High-dose Immunosuppression Research Articles

S2383 The Successful Use of a High-Dose Immunosuppression Combination Regimen for the Management of Refractory IgG4 Sclerosing Cholangitis With Progressive Multisystemic Involvement: A Case Report

S2383 The Successful Use of a High-Dose Immunosuppression Combination Regimen for the Management of Refractory IgG4 Sclerosing Cholangitis With Progressive Multisystemic Involvement: A Case Report

High Frequency of Severe Hyperglycemia Observed During Intensive Hematologic Care: A Prospective Study Using Continuous Glucose Monitoring

ObjectiveDuring intensive hematologic care, patients are exposed to high-dose chemotherapy, corticosteroids, immunosuppressants, and total parenteral nutrition. Combined with physiologic stress and increased release of cytokines and hormones, this can lead to dysglycemia, which is associated with adverse clinical outcomes. This prospective study aimed to investigate continuous glucose monitoring (CGM) to identify dysglycemia during intensive hematologic care. MethodsPatients receiving chimeric antigen receptor T-cell therapy or allogeneic or autologous stem cell transplantation were eligible. Throughout the study, glucose levels were concurrently monitored using CGM and point-of-care (POC) glucose measurements in 60 patients (71% male, median age of 64 [interquartile range, 58-68] years, and 10% with diabetes). ResultsHyperglycemia (glucose level, >10 mmol/L) was prevalent in 93% of patients, of whom 90% had no history of diabetes. Severe hyperglycemia (glucose level, >13.1 mmol/L) was present in 38%. Additionally, hyperglycemia was associated with prolonged hospitalization in patients undergoing chimeric antigen receptor T-cell treatment (β, 0.19; 95% CI, 0.04-0.35) and autologous stem cell transplantation (β, 0.16; 95% CI, 0.01-0.32). CGM outperformed POC in detecting hyperglycemia (>10 mmol/L: 1060 vs 124, detected 2.8 [interquartile range, 0.7-4.0]) hours earlier. The mean absolute relative difference between CGM and POC was 21.5%, with 99.8% of measurements in the clinical acceptable zone A + B of the Clarke error grid. ConclusionThese findings emphasize the potential and importance of glucose monitoring with CGM for improved and earlier detection of hyperglycemia, in this patient population, which seems feasible. Our results suggest a need for further studies into CGM as method to optimize glucose levels, which could improve outcomes in patients receiving intensive hematologic care.

Kidney transplantation and gut microbiota.

Kidney transplantation is an effective way to improve the condition of patients with end-stage renal disease. However, maintaining long-term graft function and improving patient survival remain a key challenge after kidney transplantation. Dysbiosis of intestinal flora has been reported to be associated with complications in renal transplant recipients. The commensal microbiota plays an important role in the immunomodulation of the transplant recipient responses. However, several processes, such as the use of perioperative antibiotics and high-dose immunosuppressants in renal transplant recipients, can lead to gut dysbiosis and disrupt the interaction between the microbiota and the host immune responses, which in turn can lead to complications such as infection and rejection in organ recipients. In this review, we summarize and discuss the changes in intestinal flora and their influencing factors in patients after renal transplantation as well as the evidence related to the impact of intestinal dysbiosis on the prognosis of renal transplantation from in vivo and clinical studies, and conclude with a discussion of the use of microbial therapy in the transplant population. Hopefully, a deeper understanding of the function and composition of the microbiota in patients after renal transplantation may assist in the development of clinical strategies to restore a normal microbiota and facilitate the clinical management of grafts in the future.

Comparative study of virus and lymphocyte distribution with clinical data suggests early high dose immunosuppression as potential key factor for the therapy of patients with BoDV-1 infection

ABSTRACT Borna disease virus 1 (BoDV-1) was just recently shown to cause predominantly fatal encephalitis in humans. Despite its rarity, bornavirus encephalitis (BVE) can be considered a model disease for encephalitic infections caused by neurotropic viruses and understanding its pathomechanism is of utmost relevance. Aim of this study was to compare the extent and distribution pattern of cerebral inflammation with the clinical course of disease, and individual therapeutic procedures. For this, autoptic brain material from seven patients with fatal BVE was included in this study. Tissue was stained immunohistochemically for pan-lymphocytic marker CD45, the nucleoprotein of BoDV-1, as well as glial marker GFAP and microglial marker Iba1. Sections were digitalized and counted for CD45-positive and BoDV-1-positive cells. For GFAP and Iba1, a semiquantitative score was determined. Furthermore, detailed information about the individual clinical course and therapy were retrieved and summarized in a standardized way. Analysis of the distribution of lymphocytes shows interindividual patterns. In contrast, when looking at the BoDV-1-positive glial cells and neurons, a massive viral involvement in the brain stem was noticeable. Three of the seven patients received early high-dose steroids, which led to a significantly lower lymphocytic infiltration of the central nervous tissue and a longer survival compared to the patients who were treated with steroids later in the course of disease. This study highlights the potential importance of early high-dose immunosuppressive therapy in BVE. Our findings hint at a promising treatment option which should be corroborated in future observational or prospective therapy studies. ABBREVIATIONS: BoDV-1: Borna disease virus 1; BVE: bornavirus encephalitis; Cb: cerebellum; CNS: central nervous system; FL: frontal lobe; GFAP: glial fibrillary acid protein; Hc: hippocampus; Iba1: ionized calcium-binding adapter molecule 1; Iba1act: general activation of microglial cells; Iba1nod: formation of microglial nodules; IL: insula; Me: mesencephalon; Mo: medulla oblongata; OL: occipital lobe; pASS: per average of 10 screenshots; patearly: patients treated with early high dose steroid shot; patlate: patients treated with late or none high dose steroid shot; Po: pons; So: stria olfactoria; Str: striatum

Systemic lupus erythematosus in a 15-year-old female with multiple splenic nodules: A case report

BACKGROUND Systemic lupus erythematosus (SLE) is a chronic inflammatory disease primarily affecting young females. SLE can invade any organ, and various forms of splenic invasion have been reported. Manifestations include splenomegaly and splenic infarction, rupture, and calcification. The study encountered a rare case of splenic involvement, with nodules of various sizes without calcifications or ruptures. CASE SUMMARY A 15-year-old girl presented with arthralgia, weight loss, fever, increased levels of inflammatory markers, and positive antinuclear antibody test results. The patient was diagnosed with SLE. She was asymptomatic while taking steroids and hydroxychloroquine. Ten months after discharge, the patient developed a fever and abdominal pain. Lupus enteritis was suspected, and abdominopelvic computed tomography (AP-CT) was performed. There were no specific findings in the gastrointestinal tract, but multiple splenic nodules were observed. Infection or hemangioma was considered; however, no specific radiological findings were observed. A biopsy of the spleen was performed to determine the possibility of malignancy. The histological findings of the spleen included extensive periarteriolar necrosis with hematoxylin bodies and numerous karyorrhectic debris. Based on the biopsy results, the patient was diagnosed with an SLE flare-up and was maintained on high-dose steroids and immunosuppressants. CONCLUSION As disease activity increased, multiple nodules in the spleen that were previously unseen were observed using AP-CT and histologically confirmed. Spleen invasion by SLE can appear in multiple nodular forms and patterns. Therefore, physicians should consider these findings when differentiating these nodules from infections and malignancies.

P024 Dermatomyositis, a blurred clinical picture

Abstract Background/Aims We present a case of MDA5 dermatomyositis(DM) in a 25-year-old male, initially presenting with seronegative inflammatory polyarthritis affecting the hands. No classic features of DM were noted and CK was normal. Sulfasalazine was started and subsequently stopped after an ALT rise. Lung-function performed prior to planned methotrexate was abnormal. A CT neck, thorax and abdomen showed unusual pulmonary appearances with focal basal ground glass opacities with reverse halo, without widespread interstitial lung disease(ILD). A bronchoscopy excluded atypical infection. He then developed scaly lesions over the extensor PIPJs, periungual lesions, periorbital swelling and sicca symptoms. CK remained normal, extended myositis screening was negative. LDH and troponins were elevated. A skin biopsy of the hand rash was consistent with dermatomyositis. Methods Muscle pain persisted and an MRI proximal muscles showed muscle oedema and inflammation. A muscle biopsy was requested but not performed as he developed an olecranon bursa with staphylococcal aureus infection. The bursa broke down, required wash-outs, antibiotics and was left to heal by secondary intention. A repeat myositis screen was positive for MDA5 antibody. Immunosuppression was delayed because of concerns that prednisolone, Mycophenolate mofetil(MMF) or Rituximab would cause further wound breakdown and increased risk of infection. The patient was monitored with serial lung-function but didn’t develop ILD. Dermatology confirmed there was active dermatomyositis in the wound edges. The wound only finally healed with additional IVIG therapy. The patient is now established on Rituximab, having been unable to tolerate MMF. Results This case highlights that continued reassessment of the evolving clinical picture is vital to reach the correct diagnosis, and that one should not be reassured by a normal CK. Instead the ALT rise (along with mild elevations of LDH and troponin) was likely reflecting muscle inflammation, not liver inflammation secondary to Sulfasalazine. The repeatedly infected olecranon bursa and large open wound raised concerns about immunosuppressive agents. However, the lack of healing was due to active DM and escalation of treatment was required rather than treatment delay. IVIG was given with excellent and rapid effect. This is licensed for refractory skin involvement in DM, to be considered when infection concern is high. Conclusion The pulmonary involvement with reverse halo sign was felt by the MDT to be nonspecific initially, with a wide differential. In the clinical context, this was reflecting an atypical presentation of MDA5 positive ILD. This antibody can be associated with rapidly progressive ILD and death in approximately one third of cases. Had our patient shown evidence of significant pulmonary progression, high dose immunosuppression would have been commenced despite potential infection risk. Not all patients testing positive for MDA5 develop rapidly progressive ILD but clinical suspicion should be high with frequent serial monitoring of lung function and radiology. Disclosure L. Maltas: None. J. Vila: None. A. Ray: None.

Sustained control of recalcitrant chronic spontaneous urticaria after initiation of inflammatory airway diseases treatment: two case reports

BackgroundCurrent classification of chronic urticaria is primarily based on clinical presentation of skin manifestations. Hence, therapeutic treatment is primarily aimed locally for immediate symptom relief. We reason that limiting therapeutic strategies to the skin pathology might be inadequate since cellular activation and inflammation might be triggered remotely.Case presentationIn this series two patients had exhausted all current treatments for recalcitrant urticaria but remained symptomatic. The first case was 26-year-old Caucasian female and the second was 63-year-old African American female. Both cases had frequent breakthrough urticaria requiring frequent pulsating courses of prednisone to control urticaria despite treatment with omalizumab and antihistamines. When inflammatory airway disease was discovered and managed with inhaled corticosteroid, urticaria is controlled much faster without the need of high dose immunosuppression over several years of observation. Coincidentally, autoimmune thyroiditis and anti-immunogobulin-E immunoglobulin-G titers dropped significantly in one case with sustained inhaled corticosteroid therapy.ConclusionsWe suggest a novel approach of controlling remote epithelial site inflammation in these two cases that resulted in sustained-control of urticaria symptoms without the need for systemic corticosteroids or immunosuppressant. The changes of autoimmune antibodies might be the consequences of tolerance breaking from chronic lower airway inflammation as observed in other epithelial inflammatory condition like in celiac disease and rheumatoid arthritis.

Dexamethasone upregulates macrophage PIEZO1 via SGK1, suppressing inflammation and increasing ROS and apoptosis

The side effects of high-dose dexamethasone in anti-infection include increased ROS production and immune cell apoptosis. Dexamethasone effectively activates serum/glucocorticoid-regulated kinase 1 (SGK1), which upregulates various ion channels by activating store-operated calcium entry (SOCE), leading to Ca2+ oscillations. PIEZO1 plays a crucial role in macrophages' immune activity and function, but whether dexamethasone can regulate PIEZO1 by enhancing SOCE via SGK1 activation remains unclear. The effects of dexamethasone were assessed in a mouse model of sepsis, and primary BMDMs and the RAW264.7 were treated with overexpression plasmids, siRNAs, or specific activators or inhibitors to examine the relationships between SGK1, SOCE, and PIEZO1. The functional and phenotypic changes of mouse and macrophage models were detected. The results indicate that high-dose dexamethasone upregulated SGK1 by activating the macrophage glucocorticoid receptor, which enhanced SOCE and subsequently activated PIEZO1. Activation of PIEZO1 resulted in Ca2+ influx and cytoskeletal remodelling. The increase in intracellular Ca2+ mediated by PIEZO1 further increased the activation of SGK1 and ORAI1/STIM1, leading to intracellular Ca2+ peaks. In the context of inflammation, activation of PIEZO1 suppressed the activation of TLR4/NFκB p65 in macrophages. In RAW264.7 cells, PIEZO1 continuous activation inhibited the change in mitochondrial membrane potential, accelerated ROS accumulation, and induced autophagic damage and cell apoptosis in the late stage. CaMK2α was identified as a downstream mediator of TLR4 and PIEZO1, facilitating high-dose dexamethasone-induced macrophage immunosuppression and apoptosis. PIEZO1 is a new glucocorticoid target to regulate macrophage function and activity. This study provides a theoretical basis for the rational use of dexamethasone.

Review of the Patterns of Clinical Presentation, Histopathological Classes, and Outcomes of Lupus Nephritis Patients at a Tertiary care facility in Johannesburg, South Africa

Abstract Background: Lupus nephritis (LN) is a significant factor in the burden of secondary glomerular disease in South Africa and has a poorer prognosis in people of African descent. Early identification and treatment are required to impact patient outcomes meaningfully. Methods: A retrospective review of biopsy-proven LN diagnosed over a 10-year period was undertaken. Clinical, histopathology, and renal outcomes data were tested with logistic regression and general discriminant analysis. Survival curves of renal outcomes were also calculated. Results: Over the 10-year study period, 47 patients were identified. The majority (72.7%) of patients were of Black African ancestry with median age at diagnosis of 26.5 years. Proliferative LN lesions predominated (66%) and were associated with higher creatinine (p = 0.007). An estimated glomerular filtration rate (eGFR) below 90mL/min/1.73m2 increased the odds of proliferative LN (OR = 5.60; CI 1.06-29.59; p = 0.043). Proliferative LN was associated with a trend towards poorer renal outcomes (p = 0.057); higher baseline eGFR was associated with better-preserved kidney function at follow-up (p = 0.003). Baseline urine white cell count inversely correlated with eGFR and directly correlated with serum creatinine at follow-up (p = 0.041 and p = 0.001, respectively) Conclusion: The present study demonstrates a possible role for baseline eGFR and leukocyturia in predicting the presence of proliferative LN. Since proliferative LN is associated with poorer kidney survival, these investigations may identify patients likely to benefit from empiric high-dose immunosuppression when access to biopsy confirmation is delayed.

Bacillary Layer Detachment as a Presenting Feature of Ocular Sarcoidosis.

Bacillary layer detachment (BALAD) is a recently described finding on optical coherence tomography (OCT) that has been reported in a variety of uveitic and retinal diseases. To add to the growing literature on conditions associated with this finding, we report on the first cases of BALADs in ocular sarcoidosis. Observational, retrospective chart review of patients with BALADs as a feature of sarcoid-associated uveitis. Three patients presented with blurry vision and bacillary layer detachments on OCT who were either known to have or found to have sarcoid-associated uveitis. All three patients had resolution of the BALAD and improvement in visual acuity with a combination of high-dose oral steroids and/or systemic immunosuppression. Patients presenting with BALAD should be assessed for sarcoidosis, if appropriate, given the systemic implications of this diagnosis. [Ophthalmic Surg Lasers Imaging Retina 2023;54:686-690.].

Glomerulonefritis agudas y rápidamente progresivas, glomerulonefritis proliferativa endocapilar y glomerulonefritis proliferativa extracapilar

Acute (post-infectious) glomerulonephritis presents rapidly with hematuria (microscopic or causes), proteinuria, a decrease in glomerular filtration rate, and sodium and water retention that usually cause an increase in blood pressure and edema. In addition, various types of chronic glomerulonephritis may present as acute nephrotic syndrome and can be clinically indistinguishable from the onset of acute abnormalities. Rapidly progressive glomerulonephritis (RPGN) represents a clinical-pathological syndrome characterized by a rapid decline in renal function (weeks to months); proteinuria generally in a subnephrotic range; and the presence of fibrous, cellular crescents in the glomerular area. Its causes can be primary or secondary. Its classification depends on clinical, serological, and histological findings; they are divided into 3 types: 1, associated with anti-glomerular basement membrane antibodies; 2, associated with immune complexes; 3 pauci-immune (ANCA-associated), or 4, a combination of types 1 and 3. Diagnosis and treatment must be early. High-dose immunosuppressants and, sometimes, plasmapheresis can be used for the purpose of restoring renal function and avoiding rapid progression to advanced or end-stage chronic kidney disease. In cases with very high clinical suspicion, performing a renal biopsy must not delay starting immunosuppressive therapy.

P056 Analysis of antibody response to SARS-CoV-2 vaccination and natural infection in a tertiary centre cohort of lupus nephritis patients

Abstract Background/Aims The immune response to SARS-CoV-2 is known to be reduced in the immunocompromised. However, extent to which immunity is affected by immunosuppression in specific disease cohorts remains poorly characterised. Furthermore, implications of the ongoing vaccination booster programme require further study. Individuals with lupus nephritis (LN) require prolonged high-dose immunosuppression in order to maintain disease control, rendering them important to study in this context. We evaluated SARS-CoV-2 nucleocapsid and spike antibody response in this cohort during the Spring/Summer 2022 booster vaccine campaign. Nucleocapsid antibody indicates previous infection whilst spike antibody indicates previous infection and/or vaccination response. Titre of spike antibody to prevent infection is not known, but presence of antibodies is likely to protect against severe disease. Methods SARS-CoV-2 spike and nucleocapsid antibody were measured in adult patients with LN attending a tertiary centre rheumatology clinic. Data was collected retrospectively on disease, immunosuppression, vaccine status and history of natural exposure. Results 35 cases of LN were investigated, of which LN III, IV and V were predominant biopsy diagnoses. Regarding immunosuppressants, the Eurolupus Cyclophosphamide protocol had been used in the majority of patients to achieve initial control, with 3/35 patients still receiving pulsed courses at data collection. 18/35 were on Mycophenolate Mofetil; a further 13/35 had previously received this. 31/35 took at least 5mg Prednisolone daily; 25/35 took Hydroxychloroquine; 7/35 took Azathioprine; 7/35 had previously been on Methotrexate, 3/35 took Tacrolimus; 1/35 took Ciclosporin. Regarding B-cell depleting monoclonal antibody therapy, 13/35 had received Rituximab and 8/35 were receiving Belimumab. Antibody levels were measured between 4 weeks and 13 months after last dose of vaccination; mean duration was 6 months. 11/35 had confirmed COVID-19 infection; a further 8/35 reported a possible history. Of the 35, 32 (91%) had mounted detectable SARS-CoV-2 spike antibody above the bottom 10% of assay detection, indicating some immunity to vaccination or natural exposure. 20 (57%) had detectable nucleocapsid antibody, suggesting natural infection with antibody response. Only 2 (6%) had not mounted any antibody response. Of note, neither were fully vaccinated: one had 1 vaccination with blood test 8 months subsequent; one had 2 vaccinations with blood test 7 months subsequent. The latter was also notably on haemodialysis. All who received 3+ vaccinations had detectable spike antibody responses, as well as 75% of those who had received 2 vaccinations. Conclusion Our study is the first analysis, to our knowledge, of SARS-CoV-2 antibody response in a LN cohort. Whilst neutralising capacity and level of antibody providing protection remains under research, these findings provide at least some reassurance that individuals with LN on immunosuppression are capable of mounting an immune response against SARS-CoV-2. Further work is required to establish extent and duration of protection with serial vaccinations in this cohort. Disclosure K. Townsend: None. A. Cove-Smith: None. R. Rajakariar: None. A. Pakozdi: None. M. Lewis: None. M. Cunningham: None. D. Pyne: None.

Update on cryptogenic organizing pneumonia.

Cryptogenic organizing pneumonia (COP) is a form of idiopathic interstitial pneumonia that results from the pulmonary reaction to various unidentified injuries. Secondary organizing pneumonia is diagnosed when the triggering factor has been identified; it is mainly caused by infections, toxic substance exposure, drugs, connective tissue diseases, malignancies, autoimmune diseases, bone marrow, or organ transplantation, and radiotherapy. There has been an increase in the number of reports of drug-induced organizing pneumonia (OP). New biological therapies, interferon, monoclonal antibodies, anti-interleukin antibodies, and PD1/PDL-1 inhibitors may induce this specific pulmonary reaction. The classical form of COP is usually subacute and does not manifest as severe disease. Patients maintain sufficient respiratory function, and treatment with steroids is usually effective. Several specific forms of OP (e.g., the cicatricial variant or acute fibrinous type) have distinct clinical and histological features, require higher doses of immunosuppressive drugs, and have a worse prognosis. In the era of administering steroid-sparing therapies for the treatment of interstitial lung diseases, connective tissue dases, and other conditions, it is important to emphasize this type of therapy for patients with COP.

The Duration of Coronavirus Disease 2019 (COVID-19) Clearance in Patients with Hematological Malignancies Can be Stratified By the Number of Chemotherapy Treatment and Severity of COVID-19

Patients with hematological malignancies (HM) have an increased risk of severe coronavirus disease 2019 (COVID-19) and subsequent mortality. Moreover, patients with HM have prolonged viral shedding and long-term infectivity. However, the infectious period varies depending on the degree of immunosuppression caused by the disease itself and intensity of chemotherapy. The infectivity of the virus can be evaluated by the cycle threshold (Ct) value obtained from reverse transcription quantitative polymerase chain reaction (RT-qPCR), which is inversely proportional to the viral load. Viral cultures are less likely to be positive when Ct values exceed 30-35, which suggests that patients with Ct values above the threshold may be less infectious. Our study evaluated the trajectories of serial Ct values of patients with HM indicated for the test-based strategy and examined the relationship between patients' characteristics and the duration of viral shedding. Seventeen patients with HM that were treated for COVID-19 at our hospital from January to April 2022 were included. We excluded three patients to whom the test-based strategy was not applied. In our test-based de-isolation strategy, RT-qPCR testing using nasopharyngeal swabs was performed twice a week in patients. We de-isolated patients when their Ct values were ≥ 30 after their symptoms resolved. The patients were categorized according to the duration needed to achieve a Ct value of >30: cluster 1 (< 20 days), cluster 2 (21-40 days), and cluster 3 (>40 days). The similarities in patients' characteristics in each cluster and the differences between the clusters were examined. A total of 14 patients were analyzed, and the median age of the patients was 71 years old (range: 28-82 years old). Eight patients had non-Hodgkin lymphoma (NHL), four had acute leukemia (AL), and two had multiple myeloma (MM). Of the patients with NHL, four were treatment-naive or on first-line chemotherapy, while the other four had relapsed or refractory (r/r) NHL. Among r/r NHL patients, two received salvage chemotherapy, and the remaining two had opted for best supportive care. Three of the four patients with AL achieved complete remission (CR) after allogeneic hematopoietic stem cell transplantation (HSCT), while the other had a relapse after receiving salvage chemotherapy. One of the patients with MM achieved CR with maintenance therapy after autologous HSCT, while the other received sixth-line chemotherapy for refractory disease. The severity of COVID-19, which was defined by the National Institutes of Health guideline, was asymptomatic in two patients, mild in eight, moderate in one, severe in three, and critical in one. A total of 117 PCR tests were performed, and Ct values were available for 114 of them. The median time for Ct value to reach >30 was 23 days (range: 14-84 days). Five patients were categorized into cluster 1, six into cluster 2, and three into cluster 3. In cluster 1, patients were untreated or received less than three courses of chemotherapy within the past year and had mild or moderate COVID-19 infection. Patients in cluster 2 received three or more courses of chemotherapy or HSCT in the past year and had severe COVID-19 infection. Cluster 3 consisted of three patients who were treated with high-dose immunosuppressant for active graft-versus-host disease, had a history of long-term chemotherapy, and were critically ill from COVID-19 infection. The duration of viral shedding in patients with HM was generally prolonged and stratified by treatment history and severity of COVID-19. The number of chemotherapy treatment and severity of COVID-19 may serve as useful indicators to determine whether a test-based de-isolation strategy should be followed in patients with HM. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A RARE MANIFESTATION OF SYSTEMIC LUPUS ERYTHEMATOSUS (SLE): DIFFUSE ALVEOLAR HEMORRHAGE

A RARE MANIFESTATION OF SYSTEMIC LUPUS ERYTHEMATOSUS (SLE): DIFFUSE ALVEOLAR HEMORRHAGE

Manipulating adrenergic stress receptor signalling to enhance immunosuppression and prolong survival of vascularized composite tissue transplants.

BackgroundVascularized composite tissue allotransplantation (VCA) to replace limbs or faces damaged beyond repair is now possible. The resulting clear benefit to quality of life is a compelling reason to attempt this complex procedure. Unfortunately, the high doses of immunosuppressive drugs required to protect this type of allograft result in significant morbidity and mortality giving rise to ethical concerns about performing this surgery in patients with non‐life‐threatening conditions. Here we tested whether we could suppress anti‐graft immune activity by using a safe β2‐adrenergic receptor (AR) agonist, terbutaline, to mimic the natural immune suppression generated by nervous system‐induced signalling through AR.MethodsA heterotopic hind limb transplantation model was used with C57BL/6 (H‐2b) as recipients and BALB/c (H‐2d) mice as donors. To test the modulation of the immune response, graft survival was investigated after daily intraperitoneal injection of β2‐AR agonist with and without tacrolimus. Analyses of immune compositions and quantification of pro‐inflammatory cytokines were performed to gauge functional immunomodulation. The contributions to allograft survival of β2‐AR signalling in donor and recipient tissue were investigated with β2‐AR−/− strains.ResultsTreatment with the β2‐AR agonist delayed VCA rejection, even with a subtherapeutic dose of tacrolimus. β2‐AR agonist decreased T‐cell infiltration into the transplanted grafts and decreased memory T‐cell populations in recipient's circulation. In addition, decreased levels of inflammatory cytokines (IFN‐γ, IL‐6, TNF‐α, CXCL‐1/10 and CCL3/4/5/7) were detected following β2‐AR agonist treatment, and there was a decreased expression of ICAM‐1 and vascular cell adhesion molecule‐1 in donor stromal cells.Conclusionsβ2‐AR agonist can be used safely to mimic the natural suppression of immune responses, which occurs during adrenergic stress‐signalling and thereby can be used in combination regimens to reduce the dose needed of toxic immunosuppressive drugs such as tacrolimus. This strategy can be further evaluated for feasibility in the clinic.

Diagnostic d’une granulomatose éosinophilique avec polyangéite sous benralizumab

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare necrotizing vasculitis affecting small vessels and associated with severe asthma and eosinophilia. Monoclonal antibodies blocking the IL-5 signaling pathway, one example being benralizumab, decrease the proliferation of eosinophils and represent an effective treatment in severe eosinophilic asthma. They are a therapeutic option currently studied for EGPA. We report the paradoxical clinical case of EGPA appearing following the initiation of treatment with benralizumab (anti-IL-5R monoclonal antibody). We describe the case of a 66-year-old female patient with severe asthma. Following the initiation of benralizumab, she showed deterioration of her general condition, associated with severe peripheral neuropathy of the lower limbs. At the same time, she developed massive hypereosinophilia. After an extensive workup, the patient was eventually diagnosed with an EGPA with multisystem involvement. Benralizumab was stopped and a course of high dose corticosteroids and immunosuppressants was initiated, enabling slow clinical recovery. Anti-IL5 monoclonal antibodies, including benralizumab, are being investigated for new therapeutic indications, including EGPA. Paradoxically, a few rare cases of EGPA associated with these molecules have been reported in the literature. The causal link of this association remains hypothetical. Close monitoring of patients on benralizumab consequently seems indispensable.

Neuromyelitis optica spectrum disorders and anti-myelin oligodendrocyte glycoprotein positive optic neuropathies.

To describe the clinical characteristics and treatments associated with antibody positive optic neuropathies including anti-myelin oligodendrocyte glycoprotein (MOG) and anti-aquaporin 4 (AQP4), alongside diagnostic modalities, investigations, and outcomes. A cross-sectional single-centre retrospective case series consisting of 16 patients including 12 anti-MOG positive patients and 4 anti-AQP4 positive patients. Each of these patients had clinical signs and symptoms of optic neuritis and consisted of all patients who had a positive blood antibody result in our centre. Clinical findings including presence of a relative afferent pupillary defect, colour vision and disc assessment were recorded. Structured clinical exam and multimodal imaging was undertaken sequentially on each. Optical coherence tomography (OCT) scanning was preformed to examine the correlation between ganglion cell layer (GCL) thickness and visual acuity (VA) at presentation and as a determinant of final visual outcome in both groups. Initial and long-term treatment is also summarised. A total of 16 patients were included in the study consisting of 12 anti-MOG and 4 anti-AQP4 positive patients. Nine of the 16 patients were female and the average age of onset was 29.2y in the MOG group and 42y in the AQP4 group. There was no statistically significant correlation (Pearson correlation) between GCL thickness and presenting and final VA [r(10)=0.081, P=0.08 and r(10)=0.089, P=0.34 respectively]. The same statistical analysis was performed for the correlation between retinal nerve fibre layer (RNFL) and VA and similar outcomes were observed [r(10)=0.04, P=0.22 and r(10)=0.09, P=0.04]. No correlation was seen for initial RNFL thickness and final visual outcome in this group either [r(2)=0.19, P=0.38]. Visual field testing and radiological findings for each group are described. No correlation between initial VA or RNFL and final visual outcome is identified. A broad range of visual field and radiographic findings are identified, a consensus on treatment of neuromyelitis optica spectrum disorders and anti-MOG positive optic neuropathies has yet to be accepted but initial high dose immunosuppression followed by low dose maintenance therapy is favoured.

Post-transplant Diabetes Mellitus: What Physicians Need to Know.

Post-transplant diabetes mellitus (PTDM) is a common problem among solid organ transplant recipients contributing to morbidity and affecting patient as well as graft survival adversely. It can occur at any period following transplantation, but maximum incidence is observed in the first few months, with a second peak after a few years after transplantation. The pathogenesis is complex and poorly understood, however, it is associated with both dysfunctional beta-cells and insulin resistance. Both nonpharmacologic and antidiabetic therapies are important for adequate glycemic control. This point of view article provides a short review on PTDM in solid organ transplantation (SOT) recipients from a general physician's perspective.

The Role of Myeloid Cells in Hepatotoxicity Related to Cancer Immunotherapy.

Simple SummaryImmune-modulating cancer treatments have proved to be highly effective in a wide range of tumour types. They interrupt the usual communication between cells in the immune system, encouraging them to become more active in identifying and destroying cancer cells. Although these therapies are very successful in treating cancer, patients frequently experience liver injury as a side effect related to over activation of the immune system. If cancer patients develop this side effect, they need to stop their cancer therapy and be given strong immunosuppressants. Researchers are now working on understanding the mechanisms involved in the development of liver inflammation. In this review we will summarise findings identifying classes of immune cells that are of particular importance in this context and highlight ways in which we can use this knowledge to improve the safety of these new cancer drugs.Drug-related hepatotoxicity is an emerging clinical challenge with the widening use of immunotherapeutic agents in the field of oncology. This is an important complication to consider as more immune oncological targets are being identified to show promising results in clinical trials. The application of these therapeutics may be complicated by the development of immune-related adverse events (irAEs), a serious limitation often requiring high-dose immunosuppression and discontinuation of cancer therapy. Hepatoxicity presents one of the most frequently encountered irAEs and a better understanding of the underlying mechanism is crucial for the development of alternative therapeutic interventions. As a novel drug side effect, the immunopathogenesis of the condition is not completely understood. In the liver, myeloid cells play a central role in the maintenance of homeostasis and promotion of inflammation. Recent research has identified myeloid cells to be associated with hepatic adverse events of various immune modulatory monoclonal antibodies. In this review article, we provide an overview of the role of myeloid cells in the immune pathogenesis during hepatoxicity related to cancer immunotherapies and highlight potential treatment options.