ACPA Antibodies Titer at the Time of Rheumatoid Arthritis Diagnosis Is Not Associated with Disease Severity.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory and destructive joint disease with the presence of autoantibodies, rheumatoid factor (RF), and anti-citrullinated protein antibodies (ACPA). The presence of RF or ACPA predicts RA severity. Data on the influence of ACPA titer on RA course are limited. OBJECTIVES: To determine the correlation between ACPA titers at the time of RA diagnosis to RA features and severity during 3 years of follow-up. METHODS: We performed a retrospective study of RA patients treated at our institution during the years 2006-2015 with known ACPA titers at RA diagnosis who completed at least 3 years of follow-up. Patients (N=133) were divided according to ACPA titer: seronegative (< 15 U/ml, n=55), weakly positive (15-49 U/ml, n=18), moderately positive (50-300 U/ml, n=29), and strongly positive (> 300 U/ml, n=31). Patient data, including disease activity score (DAS28), bone erosion on hand and/or foot X-rays, treatments with corticosteroids and disease-modifying-anti-rheumatic drugs (DMARDs), and hospitalizations, were recorded. Chi-square and Mann-Whitney method were used for statistical analysis. P < 0.05 was considered as statistically significant. RESULTS: Male gender, smoking, and RF positivity correlated with ACPA positivity and higher ACPA titers. There was no correlation between ACPA titer and the variables defined as representing RA severity: higher DAS28, bone erosions, hospitalizations, need for corticosteroids, and conventional and biological DMARDs. CONCLUSIONS: Titer of ACPA was not identified as a predictive factor for RA severity.

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.

Acute rejection after liver transplantation is less common, but predicts better prognosis in HBV-related hepatocellular carcinoma patients.

BACKGROUND: With a novel finding of significantly lower incidence of acute rejection (AR) in patients with hepatocellular carcinoma (HCC) after liver transplantation, compared with those with benign end-stage liver disease (BESLD), in a large national cohort, we analyzed the correlations among the perioperative immuno-inflammation status, postoperative AR, and prognosis in HCC and BESLD patients with same etiology of hepatitis B virus (HBV), who underwent liver transplantation. METHODS: Patients who underwent liver transplantation due to HBV-related HCC or BESLD and experienced AR between September 2008 and April 2017 were analyzed retrospectively and followed up until April 2018. HCC patients with AR were matched with those without AR according to tumor stage and immunosuppressant concentration, at a 1:3 ratio. Preoperative immuno-inflammation status and prognosis of patients in both groups were compared. RESULTS: The overall incidences of AR in patients with HCC and BESLD were 8.60% and 10.61%, respectively. The postoperative 28-day incidence of AR was significantly lower in HCC compared with BESLD patients (3.23% vs 7.08%, p = 0.031). Compared with BESLD patients, the rejection activity index and perioperative CD4/CD8 ratio were significantly lower (p = 0.047 and p < 0.001, respectively), while platelet/lymphocyte ratio was significantly higher in HCC patients (p = 0.041). Later tumor stage in HCC patients was associated with higher systemic immuno-inflammation index, neutrophil/lymphocyte ratio, monocyte/lymphocyte ratio, platelet/lymphocyte ratio, aspartate aminotransferase/lymphocyte ratio, C-reactive protein/albumin ratio and fibrinogen level, and lower CD4/CD8 ratio before transplantation. In HCC patients with AR, the percentage of regulatory T cells (CD4+/CD25+) and the level of IL-10 significantly decreased (p = 0.0023, < 0.0001, respectively), while Th1/Th2 ratio, levels of IFN-γ and IL-2 markedly increased before transplantation (p = 0.0018, 0.0059, 0.0416, respectively). Preoperative monocyte/lymphocyte ratio was an independent risk factor for overall and recurrence-free survival after liver transplantation in HCC patients (p = 0.025, < 0.001, respectively). The 1-, 3-, and 5-year survival rates were 76%, 71% and 53% in the AR group, and 67%, 37% and 25% in the non-AR group (p = 0.042). CONCLUSION: Preoperative tumor-related immunosuppression may persist after liver transplantation in HCC patients, and reduce the incidence of AR. AR after liver transplantation may indicate a better prognosis in HCC patients.

Comparison of HBsAg changes between HBeAg-negative patients who discontinued or maintained entecavir therapy.

BACKGROUND/PURPOSE: The study compared the hepatitis B surface antigen (HBsAg) changes between hepatitis B e antigen (HBeAg)-negative non-cirrhotic chronic hepatitis B patients who discontinued or maintained entecavir therapy. METHODS: A total of 250 HBeAg-negative, non-cirrhotic patients who were treated with entecavir previously and had stopped treatment for at least 12 months (discontinued group) and 231 HBeAg-negative, non-cirrhotic patients who had received entecavir treatment for at least 4 years (maintained group) were recruited. RESULTS: In the discontinued group, 71 had a persistent virological suppression (Group I), 35 experienced virological relapse but no clinical relapse or retreatment (Group II), 26 experienced clinical relapse without retreatment (Group III), and 118 experienced HBV relapse and retreatment (Group IV). Patients in Groups I, II, and III, but not in Group IV, experienced a significantly larger drop in HBsAg levels' post-treatment than during entecavir treatment. Patients in Groups I and III exhibited a greater post-treatment HBsAg decline than patients in Groups II and IV (p < 0.001). Discontinued group experienced a significantly larger drop in HBsAg levels (p < 0.001) and higher HBsAg loss rate (p = 0.001) than maintained group after adjusting for clinical features and HBsAg levels in propensity score matched patients. Patients in maintained group exhibited a smaller drop in HBsAg and lower HBsAg loss rate than patients in groups I, II, and III, but not in Group IV. CONCLUSIONS: Patients who discontinued entecavir therapy and achieved persistent virological suppression exhibited a greater HBsAg decline and higher HBsAg loss rate compared with patients who maintained entecavir therapy.

Short-term outcomes of down-referral in provision of paediatric antiretroviral therapy at Red Cross War Memorial Children's Hospital, Cape Town, South Africa: A retrospective cohort study.

BACKGROUND: The large scale-up of paediatric HIV care necessitated down-referral of many children receiving antiretroviral therapy (ART) from Red Cross War Memorial Children's Hospital (RCWMCH), Cape Town, South Africa. Few published data exist on the outcomes of these children. OBJECTIVES: To assess outcomes of children receiving ART in the first 12 months after down-referral to primary healthcare (PHC) clinics and identify determinants of successful down-referral. METHODS: A retrospective cohort study of children <15 years of age who initiated ART at RCWMCH and were subsequently down-referred to one of two PHC clinics between January 2006 and December 2012 was completed. Baseline characteristics of patients and caregivers as well as CD4+ counts, viral loads (VLs) and weights were collected 6 and 12 months after down-referral. Outcomes included retention in care and viral suppression. RESULTS: Of 116 children down-referred to the two study PHC clinics, 81.9% arrived at the designated PHC clinic and a further 8.6% continued care at other clinics, the remaining 9.5% being lost to follow-up. Of those successfully down-referred, 11.4% took >8 weeks to present, possibly experiencing treatment interruption. At 12 months after down-referral, only 81.0% remained in care. No factors were associated with retention in care in multivariable analysis. For children who remained in care at the designated PHC clinics, the clinical and immunological gains achieved prior to down-referral were sustained through 12 months of follow-up, and 54.7% of this cohort had documented viral suppression at 12 months. However, if only children with VL results are considered, 75.9% (41/54) were virally suppressed 12 months after down-referral. CONCLUSIONS: Down-referral of children on ART is complex, with risk of loss to follow-up and treatment interruption.

Cancer Immunotherapy Trials Underutilize Immune Response Monitoring.

Immune-related radiological and biomarker monitoring in cancer immunotherapy trials permits interrogation of efficacy and reasons for therapeutic failure. We report the results from a cross-sectional analysis of response monitoring in 685 T-cell checkpoint-targeted cancer immunotherapy trials in solid malignancies, as registered on the U.S. National Institutes of Health trial registry by October 2016. Immune-related radiological response criteria were registered for only 25% of clinical trials. Only 38% of trials registered an exploratory immunological biomarker, and registration of immunological biomarkers has decreased over the last 15 years. We suggest that increasing the utilization of immune-related response monitoring across cancer immunotherapy trials will improve analysis of outcomes and facilitate translational efforts to extend the benefit of immunotherapy to a greater proportion of patients with cancer.

[An assessment of the immune status of the children population as a marker of technogenic pollution of the environment].

This article describes results of the immunological study of school-aged children residing in cities with different levels of the technogenic air pollution. Children from cities with the highest level of the technogenic pollution had a high number of immature neutrophils (band cells) and eosinophils. The children living in these ecologically unfavorable areas have presented a reduction of T-cell antigen receptor CD3, CD4, CD8, CD20, CD16, CD95. This indicates to that both T-cell and B-cell immunity is suppressed. The decline of the phagocytic function in neutrophils indicates to the suppression of the nonspecific host defense mechanisms also.

[Features of immune response in chronic exposure to industrial aerosols].

There are considered features of disorders of the immune response in chronic exposure to dust aerosols. The detected changes of indices of the immune status of employees of the dust dangerous occupations and patients with chronic dust pathology of the lungs were unidirectional in the character, which is probably caused by manifestations of nonspecific response of the immune system to the dust factor. The deterioration of cellular immunity, humoral immunity and cytokine profile predisposes to the occurrence of immunopathologic states, contributing to the development of caused by both worksite and occupation pathology.

[Child and Adolescent Interepydemic Immunity to Influenza Viruses].

OBJECTIVE: Our aim was to evaluate the child and adolescent population immunity to influenza A viruses (IAV) and influenza B virus (IBV). METHODS: The concentration and specificity of antiviral antibodies was evaluated by hemagglutination inhibition assay (HAI) that was performed using commercial HAI diagnostic kits. RESULTS: The serum samples of 254 clinically healthy children and adolescents were examined in this study. 245 participants had the antibodies to IAV, 199--to IAV and IBV and only 4 children aged between 1 and 4 years and a 12-year-old boy had no immunity to IAVor IBV. The number of children with specific immunity increased in elder groups by 43% (from 81 to 116) for N0N1, and H3N2 subtypes and by 110% (from 38 to 80) for H1N1 subtype of IAV. In children younger than 4 years the titer of specific antibodies against the H1N1pdm09 was 1:210 and against the H3N2--1:270, whereas in adolescents of 10-14 years these figures were by 1.6 and 2.4 times lower (1:130 and 1:120) respectively. Antibodies to the subtypes H2N2 and H5N1 were not detected. CONCLUSION: The results indicate that 98.4% of child and adolescent population in interepidemic influenza season are immune to the various IAV (H3N2, H1N1, H0N1) as well as to the IBV. More than half of children and adolescents (57.4%) are immune to H1N1pdm09 subtype of IAV. The strength of immune response to the recent pathogens (H3N2 u H1N1pdm09) is higher in infants than in teenagers.

Detecting virological failure in HIV-infected Tanzanian children.

BACKGROUND: The performance of clinical and immunological criteria to predict virological failure in HIV-infected children receiving antiretroviral therapy (ART) is not well documented. OBJECTIVE: To determine the validity of clinical and immunological monitoring in detecting virological failure in children on ART. METHODS: A total of 218 children were included in the study. All were from care and treatment clinics in Dar es Salaam, Tanzania. Their mean age was 10.6 years, 122 (56.0%) were males, and the mean time on ART was 40.9 months. The study was conducted from August 2011 to March 2012. Data on sociodemographic and clinical characteristics and immunological and virological failure were based on World Health Organization definitions. Blood samples were collected for CD4+ T-cell count and viral load tests. RESULTS: Of 217 children with available viral load results, 124 (57.1%) had virological failure (>400 copies/mL), 25.0% immunological failure and 11.5% clinical failure. The sensitivity, specificity, positive predictive value and negative predictive value of clinical criteria were 12.9%, 90.3%, 64.0% and 43.8%, respectively, those for immunological criteria 22.6%, 73.1%, 53.3% and 41.4%, and those for the combination of clinical and immunological monitoring 25.8%, 69.9%, 53.3% and 41.4%. Children who received nevirapine (NVP)-based regimens were two times more likely (odds ratio 2.0; 95% confidence interval 1.20 - 3.64) to have virological failure than those on efavirenz and protease inhibitor-based regimens. CONCLUSIONS: The study demonstrated poor performance of currently recommended clinical and immunological criteria for monitoring HIV-infected children on ART. Moreover, children on NVP-based regimens had a higher risk of developing virological failure than those on other regimens.

The Immunology Quality Assessment Proficiency Testing Program for CD3⁺4⁺ and CD3⁺8⁺ lymphocyte subsets: a ten year review via longitudinal mixed effects modeling.

Since 1999, the National Institute of Allergy and Infectious Diseases Division of AIDS (NIAID DAIDS) has funded the Immunology Quality Assessment (IQA) Program with the goal of assessing proficiency in basic lymphocyte subset immunophenotyping for each North American laboratory supporting the NIAID DAIDS HIV clinical trial networks. Further, the purpose of this program is to facilitate an increase in the consistency of interlaboratory T-cell subset measurement (CD3(+)4(+)/CD3(+)8(+) percentages and absolute counts) and likewise, a decrease in intralaboratory variability. IQA T-cell subset measurement proficiency testing was performed over a ten-year period (January 2003-July 2012), and the results were analyzed via longitudinal analysis using mixed effects models. The goal of this analysis was to describe how a typical laboratory (a statistical modeling construct) participating in the IQA Program performed over time. Specifically, these models were utilized to examine trends in interlaboratory agreement, as well as successful passing of proficiency testing. Intralaboratory variability (i.e., precision) was determined by the repeated measures variance, while fixed and random effects were taken into account for changes in interlaboratory agreement (i.e., accuracy) over time. A flow cytometer (single-platform technology, SPT) or a flow cytometer/hematology analyzer (dual-platform technology, DPT) was also examined as a factor for accuracy and precision. The principal finding of this analysis was a significant (p<0.001) increase in accuracy of T-cell subset measurements over time, regardless of technology type (SPT or DPT). Greater precision was found in SPT measurements of all T-cell subset measurements (p<0.001), as well as greater accuracy of SPT on CD3(+)4(+)% and CD3(+)8(+)% assessments (p<0.05 and p<0.001, respectively). However, the interlaboratory random effects variance in DPT results indicates that for some cases DPT can have increased accuracy compared to SPT. Overall, these findings demonstrate that proficiency in and among IQA laboratories have, in general, improved over time and that platform type differences in performance do exist.

Statistical methods for the assessment of EQAPOL proficiency testing: ELISpot, Luminex, and Flow Cytometry.

In September 2011 Duke University was awarded a contract to develop the National Institutes of Health/National Institute of Allergy and Infectious Diseases (NIH/NIAID) External Quality Assurance Program Oversight Laboratory (EQAPOL). Through EQAPOL, proficiency testing programs are administered for Interferon-γ (IFN-γ) Enzyme-linked immunosorbent spot (ELISpot), Intracellular Cytokine Staining Flow Cytometry (ICS) and Luminex-based cytokine assays. One of the charges of the EQAPOL program was to apply statistical methods to determine overall site performance. We utilized various statistical methods for each program to find the most appropriate for assessing laboratory performance using the consensus average as the target value. Accuracy ranges were calculated based on Wald-type confidence intervals, exact Poisson confidence intervals, or via simulations. Given the nature of proficiency testing data, which has repeated measures within donor/sample made across several laboratories; the use of mixed effects models with alpha adjustments for multiple comparisons was also explored. Mixed effects models were found to be the most useful method to assess laboratory performance with respect to accuracy to the consensus. Model based approaches to the proficiency testing data in EQAPOL will continue to be utilized. Mixed effects models also provided a means of performing more complex analyses that would address secondary research questions regarding within and between laboratory variability as well as longitudinal analyses.

Comparative analysis of predicted HLA binding of immunoglobulin idiotype sequences indicates T cell-mediated immunosurveillance in follicular lymphoma.

Active immunization with the idiotype of follicular lymphoma induces tumor-specific immunity. T cells induced in vivo by idiotype vaccination recognize human leukocyte antigen (HLA)--restricted hypervariable but not conserved idiotype peptides. We hypothesized that idiotype-directed T-cell immunity occurs naturally and performed a reverse immunology analysis of idiotype HLA binding in 39 follicular lymphoma patients. For every idiotype, the sum of HLA-A or -B binding scores of the 20 highest-scoring peptides was calculated for all 39 HLA types through the BIMAS algorithm. The idiotype sum score of every patient's lymphoma was compared on the respective patient's HLA type to the mean of the sum scores of the remaining 38 idiotypes. Autologous idiotypes had lower immunogenicity than allogeneic idiotypes. Differential immunogenicity resided predominantly in all 3 complementarity-determining regions rather than in framework peptides. Idiotype immunogenicity was not changed by somatic hypermutation. These findings indicate T cell-mediated immunosurveillance of follicular lymphoma directed specifically against individual idiotype epitopes.

[CLINICAL AND IMMUNOLOGICAL FEATURES IN CHILDREN WITH A TUBERCULIN TEST CONVERSION IN RELATION TO THE ESTABLISHMENT OF CONTACT WITH A BACTERIA-EXCRETING PERSON].

Active tuberculosis infection is most likely to occur within the first year since the entry of M. tuberculosis (MBT) into the human organism. Contact duration is one of the determinants of the outcome of the meeting of MBT and a macroorganism. Patients with chronic infection foci and/or immune system dysfunction have been the particular concern of medical workers. The impaired defense system from alien information can lead to the development of tuberculosis. The repertoire of immunocompetent cells and interleukins in children with a tuberculin test conversion from epidemiological foci is similar to that in those with active tuberculosis. According to immunological characteristics, the patients with a tuberculin test conversion without an established contact differ from those with tuberculosis and children with a conversion and a contact with a bacteria-excreting person. They had an allergic constitution, which manifested itself as the higher frequency of allergic dermatosis. This fact resulted in mixed allergic reactions, which enlarged papulae during tuberculin diagnosis.

Predicting tumor outcome following cancer vaccination by monitoring quantitative and qualitative CD8+ T cell parameters.

Identification of reliable surrogate predictors for evaluation of cancer vaccine efficacy is a critical issue in immunotherapy. We analyzed quantitative and qualitative CD8+ T cell parameters in a large pool of BALB/c mice that were DNA-vaccinated against P1A self tumor-specific Ag. After immunization, mice were splenectomized and kept alive for a subsequent tumor challenge to correlate results of immune monitoring assays with tumor regression or progression in each individual animal, and to assess the prognostic value of the assays. The parameters tested were 1) percentage of in vivo vaccine-induced tumor-specific CD8+ T cells; 2) results of ELISPOT tests from fresh splenocytes; 3) percentage of tumor-specific CD8+ T cells in culture after in vitro restimulation; 4) in vitro increase of tumor-specific CD8+ T cell population expressed as fold of expansion; and 5) antitumor lytic activity of restimulated cultures. Except for the ELISPOT assay, each parameter tested was shown by univariate statistical analysis to correlate with tumor regression. However, multivariate analysis revealed that only in vitro percentage of Ag-specific CD8+ T cells was an independent prognostic factor that predicted tumor outcome. These findings should be considered in the design of new immune monitoring systems used in cancer immunotherapy studies.

The relationship between migraine and atopic disorders-the contribution of pulmonary function tests and immunological screening.

This cross-sectional clinical study was conducted in order to explore the relationship between atopic disorders and migraine. We evaluated 186 consecutive patients with migraine. Patients with a history of atopic disorders were compared with the others during headache-free intervals, for their headache characteristics, pulmonary test (PFT) performances and immunological screenings, through appropriate statistical methods. Of the patients with migraine, 77 (41.4%) reported at least one atopic disorder. PFT screening showed a general decreased pulmonary capacity and an important correlation between a positive history of atopic disorders and both increased eosinophil and IgE levels in headache-free periods. It should be discussed whether screening with PFT or immunological tests helps in early detection of progressive lung disease which might develop in these patients.

Clinical utility of tetramer-based immune monitoring in allogeneic stem cell transplantation.

The construction and use of Class I human leucocyte antigen (HLA) tetramers has, for the first time, allowed the direct enumeration of CD8(+) T lymphocytes specific for the antigen of interest. Tetramer staining can be combined with functional assays of antigen-specific T cells measuring their production of intracellular cytokines after short-term stimulation with antigen. The advantages of flow cytometric tetramer-based assays are their short turn-around time and their amenability to standardisation. Currently, their main limitation is that only a limited number of Class I HLA tetramers are available. This situation may bias the information derived from such studies. Nevertheless, clinically useful information has been obtained in tetramer-based studies of the regeneration of cytomegalovirus (CMV) and Epstein-Barr virus (EBV)-specific CD8(+) T cells after allogeneic stem cell transplantation (SCT). Following myeloablative cytoreductive therapy and SCT, a period of deep cellular immunodeficiency follows until the donor-derived immune system has sufficiently regenerated. As a result of the lack of immunosurveillance, endogenous viruses such as CMV and EBV may reactivate and cause disease. In order to prevent these complications, pre-emptive therapeutic interventions are made, in which antiviral treatment is administered based on frequent viral load measurements. In this way, overtreatment associated with prophylactic strategies is reduced; however, a subgroup of patients developing recurrent reactivations and/or disease remains. Interventions aimed at the prevention of graft versus host disease (GVHD) and the reduction of its severity greatly reduce the rate of (virus-specific) T-cell reconstitution and hence, increase the frequency and severity of viral reactivations. Specifically, T-cell depletion of SCT and the use of antithymocyte globulin as part of the conditioning regimen reduces the (virus-specific) T lymphocytes transferred with the graft, which otherwise would have contributed to the first phase of T-cell regeneration post-SCT. Consequently, patients whose CMV- and EBV-specific CD8(+) T cells fail to regenerate to levels detectable by tetramer-based flow cytometry during the first 3-6 months post-SCT were at highly increased risk for CMV disease and EBV(+) B-lymphoproliferative disease, respectively. Furthermore, delayed reconstitution of the CD4(+) T-cell compartment results in the lack of adequate help for the generation of sufficient antiviral CD8(+) T cells. Conversely, adoptive immunotherapy using CMV- or EBV-specific T cells results in the swift restoration of virus-specific T-cell immunity and the reduction of viral load, unless corticosteroids have to be administered to treat concurrent GVHD. Studies have shown the clinical utility of tetramer-based immune monitoring in the setting of allogeneic SCT and indicate that such assays, extended by functional studies of the virus-specific T cells, may constitute a valuable extension of current viral load monitoring strategies.

Therapeutic monitoring of mycophenolate mofetil in organ transplant recipients: is it necessary?

Adequate immunosuppression minimising the risk of organ rejection with acceptable tolerability of the used drugs is a crucial step in organ transplantation. The primary goal is to maintain a consistent time-dependent target concentration by tailoring individual dosage leading to the best efficacy and tolerability combination. The use of therapeutic drug monitoring (TDM) to optimise immunosuppressive therapy is routinely employed for maintenance drugs such as cyclosporin and tacrolimus. The question whether therapeutic monitoring of mycophenolic acid (MPA) in organ transplant recipients treated with mycophenolate mofetil is necessary is not definitely answered. The correlation of mycophenolic acid pharmacokinetic parameters with efficacy and toxicity makes the therapeutic monitoring of this drug promising. However, further studies are mandatory to draw the best guidelines in order to achieve higher levels of evidence that MPA-TDM may improve patient outcome.