Immunosuppressive Treatment Group Research Articles

#1170 Efficacy and safety of telitacicept in IgA nephropathy: a real-world study

Abstract Background and Aims IgA nephropathy (IgAN) is the most common primary glomerular disease in the world, and the specific therapeutic methods are limited in IgAN. Telitacicept is a humanized fusion protein composed of a transmembrane activator and calcium-modulating cyclophilin ligand interactor receptor and human IgG. This study was designed to evaluate the efficacy and safety of telitacicept in adult patients with IgAN in a real-world study. Method Biopsy-proven IgAN patients with 24-hour proteinuria greater than 0.5 g/day who received telitacicept 240 mg once a week were recruited in this study and 1:1 matched with patients who received supportive treatment only or immunosuppressive treatment by propensity score matching. The primary outcome was the change from baseline in 24-hour proteinuria over the 3-month follow-up. Results Twenty-one patients in each group were enrolled. The mean eGFR was 80.1 ml/min/1.73 m2, and the median 24-hour urine protein level was 1.48 g/day. At the end of the 3-month follow-up period, telitacicept reduced median proteinuria by 0.72 g/d (54.6%) from baseline, compared with a reduction of 0.18 g/d (20%) in the supportive treatment group (P < 0.001), and 1.12 g/d (72.1%) in the immunosuppressive treatment group (P = 0.814). Preserved eGFR levels were observed in the telitacicept group (1.9 ml/min/1.73 m2 [4.3%]), while the eGFR level declined in the supportive treatment group (- 2.9 ml/min/1.73 m2 [- 5.8%]) and immunosuppression group (- 6.1 ml/min/1.73 m2 [- 8.4%]). No serious adverse events were observed in the telitacicept treatment group. Injection site reactions were more prevalent in the telitacicept group (8/21 [38.1%]), meanwhile immunosuppression group had more respiratory tract infections (7/21, [33.3%]). Conclusion Telitacicept can reduce proteinuria in patients with IgAN and showed a favourable safety profile in patients with IgAN.

Clinicopathological features and outcome in elderly patients with idiopathic membranous nephropathy

Background Idiopathic membranous nephropathy (IMN) is the leading cause of nephrotic syndrome in the elderly. The treatment of idiopathic membranous nephropathy is quite challenging due to the particularity of elderly patients. This study intends to investigate the clinicopathological characteristics and initial therapeutic effect of idiopathic membranous nephropathy among elderly patients. Methods A retrospective study of 67 elderly patients (58.2% male, median age 69.0 years, range, 65–83 years) with biopsy-proven membranous nephropathy was conducted at Guangdong Provincial People’s Hospital from 2016 to 2020. Data on clinicopathological characteristics and initial therapeutic effects were analyzed. Results Of the 67 patients, the mean eGFR of overall patients was 66.49 mL/min/1.73m2 while the median urine protein-to-creatinine ratio (uPCR) and urine albumin-to-creatinine ratio (uACR) was 5676.73 mg/g and 2951.56 mg/g, respectively. Pathological data revealed that the membranous Churg’s stage II was the most frequent (71.64%). Moreover, glomerular PLA2R antigen fluorescence intensity of (+) and IgG4 antigen fluorescence intensity of (++) were detected in 63.6% and 86.4% of all patients, respectively. Overall, 44 patients, accounting for 65.7%, achieved remission including complete remission and partial remission within 1 year after renal biopsy. Compared with a non-remission group, the levels of uPCR (6274.6 vs. 3235.6 mg/g, p = 0.007) and uACR (3433.6 vs. 1773.2 mg/g, p = 0.017) were significantly higher in remission group. The proportion of immunosuppressive therapy in the remission group was also higher (86.4% vs. 30.4%, p < 0.01). Compared with conservative treatment, patients with combined treatment with glucocorticoid and cyclophosphamide (CTX) or glucocorticoid and calcineurin inhibitor (CNIs) achieved higher remission rate (glucocorticoid plus cyclophosphamide vs. conservative treatment, 84.6% vs. 27.3%, p = 0.001; glucocorticoid plus calcineurin inhibitor vs. conservative treatment, 88.0% vs. 27.3%, p < 0.001). Further analysis showed that compared with patients who underwent conservative treatment, the proportion of males, the levels of uPCR, uACR, BUN, Scr, CysC and PLA2R antigen-positive staining rate in kidney biopsy were higher in those who underwent combined treatment with glucocorticoid and CTX, while the levels of eGFR, TP and ALB were lower (p < 0.05). In addition, patients who received combined treatment with glucocorticoid and CNIs had higher levels of uPCR, uACR, TC and lower levels of TP, ALB than those who received conservative treatment (p < 0.05). Moreover, there were no statistically significant differences in the 1-year progression rate in eGFR between the immunosuppressive treatment group and conservative treatment group (3.3 vs. 0.2 ml/min/1.73m2, p = 0.852). Conclusions Most elderly patients diagnosed with IMN had multiple comorbidities, and the membranous Churg’s stage II was most common. The glomerular PLA2R and IgG4 antigen deposition were frequently detected accompanied by glomerulosclerosis and severe tubulointerstitial injury. For high-risk elderly patients with severe proteinuria, early initial immunosuppressive therapy could achieve a higher urinary protein remission rate. Therefore, it is crucial for clinicians to balance the risks and benefits of immunosuppressive therapy based on clinical and pathological characteristics and develop individualized treatment regimens for elderly patients with IMN.

Efficacy of eltrombopag with immunosuppressive therapy forchildren with acquired aplastic anemia.

Eltrombopag (EPAG), an oral thrombopoietin receptor agonist (TPO-RA), has been proven to improve the hematologic response without increasing toxic effects as a first-line therapy combined with standard immunosuppressive treatment (IST) in adults with severe aplastic anemia (SAA). Nevertheless, the clinical evidence on the efficacy of EPAG in children with acquired aplastic anemia is limited and controversial. We performed a single-center, retrospective study to analyze the clinical outcomes of fifteen patients aged ≤18 years with newly diagnosed acquired SAA who received first-line IST and EPAG (EPAG group) compared with those of forty-five patients who received IST alone (IST group) by propensity score matching (PSM). There was no difference in the overall response (OR) rate between the EPAG group and IST group (53.3% vs. 46.7% at 3 months, P = 0.655; 66.7% vs. 57.8% at 6 months, P = 0.543), but the complete response (CR) rate was statistically significant (20.0% vs. 4.4% at 3 months, P = 0.094; 46.7% vs. 13.3% at 6 months, P = 0.012). The median time to achieve a hematological response in the EPAG and IST groups was 105 days and 184 days, respectively. No difference was observed in the event-free survival (EFS) or overall survival (OS) rates. Adding EPAG to standard IST as the first-line treatment for children with acquired SAA improved the rapidity of hematological response and the CR rate but did not improve the OR or EFS rates.

Combination Therapy to Enable AAV Re-Dosing and Mitigate Transgene Immunity in Liver-Targeted Gene Therapy

Liver directed gene delivery with AAV has made tremendous strides in the last decade and is poised to cure disorders such as hemophilia A and B. Although AAV is typically considered to be relatively innocuous, immunogenicity to the vector, its genome, and encoded transgene has resulted in innate and adaptive immunotoxicities as well as loss of the transgene product, which not only limit efficacy, but also raise important safety concerns. A major impediment to patient re-dosing with AAV is the formation of high-titer neutralizing antibodies (NAb) to the viral capsid following first administration. The right combination of immunosuppressive (IS) drugs have the capacity to control NAb formation, as well as mitigate innate and adaptive immune responses to both the vector and the transgene product. We tested hepatic gene delivery with AAV8 in C57BL/6 mice (n=8-10), using a dose (1X1011 vg/kg) that was previously shown to induce CD8+ T cells to the model transgene, ovalbumin (OVA). We compared (i) B cell depletion with α-CD20, 2 X 250μg doses spaced 3 weeks apart), (ii) α-CD20 combined with the mTOR inhibitor rapamycin (α-CD20+rapa, oral gavage with 4mg/kg rapa, 3X/week/5 weeks), (iii) α-CD20 combined with an antibody to B cell activating factor (α-CD20+α-BAFF, 2 X 60μg doses spaced 10 days apart), a cytokine that we confirmed to be crucial for B cell survival [(J Clin Invest 2021, 15;131(8)]. IS therapies administered concurrent with AAV8 gene therapy caused a high frequency of animals (40 - 75%) to develop transgene immunity (H-2 Kb SIINFEKL tetramer+), corresponding with loss of OVA expression in the liver and in circulation. OVA-CD8+ T cells had a short-lived effector memory phenotype in blood and spleen, characterized as CD44+CD62L-CCR7-KLRG1+CX3CR1+. Interestingly, there were much higher frequencies of OVA-CD8+ T cells in the liver, even when they were undetectable in blood and spleen, and their presence in the liver did not completely correlate with loss of OVA expression. In line with this observation, OVA-CD8+ T cells in the liver expressed multiple exhaustion markers PD1, 2B4, LAG3, TIM3, highly upregulated transcription factors TBet, STAT3, and BATF, but not TCF1, and did not express KLRG1 and CX3CR1 expression. All control and IS treated groups of animals developed NAb (IgM and IgG2c, equivalent to IgG1 in human) to the AAV8 vector, which precluded re-administration with the same AAV serotype (5X1012 vg/kg of AAV8-hFIX). In contrast, when IS therapies were initiated 3 weeks prior to AAV8 gene therapy (1X1011 vg/kg), we were successfully able to re-administer AAV8-hFIX (n=6-10) to 70% of α-CD20, 75% of α-CD20+rapa, and 80% of α-CD20+α-BAFF treated animals without transgene immunity development. Re-administration was unsuccessful in animals that did not receive immune modulation. We then tested pre-IS therapy with a clinically relevant primary administration dose (5X1012 vg/kg of AAV8-OVA). We were able to re-administer AAV8-hFIX to 44% of α-CD20, 88% of α-CD20+rapa, and 67% of α-CD20+α-BAFF treated animals. Mice that were precluded from re-dosing with AAV8-hFIX in the IS treatment groups had high circulating BAFF levels, which correlated with the development of α-AAV8 IgM NAbs. To validate this finding and mitigate α-AAV8 IgM NAbs, we extended α-BAFF injections for an additional 4 weeks in the α-CD20+α-BAFF group (n=10). Extending α-BAFF treatment prevented both BAFF and IgM production, allowing not only successful re-dosing in 100% of animals but also higher circulating FIX levels (12901 ± 686.7ng/mL) as compared to mice that only received AAV8-FIX (9725 ± 415.5 ng/mL). Finally, we tested the practicality of α-CD20+extended α-BAFF treatment in the event of delayed AAV8 re-dosing, once immune compartments have completely repopulated (~14 weeks based on flow cytometry analysis). We were successfully able to re-dose 100% of α-CD20+extended α-BAFF pre-IS treated mice with AAV8-FIX following a delayed re-administration schedule (15 weeks). FIX expression levels remained stable until the last timepoint tested (16 weeks post re-dosing). We conclude that timing and duration of IS, vector dose and transgene immunogenicity are important considerations in developing effective IS therapies. We propose that pre-IS therapy with αCD20+ extended αBAFF is an effective candidate to enable re-dosing with clinically relevant doses of AAV.

The effect of immunosuppressive therapy on the development of ventilator-associated pneumonia in patients with COVID-19

Aim: It remains unclear whether immunosuppressive treatments such as corticosteroids and IL-6 receptor blockers have an effect on the development of ventilator-associated pneumonia (VAP). The aim of this study was to investigate the effect of immunosuppressive therapy on the development of VAP in critically ill patients with COVID-19.&#x0D; Material and Method: Two hundred thirty five patients with critically ill patients with COVID-19, who were treated in the intensive care unit (ICU) and received mechanical ventilator support, were evaluated retrospectively. VAP development, secondary infections, microorganisms isolated, and resistance patterns were compared between the groups that received and did not receive immunosuppressive therapy, and also the groups that did not receive immunosuppressive therapy, received only corticosteroid, received only tocilizumab, and received corticosteroid plus tocilizumab were compared in the subgroup analysis.&#x0D; Results: In the immunosuppressive treatment group, VAP development (40.2% vs. 21.2%; p=0.001), secondary infection development (48.4% vs. 29.2%; p=0.003), at least one drug resistant bacteria growth (46.7% vs. 27.4%; p=0.001), extensively-drug resistant (XDR) microorganism growth (89.8% vs. 72.7%; p=0.033) were higher than the group that did not receive immunosuppressive treatment. VAP (53.3%; p=0.004), secondary infection (73.3%; p=0.0002), the growth of bacteria resistant to at least one drug (70%; p=0.0003) were highest in the corticosteroid plus tocilizumab group in the subgroup analysis. In addition, XDR (95.5% vs. 72.7%; p=0.032) and pan-drug resistant (PDR) microorganism growth (31.8% vs. 9.1% p=0.032) were higher in the corticosteroid plus tocilizumab group than the no immunosuppressive therapy group. There was no difference between the groups in terms of mortality (p&gt;0.05).&#x0D; Conclusion: Immunosuppressive therapy has been found to potentially enhance the risk of VAP and secondary infections in critically ill patients with COVID-19 pneumonia as well as the growth of bacteria resistant to at least one drug, the length of stay in hospital and ICUs. In addition, it has been evaluated that there may be an increase in the growth of XDR and PDR microorganisms when corticosteroid and tocilizumab are used together. Although there was no difference in mortality, using immunosuppressive therapy may require careful use of targeted antibiotics and longer-term antimicrobial therapy.

Indirect Effects of Pneumococcal Childhood Vaccination in Individuals Treated With Immunosuppressive Drugs in Ambulatory Care: A Case-cohort Study.

The extent to which iatrogenically-immunosuppressed individuals benefit from indirect effects of childhood vaccination with pneumococcal conjugate vaccines (PCVs) is unknown. We determined how the sequential introduction of PCV7 (2006) and PCV13 (2011) in the Norwegian childhood vaccination program has affected the epidemiology of invasive pneumococcal disease (IPD) in individuals treated with immunosuppressants in ambulatory care. We conducted a case-cohort study comprising 7926 IPD cases reported to the Norwegian Surveillance System for Communicable Diseases in 2005-2014 and 249998 individuals randomly selected from the National Registry in 2012. We defined immunosuppressive treatment groups based on dispensed prescriptions retrieved from the Norwegian Prescription Database. Incidences and age-adjusted relative risks (RR) were estimated. IPD incidences decreased in all groups. The PCV13 incidence decreased by 5-12% across groups. The non-PCV13 incidence increased by 4-10%, mostly in individuals on chemotherapy (overlapping 95% confidence intervals). In the PCV13 era, the RR for IPD was highest (significant) and the percentage of cases caused by the polysaccharide vaccine PPV23 serotypes lowest (numerical) in individuals on chemotherapy (RR = 20.4, PPV23 = 52%), followed by individuals on corticosteroids (RR = 6.2, PPV23 = 64%), other immunosuppressants (RR = 5.6, PPV23 = 68%), and no immunosuppressants (RR = 1 [reference], PPV23 = 74%). IPD incidences declined after PCV introduction in both immunocompetent and iatrogenically-immunosuppressed individuals, underscoring the benefit of childhood vaccination for the entire population. Still, individuals treated with immunosuppressants in ambulatory care are at increased risk of IPD caused by a more diverse group of serotypes.

Combined Immunosuppressive Treatment May Improve Short-Term Renal Outcomes in Chinese Patients with Advanced IgA Nephropathy

Background/Aims: Treatment of advanced Immunoglobulin A nephropathy (IgAN) patients with estimated glomerular filtration rate (eGFR) below 45 mL/min per 1.73 m2 remains inconsistent. The aim of this study is to compare the effects of corticosteroid and immunosuppressant therapies among these patients. Methods: A total of 201 adult patients with advanced IgAN (eGFR < 45 mL/min/1.73 m2 and proteinuria > 1 g/24h at biopsy) grouped into supportive care (SC), steroids alone (CS), and steroids plus immunosuppressant (IT) groups, were investigated between 30th December 2002 and 30th June 2016. The primary endpoint was the combined endpoint of a 50% decline in eGFR and/or end stage renal disease (ESRD: eGFR < 15 mL/min/1.73 m2 or maintenance renal replacement treatment). Responses to therapy included complete remission (CR: urinary protein excretion < 0.5 g/24h, with eGFR decrease less than 10% baseline), partial remission (PR: proteinuria decrease by > 50% baseline, with eGFR decrease less than 10% baseline), no response (NR: proteinuria decrease < 50% baseline, or eGFR decrease > 10% baseline) and ESRD. Kaplan–Meier and Cox proportional hazards analyses were performed. Results: During the follow-up period (37.2 ± 22.7 months), 6.8% patients in SC group, 25.0% in CS group, and 38.0% in IT group achieved CR or PR, while 78.4%, 62.5% and 49.3% patients in these 3 groups reached primary endpoint respectively (p < 0.001). Three-year renal survival rates in SC and combined immunosuppressive treatment groups (CS and IT groups) were 33.8% vs 51.2% (p = 0.02), and 5-year renal survival rates were 12.2% vs 21.3% (p = 0.1) respectively. Multivariate Cox regression analysis showed that hypertension (HR = 2.44, 95% CI 1.51–3.95; p < 0.001), Scr (HR = 1.01, 95% CI 1.00-1.01; p < 0.001), T1-T2 lesion (HR = 1.99, 95% CI 1.35–2.93; p = 0.001) were independent indicators of poor renal outcome. Conclusion: Immunosuppressive treatment (CS and IT therapy) may improve short-term renal outcome compared with supportive treatment in advanced IgAN patients.

Immunosuppressive treatment for myocarditis: a meta-analysis of randomized controlled trials.

Immunosuppressive treatment for myocarditis is controversial. Several small-scale randomized controlled trials (RCTs) reported inconsistent outcomes for patients with myocarditis. We searched on the Medline, Embase, and Cochrane databases for articles in English language between January 1966 and May 2013, as well as on the China National Knowledge Internet (CNKI, 1979 to May 2012) and the Chinese Biomedical Literature Database (CBM, 1978 to May 2013) for articles in Chinese language. Statistical analysis was performed using Review Manager 5.0. Nine articles were finally selected, in which 342 patients were in immunosuppressive treatment group and 267 patients in conventional treatment group. The immunosuppressive treatment group showed a significant improvement in left ventricular ejection fraction at both short-term (≤3 months) [difference: 0.08, 95% confidence interval (CI): 0.05-0.10) and long-term (difference: 0.10, 95% CI: 0.00-0.21)] follow-up. Moreover, left ventricular end-diastolic dimension decreased significantly in the immunosuppressive treatment group after short-term follow-up (difference: -1.85 mm, 95% CI: -3.18 to -0.52 mm), but a long-term beneficial effect was not sustained (difference: -5.79 mm, 95% CI: -15.30 to 3.72 mm). There was no difference, however, between the two groups in the rate of death or heart transplantation (odds ratio: 1.33, 95% CI: 0.77, 2.31). Immunosuppressive treatment might be beneficial for improving left ventricular systolic function and remodeling in patients with myocarditis, which could be considered as a therapeutic alternative when optimal conventional therapy is not effective. More large RCTs, however, are required.

Clonal Changes Detected By Target Capture Sequencing and Molecular Cytogenetic Study in Patients with Aplastic Anemia

BACKGROUND: Aplastic anemia (AA) is a group of heterogenous disease. Aplastic anemia with somatic mutations or cytogenetic aberrations are considered as clonal disease either as pre-malignant stage or malignant disease and differential treatment approach from idiopathic AA need to set. The presence of clonality in aplastic anemia could be a determining point for the choice of treatment among bone marrow transplantation or immunosuppressive therapy, and the detection method of clonality could be conventional cytogenetics (CG), molecular cytogenetics or molecular genetic test. Detection sensitivity is 5% by CG, 20-30% by Sanger sequencing, and 0.5-1.0% by next generation sequencing (NGS). We aimed to investigate the frequencies of clonal changes including cytogenetic aberrations and somatic mutations and their correlation with clinical prognosis in aplastic anemia.METHODS: We reviewed clinical data of the 440 patients (mean age 38 years, M:F ratio 1.1) who were diagnosed with AA from 1997 to 2013. Results of G-banding were available in 280 patients and in all them, fluorescent in situ hybridization (FISH) for -5/5q-, -7/7q-, +8, -20/20q-, and 1q gain was performed. Target capture sequencing for 357 hematopoiesis-related genes was performed in 77 patients. Mutations were selected by running algorithms including SIFT, Polyphen2, and CADD, and normal variant was filtered by 1000Gp, ESP6500, and the in-house Korean database (n=250). We assessed disease progression, survival and response to treatment in 248 patients.RESULTS: Of 440 patients, 21(4.7%) showed disease progression: MDS in 14(66.7%), AML in 4(19.0%), PMF in 2(9.5%) and plasma cell myeloma in 1(4.8%). Mean duration of transformation to MDS was 59 months (1-151 month). Among 21, only 2 patients showed cytogenetic aberrations (CA) at initial diagnosis, but 9 patients showed cytogenetic evolution at the time of disease transformation: monosomy 7(50%), trisomy 8(25%), and 1q gain (17%). Among 280 patients in whom both G-banding and FISH panel were performed, 21 (7.5%) showed cytogenetic aberrations; numerical abnormality (13/21, 61.9%), structural abnormality (5/21, 23.8%), combined abnormality (3/21, 14.3%). FISH revealed trisomy 8 in 19.0% (7/21), -7/7q- in 9.5% (2/21), followed by 1q gain in 4.5% (1/21). Patients with aberrant FISH result for MDS was associated with disease progression (p=0.0160). Median percentage of FISH+ clonal cells were smaller (mean 3.0%), compared to those of MDS (27%) and AML (39%). In severe AA group (n=67), BMT treatment group showed better survival rate than other groups in patients with cytogenetic aberration (P =0.004), while BMT have no impact on survival rate among patients without cytogenetic aberrations (P =0.232). The average of survival duration is in BMT, immunosuppressive treatment (IST), combined BMT &IST group was 61, 153, 68 months. In normal karyotype (NK) group, survival was different depending on treatment regimen (p=0.043), but no different was noted in cytogenetic aberration group. Among 77 patients in whom target sequencing was performed, 20/77 (26%) presented at least 1 mutation. The number of mutated genes was 14 and frequently mutated genes was LRP1B (3/20, 15.0%), NOTCH1 (3/20, 15.0%), SCRIB (3/20, 15.0%), DNMT3A (2/20, 10.0%), BCOR (2/20, 10.0%), DIS3 (2/20, 10.0%), NF1 (2/20, 10.0%), ERCC6 (2/20, 10.0%), GATA2 (1/20, 5.0%), RUNX1 (1/20, 5.0%), RELN1 (1/20, 5.0%), U2AF1 (1/20, 5.0%), TCF12 (1/20, 5.0%), JAK2 (1/20, 5.0%). In patients with somatic mutations, 10% showed disease progression. But patients with somatic mutation did not show any difference in survival, treatment response and disease progression. When the patients were devided by clonal (cytogenetic aberration by G-banding or FISH or somatic mutation by NGS, 14.9%), and non-clonal (84.1%), IST in clonal group showed adverse response compared to non-clonal group (p< 0.05), while BMT treatment showed similar response between 2 groups.CONCLUSIONS: Five percent of among AA patients in Korea revealed disease progression and about half of AA patients harboring clonalities showed at the time of disease transformation. CA was strongly associated with adverse prognosis or treantment response, while somatic mutation was not. Increased sensitivity of detection for clonality could reveal the hidden clonality in AA, but significance of molecular clonal hematopoiesis in AA need to be further investigated. DisclosuresNo relevant conflicts of interest to declare.

A decision model for the watch-and-wait strategy in systemic sclerosis–associated interstitial lung disease

To develop a decision model to identify SSc-associated interstitial lung disease (ILD) patients who are eligible for watchful waiting at ILD diagnosis. One hundred and fifty-one SSc-ILD patients who received medical care at Seoul National University Hospital from 1986 to 2013 were enrolled in this retrospective cohort study. ILD was diagnosed by chest CT. Patients with and without immunosuppressive treatment were compared in terms of characteristics at ILD diagnosis to identify distinguishing variables. After multivariate analysis, a decision model for watchful waiting was formulated. Its validity was assessed by comparing the survival of patients whose management in real practice did and did not accord with the management recommended by the model. The untreated group had better survival than the immunosuppressive treatment group (P = 0.0316, by log-rank test). The untreated group was less likely to have gastrointestinal involvement (P = 0.008) and pulmonary arterial hypertension (PAH), as determined by echocardiography) (P = 0.015) and more likely to have favourable initial forced vital capacity (P = 0.0004), favourable initial lung diffusion capacity for carbon monoxide (P = 0.0002) and a low CT grade (P < 0.001). The final watchful waiting decision model included lack of PAH and limited ILD extent on CT. Application of the model to the cohort revealed that patients who were eligible for watchful waiting (as determined by the model) and underwent this management strategy had better survival than eligible patients who underwent immunosuppressive treatment (P = 0.048, by log-rank test). Watchful waiting may be effective for SSc-ILD patients who have minimal pulmonary involvement on CT and lack PAH on echocardiography at baseline.

Are antimicrobial peptides related to cyclosporine A-induced gingival overgrowth?

ObjectiveThe aim of the present study was to investigate the effect of cyclosporine-A (CsA) medication on gingival crevicular fluid (GCF) LL-37, human neutrophil peptide (HNP)1-3 and adrenomedullin (ADM) levels. DesignCsA-treated renal transplant recipients with GO (CsA GO+) and without GO (CsA GO−), tacrolimus-medicated renal transplant recipients (n=20/group), systemically healthy subjects with gingivitis (n=21) and individuals free of periodontal and systemic diseases (n=20) were included in the present study. Periodontal parameters were recorded and GCF samples were obtained from the study participants. GCF LL-37, HNP1-3 and ADM levels were analyzed by enzyme-linked immunosorbent assay. ResultsGCF LL-37 total amount was higher at GO+ sites than the other study sites (p<0.05). Total amount of GCF HNP1-3 was higher in immunosuppressive treatment groups than healthy and gingivitis groups, regardless of GO presence (p<0.05). GCF ADM total amount was similar in all study groups. GCF volume, papillary bleeding index and hyperplastic index (p<0.05) were significantly correlated with GCF LL-37 total amounts (p<0.05), but not with GCF HNP1-3 and ADM total amount at GO+ sites (p>0.05). ConclusionNeutrophil infiltration due to extended inflammation might have increased GCF LL-37 levels at GO+ sites and contributed to the pathogenesis of CsA-induced GO.

Determining Renal Resistive and Pulsatility Indexes Long-Term After Kidney Transplantation in Kidney Transplant Recipients on Cyclosporine A-, Tacrolimus-, or Sirolimus-Based Regimens

BackgroundRenal Doppler ultrasound intrarenal resistive index (RI) and pulsatility index (PI) are 2 noninvasive Doppler ultrasonographic markers to determine kidney allograft function, and have been used mainly for diagnosing allograft dysfunction during early posttransplantation periods. Little is known about the stability of RI and PI in allograft recipients receiving cyclosporine A (CyA)-, tacrolimus (TAC)-, or sirolimus (SRL)-based immunosuppressive regimens long-term after kidney transplantation. MethodsThis study assessed RI and PI by Doppler ultrasonography in 155 kidney allograft recipients between July 2012 and March 2013. The period from kidney transplantation to performance of allograft Doppler ultrasound was between 23 and 231 months in the TAC group (n = 75), 21 and 261 months in the CyA group (n = 25), and 21 and 210 months in the SRL group (n = 55). ResultsUnivariate logistic regression analysis revealed no correlation between resistance indexes and estimated glomerular filtration rate, proteinuria, cholesterol, triglyceride, graft and patient survival, human leukocyte antigen mismatches, and creatinine. There was no significant difference among the TAC, CyA, and SRL treatment groups in terms of resistance indexes (RI and PI) (P = .193 and P = .216, respectively). Univariate logistic regression analysis revealed that RI and PI values correlated significantly with the recipients' ages (R = 0.375, P < .001), but not with donor age. The results of multivariate logistic regression analysis also revealed statistically the strongest correlation between recipients' ages and RI (95% confidence interval = 0.002, R² = 20.5%, P < .001) and PI (95% confidence interval = 0.008, R² = 16.2%, P < .001) values. ConclusionsIntrarenal RI and PI remained stable over time in allograft recipients after transplantation, and there was no significant difference between calcineurin inhibitor-based and calcineurin inhibitor-free immunosuppressive treatment groups. Only recipients' ages showed a positive correlation with RI and PI values. Long-term allograft and patient survival were both excellent (100%) and associated with RI < 0.75.

Addition of immunosuppressive treatment to hemoperfusion is associated with improved survival after paraquat poisoning: a nationwide study.

Paraquat poisoning associates very high mortality rate. Early treatment with hemoperfusion is strongly suggested by animal and human studies. Although the survival benefit of additional immunosuppressive treatment (IST) in combination with hemoperfusion is also reported since 1971, the large-scale randomized control trials to confirm the effects of IST is difficult to be executed. Therefore, we designed this nationwide large-scale population-based retrospective cohort study to investigate the outcome of paraquat poisoning with hemoperfusion and the additional effects of IST combined with hemoperfusion. This nationwide retrospective cohort study utilized data retrieved from the National Health Insurance Research Database (NHIRD) of Taiwan. A total of 1811 hospitalized patients with a diagnosis of paraquat poisoning who received hemoperfusion between 1997 and 2009 were enrolled. The mean age of all 1811 study subjects was 47.3 years. 70% was male. The overall survival rate was only 26.4%. Respiratory failure and renal failure were diagnosed in 56.2% and 36% patients. The average frequency of hemoperfusion was twice. IST was added in 42.2% patients. IST significantly increases survival rate (from 24.3% to 29.3%, P<0.001). The combined IST with methylprednisolone, cyclophosphamide and dexamethasone associates with the highest survival rate (48%, P<0.001). Moreover, patients younger than 45 years of age in the IST group had the best survival (41.0% vs. 33.7%, p<0.001). Our results support the use of IST with hemoperfusion for paraquat-poisoned patients. The best survival effect of IST is the combination of methylprednisolone, cyclophosphamide and daily dexamethasone, especially in patients with younger age.

The Comparison Of Clinical Outcomes Between Matched Sibling Stem Cell Transplantation and Immunosuppressive Treatment As a First-Line Treatment For Adult Patients With Severe Aplastic Anemia

▪ BackgroundAllogeneic stem cell transplantation (SCT) from matched-sibling donor (MSD) and immunosuppressive treatment (IST) are the most widely used first-line treatments for patients with severe aplastic anemia (SAA). Overall long-term survival rates are comparable between the two groups. However, patients with age of over 40 have not been generally considered as candidates of SCT from MSD (MSD-SCT) due to higher transplant-related mortality. Recent improvements in MSD-SCT such as less intensive fludarabine-based conditioning, and use of rabbit anti-thymocyte globuline (ATG) instead of horse ATG as first-line IST may change these results. Therefore, we compared the clinical outcomes between MSD-SCT with fludarabine-based conditioning and IST with rabbit ATG and cyclosporine A (CsA). MethodsWe analyzed the clinical results of 54 adult SAA patients who were treated with MSD-SCT and 93 with IST as a first-line treatment from March 2006 to May 2012 at Seoul St. Mary's Hospital, Seoul, Korea. The patients who were treated with MSD-SCT received conditioning with fludarabine (30 mg/m2/day × 6 days), cyclophosphamide (50 mg/kg/day × 2 days), and rabbit ATG (Thymoglobulin®, 2.5 mg/kg/day × 4 days). Those who were treated with IST received rabbit ATG (2.5 mg/kg/day × 5 days) with CsA. ResultsThe median ages were not significantly different between the MSD-SCT group and IST group (38.5 years vs. 43.0 years; P=0.103). Other baseline characteristics were comparable except the interval from diagnosis to treatment (100 days vs. 40 days; P=0.013), absolute lymphocyte count (0.68 × 109/L vs. 0.93 × 109/L; P=0.013), and platelet count (10.0 × 109/L vs. 11.0 × 109/L; P=0.035). In the IST group, overall response and complete response rates at 1 year were 44.1% (95% CI, 33.8-54.8) and 10.8% (95% CI, 5.3-18.9). Treatment failure developed in 55 (59.1%) patients due to non-response in 34 (36.6%), relapse in 5 (5.4%), clonal evolution in 3 (3.2%), and treatment-related mortality in 13 (14.0%) patients. After treatment failure, 17 (18.3%) patients received SCT from MSD or unrelated donor. In the MSD-SCT group, 10 (18.5%) patients experienced treatment failure due to secondary graft failure in 5 (9.3%), clonal evolution in 1 (1.9%), and treatment-related mortality in 4 (7.4%) patients. Among the patients who experienced secondary graft failure, 4 (7.4%) patients received secondary SCT, which resulted in sustained graft function. Consequently, overall survival (OS) at 3 years in the MSD-SCT group was not significantly different compared to that in the IST group (90.7% vs. 81.0%; P=0.139). However, the MSD-SCT group showed significantly higher failure-free survival (FFS) at 3 years compared to the IST group (80.2% vs. 46.6%; P<0.001). When we analyzed the patients with age of over 40 years, OS at 3 years in the MSD-SCT group was not significantly different compared to that in the IST group (87.5% vs. 74.7%; P=0.251), whereas FFS at 3 years in the MSD-SCT group was significantly higher compared to that in the IST group (84.0% vs. 43.0%; P=0.001). ConclusionsOur data suggest that MSD-SCT is more favorable than IST as a first-line treatment, considering the curative nature of MSD-SCT even in patients over 40 years of age. Disclosures:No relevant conflicts of interest to declare.

NK Cell Subsets in Renal Transplantation

Introduction: Following kidney transplantation, the involvement of NK cells in rejection episodes or immunological tolerance is discussed controversially. The peripheral NK cell repertoire of KTx patients at 3 or 6 months post Tx was investigated in parallel to the protocol biopsy for histopathological evaluation of the graft. The alterations were correlated to the biopsy status (“unsuspicious”, T cell-mediated rejection TCMR or borderline changes) and immunosuppression, respectively. Methods: Peripheral blood lymphocytes of KTx patients (N=100) at the time of the protocol biopsy at 3 or 6 month after Tx were isolated after informed consent of the patients. In addition to the “truecount” quantification of T, B, NK cells (cell/μl), the composition of the NK cell repertoire was determined by flow cytometry for the expression of several NK receptors including KIR and CD94/NKG2. In addition to NK cells, receptor expression was also addressed in T cell subsets. In some cases, protocol biopsies and peripheral blood was available at multiple time points after Tx and, thus, changes over time and immunosuppression (CsA vs. Tac vs. mTOR inhibitors) could be defined. Results: The numbers of NK cells/μl blood differed between patients after KTx with “unsuspicious” grafts and TCMR or borderline histopathology although not at a significant level. However, the distribution of CD56bright vs. CD56dim NK cells in these patient cohorts displayed significant differences compared to healthy donors. In addition, the NK subset analyses revealed substantial differences in the numbers of KIR+ NK cells between the patient cohorts. Conclusions: In our first analyses with patients between 3 and 12 months after KTx, we could demonstrate that the numbers of NK cells in peripheral blood differs between patients with kidney grafts unsuspicious of rejection and biopsy-proven TCMR or borderline changes. In addition, a more detailed NK cell subset analysis revealed significant differences in NK subset distribution between the patient cohorts and also, for some subsets, the immunosuppressive treatment groups mTOR inhibitors, in particular. Therefore, we assume that the composition of peripheral NK cells represents an important hallmark of the immune status, rejection vs. tolerance, in kidney transplantation. (This work was funded by the IFB-Tx, DFG TRR77, A3 snd SFB738 B8 projects and the HGF Alliance Immmunotherapy).

Laryngeal Transplantation in the Setting of Cancer: A Rat Model

Traditional immunosuppressive regimens make laryngeal transplantation in cancer patients prohibitive because of the increased risk of recurrence. Everolimus, a recently developed immunosuppressant, has demonstrated significant antitumor properties. The purpose of this study was to examine the effects of everolimus alone and in combination with other immunosuppressants on tumor growth in a combined laryngeal transplantation and tumor model. Animal, prospective, randomized, controlled, and blinded. One million squamous cell carcinoma cells (SCC-158) were injected intravenously into a total of 40 rats 1 day before laryngeal transplantation. Rats were divided into four groups differing by immunosuppressive regimens. Lung surface metastases were counted 21 days after inoculation, and numerical transplantation rejection scores were recorded. A separate experiment for comparison was performed with no transplant on 24 rats, but with the same immunosuppressive treatment groups. The median number of lung surface metastases were: a) control (i.e., no immunosuppression): 85; b) everolimus 1.0 mg/kg: 25; c) tacrolimus 1.2 mg/kg: 1650; d) everolimus 1.0 mg/kg + tacrolimus 0.05 mg/kg: 1300. Rats receiving everolimus alone showed a statistically significant decrease in pulmonary surface metastases compared with the other groups. Transplanted rats had no difference in their outcomes when compared with non-transplanted rats. Everolimus significantly decreases SCC-158 growth in our combined transplantation and tumor model compared with controls and other immunosuppressants.

Anemia in the Period Immediately Following Renal Transplantation

Introduction Anemia remains frequent in the first month following renal transplantation and is a risk factor for cardiovascular accidents. The purpose of this study was to analyze the prevalence of anemia during this period notably among different immunosuppressive treatment groups. Methods In this study, we entered the patients who had received a renal allograft in our transplant unit from 1993 to 2003, including patients who had received azathioprine (AZA) from 1993 to 1996 and mycophenolate mofetil (MMF) from 1996 to 2003. No patient received rHu- erythropoietin after transplantation during that period. A mathematical model normalized the hemoglobin (Hb) threshold level at which blood transfusion was decided and Hb on admission. Results One hundred and eighty-eight patients on AZA and 223 on MMF were included in the analysis. The mean age ± SD was 41 ± 12 years in the AZA group, and 45 ± 12 years in the MMF group ( P < .006). Before the transplantation, Hb was higher in the MMF group (11.4 ± 1.9 vs 10.2 ± 2 g/dL, P < .0001). After normalization at a threshold level of transfusion of 7 g/dL, transfusions were more frequent among the MMF group (72% vs 48%, P < .0001). Double therapy with MMF (1500 mg/d) + steroids or therapy with MMF (750 mg/d) + tacrolimus + steroids increased the risk of transfusion compared to the AZA group. MMF (750 mg/d) + cyclosporine conferred a similar risk of transfusion compared with the AZA group. Conclusion MMF alone or in association with tacrolimus is associated with an increased risk of anemia and transfusion in the immediate posttransplantation period.

Detection of Polyomavirus BK and JC in Children With Kidney Diseases and Renal Transplant Recipients

Reactivation of polyomavirus is a known reason for severe renal dysfunction in adult renal transplant recipients. Testing for polyomavirus DNA in plasma has been described as a sensitive and specific method to discover viral nephropathy in adult patients. We were now interested in polyomavirus status in a pediatric patient setting. Plasma and urine samples were obtained from 80 children including 38 children after renal transplantation (group 1), 7 children with different kidney diseases receiving immunosuppressive treatment (group 2) and 35 children with different kidney diseases not receiving immunosuppressive treatment (group 3). A nested polymerase chain reaction method was used for amplification of polyomavirus DNA fragments. Differentiation between JC and BK virus was done by digestion with restriction endonucleases. Polyomavirus DNA was detected in the urine sample of 19 of 38 (50%) renal transplant recipients (group 1), of 1 of 7 (14%) patients from group 2 and in none of the 35 patients of group 3. Plasma samples from 3 (8%) of group 1 patients and from 1 child each of group 2 (14%) and group 3 (3%) were tested positive for polyomavirus DNA. Urinary polyomavirus excretion seems to be more frequent in pediatric patients with kidney diseases receiving immunosuppressive treatment and after renal transplantation than in children with various kidney diseases without immunosuppressive treatment.

Role of immunosuppression in the evolution of Legionnaires' disease.

The clinical course of legionella pneumonia in immunosuppressed patients is uncertain. This study was undertaken to determine the clinical evolution of legionellosis on the basis of the immune state and to establish the variables associated with death directly related to legionellosis. The study included 78 patients: 28 with chronic disease who had received immunosuppressive treatment (group 1), 24 with chronic disease without immunosuppressive treatment (group 2), and 26 controls. Inclusion criteria were the occurrence of nosocomially acquired pneumonia, Legionella pneumophila infection, and erythromycin therapy that was initiated within 72 hours following diagnosis. Respiratory and extrarespiratory complications were observed more frequently in groups 1 and 2. Bilateral radiological involvement was most frequent in group 1, and recurrence of legionella pneumonia was observed exclusively in group 1. None of these variables achieved statistical significance. The global mortality of the series was 11.5% (17.9%, 12.5%, and 3.8% in groups 1, 2, and 3, respectively). Variables statistically related to mortality were acute renal failure, shock, and need for mechanical ventilation. Although many of the variables analyzed lacked statistical significance, a trend was seen between complications and basal immunosuppression, as previously suggested.

Donor-specific cytotoxic lymphocyte activity from bronchoalveolar lavage during acute canine lung allograft rejection.

We investigated the relationship between acute lung rejection and donor-specific cytotoxic activity (DSCA) in recipient's lymphocytes obtained from bronchoalveolar lavage (BAL). A total of 26 mongrel dogs underwent left lung allotransplantation. Dogs received either no immunosuppressive treatment (group I), cyclosporine (group II), or cyclosporine and methylprednisolone for evidence of acute rejection (group III). DSCA was measured by a 51Cr release assay, using lymphocytes from BAL samples as effector cells and 51Cr-labeled donor skin fibroblasts as target cells. The pathologic findings of the transplanted lungs were classified according to the working formulation for classification and grading of pulmonary rejection. In addition, the degree of cellular infiltration in the perivascular, peribronchial, interstitial, and intraalveolar areas was determined based on an infiltration score. DSCA in BAL samples was elevated during mild, moderate and severe acute rejection. The accuracy of the diagnosis of mild or moderate rejection was 92.3% at effector:target (E:T) ratios of 100:1 and 50:1. The DSCA in the BAL fluid and the total infiltration score were correlated closely with correlation coefficients of 0.859 and 0.828 at E:T ratios of 100:1 in group I and group II dogs, respectively. Lung aeration improved and DSCA decreased with methylprednisolone therapy in three of four dogs with grade 2 rejection. There is a direct relationship between the DSCA in BAL fluid and the degree of tissue damage caused by acute rejection. The DSCA can be detected by a 51Cr release assay which may hold promise for future clinical applications.