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Résumé Avec une prévalence mondiale de 0,5 %, la polyarthrite rhumatoïde (PR) est une des maladies auto-immunes les plus fréquentes. L’origine de la PR n’est pas connue, cependant des facteurs génétiques et environnementaux pourraient contribuer à son développement. Le virus d’Epstein-Barr (EBV) constitue l’un de ces facteurs. Nous abordons dans cette étude plusieurs aspects du lien étroit entre EBV et la PR. Chez les patients atteints de PR, le contrôle de l’infection par EBV est altéré. Ces patients présentent en effet des titres élevés d’anticorps dirigés contre les antigènes d’EBV. Leurs lymphocytes T du sang périphérique sont moins efficaces pour contrôler la prolifération des lignées de lymphocytes B infectées par EBV. Les patients atteints de PR ont une charge virale en EBV dans leurs PBMCs augmentée d’un facteur 10 par rapport aux témoins. Le syndrome lymphoprolifératif post-transplantation (SLP-PT) correspond à une prolifération polyclonale de lymphocytes B infectés par EBV susceptible d’évoluer en un lymphome malin non Hodgkinien à lymphocytes B EBV+. Les patients atteints de PR présentent également un risque plus élevé de développer des syndromes lymphoprolifératifs (SLP) qui sont parfois associés à EBV. Il était donc nécessaire de surveiller la charge en EBV chez les patients atteints de PR lors de l’arrivée des nouveaux traitements immunosuppresseurs (biothérapies). EBV, un virus très répandu, fortement reconnu par les anticorps mais jamais éliminé, est un candidat idéal comme cible de la réponse immune dans les maladies immunitaires chroniques complexes. Les réponses sous forme d’anticorps anti-EBV doivent être considérées comme partie intégrante des réponses chroniques par autoanticorps liées au développement de la PR, de même que les anticorps anti-protéine citrullinée. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is one of the most common autoimmune diseases, with a 0.5% worldwide prevalence. The cause of RA remains unknown, however both genetic and environmental factors may contribute to its development. Among these is the Epstein-Barr virus (EBV). Here, we discuss several aspects of the close relationship between EBV and RA. Patients with RA have impaired control of EBV infection. Indeed, they have high titres of antibodies against EBV antigens. Their peripheral blood T lymphocytes are less efficient at controlling the outgrowth of EBV-infected B cells. RA patients have more EBV-infected B cells than normal controls, leading to a 10-fold systemic EBV overload. Post-transplant lymphoproliferative disorder (PTLPD) is a polyclonal EBV-positive B lymphocyte proliferation, which can evolve into an EBV-positive B cell lymphoma. RA patients also have an increased risk of developing EBV-associated lymphoproliferative disorder (LPD). Hence the need to monitor EBV load when treating RA patients with immunosuppressors. EBV, a widespread virus, highly recognized by antibodies but never eliminated, is an ideal candidate to trigger chronic immune complex disease. Anti-EBV antibody responses should be considered as one of the chronic autoantibody responses linked to the development of RA, in the same way as anti-citrullinated protein antibodies. [ABSTRACT FROM AUTHOR]

• "Omics" approaches allow us to better characterize the pathophysiology of complex diseases by finding new pathways. • Inspired by recent finding, we report the case of an association between Huntington's disease and chronic arthritis. [ABSTRACT FROM AUTHOR]

Résumé: Il existe de multiples relations entre le virus d''Epstein-Barr (EBV) et la polyarthrite rhumatoïde (PR): les malades atteints de PR ont des titres d''anticorps dirigés contre les antigènes d''EBV plus élevés par rapport à des sujets sains; la PR est caractérisée par un défaut de contrôle cellulaire de l''infection par EBV; des similitudes antigéniques entre EBV et des composants du soi ont été observées (séquences glycine–alanine d''EBNA-1 et protéines de la synoviale; glycoprotéine gp110 et épitope partagé); des réponses cellulaires dirigées contre des protéines du cycle réplicatif et contre gp110 ont été observées au niveau du liquide articulaire de PR; EBV (ses antigènes ou son génome) a été mis en évidence au niveau de la synoviale de PR par hybridation in situ ou PCR, avec un rendement variable; la charge virale en EBV des cellules mononucléées du sang circulant est élevée dans la PR comparativement aux témoins; EBNA-1 est susceptible de subir une citrullination et des anticorps antipeptides citrullinés peuvent être induits par EBV; des lymphomes compliquent la PR et certains sont associés à EBV. Ainsi, les liens EBV–PR sont nombreux et complexes, mais la relation de causalité directe n''a pas été formellement établie. Le virus d''Epstein-Barr pourrait agir indirectement dans le schéma physiopathologique de la PR, par l''intermédiaire du mauvais contrôle de l''infection et d''une exposition chronique à ses antigènes, sources de réaction inflammatoire chronique. L''effet des nouvelles thérapeutiques de la PR (biothérapies) sur la cohabitation EBV-hôte nécessite d''être analysé. [Copyright &y& Elsevier]

Abstract: Numerous associations have been documented between the Epstein–Barr virus (EBV) and rheumatoid arthritis (RA). Thus, anti-EBV antibody titers are higher in RA patients than in healthy controls. Lymphocytes from RA patients show impaired responses to EBV. Several EBV antigens share similarities with self antigens; more specifically, the glycine/alanine repeats in EBNA-1 resemble synovial proteins and the EBV gp110 glycoprotein contains a copy of the shared epitope. Cell-mediated responses to EBV replicative cycle proteins and to gp110 have been documented in joint fluid from RA patients. In situ hybridization and PCR techniques have identified EBV antigens and genetic material within the rheumatoid synovium, albeit with variable yields. The EBV burden in peripheral blood mononuclear cells is higher in RA patients than in controls. EBNA-1 can undergo citrullination, and the EBV can induce antibodies to citrullinated peptides. RA patients are at increased risk for lymphoma, including EBV-associated lymphoma. Despite these multiple and complex links between EBV and RA, proof of a causal association is lacking. EBV infection may contribute indirectly to the pathophysiology of RA by impairing immune control of EBV replication, causing increased exposure to EBV antigens and, thereby, chronic inflammation. The effect of biotherapies for RA on EBV-host relations needs to be investigated. [Copyright &y& Elsevier]

Les genes qui prédisposent a la polyarthrite rhumatoïde sont certains alleles de HLA-DR (HLA-DR4 et HLA-DR1), un ou des genes différents de HLA-DR situés dans la région HLA-DR et un allèle du gène PADI 4 qui code pour une enzyme capable de transformer les résidus arginine en citrulline. L''événement immunologique principal de la maladie est la production chronique d''autoanticorps. Parmi ceux-ci, les anticorps antiprotéines citrullinées sont très spécifiques. Le lien entre le terrain génétique et la production d''autoanticorps West pas encore compris. [Copyright 2004 Elsevier]

Psoriatic arthritis (PsA) is a type of inflammatory arthritis associated with psoriasis. HLA association studies performed in northern Europe, comparing patients with control populations, have shown that the highest risk for PsA is carried by HLA-C*06, HLA-B*57 and HLA-B*27 alleles. This retrospective association study compared HLA-A, -B, -C, and -DR alleles of 500 patients from southern France, who fulfilled the CASPAR criteria for Psoriatic Arthritis (PsA), with 2346 controls from healthy blood donors, using the chi-square test. We classified PsA patients into three different subgroups according to disease: purely axial, purely peripheral and combined axial and peripheral. The 'axial' subgroup was associated with HLA-B*27 (OR = 16.3, p = 2.7 × 10−28) and its haplotypes: HLA- B*27-C*01 (OR = 12.4, p = 1.7 × 10−12) and HLA-B*27-C*02 (OR = 8.7, p = 10 × 10−9). The 'axial and peripheral' and the 'peripheral' subgroups were associated with HLA-C*06 (respectively OR = 1.5, p = 3.6 × 10−10 and OR = 2.4, p = 3.6 × 10−12) and its haplotypes HLA-C*06-B*13 (respectively OR = 2.4, p = 1.2 × 10−6 and OR = 2.8, p = 6.4 × 10−11). This association study on a southern French PsA cohort identifies HLA-C*06 as a marker for peripheral PsA and HLA-B*27 as a marker for purely axial PsA. [ABSTRACT FROM AUTHOR]

Abstract: Embryos during pregnancy and organs during transplantation, express high levels of soluble HLA-G (sHLA-G) molecules for successful implantation and protection against maternal immune cells or recipient’s cells. We and others have shown that women with scleroderma (SSc) carry cells/DNA arising from pregnancy, so-called fetal microchimerism (Mc) more often and in higher quantities than healthy women decades after delivery. We hypothesized that high levels of fetal Mc were the consequence of a fetus with a high sHLA-G profile, therefore that children from women with SSc would have this profile more often than children from healthy women. High sHLA-G secretor profile is influenced by at least two variations in the HLA-G 3′ untranslated region (UTR): a 14bp deletion in exon 8 and the presence of cysteine (C) in position +3142 and by one variation in the 5′ Upstream Regulatory Region (URR) at position −725. By a previously developed three-step multiplex PCR SNaPshot method, we evaluated 16 HLA-G polymorphisms in DNA samples from the first-born children of 39 women with SSc and 32 healthy women. Contrary to expectations, children from women with SSc did not have a high sHLA-G profile, but rather the opposite. We discuss possible reasons for this result and future orientations for HLA-G studies in SSc. [Copyright &y& Elsevier]

Abstract: 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 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 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. [Copyright &y& Elsevier]

La polyarthrite rhumatoïde (PR) est la plus fréquente des maladies auto-immunes humaines. Son étiologie est inconnue et sa physiopathologie encore très mal comprise. Nous avons montré que plusieurs auto-anticorps spécifiquement associés à la PR avaient pour cibles des variants d’une protéine épithéliale, la (pro)filaggrine, puis que ces molécules cibles correspondaient à des protéines désiminées (« citrullinées »), c''est-à-dire des protéines dont les résidus arginyl avaient été enzymatiquement transformés en résidus citrullyl sous l’action d’une peptidyl-arginine désiminase (PAD). Notre équipe ainsi que d’autres groupes, ont ensuite établi que cette modification post-traductionnelle et donc la présence de résidus citrullyl présentés dans le contexte de séquences d’acides aminés particulières, était indispensable à la reconnaissance par ces autoanticorps. Nous avons aussi démontré que ces auto-anticorps dirigés contre les protéines citrullinées (ACPA pour « anticitrullinated protein autoantibodies ») étaient sécrétés par les plasmocytes du tissu synovial et que dans ce tissu, leurs principales cibles correspondaient à des formes citrullinées des chaînes α et β de la fibrine. Ces résultats ont amené à utiliser de nouvelles méthodes immunochimiques pour la détection des ACPA, dont certaines ont déjà conduit au développement et à la commercialisation de kits diagnostiques. Ces nouvelles méthodes ont permis de confirmer la haute valeur diagnostique des ACPA, auto-anticorps très spécifiques et présents très tôt au cours de la maladie, mais aussi leur valeur pronostique. Leur détection devrait demain permettre d’orienter la stratégie thérapeutique dès les premiers stades de la maladie. La synthèse d’ACPA dans le tissu synovial rhumatoïde et l’existence d’une cible antigénique spécifique dans ce tissu constituent de forts arguments en faveur d’une implication de ce conflit immunologique spécifique dans la physiopathologie de la PR. Il pourrait en effet induire, via divers mécanismes effecteurs pro-inflammatoires, la formation de dépôts de fibrine dont les molécules constitutives seraient ensuite citrullinées, entretenant ainsi le conflit antigène–anticorps. Nous proposons donc un nouveau modèle physiopathologique qui rend compte de l’autoentretien et de la chronicité de l’inflammation rhumatoïde. Cependant de nombreuses inconnues subsistent concernant la réponse auto-immune contre les protéines citrullinées. Les recherches doivent se poursuivre pour confirmer la validité de ce modèle. [Copyright &y& Elsevier]

Abstract: Rheumatoid arthritis (RA) is the most frequent human autoimmune disease, affecting about 1% of the adult population worldwide. A better knowledge of the autoimmune mechanisms involved is essential. We identified the epithelial targets of various autoantibodies specifically associated to RA, as variants of (pro)filaggrin. We also showed that these targets correspond to deiminated (“citrullinated”) proteins, of which arginyl residues have been posttranslationally transformed into citrullyl residues by a peptidylarginine deiminase (PAD). Moreover, we and others established that citrullyl residues are indispensable elements of the epitopes recognized by these autoantibodies but only in the context of specific aminoacid sequences. We also demonstrated that these autoantibodies to citrullinated proteins (ACPA) are secreted by plasma cells of the synovial tissue and that their major targets correspond to citrullinated forms of the α- and β-chains of fibrin, abundant in the tissue. These results have allowed the development of new efficient immunochemical methods for the detection of ACPA. Some of them are already commercially available. These new methods have permitted the high diagnostic value of ACPA which are present very early in the course of the disease, and also their prognostic value, to be confirmed. ACPA detection should therefore prove to be also a very valuable tool to guide the choice of therapeutic strategies, from the earliest stages of the disease. The synthesis of ACPA in the rheumatoid synovial tissue and the existence therein of a specific antigenic target constitute a strong argument for the involvement of this specific immunological conflict in the pathophysiology of RA. Indeed, it could lead to activation of effector mechanisms with pro-inflammatory effects, thus to formation in the tissue of new fibrin deposits, secondarily citrullinated. We therefore, propose a new pathophysiological model accounting for the self-maintenance and chronicity of rheumatoid inflammation. Numerous questions about the pathophysiological significance of the autoimmune response to deiminated proteins in RA remain to be answered to confirm this model. [Copyright &y& Elsevier]

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 3 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 Staphylococcus aureus discitis. In our patient, despite the multifocal distribution of the lesions, heretofore unreported, the 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. [Copyright &y& Elsevier]

Because of past recombination event, human leukocyte antigen (HLA) alleles that are not closely related in overall sequence may come to resemble each other in areas coding for peptide binding regions (PBR) of HLA molecules. Peptide binding is likely to be important for the role of HLA molecules in autoimmune disease. As a result, it has been suggested that a strategy of searching for HLA disease associations that groups alleles in functional categories based on PBR motifs may be more successful than conventional strategies based on studying different alleles. Using such functional categorization, we examined the possibility of discriminating subcategories of HLA-DRB1 alleles associated with rheumatoid arthritis (RA) in a Southern French population. HLA-DRB1 genotyping was performed by polymerase chain reaction with sequence-specific oligonucleotide hybridization or sequence-specific primers. HLA-DRB1 alleles were classified according to a functional categorization that defined seven similar subregion structures or restrictive supertype patterns (RSPs) within pocket 4 of HLA-DR peptide binding groove as the molecular basis for grouping these alleles. HLA-DRB1* RSPs “A,” “De,” “Q,” “Dr,” “E,” “ R,” and “a” association with susceptibility or resistance to disease was then studied in 200 RA patients versus 200 controls. DRB1* RSP “A” containing the shared epitope alleles (DRB1*0101, *0102, *0401, *0404, *0405, *0408, *1001, *1402; odds ratio [OR] = 4.35; pc < 0.001) had a predisposing effect, with double-dose effect as expected, OR 6.68 (pc < 0.001). Among the six remaining RSPs, two had significantly protective effect: DRB1* RSP “De” (DRB1*0103, *0402, *1102, *1103, *1301, *1302, *1304; OR = 0.33; pc < 0.001), and DRB1* RSP “Q” (DRB1*0701; OR = 0.40; pc < 0.001). One had non-significantly protective effect: DRB1* RSP “Dr” (DRB1*08, *1101, *1104, *1106, *12, *1303, *16; OR = 0.68; p < 0.05, pc = not significant [NS]). Three had neutral effect: HLA-DRB1* RSPs “E” (DRB1*0403, *0407, *0901, *1401; OR = 0.71; p = NS), “ R” (DRB1*0301, *0302; OR = 0.76; p = NS), and “a” (DRB1*1501, *1502; OR = 0.94; p = NS). The functional categorization allowed us to discriminate among the HLA-DRB1 alleles those that confer a predisposing effect, a neutral effect, and a protective effect in RA. [Copyright &y& Elsevier]

Unlabelled: 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 IgAλ multiple myeloma. Treatment was with ofloxacin and pristinamycin for one year. Although he started to improve only five months after treatment initiation, the outcome was favorable. Follow-up at the time of this writing is three years. [ABSTRACT FROM AUTHOR]

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 IgAλ 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. [Copyright &y& Elsevier]