Is There a Detrimental Effect of Antibiotic Therapy in Patients with Muscle-invasive Bladder Cancer Treated with Neoadjuvant Pembrolizumab?

In locally advanced and metastatic malignancies, antibiotic (ATB) therapy has a negative effect on immunotherapy efficacy. Therefore, we aimed to evaluate whether ATB therapy and use of specific ATB classes with concomitant neoadjuvant pembrolizumab affected pathologic complete response (ypT0N0) and relapse-free survival (RFS) for patients with clinical T2-4N0M0 bladder cancer enrolled in the PURE-01 study. Of the 149 patients evaluated, 48 (32%) received any concomitant ATB therapy. The ATB class most commonly administered was fluoroquinolones (16 patients; 33%). In the ATB cohort, seven patients (15%) achieved ypT0N0 status, compared to 50 (50%; p < 0.001) in the untreated group. Moreover, ATB use was negatively associated with ypT0N0 status (odds ratio 0.18, 95% confidence interval [CI] 0.05-0.48; p = 0.001). The 24-mo RFS rate was 63% (95% CI 48-83%) in the ATB group versus 90% (95% CI 83-97) in the untreated group. We found that ATB use was associated with a higher recurrence rate (hazard ratio [HR] 2.64, 95% CI 1.08-6.50; p = 0.03). Exploratory analyses showed that fluoroquinolone use was associated with a higher recurrence rate (HR 3.28, 95% CI 1.12-9.60; p = 0.03). Our study revealed an association between ATB use and neoadjuvant immunotherapy efficacy in an intention-to-cure population, highlighting the need for future studies to better investigate this relationship. PATIENT SUMMARY: The efficacy of immunotherapy for cancer is influenced by several patient and tumor factors, including the use of antibiotics. We found that antibiotics taken at the same time as immunotherapy drugs were associated with lower rates of complete response and of recurrence-free survival among patients with muscle-invasive bladder cancer. These findings need to be confirmed in future studies.

Effect of Gemcitabine based chemotherapy on the immunogenicity of pancreatic tumour cells and T-cells.

PURPOSE: Chemotherapy for advanced pancreatic cancer has limited efficacy due to the difficultly of treating established tumours and the evolution of tumour resistance. Chemotherapies for pancreatic cancer are typically studied for their cytotoxic properties rather than for their ability to increase the immunogenicity of pancreatic tumour cells. In this study Gemcitabine in combination with immune modulatory chemotherapies Oxaliplatin, zoledronic acid and pomalidomide was studied to determine how combination therapy alters the immunogenicity of pancreatic tumour cell lines and subsequent T-cell responses. METHODS: Pancreatic tumour cell lines were stimulated with the chemotherapeutic agents and markers of immune recognition were assessed. The effect of chemotherapeutic agents on DC function was measured using uptake of CFSE-stained PANC-1 cells, changes in markers of maturation and their ability to activate CD8+ T-cells. The effect of chemotherapeutic agents on T-cell priming prior to activation using anti-CD3 and anti-CD28 antibodies was determined by measuring IFN-γ expression and Annexin V staining using flow cytometry. RESULTS: These agents demonstrate both additive and inhibitory properties on a range of markers of immunogenicity. Gemcitabine was notable for its ability to induce the upregulation of human leukocyte antigen and checkpoints on pancreatic tumour cell lines whilst inhibiting T-cell activation. Pomalidomide demonstrated immune modulatory properties on dendritic cells and T-cells, even in the presence of gemcitabine. DISCUSSION: These data highlight the complex interactions of different agents in the modulation of tumour immunogenicity and immune cell activation and emphasise the complexity in rationally designing chemo immunogenic combinations for use with immunotherapy.

The impact of seropositivity on the effectiveness of biologic anti-rheumatic agents: results from a collaboration of 16 registries.

OBJECTIVES: RF and ACPA are used as diagnostic tools and their presence has been associated with clinical response to some biologic DMARDs (bDMARDs) in RA. This study compared the impact of seropositivity on drug discontinuation and effectiveness of bDMARDs in patients with RA, using head-to-head comparisons in a real-world setting. METHODS: We conducted a pooled analysis of 16 observational RA registries. Inclusion criteria were a diagnosis of RA, initiation of treatment with rituximab (RTX), abatacept (ABA), tocilizumab (TCZ) or TNF inhibitors (TNFis) and available information on RF and/or ACPA status. Drug discontinuation was analysed using Cox regression, including drug, seropositivity, their interaction, adjusting for concomitant and past treatments and patient and disease characteristics and accounting for country and calendar year of bDMARD initiation. Effectiveness was analysed using the Clinical Disease Activity Index evolution over time. RESULTS: Among the 27 583 eligible patients, the association of seropositivity with drug discontinuation differed across bDMARDs (P for interaction <0.001). The adjusted hazard ratios for seropositive compared with seronegative patients were 1.01 (95% CI 0.95, 1.07) for TNFis, 0.89 (0.78, 1.02)] for TCZ, 0.80 (0.72, 0.88) for ABA and 0.70 (0.59, 0.84) for RTX. Adjusted differences in remission and low disease activity rates between seropositive and seronegative patients followed the same pattern, with no difference in TNFis, a small difference in TCZ, a larger difference in ABA and the largest difference in RTX (Lundex remission difference +5.9%, low disease activity difference +11.6%). CONCLUSION: Seropositivity was associated with increased effectiveness of non-TNFi bDMARDs, especially RTX and ABA, but not TNFis.

Pharmacokinetics and drug interactions of medications used to treat hepatitis C virus infection in the setting of chronic kidney disease and kidney transplantation.

Hepatitis C infection in patients with chronic kidney disease or kidney transplant carries higher morbidity and mortality compared to noninfected patients. Historically, patients with advanced kidney disease and kidney transplant recipients were undertreated given the multiple adverse effects and limited efficacy of interferon-based therapies for chronic hepatitis C. The development of direct-acting antivirals in the past few years has opened an unprecedented opportunity for treating these populations. However, the impaired renal clearance of some of these medications in patients with kidney disease, and the potential interactions of antiviral therapies with immunosuppressants after kidney transplantation, present some challenges in choosing the proper regimen. This review provides an overview of the essential pharmacokinetics and drug interactions of relevant antiviral therapies in the treatment of chronic hepatitis C in patients with advanced kidney disease and after kidney transplantation.

Influence of the clinical profile of patients with refractory epilepsy on lamotrigine plasma concentration

ABSTRACT The purpose of this work was to evaluate the influence of the clinical profile on lamotrigine (LTG) plasma concentrations from patients with refractory epileptic seizures. In this cross-sectional study, therapeutic monitoring of LTG, and questionnaires with 75 patients with refractory epileptic seizures of a Hospital in Ribeirão Preto-SP-Brazil were performed. The multiple linear regression model was used to verify association between the LTG plasma concentrations and the independent variables. Covariance analysis was used to compare the mean LTG plasma concentration among the co-medication groups. The LTG plasma concentration was associated both with the LTG dosage (mg/kg/day) (p=0.0096) and with the use of first generation antiepileptic drugs (AED) (p<0.01), being carbamazepine (CBZ) and phenytoin (PHT), the AEDs showing the most prominent influence in reducing LTG plasma concentrations. Adverse events, adherence to the pharmacological treatment, and epileptic seizures frequency, did not show significant correlation with LTG plasma concentration values. The conclusion is that LTG plasma concentration is significantly influenced by the LTG dosage and by the concomitant use of a first generation AED.

Lipopolysaccharide downregulates macrophage-derived IL-22 to modulate alcohol-induced hepatocyte cell death.

Interleukin-22 (IL-22) is a Th17 cell hepatoprotective cytokine that is undergoing clinical trials to treat patients with alcoholic hepatitis (AH). Lipopolysaccharide (LPS) activation of macrophage is implicated in hepatocyte cell death and pathogenesis of AH. The role of IL-22 production from macrophage, its regulation by LPS, and effects on alcohol-induced hepatocyte cell death are unexplored and were examined in this study. Low levels of IL-22 mRNA/protein were detected in macrophage but were significantly upregulated by 6.5-fold in response to the tissue reparative cytokine IL-10. Conversely, LPS significantly decreased IL-22 mRNA levels in a temporal and concentration-dependent manner with a maximum reduction of 5-fold. LPS downregulation of IL-22 mRNA levels was rescued in the presence of a pharmacological inhibitor of c-Jun NH2-terminal kinase (JNK) and by JNK knockdown. Next, we explored whether macrophage-derived IL-22 regulated ethanol-induced hepatocyte death. Conditioned media from IL-10-stimulated macrophages attenuated ethanol-induced hepatocyte caspase-3/7 activity, and apoptosis as assessed by fluorometric assay and TdT-mediated dUTP nick-end labeling (TUNEL) staining, respectively. This effect was diminished in conditioned media from macrophages with IL-22 knockdown. Cytokine analysis in sera samples of patients with AH revealed that IL-22 levels were significantly elevated compared with healthy controls and heavy-drinking controls, implying a state of IL-22 resistance in human AH. Macrophage-derived IL-22 protects hepatocytes from ethanol-induced cell death. IL-22 downregulation is a new regulatory target of LPS in the pathogenesis of AH.

Sex-differential effects on mortality of BCG and diphtheria-tetanus-pertussis vaccines in a rural area with high vaccination coverage: observational study from Senegal.

BACKGROUND: Diphtheria-tetanus-pertussis (DTP) may be associated with increased female mortality; the effect of co-administration with BCG is not known. METHODS: Between 1989 and 1997, we examined female and male mortality rates in rural Senegal where 7824 infants received the first dose of DTP and inactivated polio vaccine (DTP-IPV) with BCG. Subsequent doses of DTP-IPV were administered alone. We analysed mortality according to sex and number of doses of DTP-IPV vaccine. RESULTS: BCG and DTP-IPV1 simultaneously reduced mortality from 60/1000 person-years in unvaccinated girls to 35/1000 person-years, but mortality increased with subsequent doses of DTP-IPV to 45/1000 person-years. Among boys, BCG and DTP-IPV1 simultaneously reduced mortality from 72/1000 person-years to 60/1000 person-years and mortality decreased further with subsequent doses of DTP-IPV to 34/1000 person-years. In age-adjusted analyses, female-male mortality rate ratios were 0.83(95% CI 0.50-1.40) among unvaccinated children and 0.58 (95% CI 0.35-0.96) among children vaccinated simultaneously with BCG and DTP-IPV1, but increased to 1.17 (95% CI 0.67-2.03) after DTP-IPV2, and 1.63 (95% CI 0.86-3.10) after DTP-IPV3. Difference in vaccination coverage could not explain these sex-differential patterns; girls had significantly better weight-for-age than boys so nutritional status did not explain the increase in female mortality after DTP-IPV3. CONCLUSIONS: Whereas BCG co-administered with DTP-IPV was associated with lower female than male mortality, subsequent DTP-IPV vaccinations were associated with an increase in female mortality relative to male mortality.

Valoración del riesgo/beneficio en el tratamiento de la enfermedad de Alzheimer. A propósito de una interacción / Risk/benefit assessment in the treatment of Alzheimer's disease. Drug interactions

Introducción. Los fármacos anticolinérgicos reducen la eficacia de los inhibidores de la acetilcolinesterasa (IACE) y se consideran inapropiados en pacientes de edad avanzada. El objetivo fue conocer la prevalencia de prescripción concomitante de IACE y anticolinérgicos en un Área de Salud, identificar pacientes afectados e informar a los médicos responsables para que valorasen la idoneidad de los tratamientos. Material y métodos. Estudio descriptivo transversal y observacional de prevalencia. Se seleccionó a pacientes en tratamiento con IACE y algún fármaco anticolinérgico en el primer trimestre de 2015. Para la identificación de anticolinérgicos, se utilizó como referencia la revisión de Durán et al., asignando una puntuación a cada fármaco en función de su potencia anticolinérgica. Se proporcionó a cada médico una nota informativa sobre la interacción, relación de pacientes afectados y recomendaciones. Resultados. Se incluyó a 486 pacientes, lo que supone el 59,0% sobre el total de pacientes con enfermedad de Alzheimer del área. El 66,0% eran mujeres, el 86,8% mayores de 75 años, con una media de 9,2 fármacos/paciente. El número medio de fármacos anticolinérgicos fue 1,6; el 38,3% de los pacientes tenían prescritos varios fármacos anticolinérgicos y el 23,9% algún fármaco de alta potencia anticolinérgica. Se encontró asociación estadísticamente significativa entre tomar IACE y anticolinérgicos de forma concomitante (p = 0,000; OR: 3,9). Conclusiones. La prevalencia de interacción entre IACE y anticolinérgicos es relevante, considerando que además afecta a población vulnerable. Proporcionar a los médicos información sobre la interacción podría ayudar a la toma de decisiones clínicas, mejorar la seguridad y los resultados en salud de los pacientes (AU)

Introduction. Anticholinergic drugs reduce the efficacy of acetylcholinesterase inhibitors (AChEI) and are inappropriate in elderly patients. The aim of this study is to determine the prevalence rate of prescription AChEI drugs and anticholinergics in a Healthcare Area, to identify the affected patients, and to inform the attending physicians, in order to evaluate the suitability of treatments. Material and methods. A descriptive cross-sectional observational study of prevalence. Patients on treatment with AChEI and any anticholinergic drug in the first quarter of 2015 were selected. The review of Duran et al. was used as reference to identify anticholinergics, assigning a score to each drug according to its anticholinergic potency. Physicians were provided with a report about the interaction, the list of affected patients, and recommendations. Results. A total of 486 patients were included in the study, representing 59.0% of total patients with Alzheimer's disease in the Area. There were 66.0% women, and 86.8% of the patients were older than 75 years, and with a mean of 9.2 drugs per patient. The mean number of anticholinergic drugs was 1.6, and 38.3% of patients were prescribed various anticholinergic drugs, with 23.9% on high potency anticholinergic drugs. A statistically significant association was found between taking an anticholinergic and AChEI concomitantly (P=.000; OR: 3.9). Conclusions. The prevalence of interactions between AChEI and anticholinergic drugs is relevant, considering that it affects vulnerable members of the population. Providing physicians with information about the interaction could help them make clinical decisions, and could improve patient safety, as well as health outcomes (AU)

Effect of Statin Use on Influenza Vaccine Effectiveness.

BACKGROUND: Recent studies suggest that statin use may reduce influenza vaccine effectiveness (VE), but laboratory-confirmed influenza was not assessed. METHODS: Patients ≥45 years old presenting with acute respiratory illness were prospectively enrolled during the 2004-2005 through 2014-2015 influenza seasons. Vaccination and statin use were extracted from electronic records. Respiratory samples were tested for influenza virus. RESULTS: The analysis included 3285 adults: 1217 statin nonusers (37%), 903 unvaccinated statin nonusers (27%), 847 vaccinated statin users (26%), and 318 unvaccinated statin users (10%). Statin use modified VE and the risk of influenza A(H3N2) virus infection (P = .002) but not 2009 pandemic influenza A(H1N1) virus (A[H1N1]pdm09) or influenza B virus infection (P = .2 and .4, respectively). VE against influenza A(H3N2) was 45% (95% confidence interval [CI], 27%-59%) among statin nonusers and -21% (95% CI, -84% to 20%) among statin users. Vaccinated statin users had significant protection against influenza A(H1N1)pdm09 (VE, 68%; 95% CI, 19%-87%) and influenza B (VE, 48%; 95% CI, 1%-73%). Statin use did not significantly modify VE when stratified by prior season vaccination. In validation analyses, the use of other cardiovascular medications did not modify influenza VE. CONCLUSIONS: Statin use was associated with reduced VE against influenza A(H3N2) but not influenza A(H1N1)pdm09 or influenza B. Further research is needed to assess biologic plausibility and confirm these results.

Top 10 Things Primary Care Physicians Should Know About Maintenance Immunosuppression for Transplant Recipients.

The success of organ transplantation allows many transplant recipients to return to life similar to nontransplant patients. Their need for regular health care, including preventive medicine, has switched the majority of responsibilities for their health care from transplant specialists to primary care physicians. To take care of transplant recipients, it is critical for primary care physicians to be familiar with immunosuppressive medications, their side effects, and common complications in transplant recipients. Ten subjects are reviewed here in order to assist primary care physicians in providing optimal care for transplant recipients.

Morbidity in older HIV-infected patients: impact of long-term antiretroviral use.

The introduction of HAART has represented a major advance in the care of people with HIV. By markedly increasing life expectancy, HAART has significantly changed the pattern of HIV infection in developed countries, the "graying" of the HIV-infected population being a powerful testament to its success. However, this has presented physicians with new challenges relating to the care of older patients with HIV, many of whom exhibit a "frailty syndrome" associated with increased comorbidity and chronic low-grade inflammation in a process which has recently been termed "inflammaging". This paper reviews the pattern of morbidity seen in older HIV-infected patients and examines the effects, both beneficial and deleterious, of antiretroviral therapy. The efficacy and tolerability of antiretroviral therapy is of particular importance in older patients, given the likelihood that increased frailty may magnify the consequences both of suboptimal viral suppression and of toxicity, and in view of the complications that may arise from the presence of comorbidities and resultant polypharmacy. The challenge is to maximize antiviral efficacy and minimize toxicity, while taking into account the often complex web of comorbidities that may be present in these patients. This challenge is being met through the refinement of existing antiretroviral therapy regimens, the development of new agents, and a growing focus on a more holistic approach to care, which acknowledges the importance of the overall "health picture" and of good communication and cooperation between treating physicians and patients.

Suspicion of a new cross-reaction between carbamazepine and olanzapine

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Teriflunomide effect on immune response to influenza vaccine in patients with multiple sclerosis.

OBJECTIVE: To investigate the effect of teriflunomide on the efficacy and safety of seasonal influenza vaccine. METHODS: The 2011/2012 seasonal influenza vaccine (containing H1N1, H3N2, and B strains) was administered to patients with relapsing forms of multiple sclerosis (RMS) treated for ≥6 months with teriflunomide 7 mg (n = 41) or 14 mg (n = 41), or interferon-ß-1 (IFN-ß-1; n = 46). The primary endpoint was the proportion of patients with influenza strain-specific antibody titers ≥40, 28 days postvaccination. RESULTS: More than 90% of patients achieved postvaccination antibody titers ≥40 for H1N1 and B in all groups. For H3N2, titers ≥40 were achieved in ≥90% of patients in the 7 mg and IFN-ß-1 groups, and in 77% of the 14-mg group, respectively. A high proportion of patients already had detectable antibodies for each influenza strain at baseline. Geometric mean titer ratios (post/prevaccination) were ≥2.5 for all groups and strains, except for H1N1 in the 14-mg group (2.3). The proportion of patients with a prevaccination titer <40 achieving seroprotection was ≥61% across the 3 treatment groups and 3 influenza strains. However, fewer patients in the 14-mg than the 7-mg or IFN-ß-1 groups exhibited seroprotection to H3N2 (61% vs. 78% and 82%, respectively). CONCLUSION: Teriflunomide-treated patients generally mounted effective immune responses to seasonal influenza vaccination, consistent with preservation of protective immune responses. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that teriflunomide generally does not adversely impact the ability of patients with RMS to mount immune responses to influenza vaccination.

Interacciones farmacológicas / Drugs interactions

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Spinal mitochondrial-derived peroxynitrite enhances neuroimmune activation during morphine hyperalgesia and antinociceptive tolerance.

Treatment of severe pain by morphine, the gold-standard opioid and a potent drug in our arsenal of analgesic medications, is limited by the eventual development of hyperalgesia and analgesic tolerance. We recently reported that systemic administration of a peroxynitrite (PN) decomposition catalyst (PNDC) or superoxide dismutase mimetic attenuates morphine hyperalgesia and antinociceptive tolerance and reduces PN-mediated mitochondrial nitroxidative stress in the spinal cord. These results suggest the potential involvement of spinal PN signaling in this setting; which was examined in the present study. PN removal with intrathecal delivery of manganese porphyrin-based dual-activity superoxide/PNDCs, MnTE-2-PyP(5+) and the more lipophilic MnTnHex-2-PyP(5+), blocked hyperalgesia and antinociceptive tolerance in rats. Noteworthy is that intrathecal MnTnHex-2-PyP(5+) prevented nitration and inactivation of mitochondrial manganese superoxide dismutase. Mitochondrial manganese superoxide dismutase inactivation enhances the superoxide-to-PN pathway by preventing the dismutation of superoxide to hydrogen peroxide, thus providing an important enzymatic source for PN formation. Additionally, intrathecal MnTnHex-2-PyP(5+) attenuated neuroimmune activation by preventing the activation of nuclear factor kappa B, extracellular-signal-regulated kinase and p38 mitogen activated protein kinases, and the enhanced levels of proinflammatory cytokines, interleukin (IL)-1ß and IL-6, while increasing anti-inflammatory cytokines, IL-4 and IL-10. The role of PN was further confirmed using intrathecal or oral delivery of the superoxide-sparing PNDC, SRI-110. These results suggest that mitochondrial-derived PN triggers the activation of several biochemical pathways engaged in the development of neuroinflammation in the spinal cord that are critical to morphine hyperalgesia and tolerance, further supporting the potential of targeting PN as an adjunct to opiates to maintain pain relief.

ß-Lapachone ameliorization of experimental autoimmune encephalomyelitis.

ß-Lapachone is a naturally occurring quinine, originally isolated from the bark of the lapacho tree (Tabebuia avellanedae) which is currently being evaluated in clinical trials for the treatment of cancer. In addition, recent investigations suggest its potential application for treatment of inflammatory diseases. Multiple sclerosis (MS) is an autoimmune disorder characterized by CNS inflammation and demyelination. Reactive T cells including IL-17 and IFN-γ-secreting T cells are believed to initiate MS and the associated animal model system experimental autoimmune encephalomyelitis (EAE). IL-12 family cytokines secreted by peripheral dendritic cells (DCs) and CNS microglia are capable of modulating T-cell phenotypes. The present studies demonstrated that ß-lapachone selectively inhibited the expression of IL-12 family cytokines including IL-12 and IL-23 by DCs and microglia, and reduced IL-17 production by CD4(+) T-cells indirectly through suppressing IL-23 expression by microglia. Importantly, our studies also demonstrated that ß-lapachone ameliorated the development on EAE. ß-Lapachone suppression of EAE was associated with decreased expression of mRNAs encoding IL-12 family cytokines, IL-23R and IL-17RA, and molecules important in Toll-like receptor signaling. Collectively, these studies suggest mechanisms by which ß-lapachone suppresses EAE and suggest that ß-lapachone may be effective in the treatment of inflammatory diseases such as MS.

Methotrexate polyglutamation in relation to infliximab pharmacokinetics in rheumatoid arthritis.

OBJECTIVE: The combination of methotrexate (MTX) with infliximab can modify infliximab pharmacokinetics and lower the incidence of antibodies against infliximab (ATIs). We hypothesised that the pharmacokinetic interaction between MTX and infliximab is related to activation of MTX to immunosuppressive MTX polyglutamates (MTXPGs). METHODS: Adult patients with rheumatoid arthritis receiving weekly MTX with infliximab for more than 3 months were enrolled in a cross-sectional study. Blood was collected at trough before the infusion of infliximab. Red blood cell (RBC) MTXPGs were measured using liquid chromatography, and circulating levels of infliximab were measured using a cell-based assay. ATIs were measured using enzyme immunoassays. Statistical analyses consisted of multiple regression and Wilcoxon tests. RESULTS: In the 61 patients enrolled in the study, ATIs were detected in 11 (18%). Regression analyses revealed that lower infliximab levels (median 3.3 µg/ml) were associated with the presence of ATIs and lower RBC MTXPG levels (median 28 nmol/l) (p<0.05). Logistic regression revealed that RBC MTXPG levels above 25 nmol/l were associated with a 4.7-fold lower likelihood of having ATIs (OR=4.7; 95% CI 1.1 to 20.8; p=0.02). None of the 12 patients with RBC MTXPG levels above 50 nmol/l tested positive for ATIs. CONCLUSIONS: These hypothesis-generating data indicate that MTXPGs are associated with infliximab pharmacokinetics and ATI formation.

Paying more than lip service to an oral lesion: a case of plasmablastic lymphoma.

Plasmablastic lymphoma (PBL) is a variant of lymphoma originally described in the oral cavity of patients with advanced HIV. Our patient developed PBL despite well-controlled HIV and a CD4 count greater than 800 cells/µl. A drug interaction with an inhaled corticosteroid and ritonavir likely contributed to the development of this malignancy through increased immune suppression.

The impact of terminal complement blockade on the efficacy of induction with polyclonal rabbit antithymocyte globulin in living donor renal allografts.

BACKGROUND: Eculizumab, a potent inhibitor of terminal complement activation, appears promising in reducing early antibody-mediated rejection in positive crossmatch kidney transplantation. However, its concomitant use with polyclonal rabbit antithymocyte globulin (rATG) might reduce the efficacy of rATG. This study aimed to evaluate the effect of eculizumab on the efficacy of rATG in vivo and determine the role of complement in rATG-induced lymphocyte cell depletion. PATIENTS AND METHODS: Thirty-six kidney transplant recipients were classified into 3 groups according to induction regime: anti-IL-2 receptor antibody alone induction group (basiliximab, n=8); rATG induction (n=20), and rATG+eculizumab induction group (n=8). Peripheral blood T-cell subsets and NK cells were measured 3-4 days after transplant (after 3 doses of rATG). RESULTS: Compared to anti-IL-2 receptor antibody induction group, both groups treated with rATG demonstrated significant depletion of all T-cell subsets (CD3-positive cells) (P<0.0001 for rATG vs. anti-IL-2 receptor antibody induction group; P<0.001 for rATG+eculizumab vs. anti-IL-2 receptor antibody group). However, while T-cell counts were low in all rATG-treated patients, eculizumab treatment resulted in higher peripheral blood T-cell counts in rATG treated patients (P=0.005). Before induction, median total lymphocyte counts were normal for the three study groups. By 1, 4 months and 1 year, median the total lymphocyte count was normal for the anti-IL-2 receptor antibody group but was below normal range or at the lower edge of normality for rATG and rATG+eculizumab groups. CONCLUSIONS: This small-sample size study suggests that peripheral T cells are depleted by rATG in the presence of terminal complement inhibition. However, eculizumab appears to have a mild inhibitory effect on peripheral blood T-cell depletion by rATG in kidney transplant recipients.