Counteracting tryptophan metabolism alterations as a new therapeutic strategy for rheumatoid arthritis.

OBJECTIVES: Alterations in tryptophan (Trp) metabolism have been reported in inflammatory diseases, including rheumatoid arthritis (RA). However, understanding whether these alterations participate in RA development and can be considered putative therapeutic targets remains undetermined.In this study, we combined quantitative Trp metabolomics in the serum from patients with RA and corrective administration of a recombinant enzyme in experimental arthritis to address this question. METHODS: Targeted quantitative Trp metabolomics was performed on the serum from 574 previously untreated patients with RA from the ESPOIR (Etude et Suivi des POlyarthrites Indifférenciées Récentes) cohort and 98 healthy subjects. A validation cohort involved 69 established patients with RA. Dosages were also done on the serum of collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA) mice and controls. A proof-of-concept study evaluating the therapeutic potency of targeting the kynurenine pathway was performed in the CAIA model. RESULTS: Differential analysis revealed dramatic changes in Trp metabolite levels in patients with RA compared with healthy controls. Decreased levels of kynurenic (KYNA) and xanthurenic (XANA) acids and indole derivatives, as well as an increased level of quinolinic acid (QUIN), were found in the serum of patients with RA. They correlated positively with disease severity (assessed by both circulating biomarkers and disease activity scores) and negatively with quality-of-life scores. Similar profiles of kynurenine pathway metabolites were observed in the CAIA and CIA models. From a mechanistic perspective, we demonstrated that QUIN favours human fibroblast-like synoviocyte proliferation and affected their cellular metabolism, through inducing both mitochondrial respiration and glycolysis. Finally, systemic administration of the recombinant enzyme aminoadipate aminotransferase, responsible for the generation of XANA and KYNA, was protective in the CAIA model. CONCLUSIONS: Altogether, our preclinical and clinical data indicate that alterations in the Trp metabolism play an active role in the pathogenesis of RA and could be considered as a new therapeutic avenue.

Inclusion-body myositis associated with Sjögren's disease: clinical characteristics and comparison with other Sjögren-associated myositis.

OBJECTIVES: To describe the characteristics of patients with Sjögren's disease (SjD) and inclusion-body myositis (IBM), and how they compare to SjD patients with other inflammatory myopathies (IM). METHODS: Patients were retrospectively recruited from 13 French centers and included if they met the ACR/EULAR criteria for SjD and for IM. They were categorized as SjD-IBM if sub-criteria for IBM were met, or as SjD-other IM if not. RESULTS: SjD-IBM patients (n = 22) were mostly females (86%), with a median [Q1; Q3] age of 54 [38.5; 64] years at SjD diagnosis, and 62 [46.5; 70] years at first IBM symptoms. Although most patients displayed glandular and immunological abnormalities, additional extra-glandular manifestations were uncommon, resulting in moderate disease activity at SjD diagnosis (ESSDAI 5.5 [1; 7.8]). Classic IBM features were frequent, such as progressive symptom onset (59%), asymmetrical (27%) and distal (32%) involvements, dysphagia (41%), low CPK (386.5 [221.8; 670.5] UI/l) and CRP (3.0 [3; 8.5] mg/l) levels. Immunosuppressants were reported as efficient in 55% of cases.Compared with SjD-IBM patients, SjD patients with other IM (n = 50) were significantly younger, displayed more frequent additional extra-glandular disease, higher ESSDAI score (11 [3; 30]), shorter delay between SjD diagnosis and myositis onset (0 [-0.5; 26]), more frequent CPK values over 1000 UI/l (36%), and less frequent classic IBM features. CONCLUSION: IBM can occur in SjD patients, with muscle features reminiscent of classic sporadic IBM characteristics, but mostly affecting women. In SjD patients with muscle involvement, extra-glandular manifestations, high ESSDAI score, elevated CPK values, and shorter delay after SjD diagnosis plead against IBM.

A specific diagnostic metabolome signature in adult IgA vasculitis.

INTRODUCTION: IgA vasculitis diagnosis relies primarily on clinical features and is confirmed by pathological findings. To date, there is no reliable noninvasive diagnostic biomarker. OBJECTIVE: We aimed to explore the baseline serum metabolome of adult patients with IgA vasculitis to identify potential diagnostic biomarkers. METHODS: We performed a study comparing the serum metabolome of patients with IgA vasculitis to that of patients with inflammatory condition, namely spondyloarthritis. Serum analyses were performed by high-performance liquid chromatography-mass spectrometry. RESULTS: Fifty-five patients with IgA vasculitis and 77 controls with spondyloarthritis (age- and sex-matched) were included in this study. The median age of IgA vasculitis patients was 53 years. Two-thirds of patients were female (n = 32). At the time of vasculitis diagnosis, 100% of patients had skin involvement and 69% presented with glomerulonephritis (n = 38). Joint and digestive involvement were observed in 56% (n = 31) and 42% (n = 23) of patients. Four discriminative metabolites between the two groups were identified: 1-methyladenosine, L-glutamic acid, serotonin, and thymidine. The multivariate model built from the serum metabolomes of patients with IgA vasculitis and spondyloarthritis revealed an accuracy > 90%. As this model was significant according to the permutation test (p < 0.01), independent validation showed an excellent predictive value of the test set: sensitivity 98%; specificity 98%, positive predictive value 97% and negative predictive value 98%. CONCLUSION: To our knowledge, this study is the first to use the metabolomic approach for diagnostic purposes in adult IgA vasculitis, highlighting a specific diagnostic metabolome signature.

Comparison of SARS-COV-2 humoral response between rheumatoid arthritis, psoriatic arthritis and spondyloarthritis patients and controls in two unvaccinated cohorts.

OBJECTIVES: To compare the humoral response after a SARS-CoV-2 infection in an inflammatory rheumatic disease population with a healthy control population in a case-control study. METHODS: Cases: between March and September 2021, all consecutive unvaccinated patients followed for rheumatoid arthritis (RA), spondyloarthritis (SpA) or psoriatic arthritis (PsA) in 16 hospitals in France were systematically screened with a SARS-CoV-2 serological test. Patients with a positive test were included in the COVID-RIC-2 cohort. CONTROLS: between June and July 2020, healthcare professionals working in the Toulouse University Hospital were screened with a SARS-CoV-2 serological test. Those with a positive test were included in the COVID-BIOTOUL cohort and matched to those from COVID-RIC-2 by age, sex and time-sampling on infection date. ANALYSES: total SARS-CoV-2 antibody titres were centrally measured and compared. RESULTS: 95 patients from COVID-RIC-2 (mean age 49 years, 76% females, median delay of COVID infection: 149 days) including 48 RA, 33 SpA and 14 PsA were compared to 95 matched controls. Globally, there was no significant difference of SARS-CoV-2 antibody titres between both populations: 155 Binding Antibody Units (BAU) (IQR:7-376) in COVID-RIC-2 vs. 120 BAU (IQR:35-320) in COVID-BIOTOUL. There was a trend towards higher antibody titres in patients from COVID-RIC-2 with severe COVID-19 symptoms. In COVID-RIC-2, there was no impact of age, sex, time-sampling or underlying disease on antibody titres and patients taking glucocorticoids, abatacept or rituximab trended toward having lower antibody titres after COVID-19 infection. CONCLUSIONS: This study provides reassuring data on humoral response after COVID-19 infection in patients treated with disease-modifying anti-rheumatic drugs.

EULAR points to consider for therapeutic drug monitoring of biopharmaceuticals in inflammatory rheumatic and musculoskeletal diseases.

OBJECTIVE: To develop EULAR points-to-consider for therapeutic drug monitoring (TDM) of biopharmaceuticals in inflammatory rheumatic and musculoskeletal diseases (RMDs). METHODS: The points-to-consider were developed in accordance with EULAR standardised operation procedures by a multidisciplinary task force from eight European countries, based on a systematic literature review and expert consensus. Level of evidence and strength of the points-to-consider were determined, and mean levels of agreement among the task force were calculated using a 10-point rating scale. RESULTS: Six overarching principles and 13 points-to-consider were formulated. The level of agreement among the task force for the overarching principles and points-to-consider ranged from 8.4 to 9.9.The overarching principles define TDM and its subtypes, and reinforce the underlying pharmacokinetic/pharmacodynamic principles, which are relevant to all biopharmaceutical classes. The points-to-consider highlight the clinical utility of the measurement and interpretation of biopharmaceutical blood concentrations and antidrug antibodies in specific clinical scenarios, including factors that influence these parameters. In general, proactive use of TDM is not recommended but reactive TDM could be considered in certain clinical situations. An important factor limiting wider adoption of TDM is the lack of both high quality trials addressing effectiveness and safety of TDM and robust economic evaluation in patients with RMDs. Future research should focus on providing this evidence, as well as on further understanding of pharmacokinetic and pharmacodynamic characteristics of biopharmaceuticals. CONCLUSION: These points-to-consider are evidence-based and consensus-based statements for the use of TDM of biopharmaceuticals in inflammatory RMDs, addressing the clinical utility of TDM.

Management and outcome of native joint septic arthritis: a nationwide survey in French rheumatology departments, 2016-2017.

OBJECTIVES: To describe current management and outcome of native joint septic arthritis (NJSA) in French rheumatology departments. METHODS: For this retrospective, nationwide multicentric study, 127 French rheumatology departments were contacted to report up to 12 cases of NJSA that occurred between 1 January 2016 and 31 December 2017. Characteristics, diagnosis procedures, therapeutic management and outcome were recorded. RESULTS: Overall, 362 patients were included (mean age 64.0±18.6 years, median Charlson comorbidity index 3.5 (0-14)). Knee was the most frequent site (n=160 (38.9%)), and Staphylococcus sp (n=185 (51.4%)), the most frequent pathogen. All patients received antibiotics for a mean duration of 46.8 (±22.0) days, including intravenous route for a mean of 17.2 (±15.4) days. Management was heterogeneous. Surgical procedure was performed in 171 (48.3%), joint immobilisation in 128 (43.8%). During follow-up, 91 (28.3%) patients have had serious complications and 28 (9.2%) of them died. Factors associated with 1-year mortality were age (OR 1.08, 95% CI 1.04 to 1.13; p<0.001), Charlson's index (OR 1.30, 95% CI 1.06 to 1.58; p=0.012), presence of bacteraemia (OR 4.02, 95% CI 1.35 to 11.99; p=0.008), antibiotic use in the previous 3 months (OR 3.32, 95% CI 1.11 to 9.87; p=0.029) and Staphylococcus aureus NJSA compared with Streptococcus sp. NJSA (OR 7.24, 95% CI 1.26 to 41.68, p=0.027). The complete recovery with no adverse joint outcome at 1 year was observed in n=125/278 patients (55.0%). CONCLUSION: Prognosis of NJSA remained severe with a high rate of morbimortality. Its management was very heterogeneous. This study highlights the importance of the new French recommendations, published after the completion of the study, in order to facilitate NJSA management.

Machine learning reveals the most important psychological and social variables predicting the differential diagnosis of rheumatic and musculoskeletal diseases.

There is an ongoing debate about the importance and the extent to which psychological and psychopathological factors, adverse childhood experiences, and socio-demographic characteristics are associated with the development of certain types of rheumatic disease. With the aim of contributing to knowledge on the subject, the present study uses machine learning modeling to determine the importance of 20 psychological and social variables in predicting two classes of rheumatic disease: inflammatory rheumatic and musculoskeletal diseases (RMD) (rheumatoid arthritis = RA, spondyloarthritis = SA, and Sjögren's syndrome = SS) versus non-inflammatory RMD, namely fibromyalgia = FM). A total of 165 French women with FM, RA, SA, and SS completed an inventory of personality traits, a psychopathology diagnosis questionnaire, and a fatigue/pain questionnaire. They also answered questions about adverse childhood experiences and socio-demographic characteristics. Random forest and logistic regression machine learning algorithms were used for data analysis. The main findings suggest that mistreatment during childhood ((MDA = 10.22), the agreeableness personality trait (MDA = 3.39), and somatic disorder (MDA = 3.25) are the main psychological and social predictors of the type of rheumatic disease diagnosed. The first two predictors (OR = 18.92 and OR = 6.11) are also more strongly associated with FM than with RA-SA-SS. Overall, adverse childhood experiences seem relatively more important than personality traits, psychopathological or demographic variables. The results of this study suggest that traumatic childhood experiences may lead to psychopathological disorders in adulthood, which in turn might underlie, at least in part, the development of FM. Since there are no imaging or biological markers of FM, the present findings contribute to the scientific literature offering information to help patients with FM understand their pathology. They may also provide physicians with more diagnostic information.

Large increase of vertebral osteomyelitis in France: a 2010-2019 cross-sectional study.

Vertebral osteomyelitis (VO) represents 4-10% of bone and joint infections. In Western countries, its incidence seems to increase, simultaneously with an increasing number of comorbidities among an ageing population. This study aimed to assess the evolution of VO epidemiology in France over the 2010-2019 decade. A nationwide cross-sectional study was conducted using the French hospital discharge data collected through the French diagnosis-related groups 'Programme de Médicalisation des Systèmes d'Information'. VOs were detected with a previously validated case definition using International Classification of Diseases 10 (ICD-10) codes, implemented with the French current procedural terminology codes. The study population included all patients hospitalised in France during the 2010-2019 decade, aged 15 years old and more. Patient and hospital stay characteristics and their evolutions were described. During the study period, 42 105 patients were hospitalised for VO in France involving 60 878 hospital stays. The mean VO incidence was 7.8/100 000 over the study period, increasing from 6.1/100 000 in 2010 to 11.3/100 000 in 2019. The mean age was 64.8 years old and the sex ratio was 1.56. There were 31 341 (74.4%) patients with at least one comorbidity and 3059 (7.3%) deceased during their hospital stay. Even if rare, device-associated VOs (4450 hospital stays, 7.3%) highly increased over the period. The reliability of the method, based upon an exhaustive database and a validated case definition, provided an effective tool to compare data over time in real-life conditions to regularly update the epidemiology of VO.

A Comparative Study of Fibromyalgia, Rheumatoid Arthritis, Spondyloarthritis, and Sjögren's Syndrome; Impact of the Disease on Quality of Life, Psychological Adjustment, and Use of Coping Strategies.

BACKGROUND: Fibromyalgia, rheumatoid arthritis, spondyloarthritis, and Sjögren's syndrome are chronic rheumatic diseases with very different clinical characteristics, but which share symptoms such as pain and fatigue. The aim of the study was to examine the impact of the disease on psychological adaptation in fibromyalgia compared with other rheumatic diseases (rheumatoid arthritis, spondyloarthritis, and Sjögren's syndrome). METHODS: In a multicenter study, 165 women with rheumatic diseases (48 with fibromyalgia, 47 with rheumatoid arthritis, 47 with spondyloarthritis, 23 with Sjögren's syndrome) completed the General Health Questionnaire-28 (emotional distress), Fatigue Severity Scale (fatigue), Fibromyalgia Impact Questionnaire (impact of the disease), Coping Strategies Questionnaire (coping), and Mini International Neuropsychiatric Interview (comorbidity with DSM IV axis-I disorders). We used the Kruskal-Wallis test, Mann-Whitney U test, and chi2 test to compare comorbid anxiety and depressive disorders and to compare the impact of the disease on patients' mental well-being and daily life and adjustment (coping strategies). RESULTS: Anxiety and depressive disorders were more common in fibromyalgia patients; they had higher scores on impact of the disease, physical symptoms, pain, and fatigue than rheumatoid arthritis patients and reported more fatigue than patients with spondyloarthritis. Overall, they used more maladaptive coping strategies (less use of distancing from pain than patients with rheumatoid arthritis and spondyloarthritis, less use of ignoring pain sensations, and more use of catastrophizing than those with rheumatoid arthritis). No differences were found between fibromyalgia and Sjögren's syndrome on impact and adjustment. CONCLUSIONS: Compared with other rheumatic diseases, fibromyalgia has a greater impact on daily life; patients have more difficulty adjusting to the disease and generally use poorer strategies to cope with pain.

CD4+ count-dependent concentration-effect relationship of rituximab in rheumatoid arthritis.

AIMS: Rituximab is approved in rheumatoid arthritis (RA). A substantial decrease in CD4+ count was observed in responders after a single cycle of treatment. This study aimed to describe and quantifying the influence of CD4+ count depletion on the concentration-response relationship of rituximab in RA patients. METHODS: In this retrospective monocentric observational study, 52 patients were assessed. Repeated measurements of rituximab concentrations (pharmacokinetics), CD4+ counts (biomarker) and disease activity score in 28 joints (DAS28, clinical response) were made. Rituximab pharmacokinetics was described using a 2-compartment model, and CD4+ cell counts and DAS28 measurements were described using indirect turnover and direct Emax pharmacokinetic-pharmacodynamic models, respectively. Delay between rituximab concentrations and responses was accounted for by including biophase compartments. RESULTS: Elimination half-life of rituximab was 18 days. The pharmacokinetic-pharmacodynamic model showed that DAS28 response to rituximab was partly associated with CD4+ cell depletion. At 6 months, a deeper DAS28 decrease was observed in patients when CD4+ cell count is decreased: median [interquartile range] of DAS28 was 3.7 [2.9-4.4] and 4.5 [3.7-5.3] in patients with and without CD4+ decrease, respectively. CONCLUSIONS: This is the first study to quantify the relationship between rituximab concentrations, CD4+ count and DAS28 in RA patients. This model showed that approximately 75% of patients had CD4+ count decrease, and that the clinical improvement is 2-fold higher in patients with CD4+ cells decrease than in others.

IgG1 Allotypes Influence the Pharmacokinetics of Therapeutic Monoclonal Antibodies through FcRn Binding.

Because IgG1 allotypes might have different half-lives, their influence on infliximab (G1m17,1 allotype) pharmacokinetics was investigated in a group of spondyloarthritis patients. Infliximab was found to have a shorter half-life in patients homozygous for the G1m17,1 allotypes than in those carrying the G1m3 with no G1m1 (G1m3,-1) allotype. Because the neonatal FcR (FcRn) is involved in the pharmacokinetics of mAbs, the interaction of different IgG1 allotypes with FcRn was examined using cellular assays and surface plasmon resonance. G1m17,1 mAbs, such as infliximab and rituximab, were shown to bind more efficiently to FcRn and to be transcytosed better than the G1m3,-1 mAb cetuximab, which explains why infliximab is a better competitor for endogenous IgG1 in G1m3,-1 allotype-bearing patients. A set of four allotype variants of adalimumab (G1m17,1; G1m17,-1; G1m3,1; and G1m3,-1) was also tested for its binding to FcRn, revealing that the G1m3,1 variant, not present in commercial mAbs, binds more efficiently to FcRn and is transcytosed better than the other three variants, all of which are found in therapeutic mAbs.

Antigenic burden and serum IgG concentrations influence rituximab pharmacokinetics in rheumatoid arthritis patients.

AIMS: Rituximab is a monoclonal antibody directed against CD20, which is approved in rheumatoid arthritis (RA). This study aimed at assessing the influence of CD19+ cell counts as target-antigen amount, and of immunoglobulin G (IgG) serum concentrations on rituximab pharmacokinetics in RA patients. METHODS: In a cohort of 64 RA patients who had received repetitive courses of rituximab, the influence of CD19+ cell count, IgG serum concentration, body surface area, sex and disease activity score in 28 joints on rituximab pharmacokinetic parameters was assessed using a population pharmacokinetic analysis. RESULTS: A two-compartment model, with first-order distribution and elimination best described the data. The volume of distribution of central compartment and clearance of rituximab were estimated at 4.7 l and 0.56 l day-1 , respectively. Distribution and elimination half-lives were 0.9 days and 17.3 days, respectively. As expected, the central volume of distribution increased with body surface area (P = 0.012) and was higher in male than in female (P = 0.004). We found that the elimination rate constant (k10 ) increased with CD19+ count (P = 0.00022) and IgG concentration (P = 7.4 × 10-8 ), and that k10 decreased with time (P = 0.00015), partly explained by a change in target-antigen amount. CONCLUSIONS: The association between CD19+ count and k10 may be explained by target-mediated drug disposition, while the association between IgG serum concentration and k10 may be explained by a saturation of the neonatal Fc receptor at high IgG concentrations, resulting in decreased recycling of rituximab.

Current Practice for Therapeutic Drug Monitoring of Biopharmaceuticals in Rheumatoid Arthritis.

The treatment of rheumatoid arthritis (RA) has largely improved in the biopharmaceutical era. These compounds, primarily tumor necrosis factor (TNF) inhibitors, are effective, but some patients may show poor response, sometimes because of the presence of antidrug antibodies (ADAs). In some instances, clinicians may increase or taper the dose depending on the clinical response. Besides the current clinical-based practice, a tailored strategy based on drug monitoring has emerged as a way to improve the use of these drugs. However, the relevance of this therapeutic drug monitoring (TDM) of biopharmaceuticals in RA is still unknown. In this literature review, we examine the most relevant articles dealing with the concentration-response relationship, ADA detection and pharmacokinetics in RA patients receiving biopharmaceuticals. A concentration-response relationship was clearly established for TNF inhibitors. Moreover, ADA positivity was associated with low drug concentrations, poor clinical outcome, and reduced drug survival for TNF-inhibitor monoclonal antibodies. Concomitant use of disease-modifying antirheumatic drugs, especially methotrexate, is associated with good clinical outcome, increased drug concentrations, and reduced immunogenicity. Strategies based on TDM of TNF inhibitors seem promising for RA, but randomized controlled trials are required to support this. A concentration-response relationship may exist with tocilizumab, and immunogenicity seems rare. Finally, the relevance of TDM for RA patients receiving rituximab and abatacept remains unclear.

Current Practice for Therapeutic Drug Monitoring of Biopharmaceuticals in Spondyloarthritis.

Treatment of spondyloarthritis (SpA) has greatly improved in the biopharmaceutical era. These compounds, primarily tumor necrosis factor inhibitors, are effective, but some patients may show poor response, sometimes due to the presence of antidrug antibodies (ADAs). In some instances, clinicians may increase or taper the dose, depending on the clinical response. Besides the current clinical practice, a tailored strategy based on drug monitoring is emerging as a way to improve the use of these drugs. However, the relevance of this therapeutic drug monitoring of biopharmaceuticals for SpA is still unknown. In this literature review, we examined the most relevant articles dealing with the concentration-response relation, ADA detection, and pharmacokinetics in SpA treated with biopharmaceuticals. ADAs were associated with low or undetectable concentration of monoclonal antibodies. The relation between drug concentration and clinical response in SpA is debated, some studies showing an association and others not. Therefore, therapeutic drug monitoring of biopharmaceuticals for SpA requires a better understanding of the association among the pharmacokinetics, pharmacodynamics, and immunogenicity of these drugs.

Current Practices for Therapeutic Drug Monitoring of Biopharmaceuticals in Pediatrics.

Biopharmaceuticals have recently emerged as effective treatments for refractory pediatric autoimmune conditions. Several reports have shown a relationship between drug concentration, antidrug antibodies, and clinical response in these patients, strongly suggesting the potential interest, usefulness, and reliability of therapeutic drug monitoring (TDM) in children. This article reviews the current state of research in juvenile idiopathic arthritis, pediatric inflammatory bowel disease, and pediatric psoriasis from a TDM point of view. There is a remarkable lack of evidence-based data in pediatric patients, which is reflected throughout the article. Most investigations of TDM are focused on research of tumor necrosis factor alpha antagonists in inflammatory bowel disease, albeit preliminary publications are emerging from pediatric rheumatologists and dermatologists. To date, immunogenicity has been a primary concern, particularly regarding infliximab and adalimumab therapy in children, as it may lead to a loss of therapeutic response. Preliminary investigations show that adjusting the dose according to blood drug concentrations improves disease outcomes by overcoming antidrug antibodies, suggesting a crucial role for TDM. Patients who receive other drugs, such as etanercept, abatacept, or tocilizumab, could benefit from TDM because dosage can be optimized by adjusting it to the minimum effective dose.

Biopharmaceuticals: Reference Products and Biosimilars to Treat Inflammatory Diseases.

Biopharmaceuticals are primarily therapeutic proteins developed to perform specific functions by acting on the disease pathophysiology. Compared with low-molecular chemically synthesized drugs, production of biopharmaceuticals is much more complex and routes of administration and pharmacokinetics differ. Biopharmaceuticals are blockbusters in the treatment of inflammatory diseases, such as psoriasis, multiple sclerosis, rheumatic diseases, and inflammatory bowel diseases, and the introduction of these drugs has revolutionized treatment. Disadvantages include their high costs and the fact that they can evoke antidrug antibodies leading to decreased efficacy. Treatment can be optimized through the development of dosing algorithms and cost can be reduced by biosimilars, after a comparable biological activity, safety, and efficacy have been demonstrated.

Rationale for Therapeutic Drug Monitoring of Biopharmaceuticals in Inflammatory Diseases.

Biopharmaceuticals bring together a number of specific characteristics as compared with other drugs. However, as it is done for most drugs, an individual adjustment of their dose may be necessary. Similar to "chemical" drugs, biopharmaceuticals used in immunoinflammatory diseases have a rather narrow therapeutic range, lack good early clinical or biological marker of response, have variable pharmacokinetics, and their serum concentrations are most often related with response. Monoclonal antibodies have additional specific sources of pharmacokinetic variability. Low concentrations may increase the risks of immunization, plasmapheresis may increase their elimination, and subcutaneous formulations may be associated with decreased adherence. For all these reasons, pharmacokinetic therapeutic drug monitoring may be useful. However, few randomized controlled therapeutic drug monitoring studies have been published. For monoclonal antibodies, a precise definition of the therapeutic concentrations is challenging because of the interindividual variability in their concentration-effect relationship.

Therapeutic Drug Monitoring of Biopharmaceuticals May Benefit From Pharmacokinetic and Pharmacokinetic-Pharmacodynamic Modeling.

Biopharmaceuticals, especially monoclonal antibodies, have been increasingly used to treat several chronic inflammatory diseases. Due to the complexity of their pharmacokinetics and concentration-effect relationship, therapeutic drug monitoring (TDM) has been used to optimize their dosing regimen. Up to date, several decisional algorithms have been developed to provide tools for monoclonal antibodies' therapeutic drug monitoring. However, these algorithms are unable to determine the individual optimal dosing scheme. The aim of this article is to deal with population pharmacokinetic (PK) and pharmacokinetic-pharmacodynamic (PK-PD) modeling. Allowing the quantification of the variability of the dose-concentration-response relationship, population pharmacokinetic-pharmacodynamic modeling may be a valuable tool to determine the optimal dosing scheme. Based on population modeling, Bayesian estimators may be developed to optimize dosing schemes for each patient using limited sampling strategies. These estimators may allow accurate dosing adjustment for each patient individually.

High incidence of vertebral osteoporotic fracture within the first year after liver transplantation.

OBJECTIVES: Bone loss is a complication for patients with liver diseases and after transplantation, which results in increased fracture risk. The aim of this study was to determine the incidence of osteoporotic vertebral fractures following liver transplantation. METHODS: We performed a prospective study of patients who were awaiting liver transplantation. Patients were seen at baseline (visit 1) and one year after transplantation (visit 2). At each visit, risk factors of osteoporosis were collected, biochemical tests were performed and bone mineral density with Vertebral Fracture Assessment was assessed. RESULTS: One hundred and fifteen patients were in the pre-transplant group and 33 patients were in the post-transplant group. In the pre-transplant group, the prevalence of vertebral fractures was 23.5%. The prevalence of densitometric osteoporosis was higher at the lumbar spine than at the femoral neck. In the post-transplant group, the prevalence of vertebral fractures at visit 1 and visit 2 was 33.3% and 60.6% respectively with an incidence of 23.1 fractures per 100 patient-years. CONCLUSIONS: Bone fragility was highly prevalent before transplantation and worsens one year after transplantation. Bone status should be evaluated in patients with liver diseases before transplantation to identify patients at high risk of fracture and help clinicians to prescribe appropriate preventive care.

Antibiotic treatment for 6 weeks versus 12 weeks in patients with pyogenic vertebral osteomyelitis: an open-label, non-inferiority, randomised, controlled trial.

BACKGROUND: Duration of treatment for patients with vertebral osteomyelitis is mainly based on expert recommendation rather than evidence. We aimed to establish whether 6 weeks of antibiotic treatment is non-inferior to 12 weeks in patients with pyogenic vertebral osteomyelitis. METHODS: In this open-label, non-inferiority, randomised controlled trial, we enrolled patients aged 18 years or older with microbiologically confirmed pyogenic vertebral osteomyelitis and typical radiological features from 71 medical care centres across France. Patients were randomly assigned to either 6 weeks or 12 weeks of antibiotic treatment (physician's choice in accordance with French guidelines) by a computer-generated randomisation list of permuted blocks, stratified by centre. The primary endpoint was the proportion of patients who were classified as cured at 1 year by a masked independent validation committee, analysed by intention to treat. Non-inferiority would be declared if the proportion of cured patients assigned to 6 weeks of treatment was not less than the proportion of cured patients assigned to 12 weeks of treatment, within statistical variability, by an absolute margin of 10%. This trial is registered with EudraCT, number 2006-000951-18, and Clinical Trials.gov, number NCT00764114. FINDINGS: Between Nov 15, 2006, and March 15, 2011, 359 patients were randomly assigned, of whom six in the 6-week group and two in the 12-week group were excluded after randomisation. 176 patients assigned to the 6-week treatment regimen and 175 to the 12-week treatment regimen were analysed by intention to treat. 160 (90·9%) of 176 patients in the 6-week group and 159 (90·9%) of 175 of those in the 12-week group met the criteria for clinical cure. The difference between the groups (0·05%, 95% CI -6·2 to 6·3) showed the non-inferiority of the 6-week regimen when compared with the 12-week regimen. 50 patients in the 6-week group and 51 in the 12-week group had adverse events, the most common being death (14 [8%] in the 6-week group vs 12 [7%] in the 12-week group), antibiotic intolerance (12 [7%] vs 9 [5%]), cardiorespiratory failure (7 [4%] vs 12 [7%]), and neurological complications (7 [4%] vs 3 [2%]). INTERPRETATION: 6 weeks of antibiotic treatment is not inferior to 12 weeks of antibiotic treatment with respect to the proportion of patients with pyogenic vertebral osteomyelitis cured at 1 year, which suggests that the standard antibiotic treatment duration for patients with this disease could be reduced to 6 weeks. FUNDING: French Ministry of Health.