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ID PMID Title PublicationDate abstract
15097933 Acute development of multiple keratoacanthomas and squamous cell carcinomas after treatmen 2004 May Infliximab, a chimeric mouse-human monoclonal antibody, blocks the action of tumor necrosis factor-alpha and is a highly effective treatment for several inflammatory disorders, including inflammatory bowel disease and rheumatoid arthritis. Although safety data are encouraging, immunosuppressive sequelae may result. We report the acute development of multiple squamous cell carcinomas and keratoacanthomas in a patient receiving infliximab for rheumatoid arthritis.
12892256 Insufficiency fractures of the sternum. 2003 Insufficiency fractures occur within weakened bones that are unable to withstand the stress of every day normal activities. The spine, pelvis, and lower long-bone extremities are common sites of insufficiency fractures. Spontaneous sternal insufficiency fracture (SIF) has rarely been reported in elderly patients. To recognise a sternal insufficiency fracture is important in selecting the adequate diagnostic procedures.
15046527 Adalimumab: a review of its use in rheumatoid arthritis. 2004 Adalimumab (Humira) is a recombinant, fully human IgG1 monoclonal antibody that binds specifically to tumor necrosis factor (TNF)-alpha, thereby neutralizing the activity of the cytokine. Subcutaneous adalimumab has been investigated in well designed trials in patients with active rheumatoid arthritis despite treatment with disease-modifying antirheumatic drugs (DMARDs). Patients receiving adalimumab 40mg every other week in combination with methotrexate (Anti-TNF Research Study Program of the Monoclonal Antibody Adalimumab [ARMADA] and DE019 trials) or standard antirheumatic therapy (Safety Trial of Adalimumab in Rheumatoid Arthritis [STAR] trial) for 24-52 weeks had significantly higher American College of Rheumatology (ACR) 20, ACR50, and ACR70 response rates than patients receiving placebo plus methotrexate or standard antirheumatic therapy. In ARMADA, an ACR20 response was achieved in 25%, 52%, and 67% of adalimumab plus methotrexate recipients at weeks 1, 4, and 24, respectively. In ARMADA and DE019, improvements in the individual components of the ACR response were significantly greater with adalimumab 40mg every other week plus methotrexate than with placebo plus methotrexate. Monotherapy with adalimumab 40mg every other week was associated with significantly higher ACR20, ACR50, and ACR70 response rates than placebo, as well as significantly greater improvements in the individual components of the ACR response. ACR responses were sustained with adalimumab according to the results of extension studies in which patients received adalimumab in combination with methotrexate (up to 30 months) or as monotherapy (up to 5 years). In both concomitant therapy and monotherapy trials, adalimumab was associated with significantly greater improvements from baseline in health-related quality of life (HR-QOL) measures than placebo; adalimumab also retarded the radiographic progression of structural joint damage to a significant extent compared with placebo. Adalimumab was generally well tolerated as both concomitant therapy and monotherapy. In ARMADA, there were no significant differences between adalimumab and placebo (in combination with methotrexate) in the incidence of adverse events; however, in STAR, the incidence of injection site reactions, rash, and back pain was significantly higher with adalimumab than with placebo (in combination with standard antirheumatic therapy). No cases of tuberculosis were reported in either trial.In conclusion, subcutaneous adalimumab in combination with methotrexate or standard antirheumatic therapy, or as monotherapy, is effective in the treatment of adults with active rheumatoid arthritis who have had an inadequate response to DMARDs. Adalimumab has a rapid onset of action and sustained efficacy. The drug also retards the progression of structural joint damage, improves HR-QOL, and is generally well tolerated. Thus, adalimumab is a valuable new option for the treatment of DMARD-refractory adult rheumatoid arthritis.
12821191 Single-tube nested quantitative PCR: a rational and sensitive technique for detection of r 2003 Jul It was reported earlier that a few patients suffering from non-Hodgkin's lymphoma had low amounts of DNA from the so-called fifth human exogenous retrovirus, HRV-5. A sensitive and rational method for large-scale screening for HRV-5 DNA was therefore developed. It is a single-tube nested quantitative PCR (stnQPCR), which uses two functionally isolated primer pairs and one probe target distinct from related endogenous retroviral sequences, yet encompassing known HRV-5 variation, allowing optimal use of sequence conservation. DNA from lymphoma, myeloma, and follicular dendritic cell lines was tested for HRV-5 positivity, as was DNA from whole blood of blood donors, non-Hodgkin's lymphoma and systemic lupus erythematosus patients, as well as DNA from lymph node biopsies of rheumatoid arthritis patients with lymphoma. One blood donor, one systemic lupus erythematosus patient, two previously known positive non-Hodgkin's lymphoma patients, and one rheumatoid arthritis lymphoma patient, came out positive. They had 24, 2, 148, 480 and 30 proviral copies per microg of DNA from PBMC or lymphoma tissue, respectively. During the completion of this work it was reported that HRV-5 is a rabbit endogenous retrovirus (RERV-H), and that HRV-5 positivity was due to presence of rabbit DNA. DNA from six RERV-H/HRV-5 positive samples was therefore retested. Three also contained rabbit mitochondrial DNA. A search for HRV-5 antibodies using synthetic peptides was negative in sera from three RERV-H/HRV-5 positive individuals, as well as in 144 other sera, according with a noninfectious origin of the RERV-H/HRV-5 DNA in human samples. A search for possible sources of rabbit DNA contamination was negative. Methods for prevention of PCR contamination were strictly adhered to. Three samples from RERV-H/HRV-5 positive individuals positive at the Uppsala laboratory were retested at one or two other laboratories, and all three were positive. Two other samples, which were positive in the Riga laboratory, were tested also in London and also found positive. One non-Hodgkin's lymphoma patient was RERV-H/HRV-5 positive in four consecutive samples, showing that positivity was a property of that patient. It is concluded that the stnQPCR developed to detect and quantify minute amounts of RERV-H/HRV-5 DNA is a principle which can be applied widely and HRV-5 is a RERV-H. Its presence in a few human blood samples could not be explained.
15104166 Assessing hydroxychloroquine toxicity by the multifocal ERG. 2004 Jan Twenty patients on Plaquenil treatment were evaluated for retinal toxicity using the (EOG) and the mfERG. Group 1 comprises 15 patients (30 eyes) with normal EOG. From these patients 11 (22 eyes) showed normal RRD of mfERG in area 1 and area 2. The rest four patients (8 eyes) the RRD were reduced. Six months after interruption of HC, the mfERG improved in three cases. Group 2 comprises 5 patients (10 eyes) with subnormal EOG. Four (8 eyes) of these showed a decrease of RRD of the mfERG in area 1 and 2. In the rest one (2 eyes) the RRD were normal. Six months after interruption of HC the mfERG and the EOG improved in 2 cases. These results postulate that the mfERG may be used as an alternative method, perhaps more sensitive, for the detection of the HC retinopathy and the follow up of the patients on hydroxychloroquine.
15095096 Serum matrix metalloproteinase-3 in systemic sclerosis. 2004 Jun To determine the serum levels of matrix metalloproteinase-3 (MMP-3) in patients with systemic sclerosis (SSc) and investigate their clinical significance in this disease, serum samples from 83 patients with SSc and 30 healthy volunteers were examined by a specific enzyme-linked immunosorbent assay (ELISA). There was no significant difference in serum levels of MMP-3 between SSc patients and healthy controls. However, in female patients, there was a significant difference in serum MMP-3 levels between patients subsequently developing accompanying rheumatoid arthritis (RA) and those not developing RA, and patients with increased levels of MMP-3 were more likely to develop RA than those with normal MMP-3 levels. Additionally, arthralgia, elevated CRP, and elevated rheumatoid factor were seen significantly more frequently in patients with increased MMP-3 levels than in those with normal MMP-3 levels. These results suggest that increased serum MMP-3 is a marker for developing RA in SSc patients. SSc patients with increased serum MMP-3 levels need to be followed up carefully because of the risk of developing overlapping RA.
12969325 The role of FcgammaRIIa as an inflammatory mediator in rheumatoid arthritis and systemic l 2003 Oct Despite their essential role in host protection, immunoglobulins are also involved in autoimmune processes where antibodies recognize the host's own tissue, triggering inflammatory responses that result in extensive tissue damage. A complex interaction of genetic predisposition, together with environment factors, is thought to trigger immune dysfunction. Although recent studies have dissected the essential role of Fc receptors in autoimmune antibody mediated processes, the uniquely human FcgammaRIIa has not been studied in detail. This Fc receptor is of particular interest, as it is the most abundantly expressed Fc receptor in humans and is implicated in immune complex disease. Investigation of its role has been hampered to date due to lack of suitable animal models. This review examines the evidence for the direct role of this receptor in diseases such as systemic lupus erythematosus and rheumatoid arthritis.
15340661 A comparative study of etanercept plus methotrexate and methotrexate alone in Taiwanese pa 2004 Aug BACKGROUND AND PURPOSE: Etanercept (Enbrel), a recombinant tumor necrosis factor receptor fusion protein, has been shown to be effective in the treatment of patients with rheumatoid arthritis (RA). The purpose of this study was to compare the efficacy and safety of etanercept in combination with methotrexate (MTX) and MTX alone in Taiwanese patients with active RA. METHODS: In this double-blind study, 58 patients with active RA who were maintained on MTX therapy at a stable dose of 12.5 to 20 mg per week for 4 weeks were randomized to receive either etanercept 25 mg (n = 29) or placebo (n = 29) by subcutaneous injection twice weekly over a period of 12 weeks. The primary endpoint was the reduction of tender and swollen joint counts by 20% (ACR 20), 50% (ACR 50), and 70% (ACR 70) as determined by the American College of Rheumatology criteria at the 12th week. RESULTS: The addition of etanercept to MTX resulted in a greater reduction in the number of tender (7.00 vs 2.45, p = 0.012) and swollen joints (8.55 vs 3.86, p = 0.017), and in serum levels of C-reactive protein (1.26 mg/dL vs 0.45 mg/dL, p = 0.014) compared to MTX alone after 12 weeks of therapy. In addition, the global assessment of disease activity by both physicians and patients, duration of morning stiffness, pain visual analog scale score, and Health Assessment Questionnaire were all improved by etanercept plus MTX therapy. Results for the overall improvement in disease activity assessed by ACR 20 (90% vs 34%), ACR 50 (66% vs 10%) and ACR 70 (24% vs 0%) all favored the etanercept plus MTX group. However, the adverse events were comparable between the 2 treatment groups. CONCLUSION: Etanercept in combination with MTX was well tolerated and provided significantly more clinical benefit than MTX alone in Taiwanese patients with active RA.
14730626 Single and combined inhibition of tumor necrosis factor, interleukin-1, and RANKL pathways 2004 Jan OBJECTIVE: To investigate the efficacy of single and combined blockade of tumor necrosis factor (TNF), interleukin-1 (IL-1), and RANKL pathways on synovial inflammation, bone erosion, and cartilage destruction in a TNF-driven arthritis model. METHODS: Human TNF-transgenic (hTNFtg) mice were treated with anti-TNF (infliximab), IL-1 receptor antagonist (IL-1Ra; anakinra), or osteoprotegerin (OPG; an OPG-Fc fusion protein), either alone or in combinations of 2 agents or all 3 agents. Synovial inflammation, bone erosion, and cartilage damage were evaluated histologically. RESULTS: Synovial inflammation was inhibited by anti-TNF (-51%), but not by IL-1Ra or OPG monotherapy. The combination of anti-TNF with either IL-1Ra (-91%) or OPG (-81%) was additive and almost completely blocked inflammation. Bone erosion was effectively blocked by anti-TNF (-79%) and OPG (-60%), but not by IL-1Ra monotherapy. The combination of anti-TNF with IL-1Ra, however, completely blocked bone erosion (-98%). Inhibition of bone erosion was accompanied by a reduction of osteoclast numbers in synovial tissue. Cartilage destruction was inhibited by anti-TNF (-43%) and was weakly, but not significantly, inhibited by IL-1Ra, but was not inhibited by OPG monotherapy. The combination of anti-TNF with IL-1Ra was the most effective double combination therapy in preventing cartilage destruction (-80%). In all analyses, the triple combination of anti-TNF, IL-1Ra, and OPG was not superior to the double combination of anti-TNF and IL-1Ra. CONCLUSION: Articular changes caused by chronic overexpression of TNF are not completely blockable by monotherapies that target TNF, IL-1, or RANKL. However, combined approaches, especially the combined blockade of TNF and IL-1 and, to a lesser extent, TNF and RANKL, lead to almost complete remission of disease. Differences in abilities to block synovial inflammation, bone erosion, and cartilage destruction further strengthen the rationale for using combined blockade of more than one proinflammatory pathway.
12044038 Potential therapeutic applications of decoy oligonucleotides. 2002 Apr Recent progress in molecular biology has provided new techniques with which to inhibit target gene expression. In particular, the application of DNA technologies, such as antisense oligonucleotide (ODN) strategies to regulate the transcription of disease-related genes in vivo, have significant therapeutic potential. Recently, transfection of cis-element double-stranded oligonucleotides (decoy ODNs) has been reported as a new powerful tool in a new class of anti-gene strategies for gene therapy. Transfection of double-stranded ODN corresponding to the cis sequence will result in attenuation of the authentic cis-trans interaction, leading to removal of trans-factors from the endogenous cis-elements with subsequent modulation of gene expression.
15457447 Cooperation of Ras- and c-Myc-dependent pathways in regulating the growth and invasiveness 2004 Sep OBJECTIVE: To study the specific contribution of MAP kinase activator c-Raf-1 and one of its downstream transcription factors, c-Myc, to the growth and invasive behavior of rheumatoid arthritis synovial fibroblasts (RASFs). METHODS: RASFs were transduced with retroviral constructs expressing dominant-negative mutants of c-Raf-1 or c-Myc (DN c-Raf-1 or DN c-Myc, respectively) or with the mock vector. The expression of wild-type and mutant proteins was confirmed by Western blotting. Growth curves of RASFs were recorded, and apoptosis was measured by flow cytometry. Invasiveness of RASFs was assessed in the SCID mouse model of RA. Immunohistochemistry was used to study the effects of DN c-Raf-1 on phosphorylated c-Jun and matrix metalloproteinase 1 (MMP-1) in RASFs implanted into SCID mice. The phosphorylation of ERK and JNK in DN c-Raf-1- and mock-transduced RASFs was determined in vitro by Western blotting. The levels of MMPs in these cells were measured by quantitative polymerase chain reaction (PCR). RESULTS: Neither DN c-Raf-1 alone nor DN c-Myc alone significantly altered proliferation or apoptosis of RASFs, but both mutants together rapidly induced apoptosis. Inhibition of c-Raf-1 or c-Myc significantly reduced the invasiveness of RASFs in the SCID mouse model. DN c-Raf-1 decreased the phosphorylation of ERK and JNK in vitro and reduced the in vivo expression of phosphorylated c-Jun as well as the expression of disease-relevant MMPs. As determined by quantitative PCR, the inhibition was most pronounced for MMP-1 and MMP-3. CONCLUSION: The data demonstrate that Ras- and c-Myc-dependent signaling events cooperate to regulate the growth and invasiveness of RASFs. Targeting of both c-Raf-1 and c-Myc may constitute an interesting therapeutic approach in RA.
12902519 A novel therapeutic approach targeting articular inflammation using the filarial nematode- 2003 Aug 15 Understanding modulation of the host immune system by pathogens offers rich therapeutic potential. Parasitic filarial nematodes are often tolerated in human hosts for decades with little evidence of pathology and this appears to reflect parasite-induced suppression of host proinflammatory immune responses. Consistent with this, we have previously described a filarial nematode-derived, secreted phosphorylcholine-containing glycoprotein, ES-62, with immunomodulatory activities that are broadly anti-inflammatory in nature. We sought to evaluate the therapeutic potential of ES-62 in vitro and in vivo in an autoimmune disease model, namely, collagen-induced arthritis in DBA/1 mice. ES-62 given during collagen priming significantly reduced initiation of inflammatory arthritis. Crucially, ES-62 was also found to suppress collagen-induced arthritis severity and progression when administration was delayed until after clinically evident disease onset. Ex vivo analyses revealed that in both cases, the effects were associated with inhibition of collagen-specific pro-inflammatory/Th1 cytokine (TNF-alpha, IL-6, and IFN-gamma) release. In parallel in vitro human tissue studies, ES-62 was found to significantly suppress macrophage activation via cognate interaction with activated T cells. Finally, ES-62 suppressed LPS-induced rheumatoid arthritis synovial TNF-alpha and IL-6 production. Evolutionary pressure has promoted the generation by pathogens of diverse mechanisms enabling host immune system evasion and induction of "tolerance." ES-62 represents one such mechanism. We now provide proof of concept that parasite-derived immunomodulatory strategies offer a novel therapeutic opportunity in inflammatory arthritis.
14762226 Characterization of plasmacytoid dendritic cells in inflammatory arthritis synovial fluid. 2004 Apr OBJECTIVE: To examine the phenotype of dendritic cell subsets in synovial fluid and peripheral blood from patients with rheumatoid arthritis (RA) or spondyloarthropathy (SpA). METHODS: Multiparameter flow cytometry was used to identify and characterize dendritic cells in mononuclear cell populations isolated from synovial fluid and peripheral blood. RESULTS: Synovial fluid contained two subsets of dendritic cells (DC), myeloid and plasmacytoid. These subsets could also be identified in peripheral blood, but there were lower numbers of DC in peripheral blood compared with synovial fluid. Plasmacytoid DC were distinguished from the myeloid subset by high expression of CD123 and lack of expression of CD11c. In comparison with myeloid dendritic cells, the plasmacytoid subset were less mature, similar to those in peripheral blood. They failed to express CD83 and DC-LAMP, and had relatively low levels of CD40 and CD86. Comparison of dendritic cells in synovial fluid from RA and SpA patients showed increased numbers of the plasmacytoid subset in SpA. CONCLUSIONS: This is the first demonstration of the plasmacytoid subset of dendritic cells in synovial fluid. Since these cells are major producers of type I interferons, their increased numbers in SpA might be relevant to pathogenesis, but the immature phenotype in SpA synovial fluid may also indicate that conditions for maturation of this subset do not pertain in SpA synovium.
12669473 Technology evaluation: MRA, Chugai. 2003 Feb Chugai, the Japanese subsidiary of Roche, is developing a humanized anti-interleukin (IL)-6 receptor monoclonal antibody MRA for the potential treatment of multiple myeloma, rheumatoid arthritis, Crohn's disease and other IL-6-related disorders. MRA is currently undergoing phase II clinical trials for these indications.
15150426 The role of interleukin-1 in the pathogenesis of rheumatoid arthritis. 2004 Jun A significant body of experimental evidence has implicated the proinflammatory cytokine IL-1 in the pathogenesis of RA. For example, IL-1beta overexpression in rabbit knee joints causes arthritis with clinical and histological features characteristic of RA, whereas IL-1 deficiency is associated with reduced joint damage. In experimental models, IL-1 blockers, including IL-1 receptor antagonist (IL-1Ra), significantly reduce clinical and histological disease parameters. In RA patients, plasma and synovial fluid concentrations of IL-1 are elevated, and these correlate with various parameters of disease activity. The production of endogenous IL-1Ra, however, appears to be insufficient to balance these higher IL-1 levels. The efficacy of blocking IL-1 in patients with active RA has been established in controlled clinical trials of anakinra, a recombinant human IL-1Ra (r-metHuIL-1ra). When used alone or in combination with methotrexate, anakinra significantly reduces the clinical signs and symptoms of RA compared with placebo. Taken together, these results indicate that IL-1 plays an important role in the pathogenesis of RA.
15210773 The regulatory C-terminal determinants within mycobacterial heat shock protein 65 are cryp 2004 Jul 1 The 65-kDa mycobacterial heat shock protein (Bhsp65) has been invoked in the pathogenesis of both adjuvant arthritis (AA) in the Lewis rat (RT.1(l)) and human rheumatoid arthritis. Arthritic Lewis rats in the late phase of AA show diversification of the T cell response to Bhsp65 C-terminal determinants (BCTD), and pretreatment of naive Lewis rats with a mixture of peptides representing these neoepitopes affords protection against AA. However, the fine specificity and physiologic significance of the BCTD-directed T cell repertoire, and the role of homologous self (rat) hsp65 (Rhsp65), if any, in spreading of the T cell response to Bhsp65 have not yet been examined. We observed that T cells primed by peptides comprising BCTD can adoptively transfer protection against AA to the recipient Lewis rats. However, these T cells can be activated by preprocessed (peptide) form of BCTD, but not native Bhsp65, showing that BCTD are cryptic epitopes. The BCTD-reactive T cells can be activated by the naturally generated (dominant) C-terminal epitopes of both exogenous and endogenous Rhsp65 and vice versa. Furthermore, certain individual peptides constituting BCTD and their self homologs can also induce protection against AA. These results support a model for the diversification of T cell response to Bhsp65 during the course of AA involving up-regulation of the display of cryptic BCTD coupled with spontaneous induction of T cell response to the cross-reactive dominant C-terminal epitopes of Rhsp65. The identification of disease-regulating cryptic determinants in Ags implicated in arthritis provides a novel approach for immunotherapy of rheumatoid arthritis.
12488514 Musculoskeletal disorders in farmers and farm workers. 2002 Dec Farming is a physically arduous occupation and this places farm workers at potential risk of musculoskeletal disorders such as osteoarthritis (OA) of the hip and knee, low back pain (LBP), neck and upper limb complaints, and hand-arm vibration syndrome (HAVS). This review considers the epidemiological evidence concerning such risks. The strongest evidence relates to OA of the hip, for which the public health impact is likely to be considerable. There is also weaker, but suggestive evidence that farmers more often have knee OA and LBP than workers in occupations with fewer physical demands. Tractor drivers, in particular, seem to have more LBP. Relatively little information exists on the risks of soft tissue rheumatism in the limbs and neck. For some outcomes, the link with occupational risk factors (such as heavy loading of joints and whole-body vibration) is sufficient to suggest the course that future prevention should take, but for several outcomes more research is first needed.
15130753 Selective COX-2 inhibitor, NS-398, inhibits the replicative senescence of cultured dermal 2004 May Cyclooxygenase 2 (COX-2) is known to be increased in aged cells. Recent studies suggest that the increased expression of COX-2 may be involved in the pathogenesis of age-associated diseases such as rheumatoid arthritis and cancer. We investigated the role of COX-2 in cell cycle arrest and collagen deficiency during the aging process. Using the replicative senescence model of dermal fibroblasts, we demonstrated the increased expression of COX-2 and increased PGE(2) levels associated with replicative senescence. Replicative senescent cells showed a decreased ability to induce cell proliferation, probably due to the increased expression of the p53 protein and the decreased expression of the PCNA protein, and also showed increased expression of MMP-1, and decreased expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) and procollagen. The selective COX-2 inhibitor, NS-398, can inhibit the senescence-associated increases of COX-2, PGE(2), p53 and MMP-1 expression, and the senescence-associated decreases of PCNA, TIMP-1 and procollagen expression. These results suggest that the increased level of COX-2 and higher level of PGE(2) in aged cells may play an important role in cellular senescence, and that selective COX-2 inhibitors may be useful for the intervention of skin aging.
15146409 Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti 2004 May OBJECTIVE: Tumor necrosis factor (TNF) is an important proinflammatory cytokine that mediates inflammatory synovitis and articular matrix degradation in rheumatoid arthritis (RA). We investigated the ability of adalimumab, a human anti-TNF monoclonal antibody, to inhibit the progression of structural joint damage, reduce the signs and symptoms, and improve physical function in patients with active RA receiving concomitant treatment with methotrexate (MTX). METHODS: In this multicenter, 52-week, double-blind, placebo-controlled study, 619 patients with active RA who had an inadequate response to MTX were randomized to receive adalimumab 40 mg subcutaneously every other week (n = 207), adalimumab 20 mg subcutaneously every week (n = 212), or placebo (n = 200) plus concomitant MTX. The primary efficacy end points were radiographic progression at week 52 (total Sharp score by a modified method [TSS]), clinical response at week 24 (improvements of at least 20% in the American College of Rheumatology core criteria [ACR20]), and physical function at week 52 (disability index of the Health Assessment Questionnaire [HAQ]). RESULTS: At week 52, there was statistically significantly less radiographic progression, as measured by the change in TSS, in the patients receiving adalimumab either 40 mg every other week (mean +/- SD change 0.1 +/- 4.8) or 20 mg weekly (0.8 +/- 4.9) as compared with that in the placebo group (2.7 +/- 6.8) (P < or = 0.001 for each comparison). In addition, there were statistically significant changes in the components of the TSS. At week 24, ACR20 responses were achieved by 63% and 61% of patients in the adalimumab 40 mg every other week and 20 mg weekly groups, respectively, versus 30% of patients in the placebo group (P < or = 0.001 for each comparison). At week 52, ACR20 responses were achieved by 59% and 55% of patients taking adalimumab 40 mg every other week and 20 mg weekly, respectively, versus 24% of patients taking placebo (P < or = 0.001 for each comparison). At week 52, physical function as measured by the HAQ demonstrated statistically significant improvement with adalimumab 40 mg every other week and 20 mg weekly compared with placebo (mean change in HAQ score -0.59 and -0.61, respectively, versus -0.25; P < or = 0.001 for each comparison). A total of 467 patients (75.4%) completed 52 weeks of treatment. Adalimumab was generally well tolerated. Discontinuations occurred in 22.0% of adalimumab-treated patients and in 30.0% of placebo-treated patients. The rate of adverse events (both serious and nonserious) was comparable in the adalimumab and placebo groups, although the proportion of patients reporting serious infections was higher in patients receiving adalimumab (3.8%) than in those receiving placebo (0.5%) (P < or = 0.02), and was highest in the patients receiving 40 mg every other week. CONCLUSION: In this 52-week trial, adalimumab was more effective than placebo at inhibiting the progression of structural joint damage, reducing the signs and symptoms, and improving physical function in patients with active RA who had demonstrated an incomplete response to MTX.
14695331 Expression and activation of mitogen-activated protein kinase kinases-3 and -6 in rheumato 2004 Jan The p38 mitogen-activated protein (MAP) kinase signal transduction pathway regulates the production of interleukin-1 and tumor necrosis factor-alpha. p38 kinase inhibitors are effective in animal models of arthritis and are currently being developed in rheumatoid arthritis (RA). However, little is known about the upstream kinases that control the activation of p38 in RA synovium. In vitro studies previously identified the MAP kinase kinases (MAPKKs) MKK3 and MKK6 as the primary regulators of p38 phosphorylation and activation. To investigate a potential role for MKK3 and MKK6 in RA, we evaluated their expression and regulation in RA synovium and cultured fibroblast-like synoviocytes (FLS). Immunohistochemistry demonstrated that MKK3 and MKK6 are expressed in RA and osteoarthritis (OA) synovium. Digital image analysis showed no significant differences between OA and RA with regard to expression or distribution. However, phosphorylated MKK3/6 expression was significantly higher in RA synovium and was localized to the sublining mononuclear cells and the intimal lining. Actin-normalized Western blot analysis of synovial tissue lysates confirmed the increased expression of phosphorylated MKK3/6 in RA. Western blot analysis demonstrated constitutive expression of MKK3 and MKK6 in RA and OA FLS. Phospho-MKK3 levels were low in medium-treated FLS, but were rapidly increased by interleukin-1 and tumor necrosis factor-alpha, although phospho-MKK6 levels only modestly increased. p38 co-immunoprecipitated with MKK3 and MKK6 from cytokine-stimulated FLS and the complex phosphorylated activating transcription factor-2 in an in vitro kinase assay. These data are the first documentation of MKK3 and MKK6 activation in human inflammatory disease. By forming a complex with p38 in synovial tissue and FLS, these kinases can potentially be targeted to regulate the production of proinflammatory cytokine production in inflamed synovium.