with organ-specific responses and symptom improvement in a phase 1/2 study (NCT03604692) in patients with cGVHD. Methods: This pivotal phase 2, open-label, randomized, multicenter study evaluated axatilimab at 3 different doses in alloHCT patients with recurrent or refractory cGVHD (AGAVE-201; NCT04710576). Eligible patients were randomized 1:1:1 to receive intravenous (IV) axatilimab at 0.3 mg/kg every 2 weeks (Q2W), 1 mg/kg Q2W, or 3 mg/kg every 4 weeks (Q4W). Randomization was stratified by severity of cGVHD and prior use of ibrutinib, ruxolitinib, or belumosudil. Concomitant use of corticosteroids, calcineurin inhibitors, or mammalian target of rapamycin inhibitors (sirolimus or everolimus) was allowed. Axatilimab treatment could be continued as long as there was clinical benefit as assessed by the investigator. The primary efficacy endpoint was overall response rate (ORR) in the first 6 cycles (24 weeks) as defined by the NIH 2014 consensus criteria; the efficacy boundary of the ORR is based on the lower bound of the 95% CI exceeding 30%. The key secondary endpoint was the proportion of patients reporting a clinically significant reduction of symptoms, as measured by the modified Lee Symptom Scale (mLSS) score with a threshold of ≥7 points. Safety endpoints included frequency and severity of treatment-related adverse events (TRAEs) and treatment-emergent adverse events (TEAEs). Results: A total of 241 patients were enrolled across 121 study sites and 239 (99.2%) patients were treated with axatilimab at the data cutoff of 7 April 2023. Patients were heavily pretreated with a median of 4 prior lines of therapy, including ruxolitinib (74%), belumosudil (23%), and ibrutinib (31%). Demographics and disease characteristics were balanced among the 3 dose cohorts (Table 1). ORR (95% CI) was 74% (63, 83) with 0.3 mg/kg Q2W, 67% (55, 77) with 1 mg/kg Q2W, and 50% (39, 61) with 3 mg/kg Q4W (Table 1). Median duration of response (DOR) has not been reached in any of the cohorts, with 60%, 60% and 53% of patients maintaining response at 12 months in the 0.3 mg/kg Q2W, 1 mg/kg Q2W, and 3 mg/kg Q4W dose cohorts, respectively. Clinical benefit, as measured by reduction in mLSS score, was reported in 55%, 54%, and 36% of patients in the 0.3 mg/kg Q2W, 1 mg/kg Q2W, and 3 mg/kg Q4W cohorts, respectively, in the first 6 cycles. Drug discontinuation owing to TEAEs occurred in 6% of patients with 0.3 mg/kg Q2W, 22% with 1 mg/kg Q2W, and 18% with 3 mg/kg Q4W. The most common TEAEs are summarized in Table 2. Fatal TEAEs occurred in 1.3%, 8.6%, and 7.6% of patients in the 0.3 mg/kg Q2W, 1 mg/kg Q2W, and 3 mg/kg Q4W dose cohorts, respectively. The frequency of TRAEs and grade ≥ 3 TRAEs were dose dependent, consistent with CSF-1R inhibition-mediated macrophage clearance. Most infections were mild, with 3 reported cytomegalovirus infections, including reactivations, in the higher dose cohorts. Conclusions: The AGAVE-201 pivotal trial met its primary endpoint for all doses studied. Axatilimabtreatment of refractory cGVHD in heavily pretreated patients resulted in robust clinical activity and durable responses in all 3 dose cohorts, with the highest ORR and least toxicity at the 0.3 mg/kg Q2W dose. Adverse events consisted primarily of transient laboratory abnormalities and other on-target effects known to be associated with CSF-1R block.

Evidence-based recommendations for the treatment of rheumatic and immunologic diseases with calcineurin inhibitors: a consensus statement

Calcineurin inhibitors (CNI), including oral cyclosporin A and tacrolimus, are intensive immunosuppressants that are extensively used in the treatment of rheumatic and immunologic diseases in China. CNI selectively inhibit the activation and proliferation of T lymphocytes and the transcription of cytokines [such as tumor necrosis factor-α, interleukin (IL)-6, and IL-17] through inhibiting the activation of calcineurin in cells and reducing the release of IL-2. To standardize the use of CNI in the field of rheumatic and immunologic diseases, this consensus statement was developed by the National Clinical Research Center for Dermatologic and Immunologic Diseases (Peking Union Medical College Hospital), in conjunction with the Chinese Association of Rheumatology and Immunology Physicians, the Chinese Research Hospital Association, the Rheumatology and Immunology Professional Committee, and the Chinese Association of Rehabilitation Medicine. The 2011 Oxford Centre for Evidence-Based Medicine Levels of Evidence was used to rate the quality of the evidence and the strength of the recommendations, and the RIGHT (Reporting Items for practice Guidelines in HealThcare) checklist was followed to report the consensus. The consensus offers recommendations addressing nine clinical challenges to Chinese clinicians. The primary objective of this consensus is to deliver scientific and detailed guidance on CNI for Chinese clinicians, and to improve the quality of patient-centered medical services.

In silico discovery of novel calcineurin inhibitors using ligand-based 3-D pharmacophore modelling and molecular dynamics simulation

Calcineurin is a serine-threonine protein phosphatase that is activated with the binding of calmodulin in the presence of increased calcium concentration and has a major role in various signaling pathways. Its role in regulating homeostasis, developmental processes, and different disease progression has already been reported. The dysregulated Ca2+/calcineurin/NFAT1-4 pathway is observed in Autoimmune disorders and hence the use of Calcineurin inhibitors like Cyclosporin A (CsA) and Tacrolimus (FK506) is widely done in such cases. Recent studies indicate the uncontrolled overexpression of the Calcineurin protein in the pathophysiological pathway of neurodegenerative diseases. The in vitro and animal model studies with standard calcineurin inhibitors (CnIs), which are widely labeled as immunosuppressant drugs, have shown a significant reduction of neurodegeneration in respective models. These results compel the identification of novel calcineurin inhibitors against neurodegenerative diseases. With this scenario, the present work focuses on the computer-aided identification of novel CnIs via ligand-based 3-D pharmacophore modelling. Known CnIs, CsA, and FK506, were used to build the pharmacophore models which were validated and screened against external databases to retrieve possible hits. Docking investigations, pharmacokinetic properties, and molecular dynamics simulations along with toxicity predictions were performed on the hits that were obtained. According to the study, a total of 5 molecules ILB 162, ILB 005, ILB 439, ILB 390, and ILB 198, were found to be the best calcineurin inhibitors with binding affinity in the range of −9.7 to −9.0 Kcal/mol with 1MF8 (PDB). The stability of interactions of these molecules was further validated via Molecular dynamics simulation studies to confirm these to be the potential calcineurin-inhibiting molecules. HIGHLIGHTS Calcineurin inhibitors can be a novel therapeutic candidate against neurodegenerative diseases. The identification of novel Calcineurin inhibitors was done in silico using ligand-based 3-D pharmacophore modelling using Ligand Scout Essential 4.4. software. The model could identify 440 hits from various external databases like PubChem (2432 molecules), ChemSpider, MayBridge, DrugBank, and e-Drug 3D by Cheminformatic Tools and Databases for Pharmacology. Out of which 5 molecules: ILB 162, ILB 005, ILB 439, ILB 390, and ILB 198, were found to be the best calcineurin inhibitors with binding affinity in the range of –9.7 to –9.0 Kcal/mol with 1MF8 (PDB) which were further confirmed to be the best CnI candidates via Molecular dynamics simulation studies. Communicated by Ramaswamy H. Sarma

Safety evaluation of the use of calcineurin inhibitor to prenatal and postpartum women in Japan from a health administrative database.

To investigate the use of calcineurin inhibitors (CNIs) in pregnant Japanese women and to evaluate their safety in infants. Data were extracted from the claims database of the Japan Medical Data Center. The prevalence of CNIs was evaluated 180 days before pregnancy onset, during pregnancy, and within180-days post partum. We investigated the characteristics of the infants, including the presence of major malformations and their diagnoses, for 1 year after birth. A total of 91,865 pregnancies in 80,049 women were included. Fifty-three women were prescribed CNIs between 180-day before pregnancy onset and 180-day postpartum; 35 of the 53 women were prescribed the drugs during pregnancy, and 10 of their infants were born preterm. Three were diagnosed with major congenital malformations, such as patent ductus arteriosus. Six preterm infants presented with infant respiratory distress syndrome. No congenital anomalies were clearly attributable to the use of CNIs during pregnancy.

Comparison of Urinary Beta-2 Microglobulin Levels in Children with SSNS and Calcineurin Inhibitor-Treated SRNS.

While the utility of beta-2 microglobulin (β2M) has been explored in various renal conditions to identify tubulointerstitial damage, it has not been adequately studied in nephrotic syndrome. The primary objective of the study was to compare urinary β2M levels in children with steroid-sensitive nephrotic syndrome (SSNS) and steroid-resistant nephrotic syndrome (SRNS) in disease remission. This cross-sectional study was done at a tertiary care hospital between April 2019 and March 2020. Sixty children (2-18 years) with SSNS and SRNS (30 in each group) in remission were enrolled. SRNS patients were included after ≥1 year of treatment with calcineurin inhibitors (CNIs). Biochemical investigations were done to confirm remission; spot samples for urinary β2M were collected and estimation was done by an enzyme-linked immunosorbent assay (ELISA)-based kit. Of the 60 children, 63% were boys. The median (interquartile range [IQR]) age at enrollment for SSNS and SRNS patients was 7 (4.1-9) and 11 (8.3-12) years, respectively. Urinary β2M levels were significantly higher in SRNS patients compared to SSNS patients (2.6 vs. 0.75 mg/ml, P < 0.0001). Patients who received cyclosporine for >2 years had higher median urinary β2M levels compared to those who received it for a shorter period (2.63 vs. 1.83 mg/ml, P = 0.03). Median β2M levels were higher in focal segmental glomerulosclerosis than minimal change disease (3.5 vs. 2.5 mg/ml). Urinary β2M levels were higher in SRNS compared to SSNS disease in remission, and β2M levels correlated well with CNI use of >2 years. It appears to be a promising noninvasive tool to identify early tubular damage and progression in patients with nephrotic syndrome, especially SRNS.

Longitudinal estimated glomerular filtration rate (eGFR) modeling in long-term renal function to inform clinical trial design in kidney transplantation.

Kidney transplantation is the preferred treatment for individuals with end-stage kidney disease. From a modeling perspective, our understanding of kidney function trajectories after transplantation remains limited. Current modeling of kidney function post-transplantation is focused on linear slopes or percent decline and often excludes the highly variable early timepoints post-transplantation, where kidney function recovers and then stabilizes. Using estimated glomerular filtration rate (eGFR), a well-known biomarker of kidney function, from an aggregated dataset of 4904 kidney transplant patients including both observational studies and clinical trials, we developed a longitudinal model of kidney function trajectories from time of transplant to 6 years post-transplant. Our model is a nonlinear, mixed-effects model built in NONMEM that captured both the recovery phase after kidney transplantation, where the graft recovers function, and the long-term phase of stabilization and slow decline. Model fit was assessed using diagnostic plots and individual fits. Model performance, assessed via visual predictive checks, suggests accurate model predictions of eGFR at the median and lower 95% quantiles of eGFR, ranges which are of critical clinical importance for assessing loss of kidney function. Various clinically relevant covariates were also explored and found to improve the model. For example, transplant recipients of deceased donors recover function more slowly after transplantation and calcineurin inhibitor use promotes faster long-term decay. Our work provides a generalizable, nonlinear model of kidney allograft function that will be useful for estimating eGFR up to 6 years post-transplant in various clinically relevant populations.

Hypomagnesemia and its association with calcineurin inhibitor use in renal transplant recipients

Background Hypomagnesemia is a common electrolyte abnormality following kidney transplantation. Increased renal magnesium (Mg) waste has been linked to calcineurin inhibitors. We aimed to assess the prevalence and risk factors of hypomagnesemia and its association with calcineurin inhibitor use in renal transplant recipients. Patients and methods This is a cross-sectional study carried out on renal transplant recipients, who underwent living-related donor kidney transplantation. All participants underwent detailed history taking and complete physical examination. Serum Mg, trough level of cyclosporine or tacrolimus, fractional excretion of Mg (FEMg), and 24 h urinary Mg, Ca, Ph, Cl, and protein were measured. Results One hundred patients were screened and 80 patients, with a mean age of 39.65 ± 12.14 years, completed the study. Fifty (62.5%) patients were on tacrolimus, and 26 (32.5%) patients were on cyclosporine. Patients had a median serum Mg of 1.80 mg/dl. Hypomagnesemia (Mg&lt;1.7) was present in 17 (21.3%) patients with a median FEMg of 3.08%. There was significant negative correlation between serum Mg level and trough level of tacrolimus and FEMg with a P value of 0.038 and 0.001, respectively. The results of multivariate analyses showed that tacrolimus trough level (P=0.010) and FEMg (P=0.025) were independently correlated with serum Mg. Hypomagnesemia was significantly higher in tacrolimus-treated patients (30%) compared with only 7.7% in cyclosporine-treated patients (P=0.027). Conclusions Hypomagnesemia is common in renal transplant recipients, especially with tacrolimus use mostly due to increased renal Mg wasting. Increased tacrolimus trough level and increased FEMg were predictors of hypomagnesemia.

PA32 Severe lichen planus with co-localization of vitiligo: a rare and unusual case

Abstract A 13-year-old boy was seen in the urology clinic for hypo­pigmented patches on the glans penis. He underwent circumcision for presumed balanitis xerotica obliterans, but histological examination of the skin showed lichen planus (LP). This prompted a full skin check by the team, which showed similar patches on the scrotum, anus and ears. A referral was made to dermatology for further assessment. Closer history revealed a 1-year history of inflamed patches behind the ears that spread to the periorbital and penile regions. Concurrent patchy hair loss was noted over this time period; otherwise, he was asymptomatic, with no relevant past medical or family history. Full skin check revealed extensive areas of well-circumscribed erythema on the penis, peri-orbitally and within the conchal bowl of both ears. Areas of scarring alopecia were present with complete loss of the eyelashes. The severity of his condition warranted the immediate commencement of high-dose oral steroid therapy and a trial of protopic 0.1% ointment. A review 6 months later showed no further erythema but areas of clearly defined depigmentation where there was previously active LP, particularly across the nose and periorbitally, consistent with vitiligo. Ongoing follow-up at 1 year showed the stable appearance of these areas, despite ongoing use of topical calcineurin inhibitor. Co-localization of vitiligo in the context of LP is a rare entity, noted in only 10 case reports in the literature. The fact that both LP and vitiligo are common, each said to affect 1–2% of the general population, may mean that their association is merely a coincidence. However, a number of publications suggest that a causal link must be present as similar immunological mechanisms are shared by the two conditions. The aetiology of both LP and vitiligo is known. Various theories exist, including the autoimmune hypothesis, as both conditions are immunologically mediated. Another assumes inflammatory mediator release from ultraviolet damage, particularly on areas of photosensitive depigmented skin. A third supposes that photodamage induces Koebner phenomenon on vitiligo-affected skin, resulting in LP on these areas. No theory has been proven definitively. In most cases, vitiligo is described as the precursor disease; rarely, both diseases occur concomitantly and progress together. We present a rare case of LP preceding vitiligo. Our case not only demonstrates the importance of a full skin examination in diagnosing lesions, but provides further evidence that this association is more than coincidental. More studies into these conditions are needed to understand this phenomenon in its entirety.

The Effect of Calcineurin Inhibitors on MMPs Activity in Heart and Their Side Effects-A Review of Literature.

This review focuses on the role of metalloproteinases in the pathogenesis of myocardial injury in various disease entities. It reveals how the expression and serum levels of metalloproteinases and their inhibitors change in many disease states. At the same time, the study offers a review of the impact of immunosuppressive treatment on this relationship. Modern immunosuppressive treatment is based mainly on the use of calcineurin inhibitors, including cyclosporine A and tacrolimus. The use of these drugs may carry a number of side effects, specifically to the cardiovascular system. The scale and degree of long-term influence on the organism remains unclear, but a significant risk of complications for transplant recipients who take immunosuppressive drugs as part of their daily treatment is to be expected. Therefore, the knowledge on this subject should be expanded and the negative effects of post-transplant therapy minimized. Immunosuppressive therapy plays an important role in the expression and activation of tissue metalloproteinases and their specific inhibitors, which leads to many tissue changes. The presented study is a collection of research results on the effects of calcineurin inhibitors on the heart, with particular emphasis placed on the participation of MMP-2 and MMP-9. It is also an analysis of the effects of specific heart diseases on myocardial remodeling through inductive or inhibitory effects on matrix metalloproteinases and their inhibitors.

#3670 THE ROLE OF CALCINEURIN INHIBITORS IN MONOGENIC PEDIATRIC STEROID RESISTANT NEPHROTIC SYNDROME: A RETROSPECTIVE, MULTICENTER STUDY

Abstract Background and Aims Response to calcineurin inhibitors (CNI) is associated with a significant improvement in long-term kidney survival of children with non-genetic steroid resistant nephrotic syndrome (SRNS). On the contrary, these agents are considered non-efficacious in monogenic SRNS and are contraindicated according to the latest International Pediatric Nephrology Association (IPNA) Clinical Practice Recommendations for SRNS. However, there is evidence suggesting that remission with CNI therapy in this subgroup of children with SRNS is possible, but no studies to date have assessed this question in a systematic way. We aimed to study the incidence of response to CNI in children with monogenic SRNS, factors predictive of remission and the effect of treatment on kidney survival. Method Retrospective cohort study of children 0–18 years with genetically confirmed SRNS treated with a CNI for at least 3 months. Demographic, clinical, genetic, biochemical, histopathologic and treatment data were collected at various time points; at clinical diagnosis, 6, 12, 24 months from CNI onset, and last available follow-up. Pathogenicity of all reported variants was assessed by a dedicated geneticist according to the American College of Medical Genetics guidelines and only patients with a pathogenic genotype were included in the analysis[1]. Patients were classified according to their response to CNI as complete, partial or non-responders based on the IPNA Clinical Practice Recommendations for SRNS[2]. Results 141 patients from 37 international paediatric nephrology centers were included in the study. At 6 months from CNI initiation and at last visit, 27.6% and 22.5%, respectively, demonstrated either complete or partial response (“at least partial response”). Median observation time between CNI initiation and last visit was 42.1 months (IQR 20.1–65.6) and was comparable between patients with no response and at least partial response (42.3 vs 41.6 months; P&amp;gt;0.05). No serious adverse effects mandating treatment discontinuation were reported. Children demonstrating at least partial response at 6 months had a lower risk of progression to kidney failure at last visit versus non-responders (hazard ratio [95%CI] 0.25, [0.10–0.62]; P = 0.003). Subgroup analysis of patients with a follow-up of at least 2 years revealed similar results with a hazard ratio of 0.35 (95%CI 0.14–0.91; P = 0.03). Of the various clinical, biochemical, genetic, histopathologic and treatment parameters tested in a multivariable logistic regression model only higher serum albumin at CNI onset was associated with higher likelihood of response at 6 months (odds ratio [95% CI] 1.16, [1.08–1.24]; P &amp;lt; 0.001). Conclusion Our findings suggest that CNI use could be considered in monogenic SRNS and that achievement of response in this setting can alter an otherwise dismal long-term kidney outcome.

Association Between the Use of Topical Calcineurin Inhibitors and the Risk of Cancer Among Patients with Atopic Dermatitis: A Nationwide, Population-Based, Retrospective Cohort Study.

The cancer risks associated with treatment withtopical calcineurin inhibitors (TCIs) in patients with atopic dermatitis (AD) remain controversial, and limited evidence exists regarding the cancer risks among patients with AD treated with TCIs in Asian populations. This study identified the association between TCI use and the risks of developing all cancers, lymphoma, skin cancers, and other cancers. This study was a nationwide, population-based, retrospective cohort study. Taiwan's National Health Insurance Research Database. Patients diagnosed at least twice with ICD-9 code 691 or at least one time with ICD-9 codes 691 or 692.9 within 1 year between 1 January 2003 and 31 December 2010 were included and followed until 31 December 2018. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using the Cox proportional hazard ratio model. Patients using tacrolimus or pimecrolimus were identified in the National Health Insurance Research Database and compared with patients using topical corticosteroids (TCSs). The main outcomes were hazard ratios (HRs) of cancer diagnoses and associated outcomes obtained from the Taiwan Cancer Registry database. After propensity score (PS) matching, the final cohort included 195,925 patients with AD, including 39,185 who were initial TCI users and 156,740 who were TCS users. Propensity score matching was performed according to age, sex, index year, and Charlson Comorbidity Index using a ratio of 1:4. Exceptfor leukemia, HR and 95% CI showed no significant associations between TCI use and the risk of developing all cancer, lymphoma, skin cancers, and other cancers. Sensitivity analysis showed that the lag time HRs for every cancer subtype continued to show no significant association between TCI use and cancer risk, except for leukemia. Our study found no evidence to support an association between TCI use and the risks of almost all cancers compared with TCS use in patients with AD, but physicians should be aware of potentially higher risks of leukemia with TCI use. This study represents the first population-based study focused on the cancer risk of TCI use among patients with AD in an Asian population.

Atopic dermatitis: a brief review of recent advances in its management.

Atopic dermatitis (AD) is a common inflammatory skin disorder characterized by recurrent eczematous lesions and intense itching. The disorder affects people of all ages and ethnicities, has a substantial psychosocial impact on patients and relatives, and is the leading cause of the global burden of skin diseases. Atopic dermatitis is associated with an increased risk of multiple comorbidities, including food allergies, asthma, allergic rhinitis, and mental health disorders. The pathophysiology is complex and involves a strong genetic predisposition, epidermal dysfunction, and T-cell-driven inflammation. Although type-2 mechanisms are dominant, there is increasing evidence that the disorder involves multiple immune pathways. Until recently, the management of AD rested mainly on the judicious use of emollients, topical steroids, and topical calcineurin inhibitors in the majority of patients, and systemic immunosuppressants were advocated in severely diseased patients. However, in the last few years, new therapeutic strategies have been designed and developed to target the various steps in the chain of molecular events that lead to the AD phenotype. This review highlights the recent advancements in the management of AD.

Encountering steroid treatment induced tinea incognito: a case report

Tinea incognito refers to a type of dermatophyte infection that affects the skin, and its signs and symptoms upon presentation tend to appear permutated due to the prior use of immunosuppressants, corticosteroids or calcineurin inhibitors. We present a 42-year-old Asian (Indian) male patient with scaly erythematous rashes, mimicking annular erythema, and developing post-corticosteroid usage after an elective hair transplant procedure. The results of the biopsy reported that erythema annulare centrifugum (EAC) was absent, and the sample was suggestive of potential infective folliculitis. By day 3 of the presentation, with fungal stain tested positive for the presence of fungal infection. Based on this, the final diagnosis of tinea incognito was made. The final treatment prescribed for tinea incognito was an anti-fungal tablet of Itraconazole at a dose of 100 mg twice a day for 4 weeks, topical luliconazole, ciclopirox and anti-histamines for itching. Topical corticosteroids can change the clinical appearance of tinea by reducing erythema and scaling while enabling the fungus to grow freely without presenting the typical clinical indications of tinea. Practitioners should follow patients on corticosteroid treatment to alert them to potential cutaneous problems due to possible fungal infections, whenever warranted.

Risk factors for acute kidney injury in pediatric patients after hematopoietic stem cell transplantation: a systematic review and meta-analysis.

Risk factors for acute kidney injury (AKI) in pediatric patients after hematopoietic stem cell transplantation (HSCT) remain controversial. This study aimed to identify risk factors for AKI following HSCT in the pediatric population. PubMed, Embase, Web of Science, Cochrane Library, and Scopus databases were searched from inception to February 8, 2023. Studies meeting the following criteria were included: (1) The study was a case-control, cohort study, or cross-sectional design, (2) the study was performed among pediatric and young patients aged 21 years or younger undergoing HSCT, (3) the study measured at least one related factor for AKI after pediatric HSCT, (4) the study included a sample of at least ten patients, and (5) original articles published in English in peer-reviewed scientific journals. Children who were undergoing pediatric HSCT. We assessed the quality of the included studies and analyzed them with a random-effect model. Fifteen studies with a total of 2,093 patients were included. All were cohort studies of high quality. The overall pooled incidence of AKI was 47.4% (95%CI 0.35, 0.60). We found significant associations between post-transplant AKI in pediatric patients and unrelated donor [odds ratio (OR) = 1.74, 95% confidence interval (CI) 1.09-2.79], cord blood stem cell transplantation (OR = 3.14, 95%CI 2.14-4.60), and veno-occlusive disease (VOD)/sinusoidal obstruction syndrome (SOS) (OR = 6.02, 95%CI 1.40-25.88). Other controversial factors such as myeloablative conditioning (MAC), acute graft vs. host disease (aGVHD), and the use of calcineurin inhibitors (CNI) were not found to be related to AKI after pediatric HSCT. Results were limited mainly by heterogeneity in the characteristics of patients and transplantation. Posttransplant AKI in children is a common complication. Unrelated donors, cord blood stem cell transplantation, and VOD/SOS might be risk factors for AKI after pediatric HSCT. Further large-scale studies are still needed to draw firm conclusions. CRD42022382361 A higher resolution version of the Graphical abstract is available as Supplementary information.

Evaluation of T-Cell Immune Status of Reduced-Dose Cyclosporine and Everolimus Combination Therapy in Kidney Transplant Patients

Kidney transplantation (KT) outcomes have significantly improved with calcineurin inhibitors (CNIs) administration. In recent years, the dose of CNIs has been reduced, and everolimus (EVR) has been used in combination with CNIs to avoid complications from the long-term use of CNIs. However, T-cell immune responses to these protocols have not been fully evaluated. This study evaluated the anti-donor T-cell responses to our CNI-sparing regimen. Fifty-five de novo KT patients were enrolled. Three months after KT, the patients were randomly assigned to either the EVR group, which received low-dose cyclosporine (CsA) (n=28), or the standard-exposure CsA control group (n=27), which was treated with both mycophenolate mofetil and methylprednisolone. Graft function, adverse events, and immunologic status were evaluated 3 years after KT. Mixed lymphocyte reaction (MLR) assays were performed to evaluate anti-donor T-cell responses in KT patients. Both groups maintained graft function well, but total cholesterol levels tended to increase annually in the EVR group. The incidence of cytomegalovirus (CMV) infection tended to be lower in the EVR group, regardless of the CMV serologic status. Immunologic evaluation by MLR assay showed that anti-donor T-cell responses were adequately maintained in both groups. EVR starting 3 months after KT can reduce the trough levels of CsA without affecting graft function or compromising the immunosuppressive effects. The EVR combination protocol is expected to reduce CNI toxicity and improve long-term prognosis after KT.

5550636 IMPROVEMENT IN ACUTE NEUROLOGICAL COMPLICATIONS RELATED TO 50 STEM CELL TRANSPLANT IN SICKLE CELL DISEASE: LESSONS FROM OUR EXPERIENCE

Background: Central nervous system (CNS) complications during hematopoietic stem cell transplantation (HSCT) in sickle cell disease (SCD) patients are a major cause of morbidity, as: posterior reversible encephalopathy syndrome (PRES), seizures, strokes or subarachnoid haemorrhage (HSA). These complications can appear for several causes, but mostly due to variations on hemodynamic status of the patient. Conditioning regimen-related toxicity, graft-versus-host disease (GvHD) and the use of calcineurin inhibitors also play an important role. Methods: A retrospective single center study was conducted in children with SCD, who underwent allogeneic HSCT from an HLA-identical sibling donor since January 2010 to July 2022. Implementation of arterial blood pressure (ABP) Holter, few weeks prior to HSCT, was established in December 2017 providing a better understanding of patient’s hemodynamic status and easing early treatment of arterial hypertension prior to HSCT. We analyze CNS transplant complications between two different periods: May 2010 to November 2017, and December 2017 to July 2022. Besides that, a change on conditioning regimen was established. Until June 2015 we used busulfan, cyclophosphamide and alemtuzumab. Afterwards, we changed to myeloablative but reduced toxicity conditioning: thiotepa, treosulfan, fludarabine, antithymocyte globulin. Also, GvHD prophylaxis used until 2019 was CsA and MTX, changing later to tacrolimus and mycophenolate mofetile (MMF). Seizure prophylaxis was provided during calcineurin inhibitors treatment, as well as maintenance of platelet threshold above 50.000/mcL, hemoglobin 11 g/dL and avoid hypomagnesemia. Epidemiological and clinical parameters were collected. Data are presented as percentages and quartiles. For the comparison of the variables under study, a bivariate analysis with non-parametric Fisher test was used. R Statistical Software was used for the numerical analysis and Survminer to represent Kaplan-Meier curves. Results: 50 allo-HCST were performed in 49 patients, median age 6.0 years (p25 2;p75 9). 22 patients in first period, 10 males (45%); and 27 patients in second, 15 males (55%). Prior to HSCT, 14/50 of HSCT had cerebrovascular disease (Moya-moya vasculopathy, silenct infarction, stroke or leukoencephalopathy); 64% (9/14) on first period and 36% (5/14) on second. During transplant, 11/50 had acute CNS complications: 91% (10/11) on first period (9/10 seizures, 5/10 HSA, 5/10 PRES and 1/10 other complications), and 9% (1/11) on second (mild toxicity to tacrolimus). HTA is present in 89% of total HSCT and in 100% with post-HSCT neurological complications, suggesting his major role in these type of situations. Global event-free survival of post-HSCT CNS complications at the end of follow-up period (12.5 years) was 77% (0.66-0.89). Statistically significant decrease on post-HSCT neurological complications on second period was observed compared to the first (seizures p<0.001; HSA p0.018; PRES p0.022), after the implementation of ABP Holter. Also, we couldn’t observe a statistically significant predisposition to have post-HSCT CNS complications according to their pre-neurological history. Conclusions: Even with reduced-toxicity conditioning and switch to tacrolimus, neurological events still happen. Mainly since the implementation of ABPH, our center have decreased acute CNS complications and improved SCD event-free survival rates during transplant, with less toxicity, morbidity and mortality.

A Comparison of Topical Corticosteroids and Topical Calcineurin Inhibitors for the Treatment of Atopic Dermatitis

Topical corticosteroids (TCS) are a mainstay of treatment for atopic dermatitis (AD). There are shared physician and patient concerns that TCS use can result in skin atrophy and systemic absorption. The clinical use of topical calcineurin inhibitors (TCI) for AD is relatively limited despite evidence that TCI are safe and effective. Understanding the differences in efficacy and adverse effects between TCS and TCI can help shape prescription practices to the benefit of patients. The objective of this review is to characterize the difference in efficacy and adverse effects between TCS and TCI. A review of the literature between 2002 and 2022 was performed using the PubMed, EMBASE, and Cochrane Library databases. Ten studies comparing TCS of varying potencies with TCI approved for AD treatment were included in the review. Outcome measures were qualified using percent reductions on the modified Eczema Area and Severity Index score and decreases in physician's global evaluation of AD severity. Tacrolimus had statistically significant (P < .05) improvement in disease severity compared with TCS in 4 of the 5 studies that compared against weak TCS. The data suggest greater treatment efficacy of tacrolimus over weak TCS, and inferior performance of pimecrolimus (TCI) compared with both tacrolimus and weak TCS. It is difficult to draw conclusions between moderate, potent, and very potent TCS and TCI due to the small number of studies making comparisons. TCI can improve disease severity, especially on thin or intertriginous skin regions most vulnerable to adverse events with TCS treatment, and their use may help overcome adherence issues due to patient bias against TCS.