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Efficacy and safety outcomes in vitamin D supplement users in the fingolimod phase 3 trials.
Hongell, K, Silva, DG, Ritter, S, Meier, DP, Soilu-Hänninen, M
Journal of neurology. 2018;(2):348-355
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Abstract
BACKGROUND Low serum levels of 25-hydroxyvitamin D have been associated with worse outcomes in multiple sclerosis (MS) patients treated with interferon-beta. Association of vitamin D nutrition on the outcomes of other MS therapies has been studied less. OBJECTIVE Whether patients in the phase 3 fingolimod trials using vitamin D supplements have better clinical, MRI and safety outcomes than non-users. MATERIALS AND METHODS Pooled data from phase 3 FREEDOMS trials was analyzed post hoc. Vitamin D use was defined as 'non-users' (n = 562), 'casual users' (n = 157) and 'daily users' (usage 100% time in the study, n = 110). RESULTS Expanded Disability Status Scale change from baseline to month 24, and annual relapse rate and proportion of patients with relapses were similar across the vitamin D user groups. Proportion of patients free of new/enlarging T2 lesions significantly favored vitamin D 'daily users' versus 'non-users'. Mean number of lesions were lower and proportion of patients free of gadolinium-enhanced T1-lesions were higher in the 'daily users'. At month 12, percent brain volume change was significantly lower in the 'daily users' versus 'non-users' and remained low at month 24 (non-significant). Incidence of depression was lower for vitamin D 'daily users' (non-significant). CONCLUSIONS We observed improved MRI outcomes on percent brain volume change and proportion of patients free of new/enlarging T2 lesions, and a trend of less depression in the 'daily users' of vitamin D supplement in patients in the FREEDOMS trials.
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Tremor induced by Calcineurin inhibitor immunosuppression: a single-centre observational study in kidney transplanted patients.
Erro, R, Bacchin, R, Magrinelli, F, Tomei, P, Geroin, C, Squintani, G, Lupo, A, Zaza, G, Tinazzi, M
Journal of neurology. 2018;(7):1676-1683
Abstract
INTRODUCTION Tremor is the most frequent and disabling neurological side effect under Calcineurin inhibitor-induced immunosuppression, but no studies have defined its phenomenology, severity, distribution, the impact on quality of life, as well as of other neurological symptoms associated. METHODS 126 consecutive kidney-transplanted patients, under treatment with Cyclosporin A, Tacrolimus and non-Calcineurin inhibitors, within therapeutic range, were enrolled. Participants underwent a deep neurological examination by two blinded to the treatment raters, and a blood sampling to assess plasmatic immunosuppressant level and nephrological function tests. Tremor and cerebellar signs were scored according to the Fahn-Tolosa-Marin and the SARA scale. Parkinsonism was excluded applying the UPDRS (part III). RESULTS Tremor was more common and severe in the Tacrolimus group, similar to impairment in ADL. Regardless of treatment, tremor involved both upper and lower limbs and was activated by action, but in about 50% of cases presented in action and rest condition. Plasmatic level of Tacrolimus was higher in patients with tremor than in those without, while cholesterol was significantly lower. Cerebellar and neuropathic signs were overall mild and were not significantly different across the three groups comparing patients with and without tremor. CONCLUSIONS Non-Calcineurin inhibitors such as Sirolimus have the lowest propensity to induce tremor and with a milder severity, while Calcineurin inhibitors, especially Tacrolimus, the highest, and regardless of the formulation. Plasmatic concentration of Tacrolimus was higher in tremulous patients; further research needs to validate the role of cholesterol plasmatic concentration in predicting the occurrence of tremor in patients on Tacrolimus.
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[Clinical and epidemiological profile of pediatric uveitis, course of inflammatory uveitis treated with anti-TNF alpha].
Osswald, D, Rameau, AC, Speeg-Schatz, C, Terzic, J, Sauer, A
Journal francais d'ophtalmologie. 2018;(5):447-452
Abstract
INTRODUCTION Uveitis is the leading cause of acquired childhood blindness with a prevalence of 30 cases per 100,000 inhabitants. There are multiple causes ; nevertheless, there is no standardized etiological assessment. The goal of our study is to define an epidemiological and clinical profile of uveitis diagnosed in a university hospital and their course when treated with anti-tumor necrosis factor (TNF) α. PATIENTS AND METHODS All cases of uveitis under 18 years old, from 1994 to 2016, were included. Post-traumatic, post-surgical, pseudo-uveitis and retinopathy of prematurity were excluded. Demographic data, patient history, initial ophthalmological status, etiologic assessment data and treatments already underway were collected. RESULTS Ninety cases of pediatric uveitis were included, among which were 16.7 % infectious uveitis, 38.9 % inflammatory uveitis and 44.4 % idiopathic uveitis. Etiologic investigations were considered incomplete in 45 % of idiopathic uveitis cases. Treatment with anti-TNFα was selected for 15.5 % of patients. In total, 33 % of patients treated with etanercept required other anti-TNFα drugs due to a lack of control of inflammation. Infliximab and adalimumab successfully managed to control inflammation in 28.6 % of cases each. DISCUSSION Diagnostic criteria based adult systemic disease are sometimes inappropriate for children. The advent of anti-TNFα appears to improve the visual prognosis of inflammatory uveitis resistant to conventional immunosuppressant therapy, but we still need to perfect protocols for their use. CONCLUSION There are neither standardized etiological assessment nor clear diagnostic and therapeutic protocols for children. TNFα inhibitors are more effective in controlling inflammation in severe pediatric uveitis.
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6-Thioguanine Nucleotide Levels Are Associated With Mucosal Healing in Patients With Crohn's Disease.
Mao, R, Guo, J, Luber, R, Chen, BL, He, Y, Zeng, ZR, Ben-Horin, S, Sparrow, MP, Roblin, X, Chen, MH
Inflammatory bowel diseases. 2018;(12):2621-2627
Abstract
BACKGROUND Level of 6-thioguanine nucleotides (6-TGN) has been reported to be associated with clinical remission in patients with Crohn's disease (CD) receiving maintenance treatment with thiopurines. Whether 6-TGN levels are associated with mucosal healing (MH) has seldom been investigated. We aimed to assess the correlation between 6-TGN levels and MH in patients with CD. METHODS This was a retrospective, cross-sectional, observational, multicenter study of 119 patients with CD treated with thiopurines in 3 inflammatory bowel disease referral centers (France, Australia, and China) between June 2012 and April 2016. Established CD patients who underwent ileocolonoscopy during thiopurine treatment were included. MH was defined as simple endoscopic score-CD <3. Univariate and multivariable regression analyses were used to evaluate variables associated with MH. RESULTS The mean concentration of 6-TGN in the MH group was higher compared with that in the non-MH group (359.0 ± 226.7 pmol/8 × 108 red blood cell count [RBC] vs 277.1 ± 170.5 pmol/8 × 108 RBC; P = 0.017). The cutoff 6-TGN concentration of 397.3 pmol/8 × 108 RBC was 86.7% specific to MH, with a sensitivity of 35.3% and area under curve (AUC) of 0.631 (P = 0.010). On multivariable analysis, 6-TGN levels were associated with MH (odds ratio [OR], 3.287; 95% confidence interval [CI], 1.348-8.017; P = 0.009) whereas late initiation of AZA (longer duration from disease onset) was inversely associated with MH (OR, 0.972; 95% CI, 0.954-0.991; P = 0.004). CONCLUSIONS Higher 6-TGN levels are independently associated with a reduced rate of endoscopically active disease and a higher rate of mucosal healing in CD patients. Prospective studies of adequate sample size are required to confirm these findings.
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Azathioprine-induced pellagra in neuromyelitis optica: A case report and review of literature.
Zhao, C, Liu, T, Ma, C, Li, H, Li, Z, Guo, J
Multiple sclerosis and related disorders. 2018;:104-107
Abstract
Neuromyelitis optica (NMO), also known as Devic's disease, is a classical autoimmune disorder of the central nervous system (CNS). The relapsing-remitting disease course contributes to application of a variety of immunosuppressants to prevent further relapses after high-dose methylprednisolone pulse therapy for acute attacks. Azathioprine is one of the most widely used immunosuppressive drugs during the remission stage of NMO due to its good efficacy and favorable side-effect profile. Even if, enough attention should be paid to some rare but devastating adverse events, such as pellagra. Herein, we reported that a well-nourished patient experienced serious pellagra while receiving oral azathioprine for treating her NMO. Moreover, literature on azathioprine-induced pellagra was reviewed to raise concerns regarding patient safety.
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Sirolimus in patients with clinically active systemic lupus erythematosus resistant to, or intolerant of, conventional medications: a single-arm, open-label, phase 1/2 trial.
Lai, ZW, Kelly, R, Winans, T, Marchena, I, Shadakshari, A, Yu, J, Dawood, M, Garcia, R, Tily, H, Francis, L, et al
Lancet (London, England). 2018;(10126):1186-1196
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BACKGROUND Patients with systemic lupus erythematosus have T-cell dysfunction that has been attributed to the activation of the mammalian target of rapamycin (mTOR). Rapamycin inhibits antigen-induced T-cell proliferation and has been developed as a medication under the generic designation of sirolimus. We assessed safety, tolerance, and efficacy of sirolimus in a prospective, biomarker-driven, open-label clinical trial. METHODS We did a single-arm, open-label, phase 1/2 trial of sirolimus in patients with active systemic lupus erythematosus disease unresponsive to, or intolerant of, conventional medications at the State University of New York Upstate Medical University (Syracuse, NY, USA). Eligible participants (aged ≥18 years) had active systemic lupus erythematosus fulfilling four or more of 11 diagnostic criteria defined by the American College of Rheumatology. We excluded patients with allergy or intolerance to sirolimus, patients with life-threatening manifestations of systemic lupus erythematosus, proteinuria, a urine protein to creatinine ratio higher than 0·5, anaemia, leucopenia, or thrombocytopenia. Patients received oral sirolimus at a starting dose of 2 mg per day, with dose adjusted according to tolerance and to maintain a therapeutic range of 6-15 ng/mL. Patients were treated with sirolimus for 12 months. Safety outcomes included tolerance as assessed by the occurrence of common side-effects. The primary efficacy endpoint was decrease in disease activity, assessed using the British Isles Lupus Assessment Group (BILAG) index and the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Blood samples of 56 matched healthy individuals were obtained as controls for immunobiological outcomes monitored at each visit. The primary efficacy endpoint was assessed in all patients who completed 12 months of treatment, and all patients who received at least one dose of treatment were included in the safety analyses. This trial is registered with ClinicalTrials.gov, number NCT00779194. FINDINGS Between March 9, 2009, and Dec 8, 2014, 43 patients were enrolled, three of whom did not meet eligibility criteria. 11 of the 40 eligible patients discontinued study treatment because of intolerance (n=2) or non-compliance (n=9). SLEDAI and BILAG disease activity scores were reduced during 12 months of treatment in 16 (55%) of 29 patients who completed treatment. Mean SLEDAI score decreased from 10·2 (SD 5·6) at enrolment to 4·8 (4·5) after 12 months of treatment (p<0·001) and the mean total BILAG index score decreased from 28·4 (12·4) at enrolment to 17·4 (10·7) after 12 months of treatment (p<0·001). The mean daily dose of prednisone required to control disease activity decreased from 23·7 mg (SD 9·6) to 7·2 mg (2·3; p<0·001) after 12 months of treatment. Sirolimus expanded CD4+CD25+FoxP3+ regulatory T cells and CD8+ memory T-cell populations and inhibited interleukin-4 and interleukin-17 production by CD4+ and CD4-CD8- double-negative T cells after 12 months. CD8+ memory T cells were selectively expanded in SRI-responders. Patient liver function and lymphocyte counts were unchanged. Although HDL-cholesterol (Z=-2·50, p=0·012), neutrophil counts (Z=-1·92, p=0·054), and haemoglobin (Z=-2·83, p=0·005) were moderately reduced during treatment, all changes occurred within a range that was considered safe. Platelet counts were slightly elevated during treatment (Z=2·06, p=0·0400). INTERPRETATION These data show that a progressive improvement in disease activity is associated with correction of pro-inflammatory T-cell lineage specification in patients with active systemic lupus erythematosus during 12 months of sirolimus treatment. Follow-up placebo-controlled clinical trials in diverse patient populations are warranted to further define the role of mTOR blockade in treatment of systemic lupus erythematosus. FUNDING Pfizer, the National Institutes of Health, and the Central New York Community Foundation.
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Pharmacogenomics of Methotrexate: Current Status and Future Outlook.
Cao, M, Guo, M, Wu, DQ, Meng, L
Current drug metabolism. 2018;(14):1182-1187
Abstract
BACKGROUND Methotrexate (MTX) is a folate analogue with high therapeutic efficiency in the treatment of cancers and autoimmune diseases. The efficacy and toxicity of MTX may be altered by genetic polymorphisms in genes involved in MTX metabolic pathway. Personalized pharmacotherapy based on gene polymorphisms enables a more efficient, compatible and cost-effective treatment of patients. OBJECTIVE The present article aims to review genetic polymorphisms associated with MTX pharmacokinetics, toxicity, and outcome, and points out future development directions of individualized MTX therapy. METHODS Details regarding the pharmacogenetics and pharmacogenomics of MTX are obtained from PubMed literatures. CONCLUSION The influences of single nucleotide polymorphisms (SNPs) in genes involved in MTX pathway are controversial. Many pharmacogenetic associations are disease specific and race specific. Present studies have almost limited to some certain ethnic groups and diseases. The data from these studies are not convincing enough to draw far-reaching conclusions about the applicability of MTX pharmacogenetics in clinical practice. Studies with large scale and multiple centers are needed in the future. MTX-PG inhibits folic metabolism through three mechanisms. TS, MTHFR and ATIC are the rate-limiting enzymes separately. The function of SNPs in these genes is often onesided. Works focusing on the analysis of polymorphism in MTX transporters should be more efficient and meaningful.
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Co-inhibitory profile and cytotoxicity of CD57+ PD-1- T cells in end-stage renal disease patients.
Kraaijeveld, R, de Graav, GN, Dieterich, M, Litjens, NHR, Hesselink, DA, Baan, CC
Clinical and experimental immunology. 2018;(3):363-372
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Blockade of the CD80/86-CD28 pathway by belatacept after kidney transplantation is associated with an increased risk of rejection compared with standard, calcineurin inhibitor (CNI)-based therapy. CD28- T cells, which express CD57, are not susceptible to belatacept treatment. High numbers of CD4+ CD57+ programmed death 1 (PD-1)- T cells pretransplantation have been associated with a higher chance of rejection, although conflicting data have been reported. To investigate the working mechanism behind this possible higher chance of rejection, we studied the expression of co-inhibitory molecules (CD223, CD244 and PD-1), proliferative capacity and cytotoxic potential of fluorescence activated cell sorted (FACS) CD4+ CD57+ PD-1- and CD8+ CD57+ PD-1- T cells, and their CD57- control populations, after alloantigen stimulation. The effect of belatacept on the cytotoxic capacity of pretransplantation peripheral blood mononuclear cells from 20 patients who received belatacept post-transplantation was also tested. Expression of co-inhibitory molecule CD223 increased by approximately 10-fold after allogeneic stimulation in all four T cell subsets. Proliferation and up-regulation of CD244 and PD-1 was observed for CD4+ CD57- PD-1- T cells after allogeneic stimulation, but no up-regulation of these markers occurred on CD8+ T cells or CD4+ CD57+ PD-1- T cells. However, CD4+ CD57+ PD-1- T cells and, to a lesser extent, CD8+ CD57+ PD-1- T cells displayed higher cytotoxicity as indicated by granzyme B expression. Belatacept inhibited the cytotoxic potential of CD4+ CD57+ PD-1- T cells (median of inhibition 31%, P < 0·01) and CD8+ CD57+ PD-1- T cells (median of inhibition 10%, P < 0·05). In conclusion, alloantigen-activated CD4+ CD57+ PD-1- T cells exhibited a less proliferative but more cytotoxic profile than their CD57- counterparts. Their cytotoxic capacity can be inhibited partly by belatacept and was not associated with development of rejection after kidney transplantation.
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Analysis of NFATc1 amplification in T cells for pharmacodynamic monitoring of tacrolimus in kidney transplant recipients.
Kannegieter, NM, Hesselink, DA, Dieterich, M, de Graav, GN, Kraaijeveld, R, Baan, CC
PloS one. 2018;(7):e0201113
Abstract
BACKGROUND Therapeutic drug monitoring (TDM) of tacrolimus, based on blood concentrations, shows an imperfect correlation with the occurrence of rejection. Here, we tested whether measuring NFATc1 amplification, a member of the calcineurin pathway, is suitable for TDM of tacrolimus. MATERIALS AND METHODS NFATc1 amplification was monitored in T cells of kidney transplant recipients who received either tacrolimus- (n = 11) or belatacept-based (n = 10) therapy. Individual drug effects on NFATc1 amplification were studied in vitro, after spiking blood samples of healthy volunteers with either tacrolimus, belatacept or mycophenolate mofetil. RESULTS At day 30 after transplantation, in tacrolimus-treated patients, NFATc1 amplification was inhibited in CD4+ T cells expressing the co-stimulation receptor CD28 (mean inhibition 37%; p = 0.01) and in CD8+CD28+ T cells (29% inhibition; p = 0.02), while this was not observed in CD8+CD28- T cells or belatacept-treated patients. Tacrolimus pre-dose concentrations of these patients correlated inversely with NFATc1 amplification in CD28+ T cells (rs = -0.46; p < 0.01). In vitro experiments revealed that 50 ng/ml tacrolimus affected NFATc1 amplification by 58% (mean; p = 0.02). CONCLUSION In conclusion, measuring NFATc1 amplification is a direct tool for monitoring biological effects of tacrolimus on T cells in whole blood samples of kidney transplant recipients. This technique has potential that requires further development before it can be applied in daily practice.
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A PRISMA-compliant systematic review and network meta-analysis on the efficacy between different regimens based on Tripterygium wilfordii Hook F in patients with primary nephrotic syndrome.
Wang, XB, Dai, EL, Xue, GZ, Ma, RL
Medicine. 2018;(27):e11282
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Abstract
BACKGROUND The present study aims to comprehensively determine the efficacy of different therapy regimens based on Tripterygium wilfordii Hook F (TwHF) for patients with primary nephrotic syndrome (PNS) using network meta-analysis method. METHODS Seven electronic databases were searched to identify randomized controlled trials (RCTs) that compared the differences between different therapy regimens based on TwHF for patients with PNS. The risk of bias in included RCTs was evaluated according to the Cochrane Handbook version 5.2.0. Network meta-analysis was performed to compare different regimens. Primary outcomes were complete remission rate and total remission rate. The secondary outcomes were hr urinary protein excretion, serum albumin, serum creatinine, and urea nitrogen. Data analysis was performed using R software. RESULTS A total of 40 studies involving 2846 patients with PNS were included. Compared with prednisone, the improvement in total remission rate and complete remission rate was associated with TwHF alone (odds ratio [OR] = 4.80, 95% credible intervals [CrI]: 2.20-10.00; OR = 6.30, 95% CrI: 2.90-13.00, respectively), TwHF+prednisone (OR = 2.10, 95% CrI: 1.30-3.50; OR = 2.40, 95% CrI: 1.50-3.80, respectively), TwHF+CPA (OR = 12.00, 95% CrI: 1.10-150.00; OR = 16.00, 95% CrI: 1.60-170.00, respectively), and TwHF+Cyclosporine A (OR = 28.00, 95% CrI: 3.20-250.00; OR = 35.00, 95% CrI: 4.50-270.00, respectively). Compared with TwHF alone, TwHF+prednisone showed less benefit in improving total remission rate and complete remission rate (OR = 0.44, 95% CrI: 0.21-0.91; OR = 0.38, 95% CrI: 0.19-0.77, respectively). TwHF alone, TwHF+prednisone could significantly reduce hr urinary protein excretion (MD = -0.69, 95% CrI: -1.30 to -0.14; MD = -1.00, 95% CrI: -1.90 to -0.14, respectively) and increase serum albumin (MD = 5.90, 95% CrI: 2.50-9.30; MD = 3.40, 95% CrI: 1.30-5.50, respectively) when compared to prednisone alone. TwHF alone showed significant reduction in serum creatinine when compared to CPA (MD = -19.00, 95% CrI: -37.00 to -0.56). CONCLUSIONS TwHF alone, the addition TwHF to prednisone showed more benefit in improving total and complete remission rate, hr urinary protein excretion, serum albumin, and serum creatinine.