Combined Immunosuppression Research Articles

Infectious Complications in Lung Transplant Recipients

Lung transplantation is a lifesaving intervention for patients with advanced lung disease. Due to a combination of immunosuppression, continuous exposure of the lungs to the environment, and complications at the anastomotic sites, lung transplant recipients are at high risk for infectious complications. The aim of this review is to summarize recent developments in the field of infectious diseases as it pertains to lung transplant recipients.

Severe biventricular thrombosis in eosinophilic granulomatosis with polyangiitis: a case report

BackgroundEosinophilic granulomatosis with polyangiitis (EGPA), formerly known as Churg–Strauss syndrome, is a rare multisystem disease characterized by asthma, rhinosinusitis, and eosinophilia. Cardiac involvement, present in half the patients, may be life threatening.Case summaryA young woman with long-standing asthma and nasal polyposis was admitted with new-onset dyspnoea, sinus tachycardia, and eosinophilia. She had severe biventricular thrombosis and severe tricuspid regurgitation (TR) on echocardiography, with preserved ejection fraction of both ventricles. Cardiac magnetic resonance (CMR) imaging showed diffuse subendocardial late gadolinium enhancement (LGE). She had a positive test for perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) confirming the diagnosis of ANCA positive EGPA. She was treated with anticoagulation, high-dose corticosteroids, cyclophosphamide, and rituximab with gradual resolution of her symptoms. Follow-up echocardiography showed significant improvement in ventricular thrombi and TR but could not reliably exclude residual ventricular thrombus. Repeat CMR at 11 months confirmed complete resolution of both ventricular thrombi and near complete resolution of LGE.DiscussionCardiac involvement in EGPA, a rare cause of heart failure, can manifest as severe biventricular thrombosis and severe TR, resulting in heart failure with preserved ejection fraction. Combined immunosuppression and anticoagulation can lead to complete remission within a year. CMR is instrumental for both diagnosis and follow-up of EGPA, allowing for safe discontinuation of oral anticoagulation.

Efficacy and Safety of Biosimilar Romiplostim in Immune Thrombocytopenic Purpura : Single Centre Retrospective Data Analysis

Introduction: Thrombopoietin receptor agonist (TPO RA) is an approved second line of treatment in Persistent and Chronic Immune Thrombocytopenic Purpura (ITP).However in India due to cost constraints, the majority prefer Immunosuppression therapy. A biosimilar of Romiplostim (Romy®) is developed and launched in India, by Intas Pharmaceuticals, India, in July 2019, its monthly cost is around $160, a huge relief to ITP patients (pts), now accessible to the masses in Lower Middle Income Country (LMIC), India. Real-world experience data on Romiplostim (Romy®) in ITP is sparse. Aim: A single centre retrospective data analysis to evaluate the Safety and Efficacy of Biosimilar Romiplostim (Romy®) in patients of Immune Thrombocytopenic Purpura. Method: A total of 54 steroid-refractory or steroid-dependent ITP pts were registered at Haemato-oncology Care Centre Vadodara from July 2019 to January 2020, who received Injection Romiplostim (Romy®) treatment. Pre-treatment Complete Blood Count(CBC) Platelet count (PLT) ,Liver Function Test ,Renal Function Tests ,PT,PTT,ANA,HIV,HBsAg,HCV,Bone Marrow,USG Abdomen, Chest X-Ray was done.All patients had pretreatment Platelet count less than 30000/cumm.The dose of Romiplostim was 1mcg /kg to 6 mcg/kg, subcutaneous once a week.12 /54 patients who had active bleeding also received concomitant Rituximab 100mg IV infusion once a week for 4 weeks. The response was assessed by CBC PLT every week for the first 4 weeks, later on, every monthly. The response was labelled as Optimum if PLT count maintained between 50000/cumm to 4,00,000/cumm, Suboptimal if PLT count increased from baseline but remained below 50,000/cumm, No response if no increment from baseline PLT count. Romiplostim was continued with the same dose if response was Optimum, escalated if response was Suboptimal, de-escalated if PLT increased above 1, 50,000/cumm and stopped if PLT increased above 4,00,000/cumm or no response found after 4 weeks of treatment. Results: Atotal of 54 pts were evaluated, 23(42%) Male, 31(58%) Female, Median age 40 years (range 8 yrs to 85yrs).Persistent ITP was the diagnosis in 38/54(70%)pts, Chronic ITP in 16/54(30%) pts, Secondary ITP in 17(30%) pts, with 14 patients had ANA positive, 2 patients had HCV positive, 1 patient had tubercular lymphadenopathy. The overall response rate (ORR) was 50/54(93%).Optimum response in 49 /54 (91%),Suboptimal response in 1/54 (2%),No response in 4/54(7%)pts. ORR in patients who received Rituximab with Romiplostim was 12/12 (100%). Time to achieve response was 1 week in 46 (85%) pts, 2 weeks in 3(5%) pts, and 3 weeks in 1 (2%) pts. Follow up assessment showed a total of 21/54 (40%) patients had sustained optimum response for more than 6 months with continuation of once a week Romiplostim,9/54 (16%) had sustained response for more than 6 months even on discontinuation of Romiplostim after 4 weeks.8/54(15%) pts with ANA positive reports required a combination of immunosuppressant with Romiplostim to maintain prolonged sustained response.4/54(7%) pts did not respond to Romiplostim hence it was stopped after 4 weeks. Mild adverse effects were observed headache 5(9%), myalgia 3 (5%), bone pains 6(11) Abdominal pain 4(7%) pts. Romiplostim was stopped in 12 (22%) pts because of thrombocytosis (PLT above 4, 50,000/cumm) after a first single dose of Romiplostim. None of the patients had serious adverse events Conclusion: Biosimilar Romiplostim, (Romy®) has shown rapid, excellent and sustained response in the majority of ITP pts in our study. Its affordable cost fulfils an unmet need of ITP patients, requiring the best second line of treatment in LMIC Disclosures No relevant conflicts of interest to declare.

Macroscopic Aspergillus Infection at the Anastomosis of a Lung Transplant Recipient

A 65-year-old female with a history of right lung transplantation (LTx) for chronic obstructive pulmonary disease (COPD) 9-years prior complicated by grade 3 bronchiolitis obliterans syndrome (BOS) was admitted to the hospital for chest pain and dyspnea on exertion (DOE). Her bronchoscopy revealed fluffy, endobronchial lesions that were adherent to the right sided anastomosis resulting in mild obstruction of the right mainstem bronchus. Pathology from biopsies of the endobronchial lesions revealed hyphal fungal organisms consistent with Aspergillus species. Following antifungal therapy with voriconazole, her follow up bronchoscopy 37 days post the original bronchoscopy revealed resolution of the endobronchial lesions. The patient’s case is unique in: presentation 9 years post-transplantation, the absence of prior Aspergillus colonization, and the appearance of the endobronchial lesions. Following Ltx, immunosuppression in combination with allograft exposure to the environment increases the risk of opportunistic infections, especially saprophytic infections including Aspergillus.

A critical evaluation of caplacizumab for the treatment of acquired thrombotic thrombocytopenic purpura

ABSTRACT Introduction: Acquired thrombotic thrombocytopenic purpura (aTTP) is a thrombotic microangiopathy caused by inhibitory autoantibodies against ADAMTS13 protein. Until recently, the combination of plasma exchange (PEX) and immunosuppression has been the standard front-line treatment in this disorder. However, aTTP-related mortality, refractoriness, and relapse are still a matter of concern. Areas covered: The better understanding of the pathophysiological mechanisms of aTTP has allowed substantial improvements in the diagnosis and treatment of this disease. Recently, the novel anti-VWF nanobody caplacizumab has been approved for acute episodes of aTTP. Caplacizumab is capable to block the adhesion of platelets to VWF, therefore inhibiting microthrombi formation in the ADAMTS13-deficient circulation. In this review, the characteristics of caplacizumab together with the available data of its efficacy and safety in the clinical setting will be analyzed. Besides, the current scenario of aTTP treatment will be provided, including the role of other innovative drugs. Expert opinion: With no doubt, caplacizumab is going to change the way we treat aTTP. In combination with standard treatment, caplacizumab can help to significantly reduce aTTP-related mortality and morbidity and could spare potential long-term consequences by minimizing the risk of exacerbation.

Extracorporeal photopheresis in solid organ transplantation

Despite the use of up-to-date immunosuppressive agents, graft rejection episodes are quite common and pose a serious threat to thousands of solid organ recipients. Continuous use of various combinations of immunosuppressants cause serious complications, such as arterial hypertension, post-transplant diabetes mellitus, renal failure, increased risk of infections, malignant neoplasms, etc. The attempts to achieve the desired or forced minimization of the graft immunosuppression are associated with the threat of its rejection, which makes it necessary to search for less toxic, non-medical, immunological, including cellular, management methods. One of the promising methods based on cell technology is extracorporeal photopheresis (ECP). ECP is a well-established second line therapy recommended for the prevention and treatment of refractory rejection of a heart transplant. ECP improves the pulmonary allograft functioning in patients with treatment resistant obliterating bronchiolitis syndrome. However, its value as a preventive method has not yet been established. ECP effectiveness for induction, maintenance, or anti-crisis therapy in transplantation of kidney, liver or other solid organs has been rather convincing, but the lack of randomized multicenter studies limits its use. The optimal ECP strategy has not been yet established. Nevertheless, current understanding of the pathophysiological and immunological aspects of ECP is sufficient to develop a standard methodology and technology for the procedure, as well as for a quality control system for ECP in kidney and liver transplant recipients. The review discusses possible mechanisms of the immunomodulating effect of ECP. ECP is being increasingly studied in prospective randomized trials with larger samples. This allows for an extension of its clinical indications with clear criteria, as well as for studying its multifactorial underlying immunomodulating mechanism of action. Further research is needed to identify biomarkers that could predict ECP effectiveness in solid organ transplantation.

RAPIDLY PROGRESSIVE INTERSTITIAL LUNG DISEASE IN ASSOCIATION WITH MDA5 ANTIBODY DERMATOMYOSITIS

SESSION TITLE: Medical Student/Resident Diffuse Lung Disease SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Clinically Amyopathic Dermatomyositis (CADM) is a subtype of dermatomyositis (DM) characterized by the presence of cutaneous lesions, without clinical evidence of muscle weakness. The presence of autoantibodies against Melanoma Differentiation-Associated protein 5 (MDA5) in this group is highly associated with rapidly progressive interstitial lung disease (RP-ILD) and a worse prognosis. We present a case of anti-MDA5 associated RP-ILD to illustrate the importance of screening for MDA5 in patients with CADM and DM. CASE PRESENTATION: Our patient was a 45-year-old woman with a history of hypothyroidism, seronegative inflammatory polyarthritis treated with hydroxychloroquine, and notably, a history of biopsy-proven DM with a negative myositis-specific antibodies (MSA) panel (which did not include MDA5 antibodies). She had been successfully treated for DM, and maintained in remission with oral steroids. Four years following the diagnosis of DM, she presented with insidious and gradually progressive dyspnea for over a year. Physical examination was unremarkable. Pulmonary function testing showed moderate restrictive lung disease. Chest X-ray was notable for bibasilar interstitial changes. Computed tomography (CT) scan of the chest revealed nonspecific, bilateral ground-glass opacities in the middle and lower lung zones, with associated bibasilar bronchiectasis in the affected areas (Figure 1). Bronchoscopic evaluation, including transbronchial biopsy, was performed, which was negative for malignancy or infection. Open lung biopsy was obtained via robotic-assisted thoracoscopy from the affected lobes, with histopathology revealing interstitial fibrosis with multiple fibrotic foci without clear evidence of honeycombing. The pattern was suggestive of usual interstitial pneumonia (UIP). Repeat testing for MSA revealed an elevated anti-MDA5 antibody level at 22 SI. The patient was consequently diagnosed with RP-ILD in conjunction with CADM, prompting the initiation of oral prednisone and azathioprine. DISCUSSION: Anti-MDA5 antibodies recognize the RNA helicase encoded by MDA5, a protein that is involved in innate immune processes. The presence of anti-MDA5 antibodies in patients with CADM has been linked to the presence of RP-ILD, and portends a poor prognosis. The mechanism of this autoantibody production is not fully understood. One meta-analysis found that the presence of these antibodies was 77% sensitive and 86% specific for the identification of RP-ILD. Additionally, anti-MDA5 antibodies can be utilized to predict clinical outcomes and monitor disease activity in these patients. Due to its high mortality rate from respiratory failure, immediate therapy with high-intensity combination immunosuppression is essential once the diagnosis is made. CONCLUSIONS: This case highlights the importance of screening for anti-MD5 antibodies in patients with CADM to elucidate their risk of developing RP-ILD. Reference #1: Li L, Wang Q, Yang F, et al. Anti-MDA5 antibody as a potential diagnostic and prognostic biomarker in patients with dermatomyositis. Oncotarget. 2017;8(16):26552–26564. doi:10.18632/oncotarget.15716 Reference #2: Chen, Z., Cao, M., Plana, M.N., Liang, J., Cai, H., Kuwana, M. and Sun, L. (2013), Utility of Anti–Melanoma Differentiation–Associated Gene 5 Antibody Measurement in Identifying Patients With Dermatomyositis and a High Risk for Developing Rapidly Progressive Interstitial Lung Disease: A Review of the Literature and a Meta-Analysis. Arthritis Care & Research, 65: 1316-1324. doi:10.1002/acr.21985 DISCLOSURES: No relevant relationships by Komal Ejaz, source=Web Response No relevant relationships by Dan Kazmierski, source=Web Response No relevant relationships by Bassel Noumi, source=Web Response No relevant relationships by Pius Ochieng, source=Web Response No relevant relationships by NISHANT SHARMA, source=Web Response No relevant relationships by Yichen Wang, source=Web Response

Clinical Characteristics, Treatment, and Outcomes in Patients with Idiopathic Inflammatory Myopathy Concomitant with Heart Failure.

This study sought to evaluate clinical features, treatment patterns, and outcomes of patients with idiopathic inflammatory myopathy (IIM) complicated by heart failure (HF). Thirty-two patients with IIM-HF admitted to the Peking Union Medical College Hospital between January 1999 and January 2018 were retrospectively reviewed, including 14 patients with polymyositis, 11 with dermatomyositis, and 7 with overlap syndrome. Survivors and no-survivors were compared on clinical characteristics and treatment. Although systemic symptoms were variable, all patients presented with elevated troponin I. Rapid atrial arrhythmia was the most frequent arrhythmia. Systolic dysfunction and restrictive diastolic dysfunction were typical presentations in echocardiography. Twenty-nine patients were followed up for a median of 2.8 years (0.1 month to 11 years). We recorded 13 deaths of cardiogenic cause, 1 of serious IIM, and 3 of infective complications. The median survival time from diagnosis of IIM-HF to all-cause mortality was 8.4 months (range from 1 month to 5 years). Both all-cause deaths and cardiogenic deaths were more reported in the methotrexate-alone group than in the combination therapy group (6/7 versus 3/10, P = 0.050; 5/6 versus 2/9, P = 0.041). Combination therapy including methotrexate (HR = 0.188, 95%CI 0.040-0.871, P = 0.033) and taking β-receptor blockers (HR = 0.249, 95%CI 0.086-0.719, P = 0.010) was associated with reduced risk of all-cause deaths. In conclusion, elevated troponin I, atrial arrhythmia, and systolic and restrictive diastolic dysfunction are typical characteristics of IIM-HF. Combined immunosuppression that includes methotrexate and β-receptor blockers seems to be important to improve survival.

Corticosteroids could improve the renal outcome of IgA nephropathy with moderate proteinuria.

The specific treatment regimens of IgA nephropathy (IgAN) patients with moderate proteinuria (1.0-3.5g/day) remain controversial. The purpose of this study was to explore the optimized therapeutic regimen for IgAN patients through analyzing the clinical data. A retrospective study was conducted, 449 patients with biopsy-proven IgAN were enrolled. Patients were divided into three groups according to proteinuria levels: urine protein 1.0-1.5g/day (UP1, n = 111), urine protein 1.5-2.5g/day (UP2, n = 213), urine protein 2.5-3.5g/day (UP3, n = 125). Clinical pathological features, treatment regimens and renal outcome were compared. Responses to therapy included complete remission (CR), partial remission (PR), no response (NR) and end-stage renal disease (ESRD). The composite endpoints of renal outcome were defined as 50% decline in eGFR and/or progressing into end-stage renal disease. During the average follow-up of 44.27months, 71 (63.9%), 150 (70.4%) and 68 (54.4%) patients achieved CR + PR among three groups, respectively. Whereas 15 (13.5%), 28 (13.1%) and 39 (31.2%) patients progressed to the primary endpoint (P < 0.001). Patients who received corticosteroids (CS) treatment had better remission rate than those with supportive care (SC) or combined corticosteroid plus immunosuppressant (CS + IT) therapy (P < 0.05). Kaplan-Meier survival analysis revealed that patients received CS and CS + IT treatments had better renal prognosis compared with SC therapy in UP2 and UP3 groups (P < 0.05). However, no statistical difference was found among three treatment regimens in UP1 group (P = 0.358). Corticosteroids therapy might better improve renal prognosis compared with supportive care alone or corticosteroids plus immunosuppressant in IgAN patients with moderate proteinuria (1.5-3.5g/day).

From Traditional to Targeted Immunotherapy in Myasthenia Gravis: Prospects for Research.

Treatment of Myasthenia Gravis (MG) is still based on non-specific immunosuppression. Long-term high dose corticosteroids is still a major cause of side effects, in young as well as in elderly patients in whom comorbidities further increase the burden of chronic immunosuppression. Moreover, awareness of the limits of traditional therapies has led to the concept of “refractory MG.” The therapeutic approach to MG is therefore progressively evolving from the classic combination of corticosteroids and immunosuppressive drugs to new biological compounds targeting different immunopathological steps. Killing of B cells with Rituximab has been proposed and tested with positive results, particularly in patients with MuSK-associated MG. Therapeutic monoclonals against B cells at different stages of their maturation, or against molecules involved in B cell activation and function, represent a new area for further investigation. A differently targeted approach involved Eculizumab, a monoclonal antibody preventing the formation of C59b-induced MAC causing destruction of the neuromuscular junction. Data from clinical trials led to the approval of Eculizumab in the United States and Europe for MG. Since Eculizumab is a complement-targeted therapy, its use is limited to anti-acetylcholine receptor-associated MG, since anti-MuSK antibodies belong to IgG4 subclass and do not fix complement. Several anti-complement compounds are under investigation. An even more recent approach is the interference with the neonatal Fc receptor leading to a rapid reduction of circulating IgGs and hence of specific autoantibodies, an approach suitable for both anti-acetylcholine- and MuSK-associated MG. The investigation of compounds that selectively target the immune system will stimulate the search for specific biomarkers of disease activity and response to treatment, setting the basis for personalized medicine in MG.

Immunosuppression in Liver Transplantation: State of the Art and Future Perspectives.

Novel drugs and combinations for immunosuppression (IS) after liver transplantation is one main reason for improved graft and patient survival seen in the last decades. The backbone of IS is still steroids and calcineurin inhibitors, although novel drugs are being introduced, such as the mammalian target of rapamycin inhibitors (mTOR inhibitor). The challenge today, along with increased patient survival, is the adverse effects of long-term use of immunosuppressive drugs, mainly nephrotoxicity and other serious adverse effects. Concepts: The ultimate outcome after liver transplantation would be achieving tolerance, a state where all IS can be withdrawn. In the meantime, different approaches to reduce and withdraw IS have been tested out in different clinical trials with the aim to reduce the adverse effects of steroids and calcineurin inhibitors. This has formed the basis of today's clinical practice. The different combinations of immunosuppressive drugs have included mTOR inhibitor such as everolimus and different induction drugs such as anti-interleukin 2 receptor antibodies. Regarding induction drugs, lymphocyte depleting (alemtuzumab and ATG) and non-depleting agents, such as basiliximab, have shown advantageous effects. Alongside steroid and calcineurin inhibitors reduction or elimination, current strategies for post-liver transplantation immunosuppression explore combinations of novel agents. The gauge (or yardstick) here is the fine balance between the adverse effects of IS drugs and the risk of rejection. Long-term maintenance IS regimens, development of tolerance and antibody-mediated rejection are also discussed in this review.

Impact of IL-34, IFN-α and IFN-λ1 on activity of systemic lupus erythematosus in Egyptian patients.

BackgroundSystemic lupus erythematosus (SLE) is an autoimmune, multi-system inflammatory disease. Among cytokines involved in SLE pathogenesis, interferons (particularly IFN-α) and interleukin 34 play a pivotal role. Interestingly, the gene signatures of type III (IFN-λ1) and type I IFNs may overlap. Increased levels of IFN-λ also have been reported in SLE.Objectives: The aim of this study was to assess serum levels of IL-34, IFN-λ1, IFN-α and the relationship between these cytokines and clinical and laboratory parameters and response to treatment in a cohort of Egyptian SLE patients.Material and methodsThe study included 82 newly diagnosed SLE patients: male 17.1% (n = 14), female 82.9% (n = 68), mean age ±SD: 48.6 ±8.2 and 60 healthy subjects matched by age and gender as a control group. Medical history, physical examination and laboratory tests for confirming SLE diagnosis and assessment of disease activity were collected. The assessment of serum levels of studied cytokines were performed using the ELISA method.All studied patients after first cytokine evaluation were treated with a combination of antimalarial drugs, glucocorticosteroids and/or immunosuppressive drugs with follow-up after six months of treatment.ResultsIn the SLE group the mean serum levels of IL-34, IFN-α and IFN-λ1 were 175.9 ±125.9 pg/ml, 109.3 ±32.5 pg/ml and 227.9 ±144.8 pg/ml respectively. These cytokine levels were significantly higher in the SLE group than in healthy controls. 39% of SLE patients (n = 32) had SLAM > 6 and 26.8% (n = 22) had SLEDAI >6. There were 21 SLE patients (25.6%) with lupus nephritis.IL-34 and IFN-λ1 were positively correlated with anti-dsDNA antibodies but negatively correlated with C3 complement component (p ≤ 0.05). IL-34, INF-α and IFN-λ1 were significantly higher in lupus nephritis patients, and correlated with poorest response to treatment.IL-34 and IFN-λ1 were correlated with higher SLAM > 6 and SLEDAI > 6 results; there was no such correlation between IFN-α and disease activity.Accumulation of three or more clinical features during follow-up was significantly associated with high levels of studied cytokines. Triple high positivity was found in 17 patients (20.7%) and correlated with presence of anti-dsDNA antibodies, low levels of C3 component of complement and lupus nephritis.ConclusionsSLE patients with high serum levels of IL-34, IFN-α and IFN-λ1 more often had lupus nephritis and poor response to immunosuppressive treatment.The triple cytokine elevation was strongly associated with higher disease activity. These results may indicate the need to distinguish this group of patients with such aggressive phenotype and consider targeted multi-therapy.

Immunosuppression Has Long-Lasting Effects on Circulating Follicular Regulatory T Cells in Kidney Transplant Recipients.

Background: FoxP3+ follicular regulatory T cells (Tfr) have been identified as the cell population controlling T follicular helper (Tfh) cells and B cells which, are both involved in effector immune responses against transplanted tissue.Methods: To understand the biology of Tfr cells in kidney transplant patients treated with tacrolimus and mycophenolate mofetil (MMF) combination immunosuppression, we measured circulating (c)Tfh and cTfr cells in peripheral blood by flow cytometry in n = 211 kidney transplant recipients. At the time of measurement patients were 5–7 years after transplantation. Of this cohort of patients, 23.2% (49/211) had been previously treated for rejection. Median time after anti-rejection therapy was 4.9 years (range 0.4–7 years). Age and gender matched healthy individuals served as controls.Results: While the absolute numbers of cTfh cells were comparable between kidney transplant recipients and healthy controls, the numbers of cTfr cells were 46% lower in immunosuppressed recipients (p < 0.001). More importantly, in transplanted patients, the ratio of cTfr to cTfh was decreased (median; 0.10 vs. 0.06), indicating a disruption of the balance between cTfr and cTfh cells. This shifted balance was observed for both non-rejectors and rejectors. Previous pulse methylprednisolone or combined pulse methylprednisolone + intravenous immunoglobulin anti-rejection therapy led to a non-significant 30.6% (median) and 51.2% (median) drop in cTfr cells, respectively when compared to cTfr cell numbers in transplant patients who did not receive anti-rejection therapy. A history of alemtuzumab therapy did lead to a significant decrease in cTfr cells of 85.8% (median) compared with patients not treated with anti-rejection therapy (p < 0.0001). No association with tacrolimus or MMF pre-dose concentrations was found.Conclusion: This cross-sectional study reveals that anti-rejection therapy with alemtuzumab significantly lowers the number of cTfr cells in kidney transplant recipients. The observed profound effects by these agents might dysregulate cTfr functions.

Intervention in Takayasu Aortitis: When, Where and How?

Takayasu arteritis is a large vessel vasculitis which commonly affects the aorta and its major branches. Active arterial inflammation is characterised by the presence of T and B lymphocytes, natural killer cells, macrophages and occasional multinucleate giant cells. Uncontrolled vascular inflammation can progress to cause arterial stenosis, occlusion or aneurysmal dilatation. Medical treatment involves combination immunosuppression and more recently biologic therapies targeting TNF-α and IL-6. Due to the typical delays in diagnosis and accumulation of arterial injury, open and endovascular surgical intervention are important and potentially life-saving treatment options for Takayasu arteritis. Common indications for surgery include aortic coarctation and ascending aortic dilatation ± aortic valve regurgitation, renal artery stenosis, ischaemic heart disease, supra-aortic disease, mesenteric ischaemia, severe limb-threatening claudication and aneurysm repair. Surgical outcomes are markedly improved in patients with clinically inactive disease and those who receive adequate periprocedural immunosuppression. Decisions regarding surgical approaches are best made as part of a multi-disciplinary team.

Usage of Tacrolimus and Mycophenolic Acid During Conception, Pregnancy, and Lactation, and Its Implications for Therapeutic Drug Monitoring: A Systematic Critical Review.

Conception, pregnancy, and lactation following solid organ transplantation require appropriate management. The most frequently used immunosuppressive drug combination after solid organ transplantation consists of tacrolimus (Tac) plus mycophenolic acid (MPA). Here, the effects of Tac and MPA on fertility, pregnancy, and lactation are systematically reviewed, and their implications for therapeutic drug monitoring (TDM) are discussed. A systematic literature search was performed (August 19, 2019) using Ovid MEDLINE, EMBASE, the Cochrane Central Register of controlled trials, Google Scholar, and Web of Science, and 102 studies were included. Another 60 were included from the reference list of the published articles. As MPA is teratogenic, women who are trying to conceive are strongly recommended to switch from MPA to azathioprine. MPA treatment in men during conception seems to have no adverse effect on pregnancy outcomes. Nevertheless, in 2015, the drug label was updated with additional risk minimization measures in a pregnancy prevention program. Data on MPA pharmacokinetics during pregnancy and lactation are limited. Tac treatment during conception, pregnancy, and lactation seems to be safe in terms of the health of the mother, (unborn) child, and allograft. However, Tac may increase the risk of hypertension, preeclampsia, preterm birth, and low birth weight. Infants will ingest very small amounts of Tac via breast milk from mothers treated with Tac. However, no adverse outcomes have been reported in children exposed to Tac during lactation. During pregnancy, changes in Tac pharmacokinetics result in increased unbound to whole-blood Tac concentration ratio. To maintain Tac concentrations within the target range, increased Tac dose and intensified TDM may be required. However, it is unclear if dose adjustments during pregnancy are necessary, considering the higher concentration of (active) unbound Tac. Tac treatment during conception, pregnancy and lactation seems to be relatively safe. Due to pharmacokinetic changes during pregnancy, a higher Tac dose might be indicated to maintain target concentrations. However, more evidence is needed to make recommendations on both Tac dose adjustments and alternative matrices than whole-blood for TDM of Tac during pregnancy. MPA treatment in men during conception seems to have no adverse effect on pregnancy outcomes, whereas MPA use in women during conception and pregnancy is strongly discouraged.

The alteration of the gut microbiome by immunosuppressive agents used in solid organ transplantation.

Studies have suggested that in addition to antimicrobials, some non-antibiotics may alter the gut microbiome. This systematic review sought to determine if there is an association between immunosuppressive agents used in recipients of solid organ transplants (SOT) and alterations in the gut microbiome. English language PubMed and Scopus searches were conducted to identify relevant articles. Inclusion criteria were defined as pertaining to solid organ transplantation, immunosuppression, and the gut microbiome. Articles were excluded if they contained only genetic microbiota descriptions, narrative reviews of bacteria, or described bacteria as a pathogen for infections. PRISMA reporting was used to guide this literature review. A preliminary search identified 665 articles, of which 75 articles met the inclusion criteria, and 10 articles remained after application of exclusion criteria. Seventy-one percent of articles discussed calcineurin inhibitors, such as tacrolimus, 38% included mycophenolate mofetil, and 52% included steroids, such as prednisone. Some studies utilized a combination of immunosuppressants or had multiple study arms. Seventy percent of the articles indicated changes in quantities of anaerobic bacteria including Ruminococcaceae, Lachnospiraceae, Firmicutes, Bacteroides, and Clostridiales. Combinations of immunosuppressant agents were associated with an increase in colonization of Escherichia coli and Enterococcus sp. Some immunosuppressants are associated with changes in gut flora, but the impact on clinical outcomes is unknown. Robust clinical trials delineating the direct effect of immunosuppressants on the gut microbiome as well as the impact on clinical outcomes are warranted.

Neuropatía periférica como manifestaciónunica de poliangeítis microscópica en la altura. Reporte de caso

La poliangeítis microscópica, es una vasculitis de vasos pequeños cuya incidencia es de 4 por 1 000 000 de habitantes y que frecuentemente se presenta asociada a manifestaciones de glomerulonefrítis rápidamente progresiva y capilaritis pulmonar. Las manifestaciones neurológicas son menos frecuentes. El diagnostico se confirma con serología positiva para Anticuerpos Anticitoplasma de neutrófilos (ANCA) y especificidad para patrón de fluorescencia perinuclear (P-ANCA) y Mieloperoxidasa (MPO). El tratamiento idóneo son los glucocorticoides e inmunosupresores. Se presenta el caso de un paciente de 69 años con poliangeitis microscópica que debuta con neuropatía periférica como única manifestación clínica, presentación que se considera atípica. Se plantea que ante la presencia de una neuropatía periférica aislada, deben efectuarse estudios para confirmar o descartar la presencia de Poliangeitis Microscópica en base a la gran variabilidad de su sintomatología clínica y potenciales formas de tratamiento.

Early Combined Immunosuppression May Be More Effective for Reducing Complications in Isolated Colonic- vs Ileal-Dominant Crohn Disease.

We assessed whether differential efficacy of early combined immunosuppression (ECI) in comparison with conventional management (CM) is present in patients with Crohn disease (CD) according to disease location. In this posthoc analysis of the Randomized Evaluation of an Algorithm for Crohn's Treatment trial, the effect of ECI vs CM modified by disease location (isolated-colonic vs ileal-dominant) in terms of time to first complication (hospitalization, surgery, or disease-related complications-presence of a new abscess, fistula, or stricture; serious worsening of disease activity; extraintestinal manifestations) was analyzed using a marginal Cox proportional hazard model to account for cluster randomization. Factors adjusted included practice size, country, and other covariates selected in a backward logistic regression analysis with the first composition as outcome and P < 0.10. Of the 1969 patients with CD, 435 had isolated colonic CD (ECI n = 257, CM n = 178) and 1534 had ileal CD (ECI n = 817, CM n = 717). Over 24 months there was a significant differential impact for ECI vs CM for reducing the risk of a CD-related complication between patients with colonic CD and ileal CD (colonic CD hazard ratio [HR] = 0.51; 95% CI, 0.30-0.85 vs ileal CD HR = 0.79; 95% CI, 0.57-1.10; P = 0.033). No difference was identified between ECI vs CM for reducing the risk of surgery (colonic HR = 0.52 vs ileal HR = 0.74; P = 0.468) or hospitalization (colonic HR = 0.77 vs ileal HR = 0.83; P = 0.806). In this posthoc analysis of the Randomized Evaluation of an Algorithm for Crohn's Treatment trial, symptom-based ECI was associated with greater efficacy for reducing the risk of CD-related complications in patients with colonic disease location relative to ileal disease location.

Therapeutic Options in IgG4-Related Disease

IgG4-related disease (IgG4-RD) is an autoimmune fibrosing condition which is being increasingly recognized. This condition has been classically managed with glucocorticoids (GC) with variable dosing and frequent relapses. Multiple observational reports studied different GC doses and steroid-sparing agents. Rituximab (RTX) was reported as an effective induction treatment, with less relapses after 1 year of treatment. In the absence of guidelines, an international management consensus was made in 2015. In the last few years, significant advances have been made to clarify IgG4-RD pathophysiology. The new classification criteria will enable investigators to design new clinical trials with more homogeneous populations. Furthermore, B and T lymphocytes have a central role in the inflammatory cascade. More solid evidence has been published supporting treatment with GC, RTX, and some other steroid-sparing agents like mofetil mycophenolate. The combination of GC and immunosuppressants has been pointed by a meta-analysis as the most effective treatment for IgG4-RD, although the number and quality of studies remains limited. The use of GC and steroid-sparing agents is effective in IgG4-RD, although the choice between rituximab and other immunosuppressants can be influenced by many factors. Novel agents will be trialed in the following years.

P0366SAFETY OF STEROID THERAPY IN IGA NEPHROPATHY: THE CLINICAL EXPERIENCE OF 48 NEPHROLOGY UNITS IN ITALY

Abstract Background and Aims Steroid therapy is efficient in inducing remission of IgA nephropathy (IgAN) and preventing end stage renal disease (ESRD) but there are concerns about their safety. The TESTING trial in particular has been stopped early because of a higher incidence of side effects than conservative treatment thus inducing a conservative therapy with RAAS (renin angiotensin antagonist system) blockers. The aim of this analysis was to evaluate the incidence of adverse events (AE) in a retrospective observational trial on the real clinical practice. Method We evaluated 1209 patients (pz) with IgAN coming from 48 Italian centers: 285 pz in RAAS blockers alone, 732 treated for 6 months with steroid and 192 with a combination of steroid and other immunosuppressants (also with RAAS blockers). The analysis was limited to the 6 months of therapy. Results The basal characteristics of the 3 groups are shown in the table below. The figure shows the frequencies of 69 adverse events related with immunosuppression: the most frequent were infections (23, 2.73% of all patients, 34.3% of all AE), impaired glycemic control (11, 0.91% of patients, 16% of all AE), severe hypertension (6, 8.7% of all AE) and leukopenia (9, 0.80% of patients, 13% of all AE). Infections were observed in 16 (2.19%) pz in steroid therapy and 7 (3.65%) pz in steroid+immunosoppressive treatment. Liver toxicity and and gastrointestinal AE were observed almost in pz receiving steroid+ immunosuppressants [1(0.14%) and 2 (1.04%) pz, respectively]. 7 pz in steroid therapy (0.96%) and 2 in steroid+ immunosuppressants experienced an impaired glycemic control. All the 9 cases of leucopenia were registered in pz in steroid+ immunosuppressants (4.69%). A slightly higher incidence of allergies was observed in the RAAS blocker group (20 cases, 0.7%). The higher rates of infections and leucopenia were observed in pz above 70 years of age (6.12%,p&amp;lt;0.05), as higher incidence of infections and impaired glycemic control were registered in pz with an eGFR&amp;lt;30 ml/min/1.73 m2 (4.64 and 1.99%,p&amp;lt;0.05). Severe hypertension and leucopenia were observed respectively in 9 and 3 pz with an eGFR &amp;lt;60 ml/min/1.73m2. No significant relationships were found between AE, proteinuria and sex. Multivariate logistic regression showed an independent association of immunosuppressive treatment and age with any AE [ODDS ratio: 3,35 (CI:2,18-5,14) and 1,02 (CI:1,01-1,04), respectively; p&amp;lt;0.05]. Death occurred for sepsis in a 70 years old pz (eGFR=21.7 ml/min/m2, 24hproteinuria=16.1 g/day) after 3 months of treatment. Conclusion the incidence of EA in our observational study is lower than that observed in the TESTING and STOP trials (5.71% vs 14.7% and 40%, respectively). The most frequent AE were almost observed in oldest subjects with impaired renal function on steroid+other immunosuppressants. Though this trial is not randomized nor controlled (RC), it considers a large cohort of pz coming from the real clinical practice of the Italian Nephrology Units and demonstrates that the significantly lower incidence of steroid related AE than that observed in some RC trials doesn’t justify the abstention from steroids in IgAN at risk of progression. Much more attention should be paid in elderly pts with severe renal dysfunction with a closer follow-up, dose adjustments and antibiotic prophilaxis.