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Journal Article

  • Benzaquen, M, Flachaire, B, Rouby, F, Berbis, P & Guis, S 2018, “Paradoxical pustular psoriasis induced by ustekinumab in a patient with Crohn's disease-associated spondyloarthropathy”, Rheumatology International.
    Résumé : Palmoplantar pustular psoriasis (PPP) is a clinical form of psoriasis, for which tumor necrosis factor alpha inhibitors (TNFi) or interleukins 12/23 inhibitor (ustekinumab) can be a therapeutic option. Paradoxical psoriatic reactions induced by TNFi are now well known. We present the exceptional case of a paradoxical PPP appeared under ustekinumab in a patient with Crohn's disease-associated spondyloarthropathy. A 58-year-old woman presented with recent peripheral inflammatory arthralgias appeared in the context of a Crohn's disease diagnosed in 2008. Three weeks after the first injection of ustekinumab 390 mg for a refractory Crohn's disease, a slight pruritic erythematous and pustular dermatosis appeared on the right hand palm. The clinical aspect was strongly in favor of a PPP. Ustekinumab was discontinued and replaced by golimumab, leading to a complete healing of PPP after 15 days of discontinuation. Causality assessment calculated using the French method was plausible for ustekinumab in the induction of PPP. It was based on a compatible chronology according to time to onset associated with complete recovery 2 weeks after cessation of treatment, and on the negative assessment of an alternative etiology (nor bacterial or viral infection, nor other treatment taken by the patient, nor previous history of psoriasis). The worsening of underlying psoriasis under ustekinumab through the appearance of generalized or palmoplantar pustules has already been reported in five cases. We describe to our knowledge the first case of paradoxical PPP under ustekinumab in a patient with no known underlying psoriasis.
    Mots-clés : Crohn’s disease, msk, Paradoxical, Pustular psoriasis, Spondyloarthropathy, Ustekinumab.


Journal Article

  • Guenoun, D, Fouré, A, Pithioux, M, Guis, S, Le Corroller, T, Mattei, J-P, Pauly, V, Guye, M, Bernard, M, Chabrand, P, Champsaur, P & Bendahan, D 2017, “Correlative Analysis of Vertebral Trabecular Bone Microarchitecture and Mechanical Properties: A Combined Ultra-high Field (7 Tesla) MRI and Biomechanical Investigation”, Spine, vol. 42, no. 20, p. E1165-E1172.
    Résumé : STUDY DESIGN: High-resolution imaging and biomechanical investigation of ex-vivo vertebrae. OBJECTIVE: The aim of this study was to assess bone microarchitecture of cadaveric vertebrae using ultra-high field (UHF) 7 Tesla magnetic resonance imaging (MRI) and to determine whether the corresponding microarchitecture parameters were related to bone mineral density (BMD) and bone strength assessed by dual-energy x-ray absorptiometry (DXA) and mechanical compression tests. SUMMARY OF BACKGROUND DATA: Limitations of DXA for the assessment of bone fragility and osteoporosis have been recognized and criteria of microarchitecture alteration have been included in the definition of osteoporosis. Although vertebral fracture is the most common osteoporotic fracture, no study has assessed directly vertebral trabecular bone microarchitecture. METHODS: BMD of 24 vertebrae (L2, L3, L4) from eight cadavers was investigated using DXA. The bone volume fraction (BVF), trabecular thickness (Tb.Th), and trabecular spacing (Tb.Sp) of each vertebra were quantified using UHF MRI. Measurements were performed by two operators to characterize the inter-rater reliability. The whole set of specimens underwent mechanical compression tests to failure and the corresponding failure stress was calculated. RESULTS: The inter-rater reliability for bone microarchitecture parameters was good with intraclass correlation coefficients ranging from 0.82 to 0.94. Failure load and stress were significantly correlated with BVF, Tb.Sp, and BMD (P < 0.05). Tb.Th was only correlated with the failure stress (P < 0.05). Multiple regression analysis demonstrated that the combination of BVF and BMD improved the prediction of the failure stress from an adjusted R = 0.384 for BMD alone to an adjusted R = 0.414. CONCLUSION: We demonstrated for the first time that the vertebral bone microarchitecture assessed with UHF MRI was significantly correlated with biomechanical parameters. Our data suggest that the multimodal assessment of BMD and trabecular bone microarchitecture with UHF MRI provides additional information on the risk of vertebral bone fracture and might be of interest for the future investigation of selected osteoporotic patients. LEVEL OF EVIDENCE: N /A.
    Mots-clés : crmbm, msk.


Journal Article

  • Guis, S, Berbis, P, Stephan, D, Bertin, D, Amatore, F, Balandraud, N, Lesavre, N & Desplat-Jégo, S 2016, “TWEAK-binding autoantibodies are generated during psoriatic arthritis and are not influenced by anti-TNF therapy”, Journal of Translational Medicine, vol. 14, no. 1, p. 185.
    Résumé : BACKGROUND: TNF weakly inducer of apoptosis (TWEAK) is member of the TNF ligand superfamily. Various data support that TWEAK produced by synovial macrophages may contribute to synovitis observed in psoriatic arthritis (PsoA). In PsoA, anti-TNF therapy has been successful in agreement with the key role of TNF in the pathogenesis and the generation by PsoA patients of anti-TNF autoantibodies referred as "beneficial autoimmunity to pro-inflammatory mediators". However, the role of TNF-alpha in the regulation of TWEAK modulation of inflammation during PsoA remains unknown. METHODS: We have studied level course during anti-TNF therapy of serum soluble TWEAK. In the same cohort, we have investigated the generation of TWEAK-binding autoantibodies by PsoA patients before and after anti-TNF therapy. RESULTS: Patients with PsoA had significantly higher serum levels of TWEAK compared with controls [respective means (±SEM) were 645 pg/ml (64) and 467 pg/ml (23); (p = 0.006)] but serum soluble TWEAK levels were not correlated with BASDAI (Spearman's coefficients <0.003, p > 0.05). Our study showed that soluble TWEAK levels were not modulated by etanercept therapy [respective Means (±SEM) were 605 (95) (week 12) and 744 (97) (week 24) pg/ml; (p > 0.23)]. Anti-TWEAK autoantibodies were detected in 9/13 (69.2 %) PsoA patients at inclusion and only in 3/57 (5.3 %) healthy blood donors (p < 0.0001). These circulating antibodies were persistent in PsoA patients and detected at similar levels during etanercept therapy. Moreover we showed that they had a down regulating effect on CCL-2 secretion by endothelial cells stimulated by rh TWEAK in vitro. CONCLUSION: Our study revealed that during psoriatic arthritis (1) serum TWEAK was up regulated and (2) TWEAK-binding autoantibodies are generated. Both parameters were not influenced by anti-TNF therapy and persisted at high levels during anti-TNF therapy. For the first time we described here TWEAK-binding IgG autoantibodies with a down regulating effect on CCL-2 secretion by endothelial cells stimulated by rh TWEAK in vitro. Finally, our results suggest that TWEAK may be involved in PsoA pathogeny. Trial registration This clinical trial was approved by the local Ethics Committee "Comité de Protection des Personnes Sud-Méditerranée V" with the registration number: 2011-002954-29, and French health minister registration number AFSSAPS A110784-42 obtained the 08/22/2011. This clinical trial is registered in Clinical under the number: NCT02164214.
    Mots-clés : Anti-cytokine, Anti-TNF therapy, Autoantibodies, msk, Psoriatic arthritis, TWEAK.

  • Mege, D, Cammilleri, S, Mundler, O, Dignat-George, F, Dubois, C, Panicot-Dubois, L & Guis, S 2016, “Circulating microparticles bearing Fibrin associated with whole-body 18FDG-PET: diagnostic tools to detect paraneoplastic polymyalgia rheumatica”, Rheumatology International, vol. 36, no. 8, p. 1099-1103.
    Résumé : Polymyalgia rheumatica (PMR), a chronic inflammatory rheumatism, can be the expression of a paraneoplastic syndrome. The same clinical symptoms are frequently observed at the early stage of the benign and malignant forms. Here, our aim was to develop diagnostic tools to differentiate paraneoplastic PMR from essential PMR. We combined an 18FDG-PET and detection of circulating procoagulant microparticles (MPs), such as fibrin positive (FibMPs), by flow cytometry. Two patients with PMR and a similar profile were selected. In the two patients, the 18FDG-PET revealed a hypermetabolic focus. However, the concentrations of fibrin+/annexin+ microparticles detected were (10 times higher in one of the two patients, who was later found to have breast cancer. The association of 18FDG-PET and the detection of microparticle fibrin positives by flow cytometry allows separating essential PMR (hypermetabolism by 18FDG-PET, low FibMPs) from paraneoplastic PMR.
    Mots-clés : Microparticles, msk, Paraneoplastic syndrome, Polymyalgia Rheumatica, Whole-body 18FDG-PET.


Journal Article

  • Silvy, F, Bertin, D, Bardin, N, Auger, I, Guzian, M-C, Mattei, J-P, Guis, S, Roudier, J & Balandraud, N 2015, “Antinuclear Antibodies in Patients with Psoriatic Arthritis Treated or Not with Biologics”, PloS One, vol. 10, no. 7, p. e0134218.
    Résumé : BACKGROUND: With the emergence of biotherapies, accurate diagnosis in early arthritis is needed. At this time, there is no biological marker of psoriatic arthritis. OBJECTIVE: To test whether antinuclear antibodies (ANA) can be used as a diagnostic tool in psoriatic arthritis (PsA), we evaluated the prevalence of ANA in biologic-naïve PsA patients and in healthy blood donors. METHODS: 232 patients from the Rheumatology department, St Marguerite's Hospital, Marseilles, who fulfilled the CASPAR criteria for PsA, underwent clinical and laboratory investigations. Antinuclear antibodies (ANA), anti-extractable nuclear antigen antibodies (ENA), rheumatoid factor (RF), anti-citrullinated protein antibodies (ACPA) were assayed. Ninety-one healthy blood donors were also tested. RESULTS: Detection of ANA by indirect immunofluorescence was significantly more frequent in sera from PsA patients than those from controls at serum dilution of 1:100 (57% compared with 40%, Odds Ratio (OR) 1.98 (1.2-3.4) p<0.02) and 1:160 (52% compared with 24%, OR 3,7 (1.9-7.2) p<0.001). No patients had lupus specific autoantibodies, 15 % had RF (34/232), and 1.7 % had ACPA (4/232). CONCLUSIONS: Detection of ANA was more frequent in sera from PsA patients than in those from healthy controls. This suggests that ANA could be a diagnosis orientation tool in PsA. Nevertheless, the specificity of these antibodies still remains to be investigated.
    Mots-clés : msk.


Journal Article

  • Cheung, PP, Dougados, M, Andre, V, Balandraud, N, Chalès, G, Chary-Valckenaere, I, Dernis, E, Gill, G, Gilson, M, Guis, S, Mouterde, G, Pavy, S, Pouyol, F, Marhadour, T, Richette, P, Ruyssen-Witrand, A, Soubrier, M, Nguyen, M & Gossec, L 2014, “The learning curve of nurses for the assessment of swollen and tender joints in rheumatoid arthritis”, Joint, Bone, Spine: Revue Du Rhumatisme, vol. 81, no. 2, p. 154-159.
    Résumé : OBJECTIVES: In rheumatoid arthritis (RA), nurses are now increasingly involved in joint count assessment but training is not standardized. The aim was to evaluate and describe the learning curve of nurses for the assessment of swollen and tender joints in RA. METHOD: Twenty nurses from university rheumatology centres inexperienced with joint counts were allocated to a rheumatologist from their centre (teacher). Acquisition of skills consisted of Phase 1: (training), a centralized 4hour training session, with (a) lecture and demonstration, and (b) practical sessions on patients with their teachers, followed by Phase 2: (practice) involving further practice on 20 patients in their own hospitals. Primary outcome was achievement of adequate swollen joint agreement between nurse and their teacher ("gold standard") at the "joint" level defined by prevalence adjusted biased adjusted kappa (PABAK)>0.60. Agreement at the "patient" level of swollen joint count (SJC), tender joint count (TJC) as well as DAS28 between nurse and their teacher were assessed with intra-class correlation coefficients (ICC). RESULTS: During the training phase, 75% of nurses achieved a swollen joint PABAK>0.60 when compared with their teachers, which further improved to 89% after the 20 practice patients (Phase 2). Median swollen joint PABAK improved from 0.64 (Q1:Q3 0.55,0.86) to 0.83 (Q1:Q3 0.77,1) by the end of Phase 2. At the "patient" level, SJC agreement remained globally stable (ICC, 0.52 to 0.66), while TJC and DAS28 agreement remained excellent throughout. CONCLUSION: Nurses inexperienced in joint counts were able to achieve excellent agreement with their teachers in assessment of tender and swollen joints through a short training session; practice further enhanced this agreement. Larger longitudinal studies are required to assess skills retention.
    Mots-clés : Arthritis, Rheumatoid, Clinical Competence, Female, Humans, Joints, Learning Curve, Male, Middle Aged, Physical Examination.


Journal Article

  • Cammilleri, S, Guzian, MC, Mattei, J-P, Mundler, O & Guis, S 2013, “Whole-Body (18) FDG-PET in an Arthritis Paraneoplastic Syndrome Revealed an Underlying Hematological Neoplasm”, Case Reports in Medicine, vol. 2013, p. 594704.
    Résumé : We showed the first image of (18)FDG-PET, which leads to a diagnosis of lymphoma in an atypical polyarthritis. About 4% of patients with lymphoma or leukemia suffered from rheumatologic paraneoplastic symptoms like arthralgia and about 10% of the patients with rheumatologic or neurologic clinical symptoms develop a solid cancer or hematological neoplasm. (18)FDG-PET is an interesting exam to identify an underlying malignancy when a paraneoplastic syndrome is suspected; it can detect the primitive lesion and/or the metastasis lesions. The use of the (18)FDG-PET can help to detect earlier hematological neoplasm in cases of paraneoplastic syndrome without a determined cause and to treat more rapidly and specifically the patient.

  • Cheung, PP, Dougados, M, Andre, V, Balandraud, N, Chales, G, Chary-Valckenaere, I, Chatelus, E, Dernis, E, Gill, G, Gilson, M, Guis, S, Mouterde, G, Pavy, S, Pouyol, F, Marhadour, T, Richette, P, Ruyssen-Witrand, A, Soubrier, M & Gossec, L 2013, “Improving agreement in assessment of synovitis in rheumatoid arthritis”, Joint, Bone, Spine: Revue Du Rhumatisme, vol. 80, no. 2, p. 155-159.
    Résumé : OBJECTIVE: Synovitis assessment through evaluation of swollen joints is integral in steering treatment decisions in rheumatoid arthritis (RA). However, there is high inter-observer variation. The objective was to assess if a short collegiate consensus would improve swollen joint agreement between rheumatologists and whether this was affected by experience. METHODS: Eighteen rheumatologists from French university rheumatology units participated in three 30 minutes rounds over a half day meeting evaluating joint counts of RA patients in small groups, followed by short consensus discussions. Agreement was evaluated at the end of each round as follows: (i) global agreement of swollen joints (ii) swollen joint agreement according to level of experience of the rheumatologist (iii) swollen joint count and (iv) agreement of disease activity state according to the Disease Activity Score (DAS28). Agreement was calculated using percentage agreement and kappa. RESULTS: Global agreement of swollen joints failed to improve (kappa 0.50 to 0.52) at the joint level. Agreement between seniors did not improve but agreement between newly qualified rheumatologists and their senior peer, which was initially poor (kappa 0.28), improved significantly (to 0.54) at the end of the consensus exercises. Concordance of DAS28 activity states improved from 71% to 87%. CONCLUSION: Consensus exercises for swollen joint assessment is worthwhile and may potentially improve agreement between clinicians in clinical synovitis and disease activity state, benefit was mostly observed in newly qualified rheumatologists.
    Mots-clés : Adult, Aged, Arthritis, Rheumatoid, Clinical Competence, Consensus, Cross-Sectional Studies, Female, Humans, Joints, Male, Middle Aged, Observer Variation, Reproducibility of Results, Rheumatology, Severity of Illness Index, Synovitis.

  • Guis, S, Mattei, J-P & Bendahan, D 2013, “Toxic myopathies”, Joint, bone, spine: revue du rhumatisme, vol. 80, no. 3, p. 231-233.
    Mots-clés : crmbm, Humans, Muscular Diseases, Myalgia, Toxins, Biological, Venoms.


Journal Article

  • D'Agostino, M-A, Saraux, A, Chary-Valckenaere, I, Marcelli, C, Guis, S, Gaudin, P, Aegerter, P, Jousse-Joulin, S, Loeuille, D, Judet, O, Lecoq, B, Hacquard-Bouder, C, Grange, L, Guzian, MC, Blum, A, Chagnaud, C, Leboime, A, Monnet, D, Rat, A-C, Timsit, MA, Said-Nahal, R & Breban, M 2012, “Can we improve the diagnosis of spondyloarthritis in patients with uncertain diagnosis? The EchoSpA prospective multicenter French cohort”, Joint, Bone, Spine: Revue Du Rhumatisme, vol. 79, no. 6, p. 586-590.
    Résumé : Power Doppler ultrasound (PDUS) has proved to be a highly sensitive tool for assessing enthesitis in spondyloarthritis (SpA). In patients with a suspected SpA, diagnosis could be improved by detecting enthesitis with PDUS. OBJECTIVE: To evaluate the performance of PDUS for the diagnosis of SpA alone or combined with other clinical, laboratory and imaging findings in patients consulting for a suspected SpA. METHODS: Prospective, multicenter French cohort study (Boulogne-Billancourt, Brest, Caen, Grenoble, Marseille and Nancy). Outpatients consulting for symptoms suggestive of SpA (inflammatory back pain [IBP], arthritis or inflammatory arthralgia [IA], enthesitis or dactylitis [ED], HLA-B27 positive uveitis [B27+U], familiarity for SpA [Fam]) were recruited and followed up for at least 2 years. Sample size was set to 500 patients (for estimated prevalence of SpA of 30±5% after 2 years). At baseline, patients were submitted to standardized physical examination, pelvic X-ray, sacroiliac joints magnetic resonance imaging (MRI), HLA-B typing, and other tests judged useful for diagnosis. For each patient, a blinded PDUS examination of 14 enthesitic sites was performed at baseline and at years 1 and 2. Patients were planned to be followed during 5 years. The diagnosis of SpA ascertained by an experts' committee, blind to PDUS results, after at least 2 years of follow-up, with a revaluation of doubtful patients at 5 years will be used as gold standard for evaluating the diagnostic performance of PDUS and the best diagnostic procedure by combining PDUS, clinical symptoms and other tests. RESULTS: Between January 2005 and September 2007, 489 patients were included (96% of the target population). Nineteen patients (0.2%) retired their informed consensus or were lost to follow-up immediately after their inclusion. At baseline, mean age of the 470 remaining patients was 40 years, mean duration of symptoms was 6.1 years; 42% of them were HLA-B27+ and 63% were female. Primary inclusion criterion was IBP in 53%, IA in 27%, ED in 9%, B27+U in 8% and Fam in 4%. Follow-up is still ongoing. CONCLUSION: We have set up a unique diagnostic cohort which includes the entire spectrum of SpA manifestations. By using PDUS we expected to improve the diagnostic procedure of SpA.
    Mots-clés : Adolescent, Adult, Aged, Cohort Studies, Female, Follow-Up Studies, France, HLA-B27 Antigen, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Prospective Studies, Sacroiliitis, Sensitivity and Specificity, Spondylarthritis, Ultrasonography, Doppler, Young Adult.

  • Devauchelle-Pensec, V, D'Agostino, MA, Marion, J, Lapierre, M, Jousse-Joulin, S, Colin, D, Chary-Valckenaere, I, Marcelli, C, Loeuille, D, Aegerter, P, Guis, S, Gaudin, P, Breban, M, Saraux, A & Study Group of Spondylarthritis, 2012, “Computed tomography scanning facilitates the diagnosis of sacroiliitis in patients with suspected spondylarthritis: results of a prospective multicenter French cohort study”, Arthritis and Rheumatism, vol. 64, no. 5, p. 1412-1419.
    Résumé : OBJECTIVE: To assess the performance of computed tomography (CT) scanning for ascertaining sacroiliitis in patients with suspected spondylarthritis (SpA). METHODS: The Echography in Spondylarthritis French cohort consists of 489 patients with suspected SpA. At baseline, all patients underwent clinical examination, HLA-B typing, and pelvic radiography. Pelvic CT scanning was performed if sacroiliitis on radiography was considered uncertain or if patients presented with buttock pain duration of >6 months. A set of 100 paired radiographs and CT scans was read in a blinded manner by 2 radiologists, and the kappa coefficient was used to assess their interreader reliability. One of the radiologists read the 173 available pairs of radiographs and CT scans performed at baseline. RESULTS: After training, interreader reliability was moderate for sacroiliitis grading on radiographs (κ = 0.59), excellent on CT scans (κ = 0.91), and excellent for ascertaining sacroiliitis on both radiographs (κ = 1) and CT scans (κ = 0.96). The first and second readers considered the quality of imaging to be excellent in 66% and 67%, respectively, of the radiographs (κ = 0.88) and in 93% and 92%, respectively, of the CT scans (κ = 0.93). Concordance between radiographs and CT scans was low for sacroiliitis grading (κ = 0.08) or ascertainment (κ = 0.16). Definite sacroiliitis was ascertained on radiographs in 6 patients (3.5%) (confirmed by CT scans in 4 patients) and on CT scans in 32 patients (18.5%). A history of uveitis was associated with definite sacroiliitis on radiographs (P = 0.04) and CT scans (P < 0.0001). CONCLUSION: Definite sacroiliitis was underestimated by radiography, as compared to CT scanning. CT scanning should facilitate the diagnosis of ankylosing spondylitis in patients with suspected SpA.
    Mots-clés : Adult, Cross-Sectional Studies, Female, Humans, Male, Observer Variation, Outpatients, Pelvis, Prospective Studies, Reproducibility of Results, Sacroiliitis, Single-Blind Method, Spondylitis, Ankylosing, Tomography, X-Ray Computed.


Journal Article

  • Bonnet, N, Guis, S, Drancourt, M, Brouqui, P & Berbis, P 2011, “Borreliosis in a patient treated with anti-TNFα therapy: first case”, Journal of the European Academy of Dermatology and Venereology: JEADV, vol. 25, no. 3, p. 367-368.
    Mots-clés : Anti-Bacterial Agents, Antirheumatic Agents, Arthritis, Rheumatoid, Doxycycline, Drug Therapy, Combination, Female, Humans, Immunoglobulin G, Immunosuppressive Agents, Lyme Disease, Methotrexate, Middle Aged, Opportunistic Infections, Prednisone, Receptors, Tumor Necrosis Factor, Treatment Outcome, Tumor Necrosis Factor-alpha.


Journal Article

  • Bonnet, N, Guis, S, Koeppel, M-C, Roudier, J, Grimaud, J-C, Jean-Pastor, M-J & Berbis, P 2010, “[Cutaneous events during anti-TNF alpha therapy: a prospective observational study of 41 cases]”, Annales De Dermatologie Et De Vénéréologie, vol. 137, no. 1, p. 12-20.
    Résumé : BACKGROUND: The cutaneous adverse effects of TNFalpha inhibitors and their potential implication in the onset of associated dermatoses remain poorly understood. PURPOSE: To describe the different clinical dermatological situations seen in patients treated with TNFalpha inhibitors. PATIENTS AND METHODS: We conducted a prospective, observational study of patients followed at the Dermatology Department of the CHU Nord university teaching hospital of Marseilles. All patients, referred by various departments, were treated with TNFalpha inhibitors and presented cutaneous events. RESULTS: Forty-one patients were included in the study. Various cutaneous manifestations were observed, including: 15 psoriatic rashes, six skin infections, three eczema rashes, three cases of lupic syndrome, two anaphylactic reactions to infusion and two cutaneous drug reactions. An original case of parapsoriasis was observed. Cutaneous tumors are rarely described. DISCUSSION: This study confirms the multiple clinical dermatological situations observed in patients treated with TNFalpha inhibitors and illustrates the need for good coordination between dermatologists and other specialists in order to ensure optimal management of this population.
    Mots-clés : Adolescent, Adult, Aged, Aged, 80 and over, Anaphylaxis, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Drug Eruptions, Eczema, Female, Humans, Immunoglobulin G, Immunosuppressive Agents, Lupus Erythematosus, Cutaneous, Male, Middle Aged, Prospective Studies, Receptors, Tumor Necrosis Factor, Skin Diseases, Infectious, Skin Diseases, Papulosquamous, Tumor Necrosis Factor-alpha, Young Adult.

  • Faucher, B, Stein, P, Granel, B, Weiller, P-J, Disdier, P, Serratrice, J, Harlé, JR, Durand, JM, Frances, Y, Guis, S, Pham, T, Bardin, N & Sanmarco, M 2010, “Low prevalence of anti-RNA polymerase III antibodies in a French scleroderma population: anti-RNA polymerase III scleroderma”, European Journal of Internal Medicine, vol. 21, no. 2, p. 114-117.
    Résumé : BACKGROUND: Anti-RNA polymerase III antibodies (anti-RNAP III) have been reported as potential immune markers of Systemic Sclerosis (SSc). Until now, their clinical use was disregarded because of technical difficulties to perform immunoprecipitation. Recently, ELISA kits became commercially available allowing an easy detection of anti-RNAP III. We intended to clarify the relevance of these antibodies in the diagnosis of SSc by ELISA detection. METHODS: The prevalence of anti-RNAP III was analyzed using two ELISA kits in 50 consecutive SSc patients from Marseilles in South of France. Controls included 66 patients with other systemic autoimmune diseases, 34 viral diseases and 50 healthy subjects. Positive results with at least one ELISA kit were controlled by immunoprecipitation which is the reference assay. RESULTS: In this study, positivity for anti-centromere and/or anti-topoisomerase I antibodies was observed in 84% of SSc patients. The prevalence of anti-RNAP III in SSc patients was 0% to 6% (3/50) depending on the ELISA kit and only 2% by immunoprecipitation. Concerning controls, two rheumatoid arthritis patients were positive using ELISA (6%), including one with immunoprecipitation confirmation. No anti-RNAP III was detected in systemic lupus erythematosus patients. Three blood donors and one viral disease control were positive using ELISA, but all were negative by immunoprecipitation. CONCLUSIONS: Anti-RNAP III was rarely detected in a French population of SSc patients. Their prevalence was even lower than the one observed in rheumatoid arthritis controls. Therefore local immunologic profiles should be established before deciding a change in clinical practice for SSc immune screening.
    Mots-clés : Aged, Antibodies, Antinuclear, Arthritis, Rheumatoid, Autoantibodies, Case-Control Studies, Centromere, DNA Topoisomerases, Type I, Enzyme-Linked Immunosorbent Assay, Female, France, Humans, Immunoprecipitation, Male, Middle Aged, Prevalence, RNA Polymerase III, Scleroderma, Systemic.


Journal Article

  • Charpin, C, Guis, S, Colson, P, Borentain, P, Mattéi, J-P, Alcaraz, P, Balandraud, N, Thomachot, B, Roudier, J & Gérolami, R 2009, “Safety of TNF-blocking agents in rheumatic patients with serology suggesting past hepatitis B state: results from a cohort of 21 patients”, Arthritis Research & Therapy, vol. 11, no. 6, p. R179.
    Résumé : INTRODUCTION: Reactivation of hepatitis B virus (HBV) infection in patients with past infection has been described in 5% to 10% of individuals undergoing immunosuppressive therapies. No data are available to date on the outcome of patients treated by tumour necrosis factor-alpha (TNFalpha) inhibitors for chronic arthritis with a serological pattern of past HBV infection. The aim of our study was to monitor HBV markers in HBV surface antigen (HBsAg)-negative/anti-HBcAb-positive patients treated with a TNFalpha inhibitor for inflammatory arthritides. METHODS: Twenty-one HBsAg-negative/anti-HBcAb-positive patients were included. HBV serological patterns were compared with those determined before starting TNFalpha inhibitors. Serum HBV DNA testing by polymerase chain reaction was additionally performed. Spearman correlation analysis was used and P < 0.05 was chosen as the significance threshold. RESULTS: Before starting therapy, mean anti-HBsAb titre was 725 IU/L, no patient had an anti-HBsAb titre <10 IU/L, and 18 patients had an anti-HBsAb >100 IU/L. At a mean time of 27.2 months following therapy introduction, mean anti-HBsAb titre was 675 IU/L and anti-HBsAb titre remained >100 IU/L in 17 patients. There was a strong correlation between the first and second anti-HBsAb titres (r = 0.98, P = 0.013). Moreover, no patient had an anti-HBsAb titre below 10 IU/L or HBV reactivation (HBsAg seroreversion or positive HBV DNA detection). However, the anti-HBsAb titre decreased by more than 30% in 6 patients. The mean anti-HBsAb titre at baseline was significantly lower (P = 0.006) and the mean duration of anti-TNFalpha therapy, although non-significant (P = 0.09), was longer in these six patients as compared to patients without a decrease in anti-HBsAb titre. CONCLUSIONS: Anti-TNFalpha treatments are likely to be safe in patients with past hepatitis B serological pattern. However, the significant decrease of anti-HBsAb titre observed in a proportion of patients deserves HBV virological follow-up in these patients, especially in those with a low anti-HBsAb titre at baseline.
    Mots-clés : Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Antirheumatic Agents, Arthritis, Rheumatoid, Cohort Studies, Female, Hepatitis B, Hepatitis B Antibodies, Hepatitis B Surface Antigens, Humans, Immunoglobulin G, Male, Middle Aged, Receptors, Tumor Necrosis Factor, Tumor Necrosis Factor-alpha, Virus Activation.

  • Rak, JM, Maestroni, L, Balandraud, N, Guis, S, Boudinet, H, Guzian, MC, Yan, Z, Azzouz, D, Auger, I, Roudier, C, Martin, M, Didelot, R, Roudier, J & Lambert, NC 2009, “Transfer of the shared epitope through microchimerism in women with rheumatoid arthritis”, Arthritis and Rheumatism, vol. 60, no. 1, p. 73-80.
    Résumé : OBJECTIVE: Rheumatoid arthritis (RA) is an autoimmune disease that affects mostly women and is associated with HLA-DRB1 genes having in common a shared epitope sequence. In parallel, cells and/or DNA originating from pregnancy (microchimerism) persist for decades and could contribute to autoimmunity. The aim of this study was to examine whether microchimerism may be a source of the shared epitope among women with RA. METHODS: Women with RA and healthy women who lacked RA-associated genes such as HLA-DRB1*01 (n=33 and n=46, respectively) and/or HLA-DRB1*04 (n=48 and n=64, respectively), were tested for DRB1*01 or DRB1*04 microchimerism by HLA-specific quantitative polymerase chain reaction assays. As controls, alleles not associated with RA (DQB1*02 and DRB1*15/16) were also analyzed. RESULTS: Compared with healthy women, women (42% with RA had a higher frequency and higher levels of DRB1*04 microchimerism versus 8%; P=0.00002) as well as DRB1*01 microchimerism (30% versus 4%; P=0.0015). Moreover, no difference in microchimerism was observed for alleles not associated with RA. CONCLUSION: Women with RA had microchimerism with RA-associated HLA alleles, but not with non-RA-associated HLA alleles, more often and at higher levels compared with healthy women. These observations are the first to indicate that microchimerism can contribute to the risk of an autoimmune disease by providing HLA susceptibility alleles.
    Mots-clés : Arthritis, Rheumatoid, Chimerism, Epitopes, Female, Genotype, HLA-DQ Antigens, HLA-DQ beta-Chains, HLA-DR Antigens, HLA-DRB1 Chains, Humans, Maternal-Fetal Exchange, Mothers, Pregnancy, Risk Factors.


Journal Article
  • Charpin, C, Balandraud, N, Guis, S, Roudier, C, Toussirot, E, Rak, J, Lambert, N, Martin, M, Reviron, D, Roudier, J & Auger, I 2008, “HLA-DRB1*0404 is strongly associated with high titers of anti-cyclic citrullinated peptide antibodies in rheumatoid arthritis”, Clinical and Experimental Rheumatology, vol. 26, no. 4, p. 627-631.
    Résumé : OBJECTIVE: To test whether the presence of RA associated HLA-DRB1*0101, HLA-DRB1*0401 and HLA-DRB1*0404 alleles individually influences anti-cyclic citrullinated peptide antibodies (anti-CCP) production. METHODS: The frequency of anti-CCP antibodies was calculated in the sera of 260 RA patients expressing either two (double dose genotypes SE+/SE+), one (single dose genotypes SE+/SE-) or no RA associated HLA-DR alleles (SE-/SE-). Anti-CCP antibodies titers were also determined. RESULTS: RA associated HLA-DR alleles are not mandatory for production of anti-CCP. We found that 68% of SE-/SE- patients were anti-CCP positive. There was no significant difference in anti-CCP between SE negative patient (SE-/SE-) and patients expressing at least one SE (SE+/SE+ and SE+/SE-) (p=0.140). We observed no statistical difference in anti-CCP between RA patients expressing one or two SE (82% vs. 77%, p=0.577). Among SE+/SE-patients, HLA-DRB1*0404 was associated with anti-CCP with a statistically significant difference compared with SE negative patients (90% anti-CCP positive, p=0.02). HLA-DRB1*0404 was also associated with high titers of anti CCP with a statistically significant difference compared with HLA-DRB1*0401 and HLA-DRB1*0101 patients (p=0.025). CONCLUSIONS: The RA-associated HLA-DRB1*0404 allele was the most strongly associated with the presence of anti-CCP in RA sera. Moreover, HLA-DRB1*0404 patients had higher titers of anti CCP than patients with other RA associated HLA-DR alleles.
    Mots-clés : Arthritis, Rheumatoid, Autoantibodies, Case-Control Studies, Female, HLA-DR Antigens, HLA-DRB1 Chains, Homozygote, Humans, Male, Middle Aged, Peptides, Cyclic, Scleroderma, Systemic.

  • Guis, S, Schiano de Colella, J-M, Bonnet, N, Andrac-Meyer, L, Balandraud, N, Mattei, J-P, Franck, B, Roudier, C, Roudier, J & Berbis, P 2008, “Cutaneous pseudolymphoma associated with a TNF-alpha inhibitor treatment: etanercept”, European journal of dermatology: EJD, vol. 18, no. 4, p. 474-476.
    Mots-clés : Antirheumatic Agents, Arthritis, Rheumatoid, Humans, Immunoglobulin G, Male, Middle Aged, Pseudolymphoma, Receptors, Tumor Necrosis Factor, Skin Diseases, Tumor Necrosis Factor-alpha.


Journal Article

  • Auger, I, Roudier, C, Guis, S, Balandraud, N & Roudier, J 2007, “HLA-DRB1*0404 is strongly associated with anticalpastatin antibodies in rheumatoid arthritis”, Annals of the Rheumatic Diseases, vol. 66, no. 12, p. 1588-1593.
    Résumé : OBJECTIVE: To test whether HLA-DR alleles influence the production of particular autoantibodies in rheumatoid arthritis (RA) patients, we screened synovial proteins with sera of RA patients homozygous for different HLA-DR alleles by using 2D blots. We found that sera of RA patients homozygous for HLA-DRB1*0404 recognised a 100-kDa synovial protein identified as calpastatin. We studied B and T cell epitopes on calpastatin and their association with HLA-DRB1*0404. METHODS: The frequency of positive sera in patients expressing different RA-associated HLA-DR allele combinations was calculated by inhouse ELISA using purified synovial calpastatin or calpastatin peptides encompassing the entire calpastatin protein as immunosorbent. Interaction between calpastatin peptides and HLA-DR alleles was tested by a direct binding assay. T cell responses to calpastatin were measured in RA patients and controls. RESULTS: We found that RA-associated HLA-DR alleles are associated with presence of autoantibodies to synovial calpastatin in RA patients' sera. HLA-DRB1*0404 is strongly associated with antisynovial calpastatin in RA sera. One linear B cell epitope is preferentially associated with HLA-DRB1*0404. Multiple peptides from calpastatin bind every tested HLA-DR allele associated or not with RA. Peptides from domain 1 and 4 of calpastatin are the best HLA-DR allele binders. The T cell response to calpastatin is frequent in RA patients and independent of the HLA-DR background. CONCLUSIONS: HLA-DRB1*0404 is strongly associated with anticalpastatin antibodies in rheumatoid arthritis.
    Mots-clés : Alleles, Arthritis, Rheumatoid, Autoantibodies, B-Lymphocytes, Calcium-Binding Proteins, Case-Control Studies, Cell Proliferation, Cells, Cultured, Chi-Square Distribution, Electrophoresis, Gel, Two-Dimensional, Enzyme-Linked Immunosorbent Assay, Epitopes, Genetic Predisposition to Disease, HLA-DR Antigens, HLA-DRB1 Chains, Humans, Protein Binding, Protein Structure, Tertiary, Synovial Membrane, T-Lymphocytes.

  • Balandraud, N, Guis, S, Meynard, JB, Auger, I, Roudier, J & Roudier, C 2007, “Long-term treatment with methotrexate or tumor necrosis factor alpha inhibitors does not increase epstein-barr virus load in patients with rheumatoid arthritis”, Arthritis and Rheumatism, vol. 57, no. 5, p. 762-767.
    Résumé : OBJECTIVE: We previously demonstrated that patients with rheumatoid arthritis (RA) have a 10-fold systemic Epstein-Barr virus (EBV) overload, very similar to that observed in healthy organ transplant recipients. Our objective was to monitor EBV load over time in patients with RA receiving methotrexate, infliximab, or etanercept to detect possible immunosuppression-associated EBV dysregulation, as described in posttransplant lymphoproliferative disease. METHODS: The EBV load in the peripheral blood mononuclear cells (PBMCs) from 19 patients receiving methotrexate, 68 patients receiving infliximab, and 48 patients receiving etanercept was monitored for durations ranging from 6 months to 5 years using a real-time polymerase chain reaction assay previously developed for that purpose. The effect of treatment duration on EBV load and the link between the Disease Activity Score in 28 joints and EBV load were analyzed by generalized estimating equations. RESULTS: Methotrexate tended to decrease EBV load over time, but this did not reach significance. Tumor necrosis factor alpha (TNFalpha) inhibitors did not significantly modify EBV load over time. Finally, high disease activity was significantly associated with high EBV load. CONCLUSION: Long-term usage of methotrexate or TNFalpha inhibitors in patients with RA does not significantly influence EBV load in PBMCs.
    Mots-clés : Antibodies, Monoclonal, Arthritis, Rheumatoid, DNA, Viral, Female, Health Status, Herpesvirus 4, Human, Humans, Immunocompromised Host, Immunoglobulin G, Male, Methotrexate, Middle Aged, Receptors, Tumor Necrosis Factor, Severity of Illness Index, Tumor Necrosis Factor-alpha, Viral Load.

  • Charpin, C, Berbis, P, Schmitz, J, Boudinet, H, Mattei, J-P, Balandraud, N, Chagnaud, C, Roudier, J & Guis, S 2007, “Neurofibromatosis type 1 with sciatica”, Joint, Bone, Spine: Revue Du Rhumatisme, vol. 74, no. 3, p. 300-301.
    Mots-clés : Humans, Magnetic Resonance Imaging, Male, Middle Aged, Neurofibromatosis 1, Sciatica.
  • Guis, S & Pellissier, JF 2007, “[Foreword - macrophage mediated myofasciites]”, Revue Neurologique, vol. 163, no. 10, p. 979-980.
    Mots-clés : Fasciitis, Humans, Macrophages.

  • Guis, S, Balandraud, N, Bouvenot, J, Auger, I, Toussirot, E, Wendling, D, Mattei, J-P, Nogueira, L, Mugnier, B, Legeron, P, Landt, O, Serre, G, Roudier, J & Roudier, C 2007, “Influence of -308 A/G polymorphism in the tumor necrosis factor alpha gene on etanercept treatment in rheumatoid arthritis”, Arthritis and Rheumatism, vol. 57, no. 8, p. 1426-1430.
    Résumé : OBJECTIVE: To determine whether the -308 A/G tumor necrosis factor alpha (TNFalpha) gene polymorphism can predict the outcome of etanercept therapy in 86 patients with rheumatoid arthritis (RA), as already observed in patients treated with infliximab. METHODS: Eighty-six RA patients treated with etanercept were genotyped for -308 A/G TNFalpha gene polymorphism by polymerase chain reaction and melting curve analysis, using specific gene primers and probes. Patients were subdivided into group A (G/A genotype) and group G (G/G genotype). We compared clinical responses to etanercept between groups A and G after 6 months, using the Disease Activity Score in 28 joints (DAS28). After 12-month treatment, 48 of 86 patients were evaluated again. RESULTS: Of 86 patients, 18 (21%) belonged in group A and 68 (79%) belonged in group G. After 6-month treatment, 55.6% of patients in group A and 82.4% of patients in group G had DAS28 improvement >1.2 (P = 0.027 by chi-square). The mean +/- SD DAS28 improvement was 1.69 +/- 1.31 in group A and 2.23 +/- 1.19 in group G (P = 0.098 by t-test). After 1-year treatment 48 patients were tested again: 10 (21%) belonged in group A and 38 (79%) belonged in group G. Forty percent of patients in group A and 87% in group G had DAS28 improvement >1.2 (P = 0.005 by chi-square). The mean +/- SD DAS28 improvement was 1.334 +/- 1.37 in group A and 2.29 +/- 1.47 in group G (Mann-Whitney U test = 115, P = 0.0057). CONCLUSION: RA patients with a -308 G/G TNFalpha genotype respond to etanercept better than patients with a -308 A/G genotype.
    Mots-clés : Adult, Aged, Antirheumatic Agents, Arthritis, Rheumatoid, Female, Genotype, Humans, Immunoglobulin G, Male, Middle Aged, Polymorphism, Single Nucleotide, Predictive Value of Tests, Receptors, Tumor Necrosis Factor, Severity of Illness Index, Treatment Outcome, Tumor Necrosis Factor-alpha.


Journal Article

  • Alcaraz, P, Aubran, C, Jaoua, S, Roudier, C, Mattei, JP, Announ, N, Chagnaud, C, Roudier, J & Guis, S 2006, “Calcaneal osteomyelitis due to fistulization of an ulcerated rheumatoid nodule”, Joint, Bone, Spine: Revue Du Rhumatisme, vol. 73, no. 1, p. 102-104.
    Résumé : Calcaneal osteomyelitis is uncommon and difficult to treat. Cases due to fistulization of an infected rheumatoid nodule are exceedingly rare. PATIENT: A 65-year-old patient with nodular rheumatoid arthritis (RA) experienced osteomyelitis of the left calcaneus due to inoculation from a fistula draining an ulcerated rheumatoid nodule. Pseudomonas aeruginosa and Enterobacter cloacae were recovered. The conventional treatment of calcaneal osteomyelitis relies on antibiotics and calcanectomy or foot amputation. We used two appropriate antibiotics and monthly intravenous injections of 90 mg of pamidronate. RESULT: One year into treatment, the patient was free of pain and the skin wound was fully healed. On a follow-up computed tomography (CT) scan, the fistulous tract was seen to be closed and the large calcaneal defect almost completely filled with new bone. CONCLUSION: Combining two antibiotics and pamidronate may be a viable alternative to excision surgery or amputation in some patients with bone infection carrying a risk of fracture.
    Mots-clés : Aged, Anti-Bacterial Agents, Bone Density Conservation Agents, Calcaneus, Cutaneous Fistula, Diphosphonates, Drug Therapy, Combination, Follow-Up Studies, Humans, Male, Osteomyelitis, Rheumatic Nodule, Tomography, X-Ray Computed, Ulcer.
  • Bendahan, D, Mattei, JP, Guis, S, Kozak-Ribbens, G & Cozzone, PJ 2006, “[Non-invasive investigation of muscle function using 31P magnetic resonance spectroscopy and 1H MR imaging]”, Revue neurologique, vol. 162, no. 4, p. 467-484.
    Résumé : 31P MRS and 1H MRI of skeletal muscle have become major new tools allowing a complete non invasive investigation of muscle function both in the clinical setting and in basic research. The comparative analysis of normal and diseased muscle remains a major requirement to further define metabolic events surrounding muscle contraction and the metabolic anomalies underlying pathologies. Also, standardized rest-exercise-recovery protocols for the exploration of muscle metabolism by P-31 MRS in healthy volunteers as well as in patients with intolerance to exercise have been developed. The CRMBM protocol is based on a short-term intense exercise, which is very informative and well accepted by volunteers and patients. Invariant metabolic parameters have been defined to characterize the normal metabolic response to the protocol. Deviations from normality can be directly interpreted in terms of specific pathologies in some favorable cases. This protocol has been applied to more than 4,000 patients and healthy volunteers over a period of 15 years. On the other hand, MRI investigations provide anatomical and functional information from resting and exercising muscle. From a diagnostic point of view, dedicated pulse sequences can be used in order to detect and quantify muscle inflammation, fatty replacement, muscle hyper and hypotrophy. In most cases, MR techniques provide valuable information which has to be processed in conjunction with traditional invasive biochemical, electrophysiological and histoenzymological tests. P-31 MRS has proved particularly useful in the therapeutic follow-up of palliative therapies (coenzyme Q treatment of mitochondriopathies) and in family investigations. It is now an accepted diagnostic tool in the array of tests which are used to characterize muscle disorders in clinical routine. As a research tool, it will keep bringing new information on the physiopathology of muscle diseases in animal models and in humans and should play a role in the metabolic characterization of gene and cell therapy.
    Mots-clés : Adenosine Triphosphate, Calibration, crmbm, Energy Metabolism, Equipment Design, Exercise Test, Humans, Hydrogen, Magnetic Resonance Spectroscopy, Metabolism, Inborn Errors, Mitochondrial Myopathies, Muscle Contraction, Muscle, Skeletal, Muscular Diseases, Myositis, Neuromuscular Diseases, Phosphates, Phosphocreatine, Phosphorus Isotopes, Rest.
  • Figarella-Branger, D, Schleinitz, N, Boutière-Albanèse, B, Camoin, L, Bardin, N, Guis, S, Pouget, J, Cognet, C, Pellissier, J-F & Dignat-George, F 2006, “Platelet-endothelial cell adhesion molecule-1 and CD146: soluble levels and in situ expression of cellular adhesion molecules implicated in the cohesion of endothelial cells in idiopathic inflammatory myopathies”, The Journal of Rheumatology, vol. 33, no. 8, p. 1623-1630.
    Résumé : OBJECTIVE: Idiopathic inflammatory myopathies (IIM) are a heterogeneous group of diseases characterized by chronic inflammation of muscles. We investigated the role of cellular adhesion molecules implicated in the cohesion of endothelial cells in IIM. METHODS: In 22 patients with IIM we investigated plasma concentrations of soluble junctional adhesion molecules [platelet-endothelial cell adhesion molecule (sPECAM-1) and sCD146] and cellular adhesion molecules [sP-selectin, sE-selectin, intercellular adhesion molecule (sICAM-1), and vascular cell adhesion molecule (sVCAM-1)] implicated in leukocyte/endothelial cell interactions. Results were compared to a control group. Muscle biopsy samples from 8 out of 22 IIM patients were studied by immunohistochemistry for tissue expression of these molecules and compared to normal muscle samples. PECAM-1 and CD146 expression was also studied using immunoblots from muscle biopsies from 5 patients and 2 controls. RESULTS: We observed distinct patterns of soluble levels and in situ expression between dermatomyositis (DM), polymyositis (PM), and sporadic inclusion body myositis (s-IBM). PM samples showed significantly increased levels of sCD146, sPECAM-1, and s-ICAM1 and increased expression of CD146, CD31, and ICAM-1 in endothelial cells, whereas CD146 and ICAM-1 were also recorded in some muscle fibers. In DM, sE-selectin, sP-selectin, and sPECAM-1 were significantly increased, with abnormal expression of ICAM-1 in endothelial cells and perifascicular muscle fibers. In the small group of s-IBM samples, results were similar to PM, but the only significant increase was the level of sPECAM-1. Immunoblots confirmed increased expression of PECAM-1 and CD146 in all IIM muscles in comparison to controls, with the highest expression in PM and IBM samples. CONCLUSION: We observed abnormal increases of soluble levels of adhesion molecules implicated in endothelial cell junctions in PM (sCD146, sPECAM-1) and to a lesser extent in DM and s-IBM (sPECAM-1). We conclude that the distinctly different profiles between PM/s-IBM and DM reflect differences in the pathophysiological background of these diseases.
    Mots-clés : Antigens, CD146, Antigens, CD31, Cell Adhesion, Cell Adhesion Molecules, Dermatomyositis, E-Selectin, Endothelial Cells, Humans, Intercellular Adhesion Molecule-1, Muscle, Skeletal, Myositis, Myositis, Inclusion Body, P-Selectin, Polymyositis, Vascular Cell Adhesion Molecule-1.

  • Guis, S, Figarella-Branger, D, Mattei, JP, Nicoli, F, Le Fur, Y, Kozak-Ribbens, G, Pellissier, JF, Cozzone, PJ, Amabile, N & Bendahan, D 2006, “In vivo and in vitro characterization of skeletal muscle metabolism in patients with statin-induced adverse effects”, Arthritis and rheumatism, vol. 55, no. 4, p. 551-557.
    Résumé : OBJECTIVE: Statins (3-hydroxymethylglutaryl-coenzyme A reductase inhibitor) are widely used to treat hypercholesterolemia. They are generally well tolerated, but myotoxic effects have been reported and the corresponding mechanisms are still a matter of debate. The aim of the present study was to determine whether impairment of calcium homeostasis and/or mitochondrial impairment could account for the adverse effects of statins in skeletal muscle. METHODS: Eleven patients with increased creatine kinase levels and myalgias after statin treatment were evaluated using in vitro contracture tests (IVCTs), histology, and 31P magnetic resonance spectroscopy (31P-MRS). RESULTS: IVCT results were abnormal in 7 of the 9 patients, indicating an impaired calcium homeostasis. The 31P-MRS investigation disclosed no anomaly at rest, and the aerobic function assessed during the postexercise recovery period was normal. On the contrary, the pH recovery kinetics was significantly slowed down as indicated by a reduced proton efflux, which could be ultimately linked to a failure of calcium homeostasis. Overall, our observations indicate a normal mitochondrial function and raise the possibility that statins may unmask a latent pathology involving an impairment of calcium homeostasis such as malignant hyperthermia (MH). CONCLUSION: In case of susceptibility to MH, statins treatment must be administered with caution, and signs of adverse effects should be checked.
    Mots-clés : Aged, Biopsy, Calcium, Creatine Kinase, crmbm, Female, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypercholesterolemia, Magnetic Resonance Spectroscopy, Male, Middle Aged, Muscle Contraction, Muscle, Skeletal, Muscular Diseases, Pain.

  • Mattei, JP, Fur, YL, Cuge, N, Guis, S, Cozzone, PJ & Bendahan, D 2006, “Segmentation of fascias, fat and muscle from magnetic resonance images in humans: the DISPIMAG software”, Magma (New York, N.Y.), vol. 19, no. 5, p. 275-279.
    Résumé : Segmentation of human limb MR images into muscle, fat and fascias remains a cumbersome task. We have developed a new software (DISPIMAG) that allows automatic and highly reproducible segmentation of lower-limb MR images. Based on a pixel intensity analysis, this software does not need any previous mathematical or statistical assumptions. It displays a histogram with two main signals corresponding to fat and muscle, and permits an accurate quantification of their relative spatial distribution. To allow a systematic discrimination between muscle and fat in any subject, fixed boundaries were first determined manually in a group of 24 patients. Secondly, an entirely automatic process using these boundaries was tested by three operators on four patients and compared to the manual approach, showing a high concordance.
    Mots-clés : Adipose Tissue, Analysis of Variance, crmbm, Fascia, Humans, Image Enhancement, Image Interpretation, Computer-Assisted, Magnetic Resonance Imaging, Muscles, Software.


Journal Article

  • Auger, I, Sebbag, M, Vincent, C, Balandraud, N, Guis, S, Nogueira, L, Svensson, B, Cantagrel, A, Serre, G & Roudier, J 2005, “Influence of HLA-DR genes on the production of rheumatoid arthritis-specific autoantibodies to citrullinated fibrinogen”, Arthritis and Rheumatism, vol. 52, no. 11, p. 3424-3432.
    Résumé : OBJECTIVE: Antibodies directed against citrullinated fibrinogen are highly specific for rheumatoid arthritis (RA). This study was undertaken to test whether RA-associated HLA-DR alleles are associated with anti-citrullinated fibrinogen in RA patient sera and whether replacement of arginyl by citrullyl residues on fibrinogen peptides modifies their binding to HLA-DR molecules and their recognition by T cells. METHODS: Antikeratin, antifilaggrin, and anti-citrullinated fibrinogen antibodies were assayed in RA patients who had undergone HLA-DR typing. Direct assays were performed to investigate binding of citrullinated or native fibrinogen peptides (encompassing the entire alpha- and beta-chains of fibrinogen) to purified HLA-DR molecules. T cell proliferative responses to citrullinated or native fibrinogen peptides were measured in RA patients and controls. RESULTS: HLA-DRB1*0404 was associated with anti-citrullinated fibrinogen in RA sera (P = 0.002). For the RA-associated alleles HLA-DRB1*0401 and HLA-DR1, there was a nonsignificant trend toward association (P = 0.07). Multiple peptides from the alpha- and beta-chains of fibrinogen bound many HLA-DR alleles; DRB1*0404 was the best fibrinogen peptide binder. Citrullination did not influence fibrinogen peptide binding to HLA-DR or fibrinogen peptide recognition by T cells. Peripheral blood T cells that recognized native or citrullinated fibrinogen peptides were common in RA patients but not in healthy controls. CONCLUSION: The RA-associated HLA-DRB1*0404 allele is also associated with production of antibodies to citrullinated fibrinogen. DRB1*0401 and DRB1*01 tend to be associated with anti-citrullinated fibrinogen, but this is not statistically significant. Citrullination of fibrinogen peptide does not influence peptide-DR-T cell interaction. Finally, T cell proliferation in response to citrullinated or uncitrullinated fibrinogen peptides is frequent in RA patients and very infrequent in controls.
    Mots-clés : Alleles, Amino Acid Sequence, Arginine, Arthritis, Rheumatoid, Autoantibodies, Cell Proliferation, Cells, Cultured, Female, Genetic Predisposition to Disease, HLA-DR Antigens, Humans, Leukocytes, Mononuclear, Male, Middle Aged, Molecular Sequence Data, Peptides, Cyclic, T-Lymphocytes.

  • Guis, S, Mattei, J-P, Cozzone, PJ & Bendahan, D 2005, “Pathophysiology and clinical presentations of rhabdomyolysis”, Joint, bone, spine: revue du rhumatisme, vol. 72, no. 5, p. 382-391.
    Résumé : Rhabdomyolysis has sparked new interest in recent years. The causes of rhabdomyolysis include drugs and other toxic agents, infections, physical exertion, crush injury, and muscle diseases (dystrophinopathies and metabolic myopathies). Prompt identification of the pathophysiological mechanism is the key to rapid control of the acute episode and to prevention of recurrences. In this update, we discuss the pathophysiological mechanisms and nosology of rhabdomyolysis, as well as diagnostic investigations, with special emphasis on noninvasive methods.
    Mots-clés : crmbm, Humans, Rhabdomyolysis.

  • Poullin, P, Announ, N, Mugnier, B, Guis, S, Roudier, J & Lefèvre, P 2005, “Protein A-immunoadsorption (Prosorba column) in the treatment of rheumatoid arthritis”, Joint, Bone, Spine: Revue Du Rhumatisme, vol. 72, no. 2, p. 101-103.
    Mots-clés : Arthritis, Rheumatoid, Humans, Immunosorbents, Staphylococcal Protein A.


Journal Article

  • Announ, N, Mattei, JP, Jaoua, S, Fenollar, F, Sati, H, Chagnaud, C, Roudier, J & Guis, S 2004, “Multifocal discitis caused by Staphylococcus warneri”, Joint, Bone, Spine: Revue Du Rhumatisme, vol. 71, no. 3, p. 240-242.
    Résumé : Staphylococcus warneri is a coagulase-negative staphylococcus that is a normal inhabitant of the skin but occasionally causes septicemia and endocarditis. We report a case of multifocal discitis caused by S. warneri in an immunocompetent patient. Only three cases of spinal S. warneri infections have been reported in the literature. They illustrate the atypical clinical presentation, with chronic pain of increasing severity in the thoracic or lumbar spine instead of the abrupt onset that characterizes S. aureus discitis. In our patient, despite the multifocal distribution of the lesions, heretofore unreported, clinical presentation suggested common low back pain. This presentation may be ascribable to the unique bacteriological characteristics of S. warneri. The case reported here illustrates the diagnostic challenges sometime raised by discitis due to coagulase-negative staphylococci.
    Mots-clés : Aged, Chronic Disease, Coagulase, Discitis, Humans, Low Back Pain, Lumbar Vertebrae, Magnetic Resonance Imaging, Male, Spinal Fractures, Staphylococcal Infections.

  • Bendahan, D, Guis, S, Monnier, N, Kozak-Ribbens, G, Lunardi, J, Ghattas, B, Mattei, J-P & Cozzone, PJ 2004, “Comparative analysis of in vitro contracture tests with ryanodine and a combination of ryanodine with either halothane or caffeine: a comparative investigation in malignant hyperthermia”, Acta anaesthesiologica Scandinavica, vol. 48, no. 8, p. 1019-1027.
    Résumé : BACKGROUND: The diagnosis of susceptibility to malignant hyperthermia (MH) is currently performed on muscle biopsies subjected to halothane-caffeine in vitro contracture tests (IVCTs). There is a consensus on our need to improve the diagnostic potential of IVCTs if we are to maximize the information available for research and diagnosis in MH. This study was designed as a pilot comparative study and we aimed at comparing the ryanodine test and new tests using a combination of ryanodine, halothane and caffeine. METHODS: One hundred and thirty-two subjects (52 MHS and 80 MHN) were included in this study and new IVCTs were performed in additional muscle biopsy specimens. The contracture time-course was compared considering the onset time of contracture (OT) and the time to reach a 10 mN contracture (10T). Cut-off values were determined using ROC analyses. RESULTS: For the ryanodine test, sensitivity and specificity calculated for OT were 84.6% and 90.4%, respectively, and were better than those obtained using 10T. Combined tests using either caffeine and ryanodine or halothane and ryanodine did provide higher sensitivities (from 85.3 to 93.9%). A better specificity was only observed for the IVC tests combining halothane (cumulated) and caffeine both with ryanodine (93.9% for both). The largest sensitivity was observed when halothane was used as a bolus and combined with ryanodine. The specificity was always larger with the combined tests as compared to the test using ryanodine alone (from 79.1 to 90.9%). This superiority was confirmed, at least in part, when comparing genetic investigations and the results of new tests in a subgroup of subjects. CONCLUSIONS: This pilot study showed a clear diagnostic potential for new IVC tests combining halothane, the triggering agent of MH, and ryanodine acting at the calcium release channel, and should be considered as a first step in the investigation of combined tests.
    Mots-clés : Anesthetics, Inhalation, Caffeine, crmbm, DNA, Halothane, Humans, In Vitro Techniques, Malignant Hyperthermia, Muscle Contraction, Muscle, Skeletal, Mutation, Phosphodiesterase Inhibitors, Predictive Value of Tests, Reverse Transcriptase Polymerase Chain Reaction, ROC Curve, Ryanodine.

  • Guis, S, Figarella-Branger, D, Monnier, N, Bendahan, D, Kozak-Ribbens, G, Mattei, J-P, Lunardi, J, Cozzone, PJ & Pellissier, J-F 2004, “Multiminicore disease in a family susceptible to malignant hyperthermia: histology, in vitro contracture tests, and genetic characterization”, Archives of neurology, vol. 61, no. 1, p. 106-113.
    Résumé : BACKGROUND: Histological anomalies associated with malignant hyperthermia (MH) have been scarcely reported. In some patients susceptible to MH (MHS), central cores have been identified and a genetic association has been proposed, but multiminicore lesions have not been systematically reported. OBJECTIVE: To analyze the association between multiminicores and MHS in a large family with MH with an approach combining histology, in vitro contracture tests, and genetic analysis. PATIENTS AND METHODS: Twenty-nine members of an MH family (147 members) were investigated. MAIN OUTCOME MEASURES: Muscle biopsy specimens were analyzed histologically and with in vitro contracture tests. Genetic analyses were performed to determine the presence of mutations in the ryanodine receptor (RYR1) gene. RESULTS: According to the gold standard in vitro contracture tests, 17 patients were diagnosed as having MHS and 10 as not being susceptible. Multiminicores were found in 16 of the 17 MHS patients and in a single nonsusceptible participant. A linkage between the MH trait and the RYR1 locus in chromosome 19 was demonstrated, whereas no already known mutations were found. Two missense heterozygous mutations (R2676W and T2787S) were identified from sequencing of the entire coding complementary DNA. Overall, we found a significant association between MHS and the presence of multiminicores (chi(2) = 26.5, P<.001) on the one hand and the presence of new mutations in the RYR1 gene (chi(2) = 19.0, P<.001) on the other hand. This remarkably high occurrence of multiminicores in an MHS family is uncommon, and genetic analyses indicate that the association between multiminicores and MHS is linked to a novel R2656W and T2787S substitution present on the same allele of the RYR1 gene. CONCLUSIONS: These results indicate that multiminicore lesions are observed in MHS patients with neither clinical signs related to multiminicore disease nor histological features of congenital myopathies. These multiminicore lesions may be secondary to mutations in the RYR1 gene. As a consequence, these patients must be distinguished from patients with multiminicore disease and from other MHS patients for whom multiminicores are not observed.
    Mots-clés : crmbm, DNA Mutational Analysis, Female, Genetic Predisposition to Disease, Humans, Male, Malignant Hyperthermia, Muscle Contraction, Muscle, Skeletal, Mutation, Myopathies, Nemaline, Myopathy, Central Core, Pedigree, Ryanodine Receptor Calcium Release Channel.
  • Guis, S, Mattei, J-P, Pellissier, J-F, Nicoli, F, Figarella-Branger, D, Le Fur, Y, Kaplanski, G, Pelletier, J, Harle, J-R, Cozzone, PJ & Bendahan, D 2004, “MRI and 31PMR spectroscopy investigations of muscle function disclose no abnormality in macrophagic myofasciitis”, The Journal of rheumatology, vol. 31, no. 11, p. 2313-2314.
    Mots-clés : Adult, crmbm, Fasciitis, Female, Humans, Macrophages, Magnetic Resonance Imaging, Magnetic Resonance Spectroscopy, Male, Muscle, Skeletal, Myositis, Phosphorus Isotopes.

  • Guis, S & Roudier, J 2004, “Comments about the editorial by Thomas Papo entitled "Macrophagic myofasciitis: focal or systemic?"”, Joint, Bone, Spine: Revue Du Rhumatisme, vol. 71, no. 2, p. 164; author rely 164-165.
    Mots-clés : Fasciitis, Hepatitis B Vaccines, Humans, Macrophages, Musculoskeletal Diseases, Myositis, Prognosis, Severity of Illness Index, Vaccination.


Journal Article
  • Civatte, M, Schleinitz, N, Krammer, P, Fernandez, C, Guis, S, Veit, V, Pouget, J, Harlé, J-R, Pellissier, J-F & Figarella-Branger, D 2003, “Class I MHC detection as a diagnostic tool in noninformative muscle biopsies of patients suffering from dermatomyositis (DM)”, Neuropathology and Applied Neurobiology, vol. 29, no. 6, p. 546-552.
    Résumé : This study is to further confirm the diagnostic value of class I MHC detection in muscle biopsies of adult patients presenting with clinical features of dermatomyositis (DM) and to address its diagnostic value in the case of nonspecific biopsies. A retrospective study was performed on muscle biopsies in 22 patients presenting with clinical features of DM. Immunohistochemical detection of class I MHC was performed in all cases. On pathological features two groups of patients were recorded: group I (14 patients) with typical features of DM and group II (eight patients) with almost normal muscle biopsies (no inflammatory exudates, no perifascicular atrophy). Abnormal sarcolemmal class I MHC expression was recorded in all cases. In all muscle biopsies of group I patients, class I MHC expression was observed in almost all fibres but was stronger in perifascicular areas (eight patients) or was restricted to perifascicular atrophic fibres (six patients). In all muscle biopsies of group II patients, only some perifascicular fibres expressed class I MHC. According to Bohan and Peter criteria, patients were classified as definite DM (nine group I and three group II patients), probable DM (five group I and two group II patients) and possible DM (three group II patients). Abnormal perifascicular class I MHC expression is of diagnostic value in patients presenting with clinical features of DM especially when muscle biopsy fails to show typical features such as inflammatory infiltrates and/or perifascicular atrophy.
    Mots-clés : Adult, Aged, Biological Markers, Biopsy, Dermatomyositis, Electromyography, Female, Histocompatibility Antigens Class I, Humans, Immunohistochemistry, Male, Microscopy, Electron, Middle Aged, Muscle, Skeletal, Retrospective Studies.

  • Guis, S, Bendahan, D, Kozak-Ribbens, G, Figarella-Branger, D, Mattei, JP, Pellissier, JF, Treffouret, S, Bernard, V, Lando, A & Cozzone, PJ 2003, “Rhabdomyolysis and myalgia associated with anticholesterolemic treatment as potential signs of malignant hyperthermia susceptibility”, Arthritis and rheumatism, vol. 49, no. 2, p. 237-238.
    Mots-clés : Cholinesterase Inhibitors, Disease Susceptibility, Female, Heptanoic Acids, Humans, Hypercholesterolemia, Malignant Hyperthermia, Middle Aged, Pain, Pyrroles, Rhabdomyolysis.

  • Guis, S, Mattéi, J-P & Lioté, F 2003, “Drug-induced and toxic myopathies”, Best Practice & Research. Clinical Rheumatology, vol. 17, no. 6, p. 877-907.
    Résumé : Drug-induced myopathies and, more rarely, rhabdomyolysis, are a common biological and clinical setting for clinical rheumatologists. The focus of this chapter is to review (i) the clinical presentation and management of these adverse drug reactions (ADR) according to pain and associated neurological symptoms, (ii) the common drugs prescribed by rheumatologists which may induce reactions such as ADR, with special reference to new drugs, (iii) the pathological classification associated with specific patterns, and (iv) the risk factors leading to myotoxicity (including genetic predisposition). Specific features to be reviewed include macrophage myofasciitis and biological agents of major importance when considering terrorist attacks with biological weapons. When diagnosis is suspected, discontinuation of the putative drug(s) is mandatory and should be carefully monitored.
    Mots-clés : Humans, Muscular Diseases.


Journal Article
  • Camacho, M, Guis, S, Mattei, J-P, Costello, R & Roudier, J 2002, “Three-year outcome in a patient with Staphylococcus lugdunensis discitis”, Joint, Bone, Spine: Revue Du Rhumatisme, vol. 69, no. 1, p. 85-87.
    Résumé : The few reported cases of bone and joint infection by Staphylococcus lugdunensis indicate that the clinical manifestations are severe, the diagnosis elusive, and the treatment difficult. We report a case of lumbar discitis caused by Staphylococcus lugdunensis in a 67-year-old man receiving chemotherapy for stage III IgA lambda multiple myeloma. Treatment was with ofloxacin and pristinamycin for 1 year. Although he started to improve only 5 months after treatment initiation, the outcome was favorable. Follow-up at the time of this writing is 3 years.
    Mots-clés : Aged, Anti-Bacterial Agents, Anti-Infective Agents, Antineoplastic Combined Chemotherapy Protocols, Discitis, Humans, Immunocompromised Host, Lumbar Vertebrae, Male, Microbial Sensitivity Tests, Multiple Myeloma, Ofloxacin, Pristinamycin, Staphylococcal Infections, Staphylococcus.

  • Guis, S, Bendahan, D, Kozak-Ribbens, G, Mattei, JP, Le Fur, Y, Confort-Gouny, S, Figarella-Branger, D, Jouglard, J & Cozzone, PJ 2002, “Investigation of fluoroquinolone-induced myalgia using (31)P magnetic resonance spectroscopy and in vitro contracture tests”, Arthritis and rheumatism, vol. 46, no. 3, p. 774-778.
    Résumé : OBJECTIVE: To investigate muscle function in patients with severe myalgia resulting from fluoroquinolone (FQ) treatment. We used histology, in vitro contracture tests (IVCTs), and (31)P magnetic resonance spectroscopy ((31)P MRS) to explore muscle contraction and metabolism. METHODS: We studied 3 patients with myalgia, hyperalgia tendinopathy, and arthralgia following FQ treatment and 3 normal subjects after taking FQs. Results were compared with those of a control group of 9 subjects free of any muscle disease and not taking FQs. Muscle biopsies were performed on the left biceps, and IVCTs were performed in accordance with the protocol recommended by the European Malignant Hyperthermia Group. (31)P MR spectra of forearm flexor muscles were recorded at 4.7T throughout a rest-exercise-recovery protocol. RESULTS: (31)P MRS showed a significant reduction of pH changes measured at the end of exercise and a faster rate of proton efflux measured during recovery in all patients. IVCTs diagnosed 1 patient as being susceptible to malignant hyperthermia. No specific histologic anomalies were observed in muscle biopsy samples, which showed normal mitochondria. CONCLUSION: The adverse effects recorded in the 3 patients are related to a preexisting muscular anomaly revealed by FQ treatment.
    Mots-clés : Adult, Exercise Test, Female, Fluoroquinolones, Humans, Hydrogen-Ion Concentration, In Vitro Techniques, Magnetic Resonance Spectroscopy, Male, Middle Aged, Muscle Contraction, Muscle, Skeletal, Muscular Diseases, Pain, Phosphorus, Reference Values.

  • Guis, S, Mattei, JP, Nicoli, F, Pellissier, JF, Kaplanski, G, Figarella-Branger, D, Manez, GC, Antipoff, GM & Roudier, J 2002, “Identical twins with macrophagic myofasciitis: genetic susceptibility and triggering by aluminic vaccine adjuvants?”, Arthritis and Rheumatism, vol. 47, no. 5, p. 543-545.
    Mots-clés : Aluminum, Fasciitis, Female, Hepatitis B Vaccines, HLA-DR Antigens, HLA-DRB1 Chains, Humans, Macrophages, Middle Aged, Myositis, Twins, Monozygotic.

  • Guis, S, Pellissier, J-F, Nicoli, F, Reviron, D, Mattei, J-P, Gherardi, RK, Pelletier, J, Kaplanski, G, Figarella-Branger, D & Roudier, J 2002, “HLA-DRB1*01 and macrophagic myofasciitis”, Arthritis and Rheumatism, vol. 46, no. 9, p. 2535-2537.
    Mots-clés : Adolescent, Adult, Diseases in Twins, Fasciitis, Female, Genotype, HLA-DR Antigens, HLA-DRB1 Chains, Humans, Macrophages, Male, Middle Aged, Myositis.


Journal Article
  • Guis, S, Jouglard, J, Kozak-Ribbens, G, Figarella-Branger, D, Vanuxem, D, Pellissier, JF & Cozzone, PJ 2001, “Malignant hyperthermia susceptibility revealed by myalgia and rhabdomyolysis during fluoroquinolone treatment”, The Journal of Rheumatology, vol. 28, no. 6, p. 1405-1406.
    Résumé : Fluoroquinolones cause myalgia, but this complication is not clearly documented. We describe a patient who developed myalgia and rhabdomyolysis during fluoroquinolone treatment. The patient was a 33-year-old man treated with norfloxacin for common cystitis. He complained of general muscular fatigue, tendon disorders, and articular pain during treatment. When the antimicrobial agent was stopped, symptoms decreased, with persistence of slight myalgia for 10 days. Rhabdomyolysis was detected. Six months later, investigation by 31P magnetic resonance spectroscopy revealed an oxidative disorder and an abnormal abundance of phosphomonoesters. In vitro contracture tests led to a diagnosis of malignant hyperthermia susceptibility. Our case shows that for any subject presenting myalgia with rhabdomyolysis triggered by fluoroquinolone treatment, the presence of a latent myopathy should be investigated.
    Mots-clés : Adult, Anti-Infective Agents, Disease Susceptibility, Humans, Male, Malignant Hyperthermia, Muscular Diseases, Norfloxacin, Pain, Predictive Value of Tests, Rhabdomyolysis.
  • Reviron, D, Foutrier, C, Guis, S, Mercier, P & Roudier, J 2001, “DRB1 alleles in polymyalgia rheumatica and rheumatoid arthritis in southern France”, European Journal of Immunogenetics: Official Journal of the British Society for Histocompatibility and Immunogenetics, vol. 28, no. 1, p. 83-87.
    Résumé : To investigate the association of HLA-DRB1 alleles with polymyalgia rheumatica (PMR) and rheumatoid arthritis (RA), 55 patients with PMR without giant cell arteritis, 203 patients with RA and 230 controls, all from the European population of Marseille, were HLA-DRB1 genotyped by PCR-SSO. HLA-DRB1*01 was significantly increased in both the PMR and RA groups compared to controls (35% versus 17%, P(c) < 0.05, and 41% versus 17%, P(c) < 0.001, respectively). HLA-DRB1*04 was significantly increased in the RA group compared to controls (48% versus 23%, P(c) < 0.001) but not in the PMR group. HLA-DRB1*04 subtype frequencies were significantly different between PMR patients and RA patients. Shared epitope-positive HLA-DRB1*04 alleles (DRB1*0401, 0404, 0405, 0408) were significantly overrepresented in RA patients compared to PMR patients and shared epitope-negative HLA-DRB1*04 alleles were overrepresented in PMR patients compared to RA patients. In conclusion, in the Mediterranean population studied, HLA-DRB1*01 is associated with RA and PMR whereas HLA-DRB1*04 is associated with RA only.
    Mots-clés : Aged, Aged, 80 and over, Alleles, Arthritis, Rheumatoid, Female, France, Genotype, HLA-DR Antigens, HLA-DRB1 Chains, Humans, Male, Middle Aged, Polymerase Chain Reaction, Polymyalgia Rheumatica.

  • Reviron, D, Perdriger, A, Toussirot, E, Wendling, D, Balandraud, N, Guis, S, Semana, G, Tiberghien, P, Mercier, P & Roudier, J 2001, “Influence of shared epitope-negative HLA-DRB1 alleles on genetic susceptibility to rheumatoid arthritis”, Arthritis and Rheumatism, vol. 44, no. 3, p. 535-540.
    Résumé : OBJECTIVE: Most patients with rheumatoid arthritis (RA) express the shared epitope (SE). It is not known whether SE-negative HLA-DRB1 alleles influence the development of RA. This study examined the influence of SE-negative HLA-DR alleles (DRB1*X) on the development of RA in 3 different French populations. METHODS: HLA-DRB1 alleles were defined by polymerase chain reaction with sequence-specific oligonucleotide hybridization or sequence-specific primers. SE-negative alleles were classified according to the electric charge of their P4 pocket. HLA-DRB1 alleles *0103, *0402, *07, *08, *11 (except *1107), *12, and *13 have a neutral or negative P4 charge and are called DRB1*XP4n. HLA-DRB1*03, *0403, *0406, *0407, *0901, *1107, *14, *15, and *16 have a positive P4 charge and are called DRB1*XP4p. RESULTS: Among the SE-negative subjects, DRB1 genotypes with 1 or 2 DRB1*XP4n alleles were significantly overrepresented in the control subjects compared with the RA patients, whereas DRB1*XP4p/XP4p genotypes were equally represented in the patients and controls. In single-dose SE-positive subjects, SE/XP4n genotypes were equally represented in the patients and controls. However, SE/XP4p genotypes were significantly overrepresented in the RA patients. CONCLUSION: The DRB1*X allele polymorphism influences susceptibility to RA. Alleles that have a neutral or negative electric charge in their P4 pocket (DRB1*XP4n), such as DRB1*0103, *0402, *07, *08, *11 (except *1107), *12, and *13, protect against RA. Alleles that have a positive electric charge in their P4 pocket (DRB1*XP4p), such as DRB1*03, *0403, *0406, *0407, *0901, *1107, *14, *15, and *16, have no influence on the predisposition to RA.
    Mots-clés : Alleles, Arthritis, Rheumatoid, Epitopes, France, Genetic Predisposition to Disease, Genotype, HLA-DR Antigens, HLA-DRB1 Chains.
  • Said-Nahal, R, Miceli-Richard, C, D'Agostino, MA, Dernis-Labous, E, Berthelot, JM, Duché, A, Le Blévec, G, Saraux, A, Perdriger, A, Guis, S, Amor, B, Dougados, M, Breban, M & Groupe Français d'Etude Génétique des Spondylarthropathies, 2001, “Phenotypic diversity is not determined by independent genetic factors in familial spondylarthropathy”, Arthritis and Rheumatism, vol. 45, no. 6, p. 478-484.
    Résumé : OBJECTIVE: To analyze the segregation of manifestations belonging to the spectrum of spondylarthropathy (SpA) among patients and unaffected siblings within SpA multiplex families. METHODS: Ninety-five multiplex families have been investigated. The diagnosis of SpA was made according to European Spondylarthropathy Study Group criteria. The prevalence of SpA manifestations was determined in unaffected siblings and compared with their prevalence in patients. RESULTS: We compared 241 SpA patients with 259 unaffected siblings. The prevalence of skeletal and extraarticular features not used as diagnostic criteria, i.e., radiographic sacroiliitis, peripheral enthesitis, uveitis, psoriasis, and inflammatory bowel disease, was significantly increased in patients compared with unaffected siblings. This result was not accounted for by sex or HLA-B27 distribution differences. CONCLUSION: In familial SpA, skeletal and extraarticular manifestations tend to segregate together, implying that all subsets are predominantly determined by a shared component, and that accessory factors must be responsible for phenotype diversity.
    Mots-clés : Adult, Female, Genetic Variation, HLA-B7 Antigen, Humans, Male, Phenotype, Prevalence, Psoriasis, Sex Factors, Spondylarthropathies.


Journal Article

  • Said-Nahal, R, Miceli-Richard, C, Berthelot, JM, Duché, A, Dernis-Labous, E, Le Blévec, G, Saraux, A, Perdriger, A, Guis, S, Claudepierre, P, Sibilia, J, Amor, B, Dougados, M & Breban, M 2000, “The familial form of spondylarthropathy: a clinical study of 115 multiplex families. Groupe Français d'Etude Génétique des Spondylarthropathies”, Arthritis and Rheumatism, vol. 43, no. 6, p. 1356-1365.
    Résumé : OBJECTIVE: To investigate the interrelationships among different phenotypes, and their relationship to the HLA-Blocus, in multiplex families with spondylarthropathy (SpA). METHODS: We recruited 115 white French families, each of which had at least 2 members with SpA. Pedigrees were established. Clinical data and pelvic radiographs were collected. The HLA-B27 status of all patients was determined. Analysis was performed to determine the prevalence of SpA manifestations according to sex, disease duration, and HLA-B status, and to examine clustering of specific manifestations in subsets of families. RESULTS: We identified 329 SpA patients. Mean +/-SD age at onset was 24+/-9.4 years. The male:female ratio was 186:143, or 1.3, with few sex differences in disease expression. Axial manifestations and HLA-B27 were each present in 97% of the patients. Inflammatory bowel disease and HLA-B35 were overrepresented in the 7 families containing HLA-B27-negative patients. The frequency of radiographic sacroiliitis increased in parallel with disease duration. Peripheral enthesitis, radiographic sacroiliitis, and psoriasis were evenly distributed in the families. Clustering independent of age was only observed for peripheral arthritis, suggesting that specific factors may predispose individuals to this manifestation. CONCLUSION: Familial SpA appears to be homogeneous, based on the high frequencies of axial skeletal involvement and HLA-B27. The lack of clustering of most manifestations in families suggests that a predominant shared component, including HLA-B27, predisposes individuals to all forms of familial SpA, and that ubiquitous genetic or environmental factors contribute to phenotype diversity.
    Mots-clés : Adult, Cluster Analysis, Female, HLA-B Antigens, HLA-B14 Antigen, HLA-B27 Antigen, Humans, Male, Middle Aged, Spinal Diseases, Time Factors.


Journal Article
  • Guis, S, Pellissier, JF, Arniaud, D, Turck, F, Witjas, T, Roux, H & Mattei, JP 1999, “Healing of Charcot's joint by pamidronate infusion”, The Journal of Rheumatology, vol. 26, no. 8, p. 1843-1845.
    Résumé : Treatment of Charcot's joints remains difficult, and involves prolonged periods without weightbearing, immobilization, and surgical salvage procedures to avoid amputation. We describe the efficacy of pamidronate in treating a patient with Charcot's joint, due to hereditary sensory neuropathy, that caused loss of pain sensation. The bone and joint destruction in our patient's left foot was stopped by bisphosphonate treatment, and signs of a reconstructive healing process were observed on the control radiographs. The treatment was administered intravenously every 4 months for 2 years, without restriction on weightbearing, since the patient had refused a plaster cast and an orthotic device. This observation suggests that treatment with bisphosphonates should be used before, or in combination with, other treatment in such cases.
    Mots-clés : Adult, Anti-Inflammatory Agents, Arthropathy, Neurogenic, Diphosphonates, Humans, Male.
  • Reviron, D, Tezenas du Montcel, S, Foutrier, C, Guis, S, Benazet, JF, Auquier, P, Busson, M, Roux, H, Mercier, P & Roudier, J 1999, “HLA DRB1, DMA, and DMB gene polymorphisms in rheumatoid arthritis”, Human Immunology, vol. 60, no. 3, p. 245-249.
    Résumé : OBJECTIVE: To study the influence of DMA and DMB genes on susceptibility to Rheumatoid Arthritis (RA). METHODS: HLA-DRB1, DMA and DMB polymorphisms were defined by PCR SSOP in 203 European Mediterranean RA patients and 181 unrelated healthy controls. RESULTS: No significant difference in the phenotype frequencies of DMA and DMB alleles was observed between patients and controls. We found decreased frequencies of DMA*0102 and DMB*0104 in patients but this did not reach significance. These decreased frequencies could be due to a positive linkage disequilibrium with DRB1*0701, an allele which is underrepresented in RA patients. In stratified analysis with RA susceptibility Epitope positive (SE) DRB1 alleles, there was no significant difference in DMA and DMB phenotype frequencies between SE/SE, SE/X, and X/X patients versus controls. Among SE/X subjects, no significant difference in DM distribution frequencies was observed in DRB1*0101/X, 0102/X, 0401/X, 0404/X and 0405/X groups. CONCLUSION: DMA and DMB polymorphism does not seem to influence susceptibility to develop RA. Differences in DMA phenotype frequencies between patients and controls are secondary to linkage disequilibrium with DRB1 alleles.
    Mots-clés : Adult, Arthritis, Rheumatoid, France, Genetic Predisposition to Disease, Histocompatibility Antigens Class II, HLA-D Antigens, HLA-DR Antigens, HLA-DRB1 Chains, Humans, Linkage Disequilibrium, Mediterranean Region, Middle Aged, Phenotype, Polymorphism, Genetic.

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