Start Of Immunosuppression Research Articles

Corticosteroids and other immunosuppressants for immune-related adverse events and checkpoint inhibitor effectiveness in melanoma

BackgroundRecent studies indicate an association between immunosuppression for immune-related adverse events (irAEs) and impaired survival in patients who received immune checkpoint inhibitors. Whether this is related to corticosteroids or second-line immunosuppressants is unknown. In the largest cohort thus far, we assessed the association of immunosuppressant type and dose with survival in melanoma patients with irAEs. MethodsPatients with advanced melanoma who received immunosuppressants for irAEs induced by first-line anti-PD-1 ± anti-CTLA-4 were included from 18 hospitals worldwide. Associations of cumulative and peak dose corticosteroids and use of second-line immunosuppression with survival from start of immunosuppression were assessed using multivariable Cox proportional hazard regression. ResultsAmong 606 patients, 404 had anti-PD-1 + anti-CTLA-4-related irAEs and 202 had anti-PD-1-related irAEs. 425 patients (70 %) received corticosteroids only; 181 patients (30 %) additionally received second-line immunosuppressants. Median PFS and OS from starting immunosuppression were 4.5 (95 %CI 3.4–8.1) and 31 (95 %CI 15-not reached) months in patients who received second-line immunosuppressants, and 11 (95 %CI 9.4–14) and 55 (95 %CI 41–not reached) months in patients who did not. High corticosteroid peak dose was associated with worse PFS and OS (HRadj 1.14; 95 %CI 1.01–1.29; HRadj 1.29; 95 %CI 1.12–1.49 for 80vs40mg), while cumulative dose was not. Second-line immunosuppression was associated with worse PFS (HRadj 1.32; 95 %CI 1.02–1.72) and OS (HRadj 1.34; 95 %CI 0.99–1.82) compared with corticosteroids alone. ConclusionsHigh corticosteroid peak dose and second-line immunosuppressants to treat irAEs are both associated with impaired survival. While immunosuppression is indispensable for treatment of severe irAEs, clinicians should weigh possible detrimental effects on survival against potential disadvantages of undertreatment.

#3999 PROTEINURIA AND PROGRESSION OF IGA NEPHROPATHY. HAVE WE REACHED THE POINT OF NO RETURN?

Abstract Background and Aims IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide, associated with an incidence of 2.5/100.000 cases per year and progression to end-stage kidney disease (ESKD) in 20% patients within 10 years. Proteinuria has been identified as the greatest risk factor for ESKD in IgAN. The aim was to evaluate the correlation between proteinuria and major adverse renal events (MARE). We define MARE as 40% decline in glomerular filtration rate (eGFR), initiation of kidney replacement therapy (either dialysis or kidney transplantation) or death whether from renal cause or cardiovascular-related. Method In this retrospective observational single-center study, we included all biopsy-proven IgAN patients older than 18 years with proteinuria >500 mg/24h, diagnosed between 2006-2017 and followed up to January 2022. Clinical, analytical, and histological findings were collected at time of diagnosis and during follow-up. Uni and multivariable Cox regression were performed to establish correlation between our data and the main event. A linear mixed-effects model was used to estimate eGFR slope. Results A total of 124 patients were included. Mean age and eGFR were 40 ±15 years and 59 ml/min (IQR: 33-94 ml/min) respectively, with a median proteinuria of 1.44 g/24h (IQR 0.7-2.3). 64% of patients were treated with corticosteroids. In the multivariate analysis, we found that IFTA >25% had a statistically significant risk of MARE (IFTA T1 HR 3.1; 95% CI 1.52-6.6; p = 0.002; IFTA T2 HR 6.6; 95% CI 1.46-16.12; p<0.001), history of cardiovascular disease presented 3.7 times higher risk of MARE (HR 3.7; 95% CI 1.46-9.6 p = 0.015). Patients with proteinuria >3 g/24h showed significantly higher hazard ratio (HR 2.36 95%CI 1.16-4.8 p = 0.01) for MARE. In the 3-year linear mixed-effects model, patients with proteinuria above 3 g/24h had an annual eGFR slope of -6.3 ml/min (-9.6 to -3.1 95%CI). Nevertheless, proteinuria between 1.5 to 3 g/24h had an annual eGFR slope of -2.1 ml/min (-4.9 to 0.62 95% CI), finding no statistical difference in comparison to patients with proteinuria <1.5 g/24h. Conclusion Typically, the threshold of proteinuria >1 g/24h has been marked as the start of immunosuppression in this nephropathy. Several studies published in recent years (as example STOP IgAN) question this paradigm. According to our data, there is a strong association between proteinuria >3 g/24h and major adverse renal events. Patients with proteinuria between 1.5 to 3 g/24h had a similar behaviour as our reference group (proteinuria <1.5 g/24h). These results might provide new evidence supporting a more conservative approach and start receiving glucocorticoids if proteinuria is > 3 g/24h.

New risk model is able to identify patients with a low risk of progression in systemic sclerosis

ObjectivesTo develop a prediction model to guide annual assessment of systemic sclerosis (SSc) patients tailored in accordance to disease activity.MethodsA machine learning approach was used to develop a model that...

Reduction in proteinuria after immunosuppressive therapy and long-term kidney outcomes in patients with immunoglobulin A nephropathy.

Background/AimsDespite controversy regarding the benefits of immunosuppressive therapy in immunoglobulin A nephropathy (IgAN), clinical outcomes may vary depending on the patient’s responsiveness to this therapy. This study evaluated long-term kidney outcomes according to the extent of proteinuria reduction after immunosuppression in IgAN patients.MethodsAmong 927 patients with biopsy-proven IgAN, 127 patients underwent immunosuppression. Time-averaged urine protein-creatinine ratio before and within 1 year after start of immunosuppression were calculated, and responsiveness to immunosuppression was assessed as the reduction of proteinuria between the two periods. Patients were classified into tertiles according to the extent of proteinuria reduction. We compared the slopes of estimated glomerular filtration rate (eGFR) decline using a linear mixed model, and estimated hazard ratios (HRs) for disease progression (defined as development of a ≥ 30% decline in eGFR or end-stage renal disease) using a Cox proportional hazard model.ResultsMedian extent of proteinuria reduction was −2.1, −0.9, and −0.2 g/gCr in the first, second, and third tertiles, respectively. There were concomitant changes in the slopes of annual eGFR decline: −2.03, −2.44, and −4.62 mL/min/1.73 m2 among the first, second, and third tertiles, respectively. In multivariable Cox analysis, the HRs (95% confidence intervals) for disease progression were 0.30 (0.12 to 0.74) in the first tertile and 0.70 (0.34 to 1.45) in the second tertile compared with the thirdtertile.ConclusionsThis study showed that greater proteinuria reduction after immunosuppression was associated with a lower risk of disease progression in patients with IgAN, suggesting that responsiveness to immunosuppression may be an important determinant of kidney outcomes.

Transient elastography in autoimmune hepatitis: Timing determines the impact of inflammation and fibrosis

There is an unmet need for the non-invasive monitoring of fibrosis progression in patients with autoimmune hepatitis (AIH). The aim of this study was to assess the diagnostic performance of transient elastography in patients with AIH and to investigate the impact of disease activity on its diagnostic accuracy. Optimal cut-offs were defined in a prospective pilot study (n=34) and the diagnostic performance of transient elastography validated in an independent second cohort (n=60). To explore the impact of disease activity on liver stiffness, patients were stratified according to biochemical response and the time interval between start of immunosuppression and transient elastography. Liver stiffness strongly correlated with histological fibrosis stage (pilot study: ρ=0.611, p<0.001; validation cohort: ρ=0.777, p<0.0001). ROC curves defined an area under the receiver operating curve of 0.95 for diagnosing cirrhosis at the optimal cut-off of 16kPa. The performance of transient elastography was impaired when patients were analysed in whom transient elastography was performed within 3months from start of treatment. In this setting, liver stiffness correlated with histological grading (ρ=0.558, p=0.001), but not with staging. In contrast, using the cut-off of 16kPa, the accuracy for diagnosing cirrhosis was excellent in patients treated for 6months or longer (area under the receiver operating curve 1.0). Liver inflammation has a major impact on liver stiffness in the first months of AIH treatment. However, transient elastography has an excellent diagnostic accuracy for separating severe from non-severe fibrosis after 6months of immunosuppressive treatment. Transient elastography is a special ultrasound scan, which assesses liver stiffness as a surrogate marker for liver fibrosis/scarring. Transient elastography has been shown to be a reliable non-invasive method to assess liver fibrosis in various chronic liver diseases, it takes less than 5min and has a high patient acceptance. The current study validated for the first time this technique in a large cohort of patients with autoimmune hepatitis (AIH) and demonstrates that it is a reliable tool to detect liver fibrosis in treated AIH. For the monitoring of potential disease progression under treatment, the validation of liver stiffness as non-invasive marker of liver fibrosis will greatly improve patient care in autoimmune hepatitis.

Diagnosis and management of acquired coagulation inhibitors: a guideline from UKHCDO

A United Kingdom Haemophilia Centre Doctors’ Organization (UKHCDO) guideline approved by the British Committee for Standards in Haematology Peter W Collins, Elizabeth Chalmers, Daniel Hart, Ian Jennings, Ri Liesner, Savita Rangarajan, Kate Talks, Michael Williams and Charles R. M. Hay School of Medicine, Cardiff University, University Hospital of Wales, Cardiff, Royal Hospital for Sick Children, Glasgow, Royal London Hospital, Barts and The London School of Medicine and Dentistry, Queen Mary University London, London, UK NEQAS Blood Coagulation, Sheffield, Great Ormond Street NHS Trust, London, Hampshire Hospital NHS Foundation Trust, Basingstoke & North Hampshire Hospital, Basingstoke, Newcastle upon Tyne Hospital NHS Foundation Trust, Newcastle, Birmingham Children’s Hospital NHS Foundation Trust, Birmingham, and Manchester University Dept of Haematology, Manchester Royal Infirmary, Manchester, UK

Immunosuppression and Prophylactic Antiviral Therapy in a Patient with Crohnʼs Disease Flare and Hepatitis B Infection

Crohn's disease patients with co-morbid Hepatitis B infection present a challenging therapeutic dilemma during IBD exacerbations because immunosuppressive therapies such as prednisone and biologics may cause a flare of their hepatitis. Several studies have previously shown that using antiviral prophylaxis with drugs such as tenofovir, entecavir, or adefovir in patients with Crohn's and Hepatitis B is frequently efficacious in preventing Hepatitis B viral load escalations during immunosuppression periods. Resistance patterns have suggested that tenofovir and entecavir may serve as superior antiviral prophylaxis medications. Studies have also shown that prophylaxis with antiviral medications should be started early (either at the start of immunosuppression or prior to immunosuppression) rather than waiting for hepatitis B reactivation to occur. A 40-year-old African American female with a past medical history of Crohn's disease presented to our gastroenterology clinic after being lost to follow-up for many years. She was first diagnosed with Crohn's disease in 1991; the extent of her disease was unknown at this time but she had been taking mesalamine 800 mg three times daily for years. Upon presentation, she complained of diffuse abdominal pain and 5-6 watery bowel movements per day for the past several weeks. She was afebrile with a normal heart rate and blood pressure. Her abdomen was diffusely tender to palpation throughout, with voluntary guarding and no rebound tenderness. She was transferred to the emergency department and admitted to the internal medicine service. Labs were significant for an elevated C-reactive protein of 14.39 mg/dL (normal range <0.9 mg/dL), normal white blood cell count and hemoglobin of 11.7 mg/dL. A Hepatitis panel revealed positive Hepatitis B surface antigen, negative Hepatitis B E antigen, plus a HBV DNA qualitative PCR 2542 IU/mL (log 3.4). A flexible sigmoidoscopy revealed diffuse inflammation, pseudopolyps and a narrowed stricture at 20 cm that was able to be traversed (see images). Biopsies were consistent with Crohn's disease. The patient was started on both intravenous steroids as well as tenofovir for her Hepatitis B infection. The patient is currently being treated on a steroid taper without hepatitis viral load flare, liver enzyme elevations, or abdominal symptoms. The surgery team was consulted early on to discuss possible need for surgical intervention and the potential role of biologics to prevent future structuring disease. The patient has achieved dramatic symptomatic improvement on tenofovir and prednisone with resolution of her loose bowel movements and debilitating abdominal pain. Through the use of tenofovir prophylaxis, we were able to prevent worsening of her Hepatitis B infection and alleviate her family and primary internal medicine team's concern that steroid immunosuppression therapy may fuel a Hepatitis B fire storm in her liver leading to hepatic complications. This case report supports the limited literature that prophylactic antiviral therapy can control Hepatitis B viral flares in patients being treated with steroids for a Crohn's Disease flare. Our plan based on the literature review is to continue tenofovir therapy with any future biologic or immunosuppressive treatment regimens.

Efficacy of liposomal amphotericin B for prophylaxis of acute or reactivation models of invasive pulmonary aspergillosis

The efficacy of antifungal prophylaxis for prevention of invasive aspergillosis (IA) may depend on whether IA results from recent inhalation of spores or reactivation of latent colonisation. Compare the efficacy of liposomal amphotericin B (LAmB) for prophylaxis in acute and reactivation models of IA. In the acute model, mice immunosuppressed from day 0 were challenged at day 3 with an aerosol of Aspergillus fumigatus. LAmB (15 mg kg(-1) ) was administered at day 0 or at challenge. In the reactivation model, naïve mice exposed to A. fumigatus remained untreated until clearance of spores from the lungs, then immunosuppressed to induce reactivation. A single LAmB dose was administered at start of immunosuppression. In the acute model, a single administration of LAmB at start of immunosuppression was not effective, but an additional administration resulted in a significant decrease in lung fungal burden (P < 0.05 vs. controls). A significant prophylactic efficacy was observed when LAmB was administered once at challenge (P < 0.01). In the reactivation model, a single LAmB administration at start of immunosuppression significantly reduced both reactivation rate and fungal burden vs. controls (P < 0.01). Our results show that the conditions under which IA develop and timing of administration of LAmB were determinant variables for prophylactic efficacy.

Malignant solid neoplasms in a population of immunosuppressed patients.

e12021 Background: Immunosuppression, whether caused by chronic use of immunosuppressive agents in solid organ transplant or by infection with human immunodeficiency virus (HIV), increases the risk of developing malignancies compared with the general population. This study aims to describe the profile of solid malignancies in immunosuppressed patients followed at the oncology clinic of the Federal University of São Paulo. Methods: Data were collected directly from the medical records of immunosuppressed patients followed in the Department of Clinical Oncology HSP / UNIFESP from January 2001 to January 2011 regarding sex, age, date of cancer diagnosis, tumor histology, primary site, time from beginning of immunosuppression, etiology of immunosuppression and survival,. Results: There were 46 patients (71.7% men). Median age was 47.1 years, 61% kidney transplant recipients and 39% HIV positive. The average time from the start of immunosuppression to the diagnosis of malignancy was 3.75 years in renal transplant recipients and 2.8 years in HIV positive patients. The most prevalent solid tumor in kidney transplant recipients was Kaposi's sarcoma (39.3%) followed by tumors of the gastrointestinal (GI) tract (21.4%) and genitourinary (GU) tract (14.2%). Kaposi's sarcoma was also the most prevalent cancer in HIV positive patients (44.4%) followed by head and neck (H&amp;N) (22.2%) and GU tumors (11.1%). More than 50% of patients are alive and in follow-up. Conclusions: Kaposi's sarcoma, GI, GU and H&amp;N tumors were the most prevalent solid neoplasms in immunosuppressed patients, in both organ transplanted and HIV patients.

Evaluation of Mucous Membrane Pemphigoid with Ocular Involvement in Young Patients

Mucous membrane pemphigoid with ocular involvement (MMPO) is a sight-threatening autoimmune disease that may lead to severe conjunctival cicatrization and keratopathy. The peak age of onset is in the seventh decade, although the disease may also occur in younger patients (< 60 years). This study was designed to evaluate the clinical features of young patients with MMPO and to assess the clinical outcome when compared with patients in the > 70 age group. Retrospective, comparative, interventional case series. Eighteen patients under the age of 60 years and 18 patients above the age of 70. Patients with documented MMPO were identified from the External Diseases Immunosuppression Database. Stage of disease (Foster, Mondino), visual acuity, and ocular complications (lid, conjunctival, corneal) were evaluated at presentation, the time when immunosuppression was commenced, and final follow-up. Disease progression, control of ocular inflammation with systemic immunosuppression, the incidence of mucocutaneous lesions, and surgical intervention were also assessed. Patients in the 2 groups (young and classic age groups) were observed for 61 (range, 29-218) and 69 (range, 12-193) months, respectively (P = 0.94). Median ages at the start of immunosuppression were 48.7 (range, 29-60) and 77.6 (range, 71-85) years. Mucocutaneous involvement was more common in the young than in the classic age group (13 [72%], 7 [39%]; P < 0.05). Ocular staging (Mondino, Foster) at presentation, the start of immunosuppression, and final follow-up was more advanced in the younger patients. There was no statistical difference in visual acuity, individual ocular complications, or incidence of surgical intervention between the 2 groups throughout the course of the study. Younger patients with MMPO present with more severe ocular and systemic disease and, despite immunosuppression, progress more rapidly.

Disseminated porokeratosis in immunosuppressed patients.

A number of case reports and small series of disseminated porokeratosis have been reported in immunosuppressed patients [4-6], leading to the opinion that immunosuppression can cause porokeratosis. In a recent large series [7] 24 cases of disseminated porokeratosis in patients given immunosuppressive agents were reported; of these 13 patients had received a renal transplant. There were no apparent differences between patients given azathioprine or cyclosporin. The mean interval between the start of immunosuppression and the onset of skin disease was around 30 months. No clear-cut correlation with sunlight exposure was seen. Age, sex, area of skin involvement and dermatological appearance were similar in immunosuppressed patients and in a control group of patients with idiopathic porokeratosis, but in more than half of immunosuppressed patients there were concomitant warts and there was an actinic keratosis in about one-fourth of cases. The mechanisms by which immunosuppressive therapy may induce disseminated porokeratosis are still unclear. Immunosuppression might trigger the expression of a mutant clone of epidermal cells, either directly or by disrupting the growth dynamics of the epidermis, or by impairing the immune surveillance. A genetic predisposition is likely. While sun exposure plays an important pathogenetic role in idiopathic cases, it does not seem to be essential for the development of porokeratosis in immunosuppressed patients. Theoretically, the chronic growth activation of keratinocytes may expose patients with porokeratosis to an increased carcinogenetic risk. However no evidence of malignancy was seen either in a histological review of 61 patients with disseminated porokeratosis [8] or in our series of 24 patients who received immunosuppressive treatment [7]. Nonetheless, in view of the increased risk for skin malignancy caused by immunosuppression, a careful clinical surveillance of immunosuppressed patients with disseminated porokeratosis is advisable.

Experimental activation of cryptosporidiosis in mice by immunosuppression

Cryptosporidium, a coccidian parasite first described by Tyzzer (1907) from a laboratory mouse, has become an important human enteric pathogen causing overwhelming diarrhea especially in immunocompromised patients such as AIDS. This parasite has been reported from over 20 countries and is recognized as a cosmopolitan species. In Korea, however, there has been no report on human as well as animal cryptosporidiosis. This study was performed so as to verify the presence of Cryptosporidium in Korea by activating the parasite from laboratory mice by immunosuppression. Total 65 conventionally-bred ICR mice including a control (5 mice) and 3 experimental groups (20 each) were used for this study. Group I was immunosuppressed with prednisolone injection (1 mg IM, every other day) for 7 weeks. Group II (prednisolone injection and tetracycline administration) and Group III (prednisolone injection and trimethoprim-sulfamethoxazole administration) were prepared to observe the effect of antibacterial agents on the activation of cryptosporidiosis. In fecal examinations of mice Cryptosporidium oocysts (4-6 microns in size) were detected from 1 week after the start of immunosuppression and the mice began to die. In H-E stained tissue sections of the lower jejunum, numerous very small (2-4 microns), dense, ovoid or spherical, slightly basophilic bodies were seen attached on the free border of mucosal epithelial cells. In scanning and transmission electron microscopic observations, these organisms were identified as various developmental stages of Cryptosporidium. The species is considered to be C. parvum.(ABSTRACT TRUNCATED AT 250 WORDS)

Factors Associated with Early Remission of Type I Diabetes in Children Treated with Cyclosporine

To improve criteria for entry into future trials of immunosuppression, we enrolled 40 children with recent-onset Type I insulin-dependent diabetes in a pilot trial of cyclosporine. Twenty-seven patients were able to discontinue insulin therapy 48 +/- 5 days after the start of immunosuppression. At four months, their fasting and postprandial blood glucose concentrations averaged 110 and 160 mg per deciliter (6.1 and 8.9 mmol per liter) with a mean hemoglobin A1c level of 6.15 percent. Seventy-five percent of these patients with early remission still did not need insulin at 12 months, and their glycemic control was similar to that at 4 months. The major differences between the 27 patients with remission and the 13 without remission were the duration of symptoms before diagnosis (26.8 vs. 48.0 days, P less than 0.01), the degree of weight loss (3.2 vs. 10 percent of body weight, P less than 0.001), the initial hemoglobin A1c level (10.7 vs. 13.2 percent, P less than 0.001), and the frequency of ketoacidosis (11 vs. 61.5 percent, P less than 0.001). The lesser degree of weight loss was the strongest independent predictor of remission. The response of C-peptide to intravenous glucagon (0.50 vs. 0.17 pmol per milliliter, P less than 0.05) was also an independent predictor. No differences were observed between the two groups of patients in age, sex, HLA phenotype, autoantibodies to insulin or islet-cell antigens, or doses or trough levels of cyclosporine. Only minimal manifestations of toxicity were detected over the period of observation. We conclude that early treatment with cyclosporine in children with recent-onset Type I diabetes can induce remission from insulin dependence, with half the patients not requiring insulin after a full year.