Search for: rheumatoid arthritis methotrexate autoimmune disease biomarker gene expression GWAS HLA genes non-HLA genes
| ID | PMID | Title | PublicationDate | abstract |
|---|---|---|---|---|
| 16393277 | Systematic review: coxibs, non-steroidal anti-inflammatory drugs or no cyclooxygenase inhi | 2006 Jan 1 | Selective cyclooxygenase-2 inhibitors have been marketed as alternatives of conventional, non-steroidal anti-inflammatory drugs with the purpose of reducing/eliminating the risk of ulcer complications. Unexpectedly, randomized-controlled trials revealed that long-term use of coxibs, such as rofecoxib, significantly increased the risk of myocardial infarction and stroke, while the use of valdecoxib was associated with potentially life-threatening skin reactions. Subsequently, rofecoxib and valdecoxib were withdrawn from the market. Although more strict precautions for other coxibs, such as celecoxib, etoricoxib, lumiracoxib and parecoxib, may be accepted/recommended by regulatory agencies, a critical review of published data suggests that their use may not be justified - even in high-risk patients - taking benefits, costs and risks into consideration. Clinicians should, therefore, never prescribe coxibs to patients with cardiovascular risk factors, and should only reluctantly prescribe coxibs to patients with a history of ulcer disease or dyspepsia to overcome persistent pain due to, e.g. rheumatoid arthritis or osteoarthritis. Instead, they should consider using conventional non-steroidal anti-inflammatory drugs in combination with a proton pump inhibitor or a prostaglandin analogue, especially for patients with increased cardiovascular risks, i.e. established ischaemic heart disease, cerebrovascular disease and/or peripheral arterial disease, or alternatively acetaminophen. An evidence-based algorithm for treatment of a chronic arthritis patient with one or more gastrointestinal risk factors is presented. | |
| 16267431 | Chronic asymptomatic contralateral wrist scapholunate dissociation. | 2005 Nov | BACKGROUND: The authors report a series of six patients who presented with scapholunate dissociation, with no significant contralateral antecedent trauma and no rheumatoid arthritis or congenital ligamentous laxity. Such patients may present with pain or a snapping/popping sensation in one wrist, undergo radiographs of both wrists, and are discovered to have scapholunate gapping bilaterally. The literature contains few reports of this condition, and this series of six is a relatively large one for this infrequently reported condition. METHODS: The six charts were reviewed retrospectively; each patient was asked to return for follow-up and radiographic examination and each participated in a telephone questionnaire about pain, activity changes, new treatments, and exacerbation of wrist problems. The average follow-up was 39 months, with a range of 6 months to 13.5 years. RESULTS: One patient with severe unilateral instability and persistent pain underwent soft-tissue surgical repair (Blatt reconstruction); another demonstrated unilateral dorsal intercalated segment instability with moderate pain symptoms but declined surgical reconstruction. The other 10 wrists, despite radiographically demonstrated widened scapholunate angles and rotatory subluxation of the scaphoid, had mild or no pain and no dorsal intercalated segment instability deformity. CONCLUSIONS: The evolution of the bilateral form of scapholunate dissociation seems to be benign unless dorsal intercalated segment instability deformity is present, which may then rapidly progress to degenerative arthritis and scapholunate advanced collapse wrist. Severe or minor repetitive trauma, inflammation, infection, tumors, and congenital ligamentous laxity have been etiologically implicated in scapholunate dissociation. The natural history of scapholunate dissociation involves volar rotation of the scaphoid and dorsal rotation of the lunate, progressing to malalignment and eventual arthrosis between the scaphoid and radius, the capitate and lunate, and the lunate and hamate bones. | |
| 17709958 | Bidirectional communication between the brain and the immune system: implications for phys | 2006 | This review describes mechanisms of immune-to-brain and brain-to-immune signaling involved in mediating physiological sleep and altered sleep with disease. The central nervous system (CNS) modulates immune function by signaling target cells of the immune system through autonomic and neuroendocrine pathways. Neurotransmitters and hormones produced and released by these pathways interact with immune cells to alter immune functions, including cytokine production. Cytokines produced by cells of the immune and nervous systems regulate sleep. Cytokines released by immune cells, particularly interleukin-1beta and tumor necrosis factor-alpha, signal neuroendocrine, autonomic, limbic and cortical areas of the CNS to affect neural activity and modify behaviors (including sleep), hormone release and autonomic function. In this manner, immune cells function as a sense organ, informing the CNS of peripheral events related to infection and injury. Equally important, homeostatic mechanisms, involving all levels of the neuroaxis, are needed, not only to turn off the immune response after a pathogen is cleared or tissue repair is completed, but also to restore and regulate natural diurnal fluctuations in cytokine production and sleep. The immune system's ability to affect behavior has important implications for understanding normal and pathological sleep. Sleep disorders are commonly associated with chronic inflammatory diseases and chronic age- or stress-related disorders. The best studied are rheumatoid arthritis, fibromyalgia and chronic fatigue syndromes. This article reviews our current understanding of neuroimmune interactions in normal sleep and sleep deprivation, and the influence of these interactions on selected disorders characterized by pathological sleep. | |
| 17042020 | Rheumatology nurse practitioners' perceptions of their role. | 2006 Jun | OBJECTIVES: To identify the current practices of rheumatology nurse practitioners and ascertain their perceptions of how their role could be enhanced. METHOD: A cross-sectional questionnaire study of currently employed nurse practitioners in rheumatology in the United Kingdom (UK) was undertaken. RESULTS: 200 questionnaires were distributed and 118 nurses responded. Ninety-five respondents met the inclusion criteria for undertaking an advanced nursing role. Typical conditions dealt with included: rheumatoid arthritis (96.8%); psoriatic arthritis (95.8%); osteoarthritis (63.2%); ankylosing spondylitis (62.8%); systemic lupus erythematosus (51.6%); and scleroderma (34.7%). Drug monitoring, education, counselling of patients and arranging basic investigations were routinely performed by more than 80% of respondents. A smaller proportion performed an extended role that included dealing with referrals, research and audit, the administration of intra-articular injections, and admission of patients. Specific attributes identified as being necessary for competence were: knowledge and understanding of rheumatic diseases (48.4%); drug therapy (33.7%); good communication skills (35.8%); understanding of the roles of the team (27.4%); working effectively (23.2%) as part of a multidisciplinary team; assessment of patients by physical examination (28.4%); teaching (26.3%), research (17.9%); organizational skills (14.7%); and the interpretation of investigations (9.5%). Factors that could enhance their role included: attendance at postgraduate courses (30.5%); obtaining further qualifications (13.7%); active participation in the delivery of medical education (41.1%); training in practical procedures (31.6%); protected time and resources for audit and research (11.6%); formal training in counselling (11.6%); and implementation of nurse prescribing (10.5%). CONCLUSION: Nurse practitioners already have a wide remit and play an invaluable part in the delivery of modern rheumatology services. An extended role could improve patient care and enhance nursing career pathways in rheumatology. | |
| 16863900 | Fever of unknown origin due to preleukemia/myelodysplastic syndrome: the diagnostic import | 2006 Jul | Fever of unknown origin (FUO) is a common clinical diagnostic dilemma. In the elderly, causes of FUO most commonly include malignancy or infection, and less commonly include collagen vascular diseases. Among the collagen vascular diseases causing FUO in the elderly, polymyalgia rheumatica/temporal arteritis, and adult Still's disease (adult juvenile rheumatoid arthritis) are difficult diagnoses to prove. Among the infectious causes of FUO in the elderly are subacute bacterial endocarditis, intra-abdominal abscesses, and extrapulmonary tuberculosis. In the elderly, neoplastic causes of FUO include lymphomas, hepatomas, renal cell carcinomas, and hepatic or central nervous system metastases. Acute leukemias, particularly during "blast" transformation, may present as acute fevers in the absence of infection, but are rare causes of FUO. Preleukemia/myelodysplastic syndromes are exceedingly rare causes of FUO. We present a case of an elderly man who presented with findings that initially suggested adult Still's disease. Prolonged and profound monocytosis provided the key clue to his subsequent diagnosis of preleukemia/myelodysplastic syndrome. In this patient, a positive Naprosyn test result also suggested a neoplastic cause for his FUO. After months of prolonged fevers, myelocytes/metamyelocytes were eventually demonstrated in his peripheral smear during hospital evaluation. These findings, in concert with the persistent monocytosis, highly elevated ferritin levels, polyclonal gammopathy on serum protein electrophoresis, and eventual presence of myelocytes/metamyelocytes on peripheral smear, prompted a bone marrow test that demonstrated blast cells confirming the diagnosis of preleukemia myelodysplastic syndrome as the cause of this patient's FUO. | |
| 16542479 | The p38 mitogen-activated protein kinase signaling cascade in CD4 T cells. | 2006 | Since the identification of the p38 mitogen-activated protein kinase (MAPK) as a key signal-transducing molecule in the expression of the proinflammatory cytokine tumor necrosis factor (TNF) more than 10 years ago, huge efforts have been made to develop inhibitors of p38 MAPK with the intent to modulate unwanted TNF activity in diseases such as autoimmune diseases or sepsis. However, despite some anti-inflammatory effects in animal models, no p38 MAPK inhibitor has yet demonstrated clinical efficacy in human autoimmune disorders. One possible reason for this paradox might relate to the fact that the p38 MAPK signaling cascade is involved in the functional regulation of several different cell types that all contribute to the complex pathogenesis of human autoimmune diseases. In particular, p38 MAPK has a multifaceted role in CD4 T cells that have been implicated in initiating and driving sustained inflammation in autoimmune diseases, such as rheumatoid arthritis or systemic vasculitis. Here we review recent advances in the understanding of the role of the p38 MAPK signaling cascade in CD4 T cells and the consequences that its inhibition provokes in T cell functions in vitro and in vivo. These new data suggest that p38 MAPK inhibitors may elicit several unwanted effects in human autoimmune diseases but may be useful for the treatment of allergic disorders. | |
| 15728381 | Cross-regulation of TNF and IFN-alpha in autoimmune diseases. | 2005 Mar 1 | Cytokines, most particularly TNF and type I IFN (IFN-alphabeta), have been long considered essential elements in the development of autoimmunity. Identification of TNF in the pathogenesis of rheumatoid arthritis and TNF antagonist therapy represent successes of immunology. IFN-alphabeta plays a major role in systemic lupus erythematosus (SLE), a prototype autoimmune disease characterized by a break of tolerance to nuclear components. Here, we show that TNF regulates IFN-alpha production in vitro at two levels. First, it inhibits the generation of plasmacytoid dendritic cells (pDCs), a major producer of IFN-alphabeta, from CD34+ hematopoietic progenitors. Second, it inhibits IFN-alpha release by immature pDCs exposed to influenza virus. Neutralization of endogenous TNF sustains IFN-alpha secretion by pDCs. These findings are clinically relevant, as five of five patients with systemic juvenile arthritis treated with TNF antagonists display overexpression of IFN-alpha-regulated genes in their blood leukocytes. These results, therefore, might provide a mechanistic explanation for the development of anti-dsDNA antibodies and lupus-like syndrome in patients undergoing anti-TNF therapy. | |
| 16212881 | Generation and characterization of novel stromal specific antibodies. | 2005 Sep | Rheumatoid synovial fibroblasts were used as an immunogen to produce monoclonal antibodies selected for their reactivity with stromal cell antigens. Mice were immunised with low passage whole cell preparations and the subsequent hybridomas were screened by immunohistochemistry on rheumatoid synovium and tonsil sections. The aim was to identify those antibodies that recognised antigens that were restricted to stromal cells and were not expressed on CD45 positive leucocytes. A significant number of antibodies detected antigen that identified endothelial cells. These antibodies were further characterised to determine whether the vessels identified by these antibodies were vascular or lymphatic. From five fusions clones were identified with predominant reactivity with: 1) fibroblasts and endothelial cells; or 2) broad stromal elements (fibroblast, endothelium, epithelium, follicular dendritic cells). A fibroblast-specific antibody that did not also identify vessels was not generated. Examples of each reactivity pattern are discussed. | |
| 17021107 | Design, construction, and evaluation of a specific chimeric antigen to diagnose chagasic i | 2006 Oct | Chagas' disease is routinely diagnosed by detecting specific antibodies (Abs) using serological methods. The methodology has the drawback of potential cross-reactions with Abs raised during other infectious and autoimmune diseases (AID). Fusion of DNA sequences encoding antigenic proteins is a versatile tool to engineer proteins to be used as sensitizing elements in serological tests. A synthetic gene encoding a chimeric protein containing the C-terminal region of C29 and the N-terminal region of TcP2beta was constructed. A 236-serum panel, composed of 104 reactive and 132 nonreactive sera to Chagas' disease, was used to evaluate the performance of the chimera. Among the nonreactive sera, 65 were from patients with AID (systemic lupus erythematosus and rheumatoid arthritis) or patients infected with Leishmania brasiliensis, Brucella abortus, Streptococcus pyogenes, or Toxoplasma gondii. The diagnostic performances of the complete TcP2beta (TcP2betaFL) and its N-terminal region (TcP2betaN) were evaluated. TcP2betaFL showed unspecific recognition toward leishmaniasis (40%) and AID Abs (58%), while TcP2betaN showed no unspecific recognition. The diagnostic utility of the chimera was evaluated by analyzing reactivity and comparing the results with those obtained with TcP2betaN. The chimera reactivity was higher than that of the peptide fractions (0.874 versus 0.564 optical density, P = 0.0017). The detectability and specificity were both 100% for the whole serum panel tested. We conclude that the obtained chimera shows an improved selectivity and sensitivity compared with other ones previously reported, therefore displaying an optimized performance for Trypanosoma cruzi infection diagnosis. | |
| 16967616 | [Ankylosing spondylitis--the current situation and new therapeutic options]. | 2006 Jul | Ankylosing spondylitis (AS) is a chronic, immunologically mediated rheumatic disease whose progression largely depends on the extent of inflammatory activity. In contrast to rheumatoid arthritis (RA), therapeutic control of AS is very limited. Therapy of ankylosing spondylitis should not only control inflammatory processes, but also prevent structural damages and maintain the functions. Until recently, physiotherapy and non-steroidal antiphlogistics (NSA) therapy was a gold standard of AS treatment. NSA therapy alleviates inflammatory pain of spine in 60 to 80% of patients. According to the most recent findings, long-term administration of NSA can affect also X-ray progression. DMARD therapy, which is efficient in RA, has insignificant effect on axial form of AS. Sulfasalazine proved to be efficacious against peripheral form of AS; administration of MTX and leflunomide is not supported by controlled studies. Peripheral arthritis and enthesitis is usually treated by short-term application of corticoids. The fact remains that an important role in AS immunopathogenesis is played by TNF alpha whose increased levels were found in patients with AS in serum, synovial fluid and SI joints. Anti-TNF therapy with infliximab and etanercept proved to be highly efficacious in patients with AS resistant to conventional therapy. Infliximab and etanercept reduced the disease activity (50% improvement in more than half of patients), improved the function and slowed down the structural damage. MRI studies of anti-TNF therapy proved reduction of inflammatory activity in SI joints and spine. Other studies verified the efficacy of adalimumab in AS therapy and showed that adalimumab is a promising drug. Also, several randomized clinical studies proved efficacy of thalidomide whose administration, however, is limited by its severe adverse effects. Until now, the results of studies focused on pamidronate therapy appear to be rather controversial. Better understanding of AS pathogenesis led to implementation of new therapeutic procedures that significantly improve activity and functional condition of patients. | |
| 16551397 | Registry of shoulder arthroplasty - the Scottish experience. | 2006 Mar | INTRODUCTION: Recognising that timely dissemination of information in the orthopaedic community was important and in the absence of any national guidelines for shoulder arthroplasty, the Scottish shoulder arthroplasty registry, a voluntary registry, was started in 1996. The goals of the registry were to assess contemporary practice, provide a benchmark against which surgeons could compare their practice, identify risk factors for a poor outcome, and to improve outcomes through continuous feedback to the participating surgeons. PATIENTS AND METHODS: A standardised proforma was used to collect information on the diagnostic and demographic data, type of procedure performed, type of implant used, any associated procedures performed in conjunction with the arthroplasty, and peri-operative complications. Postoperative pain, activity and patient satisfaction were assessed annually using another standardised proforma. RESULTS: Twenty surgeons have contributed to the register and 451 shoulder arthroplasties were registered over a 5-year period. Of patients, 23.2% were male and 76.8% female. The mean age was 65 years (range, 37-90 years). Shoulder arthroplasty was commonly performed for rheumatoid arthritis followed by trauma, osteoarthritis and avascular necrosis of the humeral head. Overall, 397 (88%) patients had a hemi-arthroplasty and 54 (12%) had a total shoulder replacement. Of the 54 cases that had a glenoid replacement, 28 were performed for inflammatory arthritis, 21 for osteoarthritis and 5 were for revisions. The humeral component was cemented in 204 (45%) cases, 160 of whom had a shoulder replacement for trauma. The glenoid component was cemented in 48 (89%) cases. Cross referencing our data with the figures of the actual number of shoulder arthroplasties performed, however, indicated that our registry at best collected only 53% of all the shoulder arthroplasties performed in Scotland annually. CONCLUSIONS: The value of a joint registry is dependent on the accuracy and completeness of the data entered. Our registry, therefore, fails as an implant registry. We believe that compliance for data registration can only be ensured if dedicated data collection staff are employed to co-ordinate the data collection and collation process. | |
| 17158801 | TNFalpha kinoid vaccination-induced neutralizing antibodies to TNFalpha protect mice from | 2006 Dec 19 | The proinflammatory cytokine TNFalpha is a potent mediator of septic shock and a therapeutic target for chronic inflammatory pathologies including rheumatoid arthritis and Crohn's disease. As an alternative to anti-human TNFalpha (hTNFalpha) mAbs and other hTNFalpha blocker approved drugs, we developed an active anti-hTNFalpha immunotherapy, based on a vaccine comprised of a keyhole limpet hemocyanin-hTNFalpha heterocomplex immunogen (hTNFalpha kinoid) adjuvanted in incomplete Freund's adjuvant. In mice transgenic for hTNFalpha (TTg mice), hTNFalpha kinoid vaccination elicited high titers of Abs that neutralized hTNFalpha bioactivities but did not result in a cellular response to hTNFalpha. The vaccine was safe and effective in two experimental models. Kinoid-immunized but not control TTg mice resisted hTNFalpha-driven shock in one model and were prevented from spontaneous arthritis, inflammatory synovitis, and articular destruction in a second model. These data demonstrate an anti-cytokine induction of autoimmune protection against both acute and chronic hTNFalpha exposure. They show that active vaccination against a human cytokine can be achieved, and that the immune response can be effective and safe. | |
| 17067439 | MAGIC or not MAGIC--does the MAGIC (mouth and genital ulcers with inflamed cartilage) synd | 2006 Sep | INTRODUCTION: In 1985, Firestein et al. described 5 patients with relapsing polychondritis and Behçet's disease (BD) and proposed the term "MAGIC" syndrome as an acronym for "Mouth and Genital ulcers with Inflamed Cartilage". We report on an additional case of this syndrome and critically review the literature. RESULTS: From 1985 to 2004 eleven cases of MAGIC syndrome were described. All patients had chondritis and oral aphthous ulcers, as well as ocular inflammation (mainly anterior uveitis or scleritis/episcleritis). Most patients also presented with genital ulcers and arthritis. In one case, aortic aneurysm, in another aortic insufficiency was described, one had meningoencephalitis, one had antiphospholipid syndrome and one was HIV positive. Before 1985, we could find 4 additional probable cases. Our own patient presented with oral and genital ulcers, auricular chondritis and episcleritis. HLA-typing was performed and revealed HLA-B*51, B*15, DRB1*04x and DRB1*11x. Only in one Japanese patient from the literature, HLA-typing was available and revealed HLA-B*56, B*62, DRB1*0406 and DRB1*0901. CONCLUSIONS: Relapsing polychondritis is associated with HLA-DRB1*04 suballeles, but not necessarily only with those being associated with RA (DRB1*0401 and 0404). In 2 MAGIC patients these suballeles were found. All patients described in the literature had typical polychondritis, but not all did fulfil the classification criteria for BD. Many features of both diseases overlap and are not specific. As polychondritis is associated with other inflammatory rheumatic conditions such as SLE, spondyloarthropathy, rheumatoid arthritis and systemic vasculitides in 30% of all cases, we suggest that MAGIC syndrome is not a disease entity, but merely the association of BD with polychondritis. | |
| 16888164 | Vasoactive intestinal peptide generates CD4+CD25+ regulatory T cells in vivo: therapeutic | 2006 Jul | CD4+ CD25+ regulatory T cells (Treg) control the immune response to a variety of antigens, including self-antigens, and several models support the idea of the peripheral generation of CD4+ CD25+ Treg from CD4+ CD25- T cells. However, little is known about the endogenous factors and mechanisms controlling the peripheral expansion of CD4+ CD25+ Treg. We have found that the immunosuppressive neuropeptide vasoactive intestinal peptide (VIP) induces functional Treg in vivo. The administration of VIP together with specific antigen to TCR-transgenic mice results in the expansion of the CD4+ CD25+, Foxp-3/neuropilin 1-expressing T cells, which inhibit responder T cell proliferation through direct cellular contact. The VIP-generated CD4+ CD25+ Treg transfer suppression, inhibiting delayed-type hypersensitivity in the hosts, prevent graft-versus-host disease in irradiated host reconstituted with allogeneic bone marrow, and significantly ameliorate the clinical score in the collagen-induced arthritis model for rheumatoid arthritis and in the experimental autoimmune encephalomyelitis model for multiple sclerosis. | |
| 16168078 | Practical approaches to minimizing gastrointestinal and cardiovascular safety concerns wit | 2005 | Nonsteroidal anti-inflammatory drugs (NSAIDs) are highly effective in treating the pain and inflammation associated with osteoarthritis and rheumatoid arthritis, but it is well recognized that these agents are associated with substantial gastrointestinal toxicity. Treatment guidelines suggest that patients with one or more risk factors for NSAID associated ulcers should be prescribed preventive treatment. However, well over 80% of such patients may not receive an appropriate therapeutic intervention. Multiple strategies are available to reduce the risk for NSAID associated gastrointestinal complications. First, risk may be reduced by using non-NSAID analgesics. Second, use of the minimum effective dose of the NSAID may reduce risk. Third, co-therapy with a proton pump inhibitor or misoprostol may be desirable in at-risk patients. Use of cyclo-oxygenase-2 inhibitors may also reduce the risk for gastrointestinal events, although this benefit is eliminated in patients who receive aspirin, and cyclo-oxygenase-2 inhibitors may increase cardiovascular adverse events. The optimal management of NSAID related gastrointestinal complications must be based on the individual patient's risk factors for gastrointestinal and cardiovascular disease, as well as on the efficacy and tolerability of both the NSAID and accompanying gastroprotective agent. | |
| 15823500 | Potential off-label use of infliximab in autoimmune and non-autoimmune diseases: a review. | 2005 Mar | TNF-alpha is a crucial cytokine in the establishment and maintenance of inflammation in multiple autoimmune and non-autoimmune disorders. A number of large placebo-controlled trials have shown that infliximab, a chimeric monoclonal antibody against TNF-alpha, is effective and well-tolerated in patients with Crohn's disease and rheumatoid arthritis (RA) and has become a widely used treatment for these diseases. More recent controlled trials have also shown the effectiveness of TNF-alpha blockers in psoriasis, psoriatic arthritis, and ankylosing spondylitis. The results of clinical trials, open-label studies, and case studies indicate that TNF inhibitors (alone or in combination with other protocols) look very promising for the treatment of a variety of other conditions, including uveitis, sarcoidosis, Sjögren's syndrome (SS), Behcet's syndrome, vasculitis, and graft versus host disease. There is a rationale for using TNF blockade even in systemic lupus erythematosus, a prototype of autoantibody-mediated disease, and a pilot study seems to confirm this potential effective approach. The neutralisation of TNF might therefore play a role in the treatment of many autoimmune and non-autoimmune disorders other than Crohn's disease or RA. We here review the current and prospective roles of infliximab in the treatment of autoimmune diseases and other conditions that do not currently have FDA or EMEA approval. | |
| 16891918 | Peripheral musculoskeletal manifestations in polymyalgia rheumatica. | 2006 Aug | OBJECTIVES: The objectives of this study were to evaluate the frequency and characteristics of the peripheral musculoskeletal manifestations in polymyalgia rheumatica (PMR), evaluate if PMR with peripheral synovitis represents a subset with a more severe disease, and examine for clinical and laboratory characteristics at onset of PMR that might later predict rheumatoid arthritis (RA). PATIENTS AND METHODS: Patients were diagnosed with PMR according to the 1982 Chuang criteria. Patients were followed up between 1990 and 2002. The following musculoskeletal manifestations at onset and during the follow up were considered: peripheral synovitis, distal extremity swelling with pitting edema, carpal tunnel syndrome, and distal tenosynovitis. RESULTS: Thirty-eight of the 74 patients (51%) showed distal musculoskeletal symptoms: 29 (39%) had peripheral synovitis, 4 (5%) presented pitting edema, 4 (5%) experienced carpal tunnel syndrome, and one (1.3%) had distal tenosynovitis. These manifestations resolved completely after corticosteroid therapy was initiated. Peripheral synovitis was oligoarticular and often transient. The joints most frequently involved were the wrist, metacarpophalangeal, and knee. Erythrocyte sedimentation rate (ESR) was normal in 7 patients. When comparing patients with PMR with and without peripheral synovitis, no statistically significant differences were found in the studied variables. Through the first year of follow up, 7 patients fulfilled the American College of Rheumatology 1987 criteria for RA, 2 patients developed giant cell arteritis, and 3 had associated malignancy. Patients who developed RA had statistically significantly increased presence of persistent synovitis and a smaller decrease in mean ESR after treatment with corticosteroids. CONCLUSION: Fifty-one percent of the patients with PMR presented distal musculoskeletal manifestations, with peripheral synovitis being the most frequent one. Patients with PMR with peripheral synovitis did not represent a high-risk subgroup with more severe disease. Seven patients who developed criteria for seronegative RA within the first year of follow up had presented statistically significant persistent synovitis compared with those who continued as PMR and also showed a smaller initial decrease in mean ESR after steroid treatment was initiated. The absence of persistent arthritis and the benign course of the arthritis permit the distinction of PMR from other inflammatory arthropathies. | |
| 16707558 | Interleukin-6 biology is coordinated by membrane-bound and soluble receptors: role in infl | 2006 Aug | Cytokine receptors, which exist in membrane-bound and soluble forms, bind their ligands with comparable affinity. Although most soluble receptors are antagonists and compete with their membrane-associated counterparts for the ligands, certain soluble receptors are agonists. In these cases, complexes of ligand and soluble receptor bind on target cells to second receptor subunits and initiate intracellular signaling. The soluble receptors of the interleukin (IL)-6 family of cytokines (sIL-6R, sIL-11R, soluble ciliary neurotrophic factor receptor) are agonists capable of transmitting signals through interaction with the universal signal-transducing receptor for all IL-6 family cytokines, gp130. In vivo, the IL-6/sIL-6R complex stimulates several types of cells, which are unresponsive to IL-6 alone, as they do not express the membrane IL-6R. We have named this process trans-signaling. The generation of soluble cytokine receptors occurs via two distinct mechanisms-limited proteolysis and translation-from differentially spliced mRNA. We have demonstrated that a soluble form of the IL-6 family signaling receptor subunit gp130, which is generated by differential splicing, is the natural inhibitor of IL-6 trans-signaling responses. We have shown that in many chronic inflammatory diseases, including chronic inflammatory bowel disease, peritonitis, rheumatoid arthritis, asthma, as well as colon cancer, IL-6 trans-signaling is critically involved in the maintenance of a disease state, by promoting transition from acute to chronic inflammation. Moreover, in all these models, the course of the disease can be disrupted by specifically interfering with IL-6 trans-signaling using the soluble gp130 protein. The pathophysiological mechanisms by which the IL-6/sIL-6R complex regulates the inflammatory state are discussed. | |
| 16048553 | Oral tolerance. | 2005 Aug | Multiple mechanisms of tolerance are induced by oral antigen. Low doses favor active suppression, whereas higher doses favor clonal anergy/deletion. Oral antigen induces T-helper 2 [interleukin (IL)-4/IL-10] and Th3 [transforming growth factor (TGF)-beta] T cells plus CD4+CD25+ regulatory cells and latency-associated peptide+ T cells. Induction of oral tolerance is enhanced by IL-4, IL-10, anti-IL-12, TGF-beta, cholera toxin B subunit, Flt-3 ligand, and anti-CD40 ligand. Oral (and nasal) antigen administration suppresses animal models of autoimmune diseases including experimental autoimmune encephalitis, uveitis, thyroiditis, myasthenia, arthritis, and diabetes in the non-obese diabetic (NOD) mouse, plus non-autoimmune diseases such as asthma, atherosclerosis, graft rejection, allergy, colitis, stroke, and models of Alzheimer's disease. Oral tolerance has been tested in human autoimmune diseases including multiple sclerosis (MS), arthritis, uveitis, and diabetes and in allergy, contact sensitivity to dinitrochlorobenzene (DNCB), and nickel allergy. Although positive results have been observed in phase II trials, no effect was observed in phase III trials of CII in rheumatoid arthritis or oral myelin and glatiramer acetate (GA) in MS. Large placebo effects were observed, and new trials of oral GA are underway. Oral insulin has recently been shown to delay onset of diabetes in at-risk populations, and confirmatory trials of oral insulin are being planned. Mucosal tolerance is an attractive approach for treatment of autoimmune and inflammatory diseases because of lack of toxicity, ease of administration over time, and antigen-specific mechanisms of action. The successful application of oral tolerance for the treatment of human diseases will depend on dose, developing immune markers to assess immunologic effects, route (nasal versus oral), formulation, mucosal adjuvants, combination therapy, and early therapy. | |
| 16260582 | Therapeutic promise of proteinase-activated receptor-2 antagonism in joint inflammation. | 2006 Mar | Biological therapies such as tumor necrosis factor-alpha inhibitors have advanced the treatment of rheumatoid arthritis, but one-third of patients do not respond to such therapy. Furthermore, these inhibitors are now usually administered in combination with conventional disease-modifying antirheumatic drugs, suggesting they have not achieved their early promise. This study investigates a novel therapeutic target, proteinase-activated receptor (PAR)-2, in joint inflammation. Intra-articular carrageenan/kaolin (C/K) injection in mice resulted in joint swelling that was associated with synovial PAR2 up-regulation. Inhibiting receptor up-regulation using small interfering RNA technology, as confirmed by immunoblotting, substantially reduced the inflammatory response in the joint. Serine proteinase-induced joint swelling was mediated primarily via PAR2 activation, since the response to exogenous application of trypsin and tryptase was absent in PAR2 knockout mice. Furthermore, serine proteinase inhibitors were effective anti-inflammatory agents in this model. Disrupting proteolytic activation of PAR2 using antiserum (B5) directed to the receptor cleavage/activation site also attenuated C/K-induced inflammation, as did the similarly targeted PAR2 monoclonal antibody SAM-11. Finally, we report the activity of a novel small molecule PAR2 antagonist, N1-3-methylbutyryl-N4-6-aminohexanoyl-piperazine (ENMD-1068), that dose dependently attenuated joint inflammation. Our findings represent a major advance in collectively identifying PAR2 as a novel target for the future treatment of arthritis. |