Duration Of Immunosuppressive Therapy Research Articles

Obinutuzumab treatment for membranous nephropathy: effectiveness and safety concerns during the COVID-19 pandemic.

Obinutuzumab is a humanized and glycoengineered anti-CD20 monoclonal antibody that has been shown to induce more profound B-cell depletion than rituximab. The effectiveness and safety of obinutuzumab in the treatment of membranous nephropathy remain unclear. This was a retrospective study conducted in Huashan Hospital, Fudan University between 1 December 2021 and 30 November 2023. Patients with membranous nephropathy were included to assess the effectiveness and safety of obinutuzumab and prevalence of severe pneumonia during the outbreak of COVID-19 in China. Eighteen patients were included in the study assessing the effectiveness of obinutuzumab. After a 12-month follow-up, 14 patients (78%) achieved remission, with six (33%) achieving complete remission and eight (44%) achieving partial remission. Among the 18 obinutuzumab-treated patients contracting COVID-19 for the first time, six (33%) developed severe pneumonia, and one died. By contrast, two of the 37 patients receiving glucocorticoids combined with cyclophosphamide, and none of the 44 patients on calcineurin inhibitors or the 46 patients on rituximab developed severe pneumonia. However, compared to patients receiving rituximab or glucocorticoids plus cyclophosphamide, the obinutuzumab-treated patients had a longer duration of membranous nephropathy and immunosuppressive therapy. Therefore, cardinal matching was employed to balance these baseline characteristics. Owing to small sample size for each regimen, patients receiving all the three non-obinutuzumab immunosuppressive regimens were grouped as a control cohort. After matching for age, gender, remission status, duration of membranous nephropathy, duration of immunosuppressive therapy, and ongoing immunosuppression, the obinutuzumab-treated patients still had a significantly higher incidence of severe pneumonia compared to those on other regimens (P=.019). Obinutuzumab was an effective treatment option for patients with membranous nephropathy. On the other hand, it was associated with a higher incidence of severe pneumonia following COVID-19 infection compared to other immunosuppressive regimens.

Evaluation of the clinical manifestations of COVID-19 in patients with aplastic anemia undergoing immunosuppressive therapy: a prospective cohort study (NICHE)

Objective: To investigate the clinical features of coronavirus disease 2019 (COVID-19) in patients with aplastic anemia (AA) undergoing immunosuppressive therapy (IST) . Methods: In this prospective cohort study, we collected the demographic and clinical data of patients with AA and COVID-19 from December 1, 2022, to January 31, 2023. We described the clinical features of COVID-19 among patients with AA and evaluated the effects of IST on the signs and severity of COVID-19. Results: A total of 170 patients with AA and COVID-19 were included. The common early symptoms, including fever, dizziness or headache, muscle or body aches, and sore throat, disappeared within 1-2 weeks. Approximately 25% of the patients had persistent fatigue within 2 weeks. Many patients experienced cough after an initial 1-3 days of infection, which lasted for more than 2 weeks. There were no differences in the duration of total fever episodes and maximum body temperature when patients were stratified according to whether or not they underwent IST, by IST duration, or by use of anti-lymphocyte globulin (ALG) (P>0.05). No differences were observed in the occurrence of symptoms in either the early or recovery stages when patients with AA were stratified according to whether or not they underwent IST, or by IST duration (P>0.05). However, patients who received ALG had fewer fever episodes within 1 week after infection (P=0.035) and more sore throat episodes within 2 weeks after infection (P=0.015). There were no other significant differences in clinical symptoms between patients who did and patients who did not receive ALG (P>0.05) . Conclusion: The majority of patients with AA and COVID-19 recovered within 2 weeks of noticing symptoms when treated with IST.

#4732 GLUCOCORTICOID-RELATED ADVERSE EFFECTS IN THE TREATMENT OF ANCA-ASSOCIATED VASCULITIS

Abstract Background and Aims Upcoming glucocorticoid (GC)-sparing treatment strategies like avacopan could potentially diminish or replace the need of GC therapy for ANCA-associated-vasculitis (AAV) in the future. Therefore, a proper assessment of GC-related morbidity in AAV is required to provide further justification of such therapies. The aim of this study was therefore to assess the incidence of common toxicities and to further investigate the effect of GC-treatment on the incidence and management of diabetes mellitus, arterial hypertension and hypercholesterolemia. Method In this single-centre-cohort-study we screened medical records for patients with a diagnosis of AAV admitted to the Robert-Bosch-hospital (RBK) in Stuttgart, Germany on a regular basis. We assessed the dosage and duration of immunosuppressive therapy used to treat AAV, as well as the incidence and therapies of arterial hypertension, diabetes mellitus and hypercholesterolemia. For this study, we observed the vasculitis time course during the acute phase (180 days) after either the initial diagnosis or relapse for each patient. Results We included 74 patients admitted to the RBK since 2004 up to the current date. Most common subtype of AAV was GPA (n = 48 patients), followed by MPA (n = 22) and EGPA (n = 4). Including relapses, a total of 127 events were observed. We followed patients for a mean time of 8 years (SD 3.9, 0.9 - 18.0 years). Mean duration of glucocorticoid therapy in total was 4.2 years (SD 3.6, 0.3-14.7 years). All of the patients received prednisolone, whereas 73% of the patients furthermore were administered methylprednisolone for induction therapy. Overall, 34% of the patients were diagnosed with diabetes before or after the diagnosis of AAV (14% pre-existing diabetes, 20% new-onset diabetes). Daily and accumulated GC-dose did not differ between patients with or without diabetes. However, there was a significant higher accumulated GC dose in patients requiring insulin-therapy for diabetes management in comparison to those with oral antidiabetics (p-value = 0.0214). 89% of the patients were treated with antihypertensive therapy (38% pre-exisiting hypertension, 51% new-onset hypertension). We found that the accumulated dose of prednisolone within the first 180 days after a vasculitis event was not significantly higher for patients with documented hypertension. However, we detected that the mean accumulated GC dose after a vasculitis event was significantly higher for the subgroup of patients in whom an escalation of antihypertensive therapy was initiated in comparison to the patients whose therapy was stable or even deescalated (p-value = 0.0001). With regard to hypercholesterolaemia, there was no statistical difference in the accumulated GC-dose during the acute course between patients requiring statin-therapy and those who did not. Conclusion GC related toxicities are common in patients with AAV. This study provides additional evidence about the incidence of treatment related harms in AAV to further promote importance of alternative reduced dose or even GC free treatment approaches. This may be relevant in detecting risk groups for whom upcoming GC-sparing treatment strategies such as avacopan are essential to reduce treatment-related harm.

Day 4 collection of granulocyte colony-stimulating factor-mobilized HLA-matched sibling donor peripheral blood allografts demonstrates no long-term increase in chronic graft-versus-host disease or relapse rates

Background aimsIn a previous pilot study of HLA-matched sibling donor hematopoietic cell transplantation (HCT), the authors determined the feasibility of day 4 versus day 5 granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood stem cell (PBSC) collection compared with a historical cohort. Given identified differences in the PBSC product (day 4 cohort with significantly lower infused total nucleated, mononuclear and CD3 cells compared with other collection cohorts), the authors performed a follow-up study to determine long-term post-HCT outcomes, including detailed characterization of chronic graft-versus-host disease (GVHD). MethodsThis was a prospective observational study, and the authors collected data on chronic GVHD, staging, sites of involvement and treatments. Performance status, incidence of relapse, overall survival and duration of immunosuppressive therapy (IST) were also evaluated. Data were examined retrospectively. To account for differences in length of follow-up among cohorts, the authors also determined performance status and chronic GVHD staging, sites and treatment at 2 years post-HCT. ResultsAt 2 years post-HCT, the overall survival rate was 71.7% in the day 4 cohort compared with 61.5%, 52% and 56% in the day 5, 2-day and historical cohorts, respectively (P = 0.283). The cumulative incidence of chronic GVHD was 65.2% in the day 4 cohort versus 46.4% in the day 5 cohort, 51.1% in the 2-day cohort and 65% in the historical cohort (P = 0.26). There was no significant difference in the maximum overall stage of chronic GVHD (P = 0.513), median number of sites involved (P = 0.401) or cumulative incidence of discontinuation of IST (P = 0.32). Death from chronic GVHD was less common in the day 4 and day 5 cohorts compared with the 2-day and historical cohorts, though this did not reach statistical significance. ConclusionsThe authors’ preliminary results demonstrated that collection of allogeneic matched sibling donor PBSCs on day 4 of G-CSF was feasible, reduced donor exposure to growth factor and was associated with an initial cost savings. Importantly, the authors now demonstrate that transplantation of day 4 mobilized PBSCs is not associated with any adverse outcomes post-HCT, including late effects such as chronic GVHD. Further investigation of donor G-CSF collection algorithms is merited in other HCT settings, including unrelated and mismatched related donors.

Predictors and outcomes of flares in chronic graft-versus-host disease.

Chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic cell transplantation (HCT) requires prolonged immunosuppressive therapy (IST), often requiring slow tapering with patients experiencing cGVHD flares and treatment failure. In 145 adult recipients developing cGVHD after matched sibling or umbilical cord blood donor HCT from 2010 to 2018, 2-year cumulative incidence of flares after cGVHD diagnosis was estimated at 60% (95% CI, 51-70%), with median time-to-first flare of 188 days (range, 16-751). Of 88 patients experiencing a flare, 32 (36%) had multiple flares (range, 2-4). First flare treatment consisted of an increase in prednisone dose in 77 patients (88%), plus topical therapy in 8 (9%) or another systemic IST in 43 patients (49%). Higher flare risk was associated with quiescent type of cGVHD at onset (HR 1.8; 95% CI: 1.1-2.7; p = 0.04). Patients without a flare required a shorter duration of IST and were more likely to achieve a durable discontinuation of systemic IST (86% vs. 31% for ≥6 consecutive months). Flares were associated with protective effect on relapse (HR 0.2, 95% CI: 0.1-0.3), however not with worsened 2-year NRM or OS. Flares of cGVHD identify a group needing better approaches to limit the duration of IST and thus the morbidity of cGVHD.

The scope of treatment of pediatric IgA vasculitis nephritis and its outcome: a Pediatric Nephrology Research Consortium study.

IgA vasculitis (IgAV) is the most common type of vasculitis in children. There is a lack of consensus for management of significant IgAV nephritis (IgAVN). This study was designed to identify the most used treatment options and describe their efficacy. This is a multicenter retrospective study of children age 1-21years with IgAVN who were managed for at least 6months by a nephrologist. Subjects with at least microscopic hematuria and proteinuria and/or decreased kidney function were enrolled. Kidney outcome was assessed by eGFR and urine protein/creatinine (UPC) ratios at 2-4weeks, 3, 6, and 12months post-diagnosis. A total of 128 subjects with median age of 7years (range 2-18) were included. Of these, 69 subjects had kidney biopsy with crescents detected in 53%. AKI (P = 0.039), nephrosis (P = 0.038), and crescents on biopsy (P = 0.013) were more likely in older patients. Patients with UPC > 1mg/mg were more likely to get a kidney biopsy (P < 0.001) and to be treated with steroids ± immunosuppressive (IS) agents (P = 0.001). Sixty-six percent of patients were treated with steroids and/or IS agents for variable durations. Anti-metabolite agents were the most common IS agents used with variability in dosing and duration. At 12months, most subjects had a normal eGFR (79%) (median 123, range 68-207mL/min/1.73 m2) and no proteinuria (median UPC 0.15, range 0.01-4.02mg/mg). IS agents are frequently used in managing IgAVN associated with heavy proteinuria, nephrosis, and/or AKI. Prospective studies are needed to determine indications and needed duration of IS therapy. A higher resolution version of the Graphical abstract is available as Supplementary information.

The effect of long-term immunosuppressive therapy on gastrointestinal symptoms after kidney transplantation

ObjectiveWe examined the relationship between compliance with long-term immunosuppressive therapy after kidney transplantation and gastrointestinal (GI) symptoms in patients discharged from hospitals in this study. MethodOur study was conducted as a descriptive study with the participation of 114 kidney transplant recipients discharged from the organ transplant center of a training and research hospital. Personal Information Form, Immunosuppressive Therapy Compliance Scale and Gastrointestinal Symptom Rating Scale were used in data collection. The data analysis was performed with IBM Statistical Package for the Social Sciences (SPSS) Statistics 25. ResultsAccording to the findings, 47.4% of kidney transplant patients were between the ages of 46 and 64, and 80.7% of them were male. 41.2% of kidney recipients used immunosuppressive agents between 91 days and 6 months. Compliance with immunosuppressive therapy was similar in all age groups. It was determined that the recipients between the ages of 18 and 30 experienced GI symptoms the most. In terms of the predictors of GI symptoms, it was determined that mycophenolate mofetil (MMF) was effective in the development of reflux and diarrhoea, cyclosporine in the development of diarrhoea and constipation, and tacrolimus in the development of indigestion, which are (p < 0.05). ConclusionFor kidney recipients to have high compliance with immunosuppressive therapy, it is of great importance that they are able to cope with GI symptoms. Our study showed that GI symptoms increase in direct proportion as the duration of immunosuppressive therapy is prolonged and the level of compliance increases. GI symptoms of kidney transplant patients should be recognized, and recipients should be helped to manage those problems.

Tumor Recurrence and Graft Survival in Renal Transplant Recipients with a History of Pretransplant Malignancy: A Matched Pair Analysis.

Organ scarcity demands critical decision-making regarding eligible transplant candidates and graft allocation to ensure best benefit from renal transplantation (RTx). Among the controversial relative contraindications is a history of pretransplant malignancy (PTM). While oncological outcomes of PTM-RTx recipients are well described, data on graft-specific outcome are scarce. A retrospective double case control matched pair analysis (60 months follow-up) was carried out and RTx-recipients were stratified for history of PTM. First, PTM-RTx recipients were matched according to age, sex and duration of immunosuppressive therapy. Next, PTM-RTx recipients were matched 1:1 for age, sex and cause of end-stage renal disease. Five-year patient and graft survival as well as oncological outcomes were analyzed. A total of 65 PTM-RTx recipients were identified. Post-RTx recurrence rate was 5%, while 20% developed second de novo malignancy, comparable to 14% in the control group. PTM-RTx recipients had a noticeable lower five-year death-censored as well as overall graft survival and Cox proportional hazard modeling showed a correlation between PTM and inferior graft survival. Although underlying reasons remain not fully understood, this study is the first to show inferior graft survival in PTM-RTx recipients and advocates necessity to focus on more meticulous graft monitoring in PTM recipients in addition to heightened surveillance for cancer recurrence.

Immunosuppression and outcomes of myocarditis patients presenting with ventricular arrhythmias

Abstract Background Effects of immunosuppressive therapy (IST) on ventricular arrhythmias (VA) have not been reported in immune-mediated biopsy-proven myocarditis patients. Furthermore, myocarditis arrhythmic risk is still unpredictable. The aim of our study was to evaluate effectiveness of IST on VA in myocarditis patients, and stratify their arrhythmic risk, using clinical and diagnostic features, including serum organ-specific anti-heart (AHA) and antiintercalated-disk autoantibodies (AIDA). Methods From a cohort of 498 consecutive patients, we enrolled 255 cases with biopsy-proven virus-negative myocarditis and evidence of VA (VF, VT, NSVT, and Lown's grade ≥2 PVC) at index hospitalization. Serum AHA and AIDA were detected by a standardised indirect immunofluorescence technique. Whenever accepted and non-contraindicated, IST was started. Controls (IST-) were chosen after 1:1 matching to IST+ cases by age, gender, ethnicity, left ventricular ejection fraction, VA type, and treatment. Prospective follow-up (FU), occurred at defined timepoints. Results 58 matched patient couples (42±13 y, 67% males, 50% IST+) were analyzed in the main study cohort. Overall, 28 (24%) had VT, and 62 (53%) were discharged with ICD. IST duration was 12±1 months. No patients died and no serious complications from IST occurred. By 24-month FU, major VA occurred in 6 IST+ vs. 10 IST- patients (p=0.420), with no cases of VT following IST termination. As compared to IST- ones, IST+ patients showed a significant reduction in NSVT and PVC burden, as well as an improvement in clinical, laboratory and imaging findings (all p&amp;lt;0.05). Major VA onset and positive AIDA status were independently associated with major VA at FU (HR 14.2, 95% CI 2.9–68.7, and 8.0, 95% CI 2.6–25.2, respectively, both p&amp;lt;0.001). Furthermore, in the whole study population (N=255), IST played as an independent protective factor from major VA (HR 0.3, 95% CI 0.2–0.7, p=0.005) at 38±21 months FU. Conclusions In immune-mediated virus-negative myocarditis patients presenting with VA, IST is feasible and effective on NSVT and PVC burden, as well as on structural, laboratory and imaging endpoints. Short-term effects are limited on major VA, which were independently associated with major arrhythmic onset and positive AIDA, in keeping with the proposed etiopathogenetic involvement of autoimmunity in virus-negative myocarditis. Funding Acknowledgement Type of funding source: None

Immunosuppressive Therapy and Risk Stratification of Patients With Myocarditis Presenting With Ventricular Arrhythmias

This study sought to investigate the effects of immunosuppression on arrhythmic myocarditis. The effects of immunosuppressive therapy (IST) on ventricular arrhythmia (VA) have not been reported in patients with immune-mediated biopsy-proven myocarditis. Furthermore, myocarditis arrhythmic risk is still unpredictable. We enrolled 255 patients with biopsy-proven virus-negative myocarditis and VA (major: ventricular fibrillation, ventricular tachycardia; minor: nonsustained ventricular tachycardia, Lown grade≥2 premature ventral complexes) at presentation. Serum cardiac autoantibodies (antiheart antibodies, anti-intercalated disk autoantibodies [AIDA]) were detected by a standardized indirect immunofluorescence technique. Whenever accepted and noncontraindicated, IST was started. Control individuals (IST-) were chosen after 1:1 matching to IST+ patients by age, sex, ethnicity, left ventricular ejection fraction, VA type, and treatment. A total of 58 matched patient couples (age 42 ± 13 years; 67% male) were analyzed in the main study cohort. IST duration was 12 ± 1months. By the 24-month prospective follow-up, major VA occurred in 6 IST+ versus 10 IST- patients (p=0.42), with no episodes following IST termination. As compared to IST- patients, IST+ patients showed a significant reduction in minor VA burden, as well as improvement in clinical, laboratory, and imaging findings (all p<0.05). Major VA onset and positive AIDA status were independently associated with major VA at follow-up (hazard ratio [HR]: 14.2; 95% confidence interval [CI]: 2.9 to 68.7 and HR: 8.0; 95%CI: 2.6 to 25.2, respectively; both p<0.001). Furthermore, in the whole study population (N=255), IST was independently associated with protection from major VA (HR: 0.3; 95%CI: 0.2 to 0.7; p=0.01) at 38 ± 21months of follow-up. In patients with immune-mediated virus-negative myocarditis presenting with VA, IST is associated with positive effects on minor VA and nonarrhythmic endpoints. Short-term effects are limited on major VA, which were independently associated with major VA onset and positive AIDA.

Organisation of lymphocytic infiltrates in ANCA-associated glomerulonephritis.

Renal involvement in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis contributes to significant morbidity and mortality in patients. In chronic inflammation, B cells are recruited to the inflamed tissue and organised lymphoid structures have been described in several autoimmune diseases. The aim of this study was to correlate the lymphoid organisation in renal biopsies with renal outcome in ANCA-associated glomerulonephritis (GN). We investigated 112 renal biopsies from patients with newly diagnosed ANCA-associated necrotising GN. We identified four different levels of the intrarenal organisation of lymphocytes: T cells without B cells, scattered B and T cells, clustered lymphocytic infiltrates and nodular compartmentally arranged B and T cell aggregates. Almost half the patients showed clusters of B and T lymphocytes in their biopsies. In 15 of these biopsies, a higher degree of organisation with lymphocytic compartments was detected. Inflammatory cell organisation was associated with renal failure, but not with tubular atrophy and interstitial fibrosis. Patients with organised lymphocytic infiltrates in their biopsy had worse renal function during follow-up and were more likely to develop end stage renal disease. In the present study, we show that the renal lymphocytic organisation is associated with renal outcome in ANCA-associated GN. The organisation of the lymphocytic infiltrate may be a morphological correlate of a perpetual and exaggerated inflammation in renal ANCA disease. Classifying the lymphocytic infiltrate could help to predict renal outcome, and might therefore be used for individualised adjustments in the intensity and duration of immunosuppressive therapy.

The need for better preventative strategies for inflammatory bowel disease patients at risk of herpes zoster virus.

Immunosuppressed inflammatory bowel disease (IBD) patients have an increased risk of herpes zoster virus (HZV) infection. The existing live-attenuated HZV vaccine is contraindicated in some of these patients and can only be used with caution in others. To describe characteristics of IBD patients suffering HZV to enable implementation of risk mitigation strategies for those at highest risk. Gastroenterologists completed a proforma for IBD patients who experienced HZV infection: IBD phenotype, details of HZV infection, immunosuppression and any change to treatment upon diagnosis of HZV. A total of 30 cases was identified: Crohn disease (CD) (n = 25) and ulcerative colitis (n = 5). In total, 80% (20/25) of the CD patients had penetrating, stricturing or perianal disease. Time from commencement of immunosuppression to HZV infection was highly variable (range: 3 months to over 10 years). A total of 90% (27/30) of patients was on at least one immunosuppressive therapy; of those, one-third was on monotherapy (9/27) and two-thirds (18/27) on dual therapy. A total of 89% (24/27) of immunosupressed patients was on a thiopurine (monotherapy; 6/27) or in combination (18/27). Complications of HZV occurred in 27% (8/30) of patients. Our series is consistent with existing epidemiological analysis that identified more severe IBD and the use of multiple immunosuppressive therapies as risk factors for HZV. If the promise of an investigational subunit HZV vaccine is realised in immunocompromised patients, better protection may be possible in the future. Thiopurine medications were the most commonly used immunosuppressant in this series. Age and duration of immunosuppressive therapy do not appear to predict HZV infection.

Cancer and mTOR Inhibitors in Transplant Recipients.

Malignancy is the second most common single cause of death observed in organ transplant recipients. The excess cancer risk is related to intensity and duration of immunosuppressive therapy and inversely to recipient age. Immunodeficiency and (chronic/oncogenic) viral infections together constitute a major risk. Nonmelanoma skin cancer, Kaposi sarcoma, and posttransplant lymphoproliferative disease have standardized incidence ratios exceeding 10- or 50-fold. The mammalian target of rapamycin (mTOR) inhibitors, sirolimus and everolimus, are increasingly used after organ transplantation with potential advantages in virus-associated posttransplant malignancies as well as anti-cancer properties. Despite a seemingly clear mechanism of action and solid rationale for their use in cancer therapy, mTORis have met only modest success rates in clinical trials with advanced malignancies except for specific tumors, such as Kaposi sarcoma and mantle cell lymphoma. Because mTORis are primarily cytostatic, not cytotoxic, the observed clinical efficacy is a reflection of disease stabilization rather than tumor regression. Nonmelanoma skin cancers, in particular cutaneous squamous cell carcinoma, have the highest standardized incidence ratios in transplant recipients. Recent meta-analyses and randomized trials on secondary prevention of squamous cell carcinoma observed a reduction in cumulative tumor load, suggesting most benefit to be gained by early conversion to an mTOR inhibitor-based maintenance regime. There is ongoing debate on the mechanisms involved including withdrawal of the carcinogenic effects of calcineurin inhibitors and/or their impact on chronic (oncogenic) viral infections. At present, there is, however, insufficient evidence for the primary use of mTORis as protective agents against most other cancer types.

Occurrence of malignancies after kidney transplantation in adults: Slovak multicenter experience.

Malignancies are one of the three major causes of renal recipient´s death with afunctioning graft after cardiovascular diseases and infections. Among the variety of risk factors, including conventional and specific to transplant recipients, the duration of immunosuppressive therapy, the intensity of therapy, and the type of immunosuppressive agent all have an impact on development of post-transplant malignancy. The aim of our retrospective study was to document the incidence, the type of malignancies, the patient/graft survival in the group of kidney transplant recipients in Slovak Republic, and to identify the factors which influenced the outcome. We analyzed the data of 1421 patients who underwent renal transplantation from deceased or living donors in the period from 2007 to 2015 in the Slovak transplant centers. The incidence of malignant tumors was 6%, the malignancy was diagnosed in 85 patients at the age of 54.1 ± 9.8 years, more frequently in men (68.2 %; P< 0.0001). The mean time of malignancy occurrence was 45 months after transplantation. The most frequent malignancies were skin cancers- basal cell carcinoma (BCC) in 17.6%, squamous cell carcinoma (SCC) in 8.2%, and malignant melanoma (MM) in 2.4% of patients, followed by non-skin tumors such as renal cell carcinoma (RCC) in 16.5%, cancer of colon in 12.9%, prostatic cancer in 9.4%, breast cancer in 9.4%, cancer of lung in 7.1%, post-transplant lymphoproliferative disease (PTLD) in 2.4%, cancer of urine bladder in 2.4%, and cancer of sublingual gland in 1.17% of patients. Surgical treatment was used in 40% of patients, chemotherapy in 7.1%, radiotherapy in 2.4%, treatment with biological agents in 15.3%, combined therapy in 29.4% and palliative treatment in 5.9% of patients. 55.3% of patients underwent conversion from other immunosuppressive agents into mTORi at the time of malignancy occurrence. The remission was achieved in 48.2% of patients, 28.2% of patients were in the oncology treatment in the end of the year 2015, and 23.5% of patients died. There was no difference in the kidney function at the time of malignancy occurrence (s-creat 133.7 ± 59.8 µmol/l) and one year later (s-creat 131.1 ± 47.9 µmol/l) (P = 0.7768). The patients after successful treatment more frequently suffered from BCC (P = 0.0140), did not undergo palliative treatment (P = 0.0033), but were more frequently treated surgically (P < 0.0001).

Ipilimumab-induced toxicities and the gastroenterologist.

Ipilimumab has been shown to improve overall survival in patients with advanced melanoma. Ipilimumab acts through immune-modulation, and is recognized to cause potentially severe immune-related adverse events (irAEs) including dermatitis, colitis, thyroiditis, hypophysitis, and hepatitis. The acceptance of ipilimumab as a treatment for metastatic melanoma means patients will continue to be treated with this agent and gastroenterologists will be increasingly called upon to assist in managing severe autoimmune-related hepatitis and colitis. To date, the recommendations for managing irAEs secondary to ipilimumab have been steroids at a moderate dose of prednisolone (1 mg/kg) as well as immunosuppressive agents such as mycophenolate mofetil (MMF) for steroid-refractory hepatitis and infliximab in the management of corticosteroid-refractory colitis. However, the dosing and the duration of immunosuppressive therapy have not been systematically studied in the setting of treating ipilimumab-induced irAEs. Therefore, additional immune-modifying agents and/or a change in dosing may be required to manage severe irAEs unresponsive to existing treatment recommendations. We describe a treatment paradigm illustrated by a series of five patients who experienced irAEs. In three cases of metastatic melanoma, ipilimumab-induced hepatitis was successfully treated with high-dose parenteral pulsed methylprednisolone. In two other melanoma patients with ipilimumab-induced colitis, one patient had satisfactory resolution of his colitis with high-dose corticosteroid therapy alone and the other patient required infliximab infusion. We have reviewed the current literature and management algorithms for ipilimumab-induced irAEs. Treatment options and the rationale for their use are discussed, including the use of pulsed high-dose steroids, MMF, azathioprine and calcineurin inhibitors.

Phase II Clinical Trial of Etanercept Plus Extracorporeal Photopheresis GVHD Prophylaxis Following Unrelated Donor Reduced Intensity Transplant

s / Biol Blood Marrow Transplant 21 (2015) S322eS354 S337 GVHD grading but were included for the other analyses. Initial treatment included beginning or increasing systemic steroids (69%), continuing calcineurin inhibitors (64%) or beginning topical treatment (52%). Additional treatment was added within the first 28 days for 31% patients. Median lines of treatment for the total duration of follow-upwere 1 (range 0-4). Of the evaluable patients, 63/85 and 56/66 had a clinical response (CR/PR) at 28 days and at 180 days respectively. 36% developed recurrence of LA GVHD after a documented CR. 26% developed chronic GVHD after LA GVHD at a median of 169 (range 25-383) days after diagnosis of LA GVHD. Median number of hospital days in the first 6 months after the diagnosis of LA GVHD was 15 (range 1-120) days. 25% had discontinued immunosuppressive therapy (IST) at the time of last follow-up with the median duration of IST being 12.8 (range 6.1-24.7) months after HCT. 9% relapsed and 22% died with themain causes of death being GVHD, infection ormulti organ failure. Median failure free survival (FFS) as defined by absence of relapse, death, addition of new IST or development of chronic GVHD was 3.6 months (95% CI: 1.7-6.8) (Figure). Median overall survival (OS) was 25.3 months. No patient/transplant or GVHD related factors emerged as significant predictors for FFS or OS in univariate analysis. Conclusions: The overall incidence of LA GVHD is low, but it is associated with prolonged immunosuppression, poor failure free and overall survival.

Pneumocystis Jirovecii Pneumonia (PCP) in Children with Cancer: A Retrospective Cohort Analysis from the Pediatric Health Information System (PHIS) Database, 2004-2009

Background: Pneumocystis jirovecii pneumonia (PCP) is an opportunistic fungal infection that can develop in the setting of deficient cell-mediated immunity. Children with hematologic malignancies and children undergoing immunosuppressive treatment for other types of cancer are at risk of developing PCP. However, the epidemiology of PCP in children with cancer is not well described. We sought to determine the prevalence of PCP in hospitalized children with cancer in the U.S. and to identify risk factors for PCP in this population.Methods: This retrospective cohort study included pediatric patients with newly diagnosed cancer at 45 children’s hospitals in the U.S. between January 1, 2004, and December 31, 2009. Data was obtained from the Pediatric Health Information System (PHIS). Patients were included if they were 0 to 20 years of age and had an index hospitalization with an ICD-9 diagnosis code for a malignant condition (140 to 239.39). Patients who had a benign tumor, >1 cancer type, or non-specific cancer codes, and those who received a hematopoietic stem cell transplant were excluded. Groups were defined for cancer types by ICD-9 codes: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), Non-Hodgkin lymphoma (NHL), Hodgkin disease (HD), central nervous system (CNS), and solid non-CNS tumors. Patients within the cohort who had a diagnosis of PCP (ICD-9 code 136.3) within 3 years of their cancer diagnosis were considered PCP cases. The relative risk for PCP was calculated according to demographics and cancer types. The data were analyzed for trends in the incidence of PCP cases by year, the time to PCP diagnosis following cancer diagnosis, and the regional distribution of PCP in the U.S.Results: A total of 33,067 pediatric cancer patients met the criteria for inclusion in the study. Of these patients, 169 (0.5%) were classified as PCP cases (Table 1). Patients with ALL and AML had the highest relative risks of PCP, when compared with other cancer types. Patients of Asian race had the highest relative risk of PCP, when compared with patients of other races. [Display omitted] Figure 1 depicts that the time to the development of PCP was relatively short in patients with NHL (median 33 days, IQR: 0-253 days) and AML (median 70 days, IQR: 0-149 days). In contrast, PCP was diagnosed later in patients with ALL, (median 347 days, IQR; 168-675 days). The number of new PCP cases did not significantly vary by year of diagnosis. Regional differences in the diagnosis of PCP by the locations of PHIS institutions were not identified. [Display omitted] Conclusions: This study represents the largest cohort analysis of PCP in children with cancer. Among children with cancer who were hospitalized at major U.S. children’s hospitals during the study period, the prevalence of PCP was 0.5%. The relative risk of PCP was increased in patients with leukemia when compared with other cancer types. However, PCP was identified in all cancer types. The variation in time to diagnosis of PCP is hypothesized to be due to differences in the intensity and duration of immunosuppressive therapy by cancer type. DisclosuresNo relevant conflicts of interest to declare.

EBV-positive mucocutaneous ulcer in organ transplant recipients: a localized indolent posttransplant lymphoproliferative disorder.

Epstein-Barr virus (EBV)-positive mucocutaneous ulcer (EBV MCU) is a B-cell lymphoproliferative disorder occurring in elderly or iatrogenic immunocompromised patients. It has not been reported in solid organ transplant recipients. We observed 7 patients with EBV MCU in a cohort of 70 transplant recipients with EBV posttransplant lymphoproliferative disorder (PTLD). Transplants included: 5 renal, 1 heart, and 1 lung. Median patient age was 61; 5 were male. EBV MCU was observed in oral mucosa in 4 and gastrointestinal tract in 3. Duration of immunosuppressive therapy before EBV MCU was 0.6 to 13 years. Ulcers were undermined by inflammatory cells and polymorphic or monomorphic large cell lymphoproliferation. Reed-Sternberg-like cells were present in 5/7. Large B cells were CD20, CD30, and EBV-encoded RNA positive in all cases. Diagnosis in 3 recent patients was EBV MCU; 4 patients diagnosed before familiarity with EBV MCU were classified as monomorphic large cell (n=3) and polymorphic (n=1) PTLD. None of the patients had EBV DNA in their blood (<1000 copies/mL) at diagnosis or follow-up versus 35/44 transplant patients with systemic PTLD (P<0.001). All lesions resolved with reduced immunosuppression (7/7), change in immunosuppression (2/7), and rituximab (3/7). Five patients are living: 4 healthy, 1 awaiting second renal transplant. Two patients died 3 and 5 years after resolution of EBV MCU. No patient recurred with EBV MCU or other PTLDs. EBV MCU mimics more aggressive categories of PTLD but lacks EBV DNA in blood, which may be a useful distinguishing feature. Lesions are likely to resolve with conservative management. Awareness of EBV MCU in the posttransplant setting is necessary for appropriate diagnosis and treatment.

Incidence, Risk Factors, and Long-Term Outcomes of Sclerotic Graft-versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation

Sclerotic chronic graft-versus-host disease (sclGVHD) is associated with significant morbidity and a poor quality of life. We reviewed 502 patients diagnosed with chronic GVHD and analyzed the incidence and risk factors of sclGVHD and long-term outcomes and immunosuppressive therapy (IST) cessation in patients with sclGVHD. With a median onset at 18 months the cumulative incidence of sclGVHD was estimated at 22.6% at 5 years (95% confidence interval, 18.6% to 26.8%). Univariate and multivariate analysis identified 2 risk factors for sclGVHD: non-T cell depletion (hazard ratio [HR] 9.09, P < .001) and peripheral blood stem cell (HR 3.87, P < .001). Overall survival (OS) at 5 years was significantly better in the sclGVHD group (88.1%) compared with the non-sclGVHD group (62.7%; P < .001), as were nonrelapse mortality (7.3% versus 21.5% at 5 years) and relapse rates (9.1% versus 19.3% at 5 years). There was no difference in the rate of IST cessation at 5 years (44.8% versus 49.9%, P = .312), but there was a trend of longer IST duration in the sclGVHD group compared with the non-sclGVHD group (median 71.6 months versus 62.9 months). In conclusion, T cell depletion and graft source affect the risk of sclGVHD. SclGVHD did not adversely affect long-term outcomes or IST duration.

Phospholipase A2 Receptor Antibodies in Membranous Nephropathy

The discovery of the M-type phospholipase A2 receptor (PLA2R) as a major antigen in idiopathic membranous nephropathy (iMN) was a breakthrough and established iMN as an autoimmune disease.1 Subsequent studies confirmed that antibodies against PLA2R were present in approximately 70% of incident iMN patients (reviewed by Hofstra and Wetzels2). The potential role of measuring PLA2R antibodies for clinical practice was suggested by studies showing that the presence of PLA2R antibodies supported a diagnosis of iMN,2–4 changes in antibody levels paralleled clinical disease activity,5 disappearance of antibodies preceded and predicted subsequent decrease of proteinuria,6 and high titers of antibodies were associated with a low likelihood of spontaneous remission.7 In this issue of JASN, Hoxha et al. report their findings in a large cohort of 163 patients with MN.8 PLA2R antibodies (both IgG and IgG4) were measured in serum obtained within 6 months from kidney biopsy. The authors used an ELISA assay and immunofluorescence testing (IFT) (both commercially available in Europe).9 PLA2R antibodies were detected in 133 patients (82%). The median follow-up was 12 months, and the majority of patients (101 of 133) started immunosuppressive therapy within 3 months after presentation. Hoxha et al. show that PLA2R antibodies decreased during follow-up. The decrease in PLA2R antibodies preceded the decrease in proteinuria. The authors concluded that “there was a remarkable time lag between the rather rapid fall in antibody levels at 3 months and the protracted reduction in proteinuria.”8 These data confirm earlier findings and indicate that an immunologic remission precedes clinical remission in patients with iMN.6,10 Although no PLA2R antibodies were found in patients with complete remission, PLA2R antibodies were still present in a low titer in 50% of patients with a partial remission. These data indicate that a partial remission may not always reflect the absence of disease activity. The authors next analyzed the association between antibody levels at baseline and remission at 12 months after presentation. PLA2R antibody levels were significantly higher in 28 patients without remission than in 39 patients with remission. The median time to remission was significantly longer in patients with antibody levels above versus below the median (15 versus 9 months). The authors concluded that the PLA2R antibody level was “an independent risk factor for not achieving remission.”8 Such a conclusion, if valid and applicable to untreated patients, could improve individualized patient care. However, the data from the study by Hoxha et al. do not allow to conclude that antibody levels can help to accurately identify patients who will develop a spontaneous remission because most of Hoxha's patients were treated. Moreover, because treated patients nearly all developed a remission, the antibody levels merely predicted the time to remission. Although their patient cohort is large, the study by Hoxha et al. is limited because of the relatively short follow-up period, the use of various immunosuppressive treatment regimens, and the unnecessary early start of immunosuppressive therapy in many patients. The reported findings cannot change current guidelines for diagnosis and treatment of patients with iMN. Evidently, more rigid study protocols are needed to reliably answer the most relevant questions. Certainly, Hoxha et al. could perform additional analyses to answer some of the following unresolved questions.