Publications by authors named "Christine Bonnet"

18 Publications

  • Page 1 of 1

Increased high molecular weight adiponectin and lean mass during tocilizumab treatment in patients with rheumatoid arthritis: a 12-month multicentre study.

Arthritis Res Ther 2020 09 29;22(1):224. Epub 2020 Sep 29.

Laboratoire de Biochimie Médicale, UF de Biochimie Endocrinienne et Métabolique, CHU de Besançon; EA 3920 Marqueurs pronostiques et facteurs de régulation des pathologies cardiaques et vasculaires, Université de Bourgogne Franche Comté, Besançon, France.

Background: Patients with rheumatoid arthritis (RA) have an increased risk of cardiovascular (CV) disease. Adiponectin is involved in the metabolism of glucose and lipids with favourable effects on CV disease, especially its high molecular weight (HMW) isoform. Body composition changes are described in RA with various phenotypes including obesity. The effects of tocilizumab on serum adiponectin and body composition, especially fat mass, in patients with RA are not well determined.

Methods: Patients with active RA despite previous csDMARDs and/or bDMARDs and who were tocilizumab naïve were enrolled in a multicentre open-label study. They were evaluated at baseline, 1, 3, 6 and 12 months. Clinical assessment included body mass index (BMI) and anthropometric measurements. Lipid and metabolic parameters, serum adiponectin (total and HMW), leptin, resistin and ghrelin were measured at each time point. Body composition (lean mass, fat mass, % fat, fat in the android and gynoid regions) was evaluated at baseline, 6 and 12 months.

Results: One hundred seven patients were included. Both total and HMW adiponectin significantly increased from baseline to month 3, peaking respectively at month 3 (p = 0.0105) and month 1 (p < 0.0001), then declining progressively until month 6 to 12 and returning to baseline values. Significant elevation in HMW adiponectin persisted at month 6 (p = 0.001). BMI and waist circumference significantly increased at month 6 and 12, as well as lean mass at month 6 (p = 0.0097). Fat mass, percentage fat and android fat did not change over the study period. Lipid parameters (total cholesterol and LDL cholesterol) increased while glycaemia, insulin and HOMA-IR remained stable. Serum leptin, resistin and ghrelin did not change during follow-up.

Conclusions: Tocilizumab treatment in RA patients was associated with a significant increase in total and HMW adiponectin, especially at the onset of the treatment. Tocilizumab also induced a significant gain in lean mass, while fat mass did not change. These variations in adiponectin levels during tocilizumab treatment could have positive effects on the CV risk of RA patients. In addition, tocilizumab may have an anabolic impact on lean mass/skeletal muscle.

Trial Registration: The ADIPRAT study was a phase IV open-label multicentre study retrospectively registered on under the number NCT02843789 (date of registration: July 26, 2016).
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September 2020

Non-TNF-Targeted Biologic vs a Second Anti-TNF Drug to Treat Rheumatoid Arthritis in Patients With Insufficient Response to a First Anti-TNF Drug: A Randomized Clinical Trial.

JAMA 2016 Sep;316(11):1172-1180

Department of Epidemiology and Biostatistics, Hotel Dieu, Paris, France.

Importance: One-third of patients with rheumatoid arthritis show inadequate response to tumor necrosis factor α (TNF-α) inhibitors; little guidance on choosing the next treatment exists.

Objective: To compare the efficacy of a non-TNF-targeted biologic (non-TNF) vs a second anti-TNF drug for patients with insufficient response to a TNF inhibitor.

Design, Setting, And Participants: A total of 300 patients (conducted between 2009-2012) with rheumatoid arthritis, with persistent disease activity (disease activity score in 28 joints-erythrocyte sedimentation rate [DAS28-ESR]  ≥ 3.2 [range, 0-9.3]) and an insufficient response to anti-TNF therapy were included in a 52-week multicenter, pragmatic, open-label randomized clinical trial. The final follow-up date was in August 2013.

Interventions: Patients were randomly assigned (1:1) to receive a non-TNF-targeted biologic agent or an anti-TNF that differed from their previous treatment. The choice of the biologic prescribed within each randomized group was left to the treating clinician.

Main Outcomes And Measures: The primary outcome was the proportion of patients with good or moderate response according to the European League Against Rheumatism (EULAR) scale at week 24. Secondary outcomes included the EULAR response at weeks 12 and 52; at weeks 12, 24, and 52; DAS28ESR, low disease activity (DAS28 ≤3.2), remission (DAS28 ≤2.6); serious adverse events; and serious infections.

Results: Of the 300 randomized patients (243 [83.2%] women; mean [SD] age, 57.1 [12.2] years; baseline DAS28-ESR, 5.1 [1.1]), 269 (89.7%) completed the study. At week 24, 101 of 146 patients (69%) in the non-TNF group and 76 (52%) in the second anti-TNF group achieved a good or moderate EULAR response (OR, 2.06; 95% CI, 1.27-3.37; P = .004, with imputation of missing data; absolute difference, 17.2%; 95% CI, 6.2% to 28.2%). The DAS28-ESR was lower in the non-TNF group than in the second anti-TNF group (mean difference adjusted for baseline differences, -0.43; 95% CI, -0.72 to -0.14; P = .004). At weeks 24 and 52, more patients in the non-TNF group vs the second anti-TNF group showed low disease activity (45% vs 28% at week 24; OR, 2.09; 95% CI, 1.27 to 3.43; P = .004 and 41% vs 23% at week 52; OR, 2.26; 95% CI, 1.33 to 3.86; P = .003).

Conclusions And Relevance: Among patients with rheumatoid arthritis previously treated with anti-TNF drugs but with inadequate primary response, a non-TNF biologic agent was more effective in achieving a good or moderate disease activity response at 24 weeks than was the second anti-TNF medication.

Trial Registration: Identifier: NCT01000441.
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September 2016

Etiology and associated GJB2 mutations in Mauritanian children with non-syndromic hearing loss.

Eur Arch Otorhinolaryngol 2016 Nov 11;273(11):3693-3698. Epub 2016 Apr 11.

Unité de Recherche sur les Biomarqueurs dans la Population Mauritanienne, Université des Sciences de Technologies et de médecine (USTM), Nouakchott, Mauritania.

Origins of all hearing impairment forms may be divided into genetic mutations and acquired influence. Both carry damage to the inner ear structure resulting in a mild to profound dysfunction of the auditory system. The purpose of this study was to assess the different etiologies of deafness in two reference centers for hearing-impaired children in Nouakchott/Mauritania. Data on gender, age, consanguinity, etiology and family history of deafness were gathered by interviewing the custodians of 139 children with hearing loss. DNA of pupils with hereditary non-syndromic deafness was then screened for GJB2 mutations by sequencing methods. Postnatal hearing loss was found in 36 (25.8 %) out of the 139 children surveyed. The main etiologies of this group were infections caused by meningitis (12.9 %) and measles (2.8 %). Unknown and ototoxic origins accounted for, respectively, 5.7 and 3.5 %. In 103 (74.1 %) children, deafness was identified near after the time of birth and, therefore, presumed as congenital. 56.8 % of deaf children had consanguineous parents. Two GJB2 mutations, c.del35G with an allele frequency of 4.7 % and R32C (3.7 %) were detected. Infections such as meningitis and measles were the most prevalent causes of postnatal deafness. In cases of congenital hearing impairment, two GJB2 allele variants, i.e., del35G and R32C (3.7 %) were detected. Extended genetic testing is recommended for a more comprehensive determination of congenital causes.
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November 2016

Musculoskeletal symptoms in patients with cryopyrin-associated periodic syndromes: a large database study.

Arthritis Rheumatol 2015 Nov;67(11):3027-36

La Cavale Blanche University Hospital, Brest and EA2216 Brittany University (UBO), Brest, France.

Objective: To determine the type and frequency of musculoskeletal symptoms at onset and during followup of cryopyrin-associated periodic syndromes (CAPS).

Methods: We retrospectively recorded the articular and muscular symptoms of patients with CAPS followed up in French hospitals. Data were presented as frequencies or the median (range), and patient groups were compared using chi-square test, Fisher's exact test, and Mann-Whitney test.

Results: The study included 133 patients (33 children), 20 with familial cold autoinflammatory syndrome, 88 with Muckle-Wells syndrome, 22 with chronic infantile neurologic, cutaneous, articular syndrome, and 3 with unclassified CAPS. The median age was 35 years (range 0-78 years) at the time of the study, 1 year (range 0-41 years) at symptom onset, and 23 years (range 0-58 years) at diagnosis. The disease was sporadic in 17% of the patients. Cutaneous symptoms predominated at onset (77%), followed by articular symptoms (30%). The p.Thr348Met and p.Arg260Trp NLRP3 mutations were significantly associated with the presence and absence of articular symptoms at onset, respectively. During followup, 86% of the patients had musculoskeletal symptoms, 88% had arthralgia, and 58% had arthritis, but only 9% had joint destruction. Tendinopathies occurred in 21.5% of the patients, tender points in 16.5%, and myalgia in 33%. Only 3 patients had typical knee deformities. Radiographs were rarely obtained. Except for bone deformities, osteoarticular symptoms occurred at similar frequencies in the different CAPS phenotypes.

Conclusion: Joint manifestations were frequent in all CAPS phenotypes. Bone deformities were rare. Musculoskeletal manifestations varied within given families but tended to worsen over time.
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November 2015

PCR on yeast colonies: an improved method for glyco-engineered Saccharomyces cerevisiae.

BMC Res Notes 2013 May 20;6:201. Epub 2013 May 20.

Background: Saccharomyces cerevisiae is extensively used in bio-industries. However, its genetic engineering to introduce new metabolism pathways can cause unexpected phenotypic alterations. For example, humanisation of the glycosylation pathways is a high priority pharmaceutical industry goal for production of therapeutic glycoproteins in yeast. Genomic modifications can lead to several described physiological changes: biomass yields decrease, temperature sensitivity or cell wall structure modifications. We have observed that deletion of several N-mannosyltransferases in Saccharomyces cerevisiae, results in strains that can no longer be analyzed by classical PCR on yeast colonies.

Findings: In order to validate our glyco-engineered Saccharomyces cerevisiae strains, we developed a new protocol to carry out PCR directly on genetically modified yeast colonies. A liquid culture phase, combined with the use of a Hot Start DNA polymerase, allows a 3-fold improvement of PCR efficiency. The results obtained are repeatable and independent of the targeted sequence; as such the protocol is well adapted for intensive screening applications.

Conclusions: The developed protocol enables by-passing of many of the difficulties associated with PCR caused by phenotypic modifications brought about by humanisation of the glycosylation in yeast and allows rapid validation of glyco-engineered Saccharomyces cerevisiae cells. It has the potential to be extended to other yeast strains presenting cell wall structure modifications.
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May 2013

N-glycosylation humanization for production of therapeutic recombinant glycoproteins in Saccharomyces cerevisiae.

Methods Mol Biol 2013 ;988:45-57

Glycode SAS, Uzerche, France.

The production of therapeutic recombinant glycoproteins deals with three main issues: cost, production capacities, and glycosylation. Nowadays, such proteins are expressed in various complex expression systems (CHO, bacteria, etc.); the processes related to those production hosts are time consuming and expensive, or the question of posttranslational modifications (as glycosylation) control is still unresolved. There is a need to find an alternative approach, while maintaining high quality level: the new system must be able to add complex N-glycan structures to proteins of interest. Developed in several strains of Saccharomyces cerevisiae, GlycodExpress™ is an innovative technology that allows production of therapeutic recombinant glycoproteins with humanized and homogeneous N-glycan moieties. We show how to delete mannosyltransferases involved in host N-glycosylation to obtain more than 90% of homogeneity in glycan structures. The methodology developed to select the optimal fusion between a heterologous glycosyl-enzyme and a localization sequences is also presented. Finally, the screening of the best producing strain is illustrated.
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August 2013

A randomised, double-blind, placebo-controlled trial of dolasetron, a 5-hydroxytryptamine 3 receptor antagonist, in patients with fibromyalgia.

Eur J Pain 2011 May 30;15(5):509-14. Epub 2010 Oct 30.

Pain Center and Department of Rheumatology, University Hospital of Limoges, Limoges, France.

Objective: The purpose of the study was to evaluate the efficacy and safety of dolasetron for symptomatic relief of pain associated with fibromyalgia (FM).

Methods: This prospective, double-blind, placebo-controlled trial randomly assigned 60 patients with FM to receive placebo (n = 31) or dolasetron (n = 29) 12.5mg/d via the intravenous route on 4 days at baseline (M0), 1 month (M1), 2 months (M2) and 3 months (M3) with follow-up to month 12. The primary outcome variable was the reduction in pain intensity measured by visual analogue scale (VAS) between M0 and M3. The secondary outcome variables were patient global impression of change (PGIC), the FM impact questionnaire, assessment of quality of life (SF-36), the hospital anxiety and depression scale, the manual tender point count, and functional symptoms associated with FM.

Results: Reduction in pain intensity at M3 was significantly greater in dolasetron-treated patients (p = 0.04, -21.3 on a 0-100 scale) compared with placebo controls (-5.9). More patients in the dolasetron group had ≥ 30% and ≥ 50% improvement in pain (42.5% and 28% respectively in the dolasetron group versus 25% and 16% in the placebo group). The PGIC was significantly greater in the dolasetron group at M3 (p = 0.02). The other secondary outcomes failed to reach statistical significance. The most common adverse events were constipation, nausea, dizziness and headache, with no significant differences between the two groups.

Conclusion: Intermittent IV dolasetron was safe and efficacious for the reduction of pain intensity associated with FM at 3 months.
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May 2011

Safety and efficacy of rituximab in systemic lupus erythematosus: results from 136 patients from the French AutoImmunity and Rituximab registry.

Arthritis Rheum 2010 Aug;62(8):2458-66

Bicêtre Hospital, Assistance Publique-Hôpitaux de Paris, and Paris 11 University, Le Kremlin Bicêtre, France.

Objective: A number of open-label studies have suggested the potential benefit of rituximab (RTX) in systemic lupus erythematosus (SLE). However, in 2 recent randomized controlled trials (RCTs) of RTX, the primary end points were not met. We undertook this study to evaluate the safety and efficacy of RTX in off-trial patients with SLE seen in regular clinical practice.

Methods: We analyzed prospective data from the French AutoImmunity and Rituximab (AIR) registry, which includes data on patients with autoimmune disorders treated with RTX.

Results: One hundred thirty-six patients received treatment for SLE. The mean +/- SD score on the Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the SLE Disease Activity Index (SLEDAI) was 11.3 +/- 8.9 at baseline. Severe infections were noted in 12 patients (9%), corresponding to a rate of 6.6/100 patient-years. Most severe infections occurred within the first 3 months after the last RTX infusion. Five patients died, due to severe infection (n = 3) or refractory autoimmune disease (n = 2). Overall response was observed in 80 of 113 patients (71%) by the SELENA-SLEDAI assessment. Efficacy did not differ significantly between patients receiving RTX monotherapy and those receiving concomitant immunosuppressive agents (who had higher baseline disease activity). Articular, cutaneous, renal, and hematologic improvements were noted in 72%, 70%, 74%, and 88% of patients, respectively. Among responders, 41% experienced a relapse of disease, with a response in 91% after retreatment with RTX.

Conclusion: Data from the AIR registry show a satisfactory tolerance profile and clinical efficacy of RTX in patients with SLE. The contrasting results with those from recent RCTs leave open the question of the therapeutic use of RTX in SLE. Additional controlled studies with new designs are needed to define the place of RTX in the therapeutic arsenal for SLE.
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August 2010

Ultrasonography in chondrocalcinosis.

Joint Bone Spine 2010 May 25;77(3):218-21. Epub 2010 Jan 25.

Service de rhumatologie, CHU Dupuytren, 2, avenue Martin-Luther-King, 87042 Limoges cedex, France.

Ultrasonography can visualize calcific deposits within soft tissues. The appearance and location of the deposits distinguishes articular chondrocalcinosis from other crystal deposition diseases. The most common findings are hyperechoic dots or lines running parallel to the joint surface, hyperechoic images within fibrous cartilage (menisci and triangular fibrocartilage complex), and deposits within tendons (Achilles tendon). Studies found that ultrasonography was highly sensitive and specific for detecting calcifications, using calcium pyrophosphate dihydrate crystal detection in joint fluid as the reference standard. Good agreement has been demonstrated between radiographs and ultrasonography for the detection of calcifications. Thus, ultrasonography is valuable for diagnosing articular chondrocalcinosis via the detection of calcifications within the joint cartilage, fibrocartilage, and tendons. In addition, ultrasonography is a noninvasive, widely available, inexpensive investigation that requires no radiation exposure.
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May 2010

[Not Available].

Therapie 2008 Sep-Oct;63(5):409-10

Clinique Thérapeutique et Rhumatologique, CHU Dupuytren, Limoges, France.

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July 2016

[Contribution of sacroiliac magnetic resonance imaging (MRI) to the evaluation of infliximab efficacy in spondyloarthropathy (a prospective study of 34 patients)].

Bull Acad Natl Med 2006 Apr-May;190(4-5):995-1003; discussion 1003-5

Service de Rhumatologie et de Thérapeutique, Hôpital universitaire Dupuytren, 2, avenue Martin-Luther-King, 87042 Limoges.

Thirty-four patients who met ESSG criteria for spondylarthropathy and were eligible for anti-TNFalpha treatment (infliximab) were enrolled in this open-label study lasting 14 weeks. The aims were to evaluate the progression of sacroiliitis by means of MRI, and to determine the positive predictive value of this exam for the treatment response. Patients underwent MRI of the sacroiliac region at baseline (W0), and also at 14 weeks if the baseline MRI showed sacroiliitis. Two blinded readers reviewed all imaging studies. The patients also had a physical examination and ESR and CRP assays at W0 and W14. Sacroiliitis was found in 22 patients (65%) at W0, but only 18 of these patients had a second MRI at W14, for technical reasons. After 14 weeks of therapy, MRI signs of sacroiliac inflammation diminished by 77.7% on average. Clinical and biological parameters also improved. However, MRI was not predictive of the treatment response. Sacroiliac MRI seems to be interesting for objective therapeutic evaluation and monitoring of patients with spondyloarthropathy.
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March 2007

Is restless legs syndrome underrecognized? Current management.

Joint Bone Spine 2006 Jul 18;73(4):369-73. Epub 2005 Jul 18.

Rheumatology and Therapy department, CHU Dupuytren, 2, av Martin-Luther-King, 87042 Limoges cedex, France.

Restless legs syndrome (RLS) is a poorly understood sensory-motor neurological disorder whose prevalence in Caucasian populations ranges from 10% to 15%. The patient reports unpleasant sensations in the lower limbs with dysesthesia resulting in an urge to move the legs. The symptoms occur during periods of inactivity, increasing in the evening and at night. Moving the legs provides relief. In 80% of cases, polysomnography shows periodic leg movements during sleep. Patients with idiopathic RLS often report similar symptoms in family members. Secondary RLS may be due to medications, diabetes mellitus, renal failure, iron deficiency, neurological disorders, or rheumatoid arthritis. In secondary RLS, the management rests on treatment of the cause. Symptomatic treatment is warranted in patients with moderate-to-severe symptoms that adversely affect the quality of life. Dopaminergic agents are tried first. When they fail or induce adverse effects, weak opioids, benzodiazepines, anticonvulsants or, if needed, strong opioids, may be used.
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July 2006

Validation of bioelectrical impedance analysis in patients with amyotrophic lateral sclerosis.

Am J Clin Nutr 2003 May;77(5):1179-85

Nutrition Unit & Hepato-Gastroenterology Service, Dupuytren University Hospital, Limoges, France.

Background: Amyotrophic lateral sclerosis (ALS) is a neurologic disease with an unfavorable prognosis that may be accompanied by malnutrition or overweight. Nutritional status is difficult to evaluate in these patients because of their physical limitations and the asymmetry of their disease involvement. Bioelectrical impedance analysis (BIA), which enables bedside analysis of body compartments, has not been adequately validated for use in patients with ALS.

Objective: We compared reference measures of fat-free mass (FFM(a)), obtained by dual-energy X-ray absorptiometry, with FFM obtained by BIA and by the skinfold-thickness technique.

Design: We measured FFM(a) in 32 ALS patients. Anthropometric measures included weight, height, skinfold thickness, and arm and wrist circumferences. The fat mass obtained from the skinfold-thickness measures enabled us to calculate FFM. BIA was performed by measuring the bioimpedances at 5, 50, and 100 kHz of each side of the body and from one side to the other. FFM was calculated by using the instrument's internal software and by using 3 standard equations. The concordance between the methods was evaluated by the Bland-Altman test.

Results: Two of the 16 measured FFM values were not significantly different from FFM(a). However, the risk of dispersion was too high to be acceptable in practice. An equation was then developed by using multivariate analysis, with impedance at 50 kHz. This equation was validated in a second population of 15 ALS patients and with the use of 2 successive measurements performed on 18 patients.

Conclusion: BIA is a simple technique that is valid for use in ALS patients, both for a single exam measure and for longitudinal monitoring, with the use of an adapted equation and a frequency of 50 kHz.
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May 2003

Is the relationship between spondyloarthropathy and Sjögren's syndrome in women coincidental? A study of 13 cases.

Joint Bone Spine 2002 Jun;69(4):383-7

Department of Rheumatology and Therapeutic, University Hospital Dupuytren, Limoges, France.

Objective: To determine the prevalence of Sjogren's syndrome (SS) in women with spondyloarthropathy (SpA).

Methods: Forty-one women with SpA manifesting as inflammatory back pain and/or peripheral arthritis were diagnosed as having ankylosing spondylitis, undifferentiated spondyloarthropathy, psoriatic arthritis, or enteropathic arthropathy based on accepted criteria. A validated questionnaire was used to look for sicca symptoms in the SpA group and in 102 controls with degenerative rheumatic diseases. Women with SpA and sicca symptoms and/or positive antinuclear antibodies (ANA) were investigated for SS by minor salivary gland biopsy. In the SpA group, the following tests were done: HLA B27; HLA DR, DQ; ENA; and serology for CMV, EBV, HIV, hepatitis B, and hepatitis C.

Results: Thirteen women (31.7%) met European criteria for SS, compared to three (2.9%) of the controls. Of the 41 women with SpA, 16 (39%) were ANA-positive. ANA were detected in eight of the 16 (50%) patients with SS. HLA B27 was present in 11 of the 13 (84.6%) SS patients. HLA DR 04.04 and DQ 03.03 seemed more common in SS patients, but the difference was not statistically significant.

Conclusion: SS was far more common in the women with SpA (31.7%) than in the controls (2.9%), suggesting that the SpA-SS association may not be coincidental.
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June 2002

A pilot study on the recovery from paresis after lumbar disc herniation.

Spine (Phila Pa 1976) 2002 Jul;27(13):1426-31; discussion 1431

Service de Rhumatologie, CHU Pitié-Salpêtrière, Paris, France.

Background: Although the existence of a motor defect in discogenic sciatica is a sign of severity, the literature does not provide evidence for an immediate requirement for surgery.

Objective: To assess the course of sciatica with discogenic paresis and to determine possible prognostic factors for recovery or improvement.

Study Design: This open prospective multicenter study included patients with discogenic sciatica with paresis that had been developing for less than 1 month and was rated < or =3 on a 5-grade scale. Pain, the strength of 11 muscles, return to work, and analgesic intake were assessed at 1, 3, and 6 months. Recovery and improvement were defined by pain not exceeding 20 mm or < or =50% of the initial pain score and a score of either 5 (recovery) or 4 (improvement) for the weakest muscle at inclusion.

Results: Sixty-seven patients were enrolled; 39 (58%) patients were treated surgically and 28 (42%) medically. Surgically treated patients differed from medically treated patients by a higher rate of extruded herniation, a higher number of paretic muscles (6.3 vs. 5; P = 0.051), and a longer course of sciatica (31.4 vs. 17.3 days; P = 0.034). At 6 months, 7 (10.4%) patients were lost to follow-up; 32 (53.3%) had improved, including 18 (30%) recovered, 33 (85%) back to work and having a professional activity, and 22 (39%) still taking analgesics. The only significant difference between recovered and not recovered patients was mean age at inclusion (43 vs. 51 years, P = 0.034). There were no significant differences between improved and not improved patients. Moreover, the outcome was not different in the two treatment groups: there were 17 (53%) improvements in surgically treated patients, including 8 (25%) recoveries, and 14 (56%) improvements in medically treated patients, including 8 (40%) recoveries.

Conclusion: This pilot study showed no difference between surgical or medical management for recovery or improvement in patients with discogenic paresis. These results need confirmation by a randomized study.
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July 2002