Induction of remission with tacrolimus in a patient with severe acute, cortisone refractory ulcerative colitis and severe Covid-19 pneumonia: a case report

Background Therapy regimens used in patients with inflammatory Bowel Disease (IBD) have been associated with enhanced risk of viral infections or viral reactivation. Moreover, it is uncertain whether IBD patients have increased risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or infected patients may have an increased risk for severe coronavirus disease 2019 (Covid-19). Managing severe acute flare in ulcerative colitis during the Covid-19 pandemic is a challenge for clinicians and their patients. The results of the published studies mainly report on the role of the prior medication, but not how to treat severe acute flare of IBD patients with severe Covid-19 pneumonia. Case presentation We report the case of a 68-year-old patient with a long history of ulcerative colitis. He was initially admitted to an external hospital because of severe acute flare. The initiation of a high-dose oral cortisone therapy did not improve the clinical symptoms. During the inpatient treatment, he was tested positive for SARS-CoV-2. At admission to our hospital the patient showed severe flare of his ulcerative colitis and increased Covid-19 symptoms. A cortisone-refractory course was noticed. After detailed multidisciplinary risk–benefit assessment, we initiated an intravenous tacrolimus therapy and dose of prednisolone was tapered gradually. After clinical response, the therapy was adjusted to infliximab. Additionally, the Covid-19 pneumonia was kept under control despite immunosuppression and the patient could be discharged in clinical remission. Conclusions This case suggest the use of tacrolimus as a bridging therapeutic option for severe acute, cortisone refractory ulcerative colitis in Covid-19 patients. Nevertheless, the best treatment strategy for IBD patients presenting a flare during the outbreak has yet to be defined. Further data for IBD patients under calcineurin inhibitor therapy are urgently needed.

Tacrolimus as an alternative treatment for patients with juvenile idiopathic arthritis

ABSTRACT Objective To evaluate the efficacy and safety of tacrolimus in patients with juvenile idiopathic arthritis (JIA). Methods We retrospectively analysed 27 patients with JIA who received tacrolimus therapy at the Department of Pediatric Rheumatology of the Tokyo Medical and Dental University between April 2019 and August 2020. We collected background and clinical characteristics at the time of add-on tacrolimus therapy initiation (baseline; Month 0) and after 3, 6, and 12 months. The primary outcome was successful medication reduction after 12 months. Patients requiring reduced and additional treatments were assigned as ‘did not require additional treatment patients’ and ‘required additional treatment patients’, respectively. The Wilcoxon signed-rank test was used to evaluate the continuous distribution of laboratory data and Juvenile Arthritis Disease Activity Score-27 at 3, 6, and 12 months relative to baseline values. Statistical significance was set as p < .05. Results Among the 27 included cases, 17 patients were classified as did not require additional treatment patients, and there was a significant improvement in Juvenile Arthritis Disease Activity Score-27 scores in this group (p < .05). No patients presented tacrolimus-related adverse events throughout the study period. Conclusion Tacrolimus is an effective and safe therapeutic alternative for approximately 60% of patients with JIA.

MO974PREDICTORS OF MORTALITY IN KIDNEY TRANSPLANT PATIENTS INFECTED BY SARS-COV-2 IN SOUTH OF SPAIN

Background and Aims Covid-19 pandemic has especially affected kidney transplant (KT) recipients, who are more vulnerable than the general population due to their immunosuppressive status and added comorbidities. The objetic of this study was to determine risk factors related to infection and mortality from Covid-19 in KT. Method We included 53 KT who had PCR-confirmed COVID-19 infection between march 21st and november 24th, from a total of 2030 KT. Outcomes related to patient survival were analyzed. Results 39 (73%) patients were men, with a mean age of 56±15 years old. Median time after KT where the infection took place was 104 months (IQR: 55-160). One patient was infected 40 days after transplant. 90% were on Tacrolimus therapy and 79% on MMF. 81% of patients were hypertensive, 36% diabetic and 19% had ischemic heart disease. 65% were on ARAII treatment. Clinical presentation consisted on pneumonia (64%), fever (55%), cough (70%), dyspnoea (45%), lymphopenia (66%) and gastrointestinal symptoms (36%). 21% required intubation and admission in ICU. 8 patients were asymptomatic. 18% received Hydroxychloroquine therapy plus Azithromycin, 11% Tocilizumab, 11% Ritonavir-Lopinavir, 59% steroids, 7.7% Remdesivir and 13.5% convalescent plasma. Immunosuppression was reduced in all symptomatic patients. 10 patients (19%) died. Table 1 compares the characteristics of these patients with those who survived. Conclusion We concluded that mortality in KT is very high, more than reported in general population. Risk factors are patient age, time after KT, baseline renal function, the presence of pneumonia, as well as higher CRP levels at the time of diagnosis. More experience is needed to optimize our protocols and therapy for Covid-19 in KT.

Vitiligo Skin Biomarkers Associated With Favorable Therapeutic Response

Vitiligo is an acquired depigmentation skin disease caused by immune-mediated death of melanocytes. The most common treatment for vitiligo is narrow band ultraviolet B phototherapy, which often is combined with topical therapies such as tacrolimus. However, patients’ responses to these treatments show large variations. To date, the mechanism for this heterogeneity is unknown, and there are no molecular indicators that can predict an individual patient’s response to therapy. The goal of this study is to identify clinical parameters and gene expression biomarkers associated with vitiligo response to therapy. Six patients with segmental vitiligo and 30 patients with non-segmental vitiligo underwent transcriptome sequencing of lesional and nonlesional skin at baseline before receiving combined UBUVB and tacrolimus therapy for 6 month, and were separated into good response and bad response groups based on target lesion achieving > 10% repigmentation or not. Our study revealed that treatment-responsive vitiligo lesions had significantly shorter disease duration compared with non-responsive vitiligo lesions (2.5 years vs 11.5 years, p=0.046, t-Test), while showing no significant differences in the age, gender, ethnicity, vitiligo subtype, or disease severity. Transcriptomic analyses identified a panel of 68 genes separating the good response from bad response lesions including upregulation of immune active genes, such as CXCL10, FCRL3, and TCR, Further, compared with vitiligo lesions with long disease duration, the lesions with short duration also have much higher level of expression of immune-active genes, including some (such as FCRL3 and TCR genes) that are associated with favorable therapeutic response. In conclusion, our study has identified clinical parameters such as short disease duration and a panel of immune active and other gene expression biomarkers that are associated with favorable response to immune suppressive NBUVB + tacrolimus therapy. These markers may be useful clinically for individualized therapeutic management of vitiligo patients in the future.

Tacrolimus-induced bilateral optic neuropathy: A case report

Intrduction. Tacrolimus (fujimycin or FK506) is a potent immunosuppressive drug with growing usage. It is usually used in prevention of transplanted organ rejection. Its use is highly valuable, but like other immunosupressants, it has adverse effects. One of them is optic neuropathy. Case report. A 47-year-old white male patients who had received tacrolimus therapy for nine years, after kidney transplantation, developed a subacute, painless vision loss on both eyes. He was thoroughly examined on different possible optic neuropathies and other causes of vision loss. After exclusion of other possible causes, the diagnosis of toxic optic neuropathy was established. His therapy was converted to cyclosporine, by his nephrologist, but his vision had improved only slightly. Conclusion. Toxic optic neuropathies are presented in everyday ophthalmological practice, but they are underestimated. Diagnosis can be demanding, especially when it comes to drugs and substances whose possible toxic effect on the optic nerve is not widely known. Unlike other adverse effects of tacrolimus therapy on nervous system, optic neuropathy can causes great and permanent functional impairment.

Fanconi Syndrome Induced by Concomitant HIV PrEP and Tacrolimus

Fanconi syndrome (FS) is a severe grade of drug-induced proximal tubule toxicity. There are numerous causes for acquired FS, and drug toxicity is one of the most common. FS is known to be associated with the nucleoside reverse transcriptase inhibitor (NRTI) tenofovir disoproxil fumarate (TDF). TDF is often used in combination with emtricitabine (FTC) for preexposure prophylaxis (PrEP) of human immunodeficiency virus (HIV) infection. TDF/FTC-induced FS has been observed as a dose-related phenomenon that is directly correlated to kidney function, high levels of absorption of the drug into the proximal tubule, and interactions with other medications. This case report describes a patient who acquired FS after starting TDF/FTC for PrEP in the setting of chronic kidney disease (CKD) with concomitant tacrolimus therapy, a known nephrotoxic agent.

Differentially expressed urinary exo-miRs and clinical outcomes in kidney recipients on short-term tacrolimus therapy: a pilot study

Aim: To analyze the expression of urinary exosome-derived miRNAs (exo-miRs) in kidney recipients on tacrolimus-based therapy. Patients & methods: Clinical and drug monitoring data were recorded from 23 kidney recipients. Expression of 93 exo-miRs was measured by quantitative PCR array and mRNA targets were explored. Results: 16 exo-miRs were differentially expressed, including marked upregulation of miR-155-5p, and downregulation of miR-223-3p and miR-1228-3p. Expression of miR-155-5p and miR-223-3p correlated with tacrolimus dose (p < 0.05), miR-223-3p with serum creatinine (p < 0.05), and miR-223-3p and miR-1228-3p with blood leukocytes (p < 0.05). 12 miRNAs have predicted targets involved in cell proliferation, apoptosis, stress response, PIK3/AKT/mTOR and TGF-β signaling pathways. Conclusion: Differentially expressed urinary exo-miRs may be useful markers to monitor tacrolimus therapy and graft function in kidney transplantation.

Tacrolimus Improves the Implantation Rate in Patients with Elevated Th1/2 Helper Cell Ratio and Repeated Implantation Failure (RIF)

Introduction An abnormal endometrial immune response is involved in the pathogenesis of repeated implantation failure (RIF), so we investigated the effectiveness of tacrolimus treatment on the endometrium of RIF patients. Materials and Methods Ten RIF patients with elevated T-helper 1/T-helper 2 (Th1/Th2) cell ratios were recruited into a clinical study. The expression of p53, leukemia inhibitory factor (LIF), interleukin (IL)-4, IL-10, IL-17, and interferon gamma (IFN-γ) in the endometrium of patients with and without tacrolimus treatment and the association of these factors with assisted reproductive technology (ART) outcomes were investigated. Results Tacrolimus significantly increased the expression of LIF, IL-10, and IL-17 and decreased the expression of IL-4, IFN-γ, and the IFN-γ/IL-10 ratio in RIF patients. Tacrolimus treatment resulted in an implantation rate of 40%, a clinical pregnancy rate of 50%, and a live birth rate of 35% in RIF patients with elevated Th1/Th2 ratios who had previously failed to become pregnant despite at least three transfers of embryos. We also found a significant positive correlation between IL-10 levels and the implantation rate. Conclusions Our findings suggest that RIF patients with a higher Th1/Th2 ratio could be candidates for tacrolimus therapy and that this immunosuppressive drug could be acting through upregulation of LIF, IL-10, and IL-17.