Number Of Immunosuppressive Agents Research Articles

Risk Factors and Outcomes of Mucorales Infection in a Modern Cohort of Solid Organ Transplant, Hematopoietic Cell Transplant, and Chimeric Antigen Receptor T-cell Therapy Recipients

Mucorales infections continue to cause significant morbidity and mortality in immunocompromised hosts despite the advent of new approaches for diagnosis and treatment of fungal infections. We aimed to evaluate risk factors and outcomes of Mucorales infection in solid organ transplant, hematopoietic cell transplant, and chimeric antigen receptor T-cell therapy recipients. This single-center retrospective study included solid organ transplant, hematopoietic cell transplant, and chimeric antigen receptor T-cell patients with cultures positive for Mucorales. Forty-three patients were included for analysis; 34 solid organ transplant (79%) and 9 hematopoietic stem cell transplant or chimeric antigen receptor T-cell (21%). Infection with Mucorales occurred a median of 184 days after transplant. At the time of diagnosis, 36 patients were on antifungal prophylaxis with the majority receiving posaconazole (53%). Thirty-three had clinically significant disease; 30 received definitive anti-Mucorales therapy and 3 empiric antifungal therapy. Isavuconazole was the most common azole used for treatment in monotherapy recipients. All-cause mortality was 64% and, of these deaths, 18 (75%) were directly related to Mucormycosis. The highest mortality was seen in disseminated and intra-abdominal disease (100%), followed by pulmonary disease (50%). There was no significant association with mortality and transplant type or number of immunosuppressive agents. Mucormycosis is an important cause of morbidity and mortality in immunocompromised patients. Breakthrough infection was not uncommon in this study. Data regarding the incidence of infection at approximately 6 months after transplantation can inform prophylaxis and treatment regimens. The spectrum of antifungal regimens used reflects the lack of consensus on ideal regimens for these organisms and a need for more studies.

Use of immune checkpoint inhibitors in solid organ transplant recipients with advanced cutaneous malignancies.

Immune checkpoint inhibitors (ICI) are standard of care therapy for patients with cutaneous malignancies, the most frequently diagnosed cancers in solid organ transplant (SOT) recipients. The activity and rate of allograft rejection in SOT recipients with advanced skin cancers treated with ICI is understudied. We conducted a retrospective analysis of SOT recipients with advanced melanoma, cutaneous squamous cell carcinoma (cSCC), and merkel cell carcinoma (MCC) who were treated with ICI. Unpublished cases from our institution and published cases from the literature were aggregated. Demographics, type of immunosuppressive therapy, type of ICI(s) administered, prior systemic therapies, tumor response to ICI, and evidence of organ rejection and/or failure were recorded. Objective response rates (ORR) and rates of graft rejection and failure are reported. Ninety patients were identified; four patients from our institution and 86 unique patients from a literature review. ORR to first-line ICI for the entire cohort was 41.1% (37/90). ORR by tumor type was 31% (18/58), 64.3% (18/28), and 25.0% (1/4) for melanoma, cSCC, and MCC, respectively. The rate of graft rejection was 37.8% (34/90) with 61.8% (21/34) of these cases progressing to graft failure. Number of immunosuppressive agents (0, 1, 2, or 3) was inversely associated with rate of graft failure. In this retrospective analysis, ICIs demonstrate clinical activity in SOT recipients with cutaneous malignancies; however, the rate of graft rejection is high. Treatment plans should be individualized through thorough interdisciplinary discussion. Immunosuppressive modifications may be considered prior to starting treatment, but when feasible, enrollment on clinical trials is preferred.

The impact of Treosulfan-based conditioning for inborn errors of immunity: Is dose monitoring crucial?

In children with inborn errors of immunity (IEI) who will receive a hematopoietic stem cell transplant (HSCT) treosulfan-based conditioning is currently preferred. The aim of this study was to investigate early and late outcomes in pediatric IEI patients receiving pre-HSCT treosulfan and to examine the effect of treosulfan dose monitoring on outcomes. Seventy-three pediatric patients receiving this management between 2015 and 2022 were included. Overall survival rate was 80%, and event-free survival was 67.8%. A larger treosulfan dose AUC after first application increased the rate of early toxicity (p=.034) and slowed lymphocyte engraftment (r=.290; p=.030). Underlying disease, treosulfan AUC, donor type, stem cell type, number of immunosuppressive agents, the dose of anti-thymocyte globulin, and post-transplantation cyclophosphamide did not to increase risk of acute graft-versus-host disease. The risk of mixed chimerism (MC) in patients with autoimmune lymphoproliferative syndrome and leukocyte adhesion deficiency were higher than those with severe combined immunodeficiency (p=.021 and p=.014, respectively). The risk of MC was lower in those receiving peripheral blood stem cells (SC) compared with bone marrow derived SC (OR=.204, p=.022). The AUC of the treosulfan dose was not associated with poorer late outcomes. Treosulfan is an agent that can be used safely in the IEI patient group, level measurement appears essential to identify early toxicities. Prospective studies with more extended follow-up periods are needed.

Discordance Between SARS-CoV-2-specific Cell-mediated and Antibody Responses Elicited by mRNA-1273 Vaccine in Kidney and Liver Transplant Recipients.

We included 44 (28 kidney, 14 liver, and 2 double organ) recipients who received the full series of the mRNA-1273 vaccine. SARS-CoV-2-CMI was evaluated at baseline, before the second dose, and at 2 wk after completion of vaccination by an ELISpot-based interferon-γ FluoroSpot assay using overlapping peptides covering the S1 domain. SARS-CoV-2 immunoglobulin G seroconversion and serum neutralizing activity against the spike protein were assessed at the same points by commercial ELISA and an angiotensin-converting enzyme-2/spike antibody inhibition method, respectively. Postvaccination SARS-CoV-2-CMI was compared with 28 healthcare workers who received the BNT162b2 vaccine. Positive SARS-CoV-2-CMI increased from 6.8% at baseline to 23.3% after the first mRNA-1273 dose and 59.5% after the completion of vaccination (P < 0.0001). Lower rates were observed for immunoglobulin G seroconversion (2.3%, 18.6%, and 57.1%, respectively) and neutralizing activity (2.3%, 11.6%, and 31.0%). There was a modest correlation between neutralizing titers and the magnitude of SARS-CoV-2-CMI (Spearman's rho: 0.375; P = 0.015). Fifteen recipients (35.7%) mounted SARS-CoV-2-CMI without detectable neutralizing activity, whereas 3 (7.1%) did the opposite, yielding poor categorical agreement (Kappa statistic: 0.201). Rates of positive SARS-CoV-2-CMI among SOT recipients were significantly decreased compared with nontransplant controls (82.1% and 100.0% after the first dose and completion of vaccination, respectively; P < 0.0001). Kidney transplantation, the use of tacrolimus and prednisone, and the number of immunosuppressive agents were associated with lower cell-mediated responses. Results remained unchanged when 3 recipients with prevaccination SARS-CoV-2-CMI were excluded. Two-thirds of SOT recipients mounted SARS-CoV-2-CMI following vaccination with mRNA-1273. Notable discordance was observed between vaccine-induced cell-mediated and neutralizing humoral immunities. Future studies should determine whether these patients with incomplete responses are effectively protected.

Review on long‐term non‐renal complications of childhood nephrotic syndrome

Nephrotic syndrome (NS) is the most common glomerular childhood disease. A body of literature has described the long-term renal prognosis of childhood-onset idiopathic NS. However, the nonrenal outcomes have not been studied as much. We aimed to discuss the long-term non-renal outcomes of childhood NS, highlighting studies with a follow-up period of more than 10 years. We reviewed the literature and found that a number of immunosuppressive agents have stopped inflammation, stabilised the podocyte cytoskeleton and reduce proteinuria. However, prolonged treatment has frequently been associated with a high risk of renal and non-renal complications in patients with a complicated disease course, defined as frequent relapses or steroid dependency. Non-renal complications may include impaired longitudinal growth and pubertal development, undesirable fertility outcomes, ocular complications, bone mineral diseases and potential malignancies. This review discusses and summarises the non-renal outcomes of idiopathic childhood NS.

Clinical Analysis of Immunodeficiency-Associated Lymphoproliferative Disorders in a Single Institution

BackgroundRecent progress in medicine faces more patients to iatrogenic immunosuppressive state, which increases the risk of following immunodeficiency-associated lymphoproliferative disorders (LPD), such as post-transplant lymphoproliferative disorders (PTLD) which arise after solid organ or hematopoietic stem cell transplantation (HSCT), and other lymphoid proliferations or lymphomas which arise in patients treated with immunosuppressive agents for any reasons. Methotrexate for patients with rheumatoid arthritis (RA) has been the most discussed immunosuppressive agent associated with iatrogenic LPD. Nevertheless, the number of patients treated with other immunosuppressive agents such as biological response modifiers for RA and calcineurin inhibitors after HSCT has recently increased and clinical assessment of iatrogenic-LPD under this recent immunosuppressive setting is still limited. Clinical prognostic factors remain controversial due to the heterogeneity of this disease concept, patients' background and treatment.Methods: A total of 71 patients diagnosed as iatrogenic immunodeficiency-associated lymphoproliferative disorders (PTLD, n=26; other LPD, n=45) over last 20 years in Kyoto University Hospital were reviewed. Cox regression analysis was used to examine the impact of patient characteristics including immunological backgrounds and tumor status on outcomes.Results: Median age at diagnosis of LPD was 63 (range, 3-83; PTLD, 50; other LPD, 66). Regarding the PTLD patients, 12 were recipients of liver transplantation, 8 were of HSCT, 4 were of lung and 2 were of kidney transplantation. Background diseases of the other LPD were RA in 43, systemic lupus erythematosus in 1 and systemic sclerosis in 1. Median time from the initiation of immunosuppressive agents to LPD diagnosis was 82 months (range, 1.5-348.5; PTLD, 35.4; other LPD, 116.5). The number of immunosuppressive agents given at LPD diagnosis was 0 in 1 patient, 1 in 14, 2 in 42, 3 in 12 and 4 in 1 patient. Twenty-nine percentage of those receiving multiple immunosuppressive agents were administered methotrexate in combination with PSL or biological response modifiers. Ann Arbor stage at diagnosis was I in 8 patients, II in 13, III in 20 and IV in 28 patients. Histologic subtypes of PTLD were monomorphic (n=19), polymorphic (n=4), and non-destructive PTLD (n=3). Pathological diagnosis of other LPD were DLBCL (n=20), polymorphic LPD (n=5), classical Hodgkin lymphoma (n=6), Hodgkin-like lesion (n=3), Burkitt lymphoma (n=1), EBV-positive mucocutaneous ulcer (n=3), and other B-cell lymphomas (n=7). EBER in situ hybridization was positive in 38 (63.3%) and systemic EBV reactivation was detected in 17 (43.6%).First line therapy included reduction of immunosuppressive agents without chemotherapy in 33 patients (PTLD, n=4; other LPD, n=29), RTX-containing chemotherapy in 23 (PTLD, n=14; other LPD, n=9), other chemotherapies in 7 (PTLD, n=4; other LPD, n=3), radiation therapy in 2, and no additional treatment in 2 patients.After the first line therapy, complete remission was achieved in 35 patients, partial response in 13, and stable or progressive disease in 14. A total of 4 patients died during the first line therapy. Five-year survival rate was 49.9% (PTLD, 39.0%; other LPD, 54.0%; P=0.101).Multivariate analysis showed that low number of lymphocyte count (< 890/µl, median lymphocyte count) at diagnosis (HR, 5.55; P=0.013), hypoalbuminemia (serum albumin value <3.2 g/dl) at diagnosis (HR, 6.36; P=0.015) and higher IPI (high-risk group vs others, HR, 2.71; n=0.021) were risk factors for poor prognosis. In subgroup analysis for PTLD, low IgG (<825 mg/dl, lowest limiting value of our center) was also an independent prognostic factor for inferior outcome (HR, 15.5; P=0.011).Conclusions: Overall survival of immunodeficiency-associated lymphoproliferative disorders under recent immunosuppressive settings, especially PTLD, was still poor. We found that low number of lymphocyte count could be a new risk factor for poor prognosis, along with known factors as IPI and hypoalbuminemia. Low IgG value was also suggested to be a prognostic factor for inferior outcome in PTLD patients. DisclosuresNishikori:Eisai: Research Funding; Ono Pharmaceuticals: Research Funding.

DOP006 A multicentre cohort study to assess the safety of vedolizumab for inflammatory bowel disease

We aimed to quantify rates and identify predictors of serious adverse events (SAE) with vedolizumab (VDZ) for Crohn’s disease (CD) and ulcerative colitis (UC). This was a review of a multicentre, US-based consortium of CD and UC patients treated with VDZ. Serious infections (SI) were defined as those requiring antibiotics or hospitalisation, or resulting in discontinuation of VDZ or death. SAE were defined as SI or adverse events resulting in discontinuation of VDZ or death. Multivariable logistic regression analyses with odds ratio (OR) and 95% confidence intervals (CIs) are reported for independent predictors of SI and SAE. 1087 patients (n = 650 CD; 45% male) with a median follow-up of 302 days (interquartile range 171–434) were included. SI occurred in 66 patients (6%); the most common SI were C. difficile (n = 24), abscess (n = 11), respiratory tract infections (n = 10), zoster (n = 7), and bacteraemia (n = 6). SAE occurred in 73 patients (7%), with no reported malignancies. Transverse myelitis (n = 1) and optic neuritis (n = 1) were the only two reported central nervous system adverse events. SI and SAE were observed in 3.7% and 4.3% of patients on VDZ monotherapy, 6.1% and 6.7% of patients on VDZ in combination with steroids or an immunomodulator (azathioprine, 6-mercaptopurine, methotrexate), and 9.8% and 10.7% of patients on VDZ in combination with both steroids and an immunomodulator. On multivariable analyses, after adjusting for inflammatory bowel disease type (CD vs. UC), age, and sex, concomitant immunosuppressive (steroid or immunomodulator) therapy was the only independent predictor of SI (OR 1.67 per number of immunosuppressive agents used, 95% CI 1.17–2.38) and SAE (OR 1.65 per number of immunosuppressive agents used, 95% CI 1.17–2.31). VDZ is well tolerated in clinical practice, with SI and SAE being reported in 6% and 7% of patients, respectively. The strongest predictor of SI or SAE is the use of concomitant steroids or immunomodulators, with the greatest risk seen in patients on triple therapy with VDZ, steroids, and immunomodulator therapy. Further studies are needed to identify patients who will most benefit from concomitant immunosuppressive therapy use with VDZ to optimise the safety profile in clinical practice.

Influence of atopy on prognosis of juvenile-onset systemic lupus erythematosus

Objective To evaluate the influence of atopy on the prognosis of juvenile-onset systemic lupus erythematosus (JSLE). Methods The study was performed on 60 cases with JSLE diagnosed at the Department of Pediatrics, Renji Hospital Affiliated to School of Medicine of Shanghai Jiaotong University from October 2005 to April 2015.These patients were enrolled by mixed cohort study and subdivided into atopic group(26 cases) or non-atopic group(34 cases). The clinical and laboratory data of the disease onset, disease assessment scores, medications during follow-ups and remission/flare of the disease were recorded and analyzed to compare the difference between 2 groups. Results (1)The systemic lupus erythematosus disease activity index(SLEDAI) score[(17.080±5.628) scores vs (12.590±4.856) scores], anti-double-stranded DNA (anti-dsDNA)[(62.590±43.602) IU/mL vs (40.230±30.189) IU/mL], erythrocyte sedimentation rate (ESR) [(59.150±40.315) mm/1 h vs (40.350±31.865) mm/1 h]were significantly elevated at onset in the atopic group compared with non-atopic controls (all P<0.05), while the complement C3[(0.450±0.218) g/L vs(0.640±0.333) g/L], C4[(0.047±0.024) g/L vs(0.116±0.172) g/L] in atopic group was lower than those in the non-atopic group (all P<0.05). (2)During the follow-ups of 1 and 6 months to 1 year, the JSLE patients with atopy always had higher SLEDAI score compared with the non-atopic controls(all P<0.05). (3)For medications, the daily cumulative glucocorticoid dose received by patients in the atopic group were larger than that of the non-atopic group, and the number of immunosuppressive agents used in the atopic group was more than that in the non-atopic controls (P<0.05). (4)During the 1-year follow-up, the rate of disease relapse in the atopic group was higher than that in the non-atopic group and the atopic group also needed much more time to reach disease remission (P<0.05). Conclusion JSLE patients combined with atopy may have an adverse influence on the prognosis of JSLE. Key words: Atopy; Juvenile-onset systemic lupus erythematosus; Prognosis

Risk of Early and Late Non-Hodgkin Lymphoma (NHL) in Australian Liver and Cardiothoracic Transplant Recipients.

Aims: To determine whether risk of NHL is increased in cardiothoracic compared to liver transplant recipients, after adjustment for extent of immunosuppression and competing risk of death. Methods: A retrospective cohort study in Australia using population-based liver (n=1924) and cardiothoracic (n=2631) transplant registries (1984-2006). NHL incidence was ascertained by probabilistic record linkage with the Australian Cancer Database. Adult and pediatric transplant unit medical records were retrospectively reviewed to ascertain putative risk factor data, including demographics, co-morbid conditions, immunosuppressive agents received at transplantation and at regular intervals during follow-up, and serum viral antibody status at transplantation. Multiple imputation was used to impute missing Epstein-Barr virus (EBV) data. Adjusted hazard ratios (HR) for early (n=31) and late-onset (n=69) NHL were estimated using the Fine and Gray proportional subdistribution hazards model. Results: After imputation there were 22 early (<1yr) and 45 late (≥1yr) NHL cases available for multivariate analysis. Compared to liver recipients, lung recipients were at increased risk of early NHL (HR 5.18, 95%CI 1.39-19.3) after adjustment for recipient EBV seronegativity at transplantation (HR 3.33, 95%CI 1.08-10.4), receipt of OKT3 antibody (HR 10.0, 95%CI 2.50-40.0), male gender (HR 3.47, 95%CI 1.44-8.37), age, calendar year of transplant, receipt of ATG/ALG, and current dose of immunosuppressive agents. For late NHL, heart recipients were at increased risk compared to liver recipients (HR 3.66, 95%CI 1.33-10.0) after adjusting for EBV serostatus, age, sex, calendar year of transplant, time since transplantation, receipt of OKT3 and ATG/ALG, and the current dose and number of immunosuppressive agents. Imputed and non-imputed results were similar. Conclusions: Differences in immunosuppressive regimen do not appear to explain the excess risk of NHL in heart and lung compared to liver transplant recipients. There is growing evidence of heterogeneity in the risk factors for early and late NHL after solid organ transplantation.

Treatment of refractory posterior uveitis with infliximab: a 7‐year follow‐up study

Objective: To describe, in a 7‐year follow‐up study, the use of infliximab in patients with refractory posterior uveitis and scleritis.Methods: A 7‐year follow‐up case series study was performed. Patients with posterior uveitis and scleritis refractory to conventional therapies (steroids and at least one immunosuppressive agent) were included. Three infliximab intravenous doses of 5 mg/kg were administered at weeks 0, 2, and 6. Further infusions were allowed in patients undergoing a relapse of the uveitis after initial remission. All patients were followed up for at least 8 months. We defined uveitis improvement as an increase in the best‐corrected visual acuity or an objective and significant improvement in retinal exudates and/or haemorrhages, cystoid macular oedema (CME), and vitreous haze. Infliximab‐related adverse events, final prednisone doses, and the number of immunosuppressive agents used were recorded. A descriptive analysis was performed.Results: A total of 11 patients (17 eyes were affected at baseline) were included, 63% were women, the mean age was 43±14 years, and the median follow‐up was 80 months (p25–p75: 50–80). After infliximab treatment, six eyes maintained their basal visual acuity, nine eyes showed improvement, and two worsened (in the two patients diagnosed with choroiditis). Vitreous haze, active retinal vasculitis, and CME, but not chorioretinal lesions, improved in all patients. All patients tapered their daily steroid dose and the number of immunosuppressive agents. No infliximab‐related adverse events were reported.Conclusions: Infliximab could be an effective and safe treatment in patients with posterior uveitis and scleritis refractory to conventional therapy.

The expanding role of the transplant pharmacist in the multidisciplinary practice of transplantation.

The burgeoning clinical discipline and growth of organ transplantation has resulted in an expansion in the number of healthcare specialists to support clinical care and research. The past 10 yrs have seen a dramatic increase in the number of immunosuppressive agents and other medications used in transplantation, resulting in more complex medication regimens and greater potential for interactions, adverse effects and increased costs. To determine how transplant pharmacists are being integrated into transplant clinical practice. Transplant centres were identified through UNOS Transplant Administrators Committee list serve. A survey was then distributed via e-mail to 159 individuals representing 118 solid organ transplant centres. Forty-one (35%) of the 118 centres responded, with 36 evaluable surveys. Of the 36 centres, 28 (78%) had transplant pharmacist support and eight did not have a pharmacist dedicated to transplant (two of the eight were recruiting). A majority of the respondents had multi-organ transplant responsibilities. Eighty-six per cent of pharmacists were involved in kidney transplant, 71% in liver, 50% in pancreas, 25% in heart, and 7% in lung. Pharmacist salaries were most often funded by a department of pharmacy (74%), followed by college of pharmacy (12%), transplant centre (8%) and department of surgery (6%). Almost all of the pharmacist's clinical practice time focused on post-transplant care (99%). The average percentage of the pharmacist's time was: 43% inpatient, 15% outpatient, 14% research, 6% other transplant related, and 22% non-transplant related. Of the 28 pharmacists, 25 had a PharmD degree, two a BS and one had a PhD in Pharmacy. The average number of organs transplanted among the responding centres was 99 kidneys, 45 livers, 28 pancreas, 14 heart, and 26 lungs. The number of transplants did not differ between the programmes with pharmacist clinical support vs. those without designated pharmacist support. The survey indicates that many solid organ transplant centres have incorporated transplant pharmacists into the multidisciplinary transplant clinical team. Transplant pharmacists are funded most often by the hospital pharmacy. Most transplant pharmacists spend the majority of their time in clinical practice, but also play a key role in research.

Use of immunosuppressive agents in uveitis.

This review summarizes current patterns in the use of immunosuppressive agents in patients with uveitis. A number of immunosuppressive agents are currently available for the treatment of uveitis. Reports of safety and efficacy, although numerous, have been largely nonrandomized and performed without controls, limiting, to some extent, the strength and generalizability of their conclusions. Nonetheless, the volume of case reports and case series provides compelling evidence that immunosuppressive agents are effective at providing long-term control in patients with moderate to severe chronic or recurrent uveitis. The choice of immunosuppressive agent is complex, and depends on the cause and severity of the patient's underlying inflammation, the presence or absence of associated systemic inflammation, and the patient's prior response to immunosuppressive treatments. Although corticosteroids remain the primary initial treatment for patients with uveitis, use of noncorticosteroid immunosuppressive agents in selected patients with uveitis allows for improved control and decreased risk of corticosteroid-induced side effects.

High-dose intravenous immunoglobulin therapy in dysimmune neuropathies

Immune-mediated neuropathies, including Guillain-Barre syndrome, Miller Fisher syndrome, chronic inflammatory demyelinating neuropathy, multifocal motor neuropathy, neuropathies associated with monoclonal gammopathy, and paraneoplastic subacute sensory neuronopathy (Table 1), are a group of disorders believed to be caused by an immune response directed against peripheral nerve antigens. The role of the immune system in the pathogenesis of these neuropathies has been first convincingly demonstrated by Latov et al. in 1980 [1] in a patient with neuropathy associated with IgM monoclonal gammopathy, whose IgM were found to react with the myelin-associated glycoprotein (MAG), a minor component of nerve myelin. Since then antibody reactivities against a number of peripheral nerve antigens have been reported in patients with different forms of dysimmune neuropathies, contributing not only to clarify their pathogenesis [2] but also to their identification and diagnosis. Several immune therapies including steroids, plasma exchange (PE) and a number of immunosuppressive agents, have been reported to be effective in these neuropathies. These therapies are however far from being invariably effective and may be associated with a number of side effects which limit their use, leading to the search for new immune therapies. In particular, in the last decade high-dose intravenous immunoglobulin (IVIg) therapy has been shown to be particularly effective in some of these neuropathies, broadening the spectrum of therapeutical options for these diseases (reviewed in [3, 4]). We review the rationale for using IVIg therapy and the results of its application in these neuropathies, in order to give some indications for its use in these diseases.