Rheumatoid Arthritis: Abramson SB

Lipsky PE, Abramson SB, Breedveld FC, Brook P, Burmester R, Buttgereit F, Cannon GW, Catella-Lawson F, Crofford LJ, Doherty M, Dougados M, DuBois RN, Froelich J, Garcia Rodriguez LA, Gibofsky A, Hernandez-Diaz S, Hochberg MC, Krause A, Liang MH, Machold K, Peloso PM, Raisz LG, Schayes B, Scheiman JM, Simon LS, Smolen J. · No affiliation provided · J Rheumatol. · Pubmed #10852251 No free full text.

This publication has no abstract.

Abramson SB, Attur M, Yazici Y. · New York University Hospital for Joint Diseases, New York, NY 10003, USA. · Nat Clin Pract Rheumatol. · Pubmed #16932709 No free full text.

Abstract: Osteoarthritis (OA) can be a progressive, disabling disease, leading to diminished quality of life, and, for over 500,000 individuals annually in the US, total joint replacement. The etiology of OA will vary among individuals, with potential roles for systemic factors (such as genetics and obesity) as well as for local biomechanical factors (such as muscle weakness, joint laxity and traumatic injury). Joint deterioration occurs over extended periods of time, and the diverse molecular mechanisms that mediate pathogenic events of early, mid and late disease are not yet fully understood. The success of biologic therapies in the treatment of rheumatoid arthritis has demonstrated that the blockade of a single dominant cytokine or regulatory molecule can prevent cartilage destruction in a complex disease, and has raised expectations that mechanism-based treatments could also be developed for patients with OA. In this review, we will address the biological mechanisms that mediate structural damage in OA and examine current targets that are candidates for disease modification. The challenges to drug development and the obstacles to disease modification strategies will also be addressed.

Abramson SB, Yazici Y. · New York University School of Medicine, Hospital for Joint Diseases, 301 East 17th Street, New York, NY 10003, USA. · Adv Drug Deliv Rev. · Pubmed #16567019 No free full text.

Abstract: The osteoarthritis disease process affects not only the cartilage but also the entire joint structure, including the synovium, bone and periarticular muscles. Characteristically, abnormal biomechanical forces result in an imbalance between chondrocyte anabolic and catabolic pathways, which ultimately leads to progressive joint destruction. Within cartilage and synovium, pro-inflammatory cytokines, particularly IL-1b and TNF-a, auto-catalytically stimulate their own production and induce chondrocytes to produce additional catabolic mediators, including proteases, chemokines, nitric oxide, and prostaglandins. The success of targeted biological therapy in rheumatoid arthritis has taught that the blockade of a single dominant cytokine can lead to remarkable clinical benefit, even in complex disease. The effectiveness of biologicals in inflammatory arthritides as disease modifying agents has increased the likelihood that similar strategies can be developed to target specific molecular mechanisms in osteoarthritis (OA). However, since the clinical development program for disease-modifying OA drugs (DMOADs) is complicated by the slow progression of disease in many patients, the introduction of DMOADs will be greatly enhanced by advances in imaging and biomarkers that serve as validated surrogate endpoints for meaningful clinical outcomes.

Park JY, Pillinger MH, Abramson SB. · The Division of Rheumatology, Department of Medicine, New York University School of Medicine, New York, NY 10016, USA. · Clin Immunol. · Pubmed #16540375 No free full text.

Abstract: Prostaglandin E2 (PGE2) is a principal mediator of inflammation in diseases such as rheumatoid arthritis and osteoarthritis. Nonsteroidal anti-inflammatory medications (NSAIDs) and selective cyclooxygenase-2 (COX-2) inhibitors reduce PGE2 production to diminish the inflammation seen in these diseases, but have toxicities that may include both gastrointestinal bleeding and prothrombotic tendencies. In cells, arachidonic acid is transformed into PGE2 via cyclooxygenase (COX) enzymes and terminal prostaglandin E synthases (PGES). Accumulating data suggest that the interaction of various enzymes in the PGE2 synthetic pathway is complex and tightly regulated. In this review, we summarize the synthesis and secretion of PGE2. In particular, we focus on the three isoforms of the terminal PGES, and discuss the potential of targeting PGES as a more precise strategy for inhibiting PGE2 production.

Mor A, Abramson SB, Pillinger MH. · Division of Rheumatology, NYU School of Medicine and The Hospital for Joint Disease, New York, NY 10003, USA. · Clin Immunol. · Pubmed #15885632 No free full text.

Abstract: Although multiple cell types are present in the rheumatoid joint, the fibroblast-like synovial cell (FLS) is among the most prominent. It is now appreciated that the FLS is not only space-filling, but is directly responsible for cartilage destruction, and also drives both inflammation and autoimmunity. In this article, we consider the normal role of the FLS in healthy joints, and review evidence that implicates the FLS as a central player in the propagation of rheumatoid arthritis.

Imperato AK, Bingham CO, Abramson SB. · Department of Rheumatology/Medicine, Hospital for Joint Diseases, New York University, 301 East 17th Street, New York, New York 10003, USA. · Clin Exp Rheumatol. · Pubmed #15552523 No free full text.

Abstract: Targeted tumor necrosis factor-alpha antagonists, first approved by the FDA in 1998, have had a significant impact on the treatment of patients with rheumatoid arthritis. In general, the benefit/ risk ratio for these agents and the IL-1 receptor antagonist, anakinra, has been quite favorable. However, infrequent adverse events can be serious and require continued pharmacovigilance. Infections, particularly tuberculosis and less commonly fungal infections, are among the most serious adverse events, especially given delays in diagnosis due to subtle or atypical presentations. Questions have also arisen regarding whether anti-TNF-alpha agents increase the risk of lymphoma, a complicated issue confounded by the multiple risk factors for lymphoma in patients with rheumatoid arthritis and low observed incidence rates of lymphoma, requiring prolonged monitoring. Additional rare reported complications include systemic lupus erythematosus-like syndromes, congestive heart failure and demyelinating syndromes (including cases resembling progressive multifocal leukoencephalopathy). Ongoing post-marketing surveillance of these and other serious adverse events is necessary to determine the true incidence rates, and whether a reassessment of the overall risk-benefit of tumor necrosis factor-alpha antagonists will be required.

Imperato AK, Smiles S, Abramson SB. · New York University School of Medicine/Hospital for Joint Diseases, 301 East 17th Street, Room 1410, New York, NY 10003, USA. · Curr Opin Rheumatol. · Pubmed #15103245 No free full text.

Abstract: PURPOSE OF REVIEW: The introduction of tumor necrosis factor-alpha antagonists in 1998 has had a significant impact on the treatment of rheumatoid arthritis. However, as use of these agents has increased worldwide, infrequent adverse events that were not apparent in pivotal controlled clinical trials required for registration have emerged. RECENT FINDINGS: These adverse events include serious infections, particularly tuberculosis, which may be atypical in presentation. Concern regarding increased risk of lymphoma has also emerged, although it remains unclear whether the risk exceeds that observed in other rheumatoid arthritis patients with comparable disease activity. Development of a systemic lupus erythematosus-like syndrome, which typically abates after discontinuation of the drug, is another rare complication that was further reported during the past year. Finally, additional cases of congestive heart failure and demyelinating syndromes (including cases resembling progressive multifocal leukoencephalopathy) have been reported that appear to be related to the tumor necrosis factor-alpha antagonists. SUMMARY: Additional postmarketing surveillance of these and other serious adverse events is necessary to determine the true risk of their occurrence, and whether a reassessment of the overall risk-benefit of tumor necrosis factor-alpha antagonists will be required.

Abramson SB, Amin A. · Department of Rheumatology, Hospital for Joint Diseases, New York University of Medicine, 301 East 17th Street, New York, NY 10003, USA. · Rheumatology (Oxford). · Pubmed #12209029 links to  free full text

Abstract: Destruction of articular joints occurs progressively in patients with rheumatoid arthritis (RA). Although the exact aetiology of RA has not been fully elucidated, a large body of evidence supports a role for interleukin-1 (IL-1) in cartilage and bone erosion. In vitro studies suggest that IL-1 can cause cartilage destruction by stimulating the release of matrix metalloproteinases and other degradative products, and it can increase bone resorption by stimulating osteoclast differentiation and activation. In animal models of RA, blocking the effects of IL-1 with either IL-1 receptor antagonist (IL-1Ra; endogenous), anti-IL-1 monoclonal antibodies, or soluble IL-1 type II receptors significantly reduced cartilage destruction and bone erosion. Gene therapy with IL-1Ra was also effective in reducing joint destruction in experimental RA and osteoarthritis (OA) models. In clinical studies, anakinra, a human recombinant IL-1 receptor antagonist (IL-1ra; exogenous), significantly slowed radiographic progression of RA relative to placebo and significantly reduced clinical symptoms when used as monotherapy or in addition to existing methotrexate therapy. These results demonstrate that blocking IL-1 protects bone and cartilage from progressive destruction in RA.

Simon LS, Smolen JS, Abramson SB, Appel G, Bombardier C, Brater DC, Breedveld FC, Brune K, Burmester GR, Crofford LJ, Dougados M, DuBois RN, Fitzgerald GA, Frishman W, García Rodríguez LA, Hochberg MC, Kalden JR, Laine L, Langman MJ, Prescott SM, van de Putte LB, Whelton A, White WB, Willaims GH. · Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. · J Rheumatol. · Pubmed #12136912 No free full text.

This publication has no abstract.

Abramson SB, Amin AR, Clancy RM, Attur M. · Hospital for Joint Diseases/New York University School of Medicine, 301 East 17th Street, New York, NY 10003, USA. · Best Pract Res Clin Rheumatol. · Pubmed #11812024 No free full text.

Abstract: Nitric oxide (NO) is synthesized via the oxidation of arginine by a family of nitric oxide synthases (NOS), which are either constitutive (ie. endothelial (ec)NOS and neuronal (nc)NOS) or inducible (iNOS). The production of nitric oxide plays a vital role in the regulation of physiological processes, host defence, inflammation and immunity. Pro-inflammatory effects include vasodilation, oedema, cytotoxicity and the mediation of cytokine-dependent processes that can lead to tissue destruction. Nitric oxide-dependent tissue injury has been implicated in a variety of rheumatic diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis and osteoarthritis. Conversely, the production of NO by endothelial cell NOS may serve a protective, or anti-inflammatory, function by preventing the adhesion and release of oxidants by activated neutrophils in the microvasculature. In this chapter we describe the multifaceted role of nitric oxide in inflammation and address the potential therapeutic implications of NOS inhibition.

Abramson SB, Furst DE, Hochberg MC, Patrono C. · Department of Rheumatology/Medicine, Hospital for Joint Surgery/NYU School of Medicine, New York, NY, USA. · Clin Exp Rheumatol. · Pubmed #11695257 No free full text.

This publication has no abstract.

Golden BD, Abramson SB. · Department of Rheumatology, Hospital for Joint Diseases, New York, New York, USA. · Rheum Dis Clin North Am. · Pubmed #10356423 No free full text.

Abstract: The identification of COX-2 less than a decade ago has been followed by an unprecedented period of discovery and drug development. An awareness of the existence of two COX isoforms has led to potential novel insights into disease pathogenesis (arthritis, Alzheimer's disease, cancer) and the regulation of normal physiology (brain, kidney). The preliminary in vivo experience with COX-2-selective inhibitors has provided evidence for proof of concept for the COX-1 and COX-2 hypothesis, namely that the selective inhibition of COX-2-derived prostaglandins is sufficient to inhibit inflammation and is nonulcerogenic. It may be that we have moved closer to the "better aspirin" envisioned by Sir John Vane for the treatment of degenerative and inflammatory arthritides; however, caution is still warranted. Some toxicities of current NSAIDs may result from COX-2 inhibition, as in the kidney and brain; such side effects may be shared by the selective compounds. In addition, unexpected toxicities may arise simply because new chemical compounds will be widely prescribed. Finally, since the efficacy of traditional NSAIDs derives largely from their capacity to inhibit COX-2, it may be that the COX-2 selective drugs will not prove to be therapeutically superior to available agents. Given the well-recognized toxicity of NSAIDs, however, the availability of COX-2-selective agents promises to provide significant advantage to patients with chronic diseases, such as RA and OA.

Amin AR, Attur M, Abramson SB. · Department of Rheumatology and Medicine, Hospital for Joint Diseases, NYU School of Medicine, New York, New York 10003, USA. · Curr Opin Rheumatol. · Pubmed #10328580 No free full text.

Abstract: Nitric oxide (NO) and prostaglandin E2 (PGE2) are two pleiotropic inflammatory mediators overproduced in arthritis-affected joints. The inducible isoform of nitric oxide synthase (iNOS) and cyclooxygenase (COX-2) are found both in the synovial tissue and in the cartilage. Their expression is regulated by catabolic cytokines, such as interleukin-1beta and tumor necrosis factor-alpha. These inflammatory mediators play a profound role in the pathogenic processes that arise in the pannus of rheumatoid arthritis and also interfere with cartilage homeostasis in osteoarthritis. Several drugs, including nonsteroidal anti-inflammatory drugs, immunosuppressive agents, and tetracyclines, attenuate the activity of NO and PGE2. These pleiotropic mediators are targets for pharmacologic intervention and gene therapy.

Greenberg JD, Fisher MC, Kremer J, Chang H, Rosenstein ED, Kishimoto M, Lee S, Yazici Y, Kavanaugh A, Abramson SB. · New York University Hospital for Joint Diseases, New York, NY. · Clin Exp Rheumatol. · Pubmed #19604430 No free full text.

Abstract: OBJECTIVE:To examine effects of the COX-2 inhibitor market withdrawals on NSAID utilization among patients at increased risk of gastrointestinal (GI) and cardiovascular (CV) toxicities. METHODS:A prospective cohort study was conducted using patients enrolled in the Consortium of Rheumatology Researchers of North America (CORRONA) Registry. The study population included rheumatoid arthritis (RA) and psoriatic arthritis (PsA) patients prescribed NSAIDs by rheumatologists from 1/1/2003 to 12/31/2005. Three cohorts were defined based on calendar year. The primary outcome assessed whether or not an NSAID gastroprotective strategy was prescribed. Secondary outcomes included rates of COX-2 inhibitor utilization and gastroprotective co-therapy utilization, stratified by the presence of cardiac and GI risk factors. RESULTS:NSAID gastroprotection utilization decreased from 65.1% in 2003 to 47.7% (p<0.001) in 2005. COX-2 inhibitor use decreased from 55.1% to 29.2% (p<0.001), whereas nonselective NSAIDs (nsNSAIDs) use increased from 50.2% to 73.9% (p=<0.01). Among patients with two or more risk factors for NSAID related GI bleeding, gastroprotection decreased from 74.4% in 2003 to 60.9% (p<0.01). For patients with two or more CV risk factors from 2003 to 2005, COX-2 inhibitor utilization decreased significantly, whereas nsNSAID utilization increased significantly.CONCLUSIONS:The COX-2 inhibitor withdrawals resulted in a rapid decline in NSAID gastroprotection prescribed by participating U.S. rheumatologists despite the availability of other gastroprotective options. Channeling toward nsNSAID use was widespread, including among patients at increased CV risk. Longer term follow-up is required to determine the clinical significance of these changes in NSAID prescribing, particularly for NSAID-related GI and CV-related toxicities.

Tagoe CE, Marjanovic N, Park JY, Chan ES, Abeles AM, Attur M, Abramson SB, Pillinger MH. · Division of Rheumatology, New York University School of Medicine/Hospital for Joint Diseases, New York, NY 10003, USA. · J Immunol. · Pubmed #18684973 No free full text.

Abstract: Annexins are intracellular molecules implicated in the down-regulation of inflammation. Recently, annexin-1 has also been identified as a secreted molecule, suggesting it may have more complex effects on inflammation than previously appreciated. We studied the role of annexin-1 in mediating MMP-1 secretion from rheumatoid arthritis (RA) synovial fibroblasts (SF) stimulated with TNF-alpha. TNF-alpha induced a biphasic secretion of annexin-1 from RA SF. Early (< or = 60 min), cycloheximide-independent secretion from preformed intracellular pools was followed by late (24 h) cycloheximide-inhibitable secretion requiring new protein synthesis. Exogenous annexin-1 N-terminal peptide Ac2-26 stimulated MMP-1 secretion in a dose- (EC(50) approximately 25 microM) and time- (8-24 h) dependent manner; full-length annexin-1 had a similar effect. Down-regulation of annexin-1 using small interfering RNA resulted in decreased secretion of both annexin-1 and MMP-1, confirming that annexin-1 mediates TNF-alpha-stimulated MMP-1 secretion. Erk, Jnk, and NF-kappaB have been implicated in MMP-1 secretion. Erk, Jnk, and NF-kappaB inhibitors had no effect on annexin-1 secretion stimulated by TNF-alpha but inhibited MMP-1 secretion in response to Ac2-26, indicating that these molecules signal downstream of annexin-1. Annexin-1 stimulation of MMP-1 secretion was inhibited by both a formyl peptide receptor antagonist and pertussis toxin, suggesting that secreted annexin-1 acts via formyl peptide family receptors, most likely FPLR-1. In contrast to its commonly appreciated anti-inflammatory roles, our data indicate that annexin-1 is secreted by RA SF in response to TNF-alpha and acts in an autacoid manner to engage FPRL-1, activate Erk, Jnk, and NF-kappaB, and stimulate MMP-1 secretion.

Greenberg JD, Reddy SM, Schloss SG, Kurucz OS, Bartlett SJ, Abramson SB, Bingham CO. · Department of Rheumatology, NYU-Hospital for Joint Diseases, New York, New York, USA. · J Rheumatol. · Pubmed #18322990 No free full text.

Abstract: OBJECTIVE: Recommendations for screening for latent Mycobacterium tuberculosis (MTB) infection have been proposed but are not well studied in patients with rheumatoid arthritis (RA). We estimated the prevalence of anergy in RA and evaluated different methods to detect MTB exposure. METHODS: This was a prospective pilot study of 61 patients with RA and 42 healthy controls. Tuberculin skin test (TST) antigen, Candida, and tetanus toxoid were injected intradermally using the Mantoux method. Subjects negative for TST returned for a second-step test. Whole-blood interferon-gamma (IFN-gamma) release to mycobacterial antigens was evaluated with the first-generation QuantiFeron test (QIFN). RESULTS: Cutaneous anergy in patients with RA was not significantly different than healthy controls (p = 0.154), and was not affected by disease modifying antirheumatic drugs (p = 0.270). In patients with RA, 16.4% had positive TST with 10 mm cutoff vs 11.9% of controls. Using a 5 mm cutoff, 21.3% of patients with RA were positive, and this increased to 29.5% with a second-step TST. QIFN detected MTB exposure in 18% of patients with RA and 19% of controls (p = 0.897). However, indeterminate QIFN tests were higher in RA patients (11.5%) compared to controls (2.4%), demonstrating a lower sensitivity to detect latent MTB. CONCLUSION: Cutaneous anergy may be less common than previously reported in patients with RA. patients. However, the single-step TST and 10 mm cutoff may fail to detect all cases of latent exposure in RA patients. High rates of indeterminate results in QIFN testing suggest that QIFN should not be employed as an alternative, single-screening test in patients with RA. These pilot results require confirmation in larger studies to determine the optimal screening strategy in RA.

Yazici Y, Abramson SB. · New York University School of Medicine, New York, NY, USA. · Bull NYU Hosp Jt Dis. · Pubmed #18081549 links to  free full text

Abstract: Rheumatoid arthritis (RA) treatment has witnessed major advances over the last 10 to 20 years. Methotrexate has emerged as the cornerstone of treatment with new biologic agents being used in addition in severe and resistant patients. New drugs being developed with novel modes of action are promising to expand treatment options and help provide better disease control for RA patients. In addition to medications, equally important is aggressive disease activity monitoring using one of the composite scores available in order to match treatments to disease activity. Disease activity score (DAS), DAS28 (with a 28 joint count), clinical disease activity index (CDAI), simplified disease activity index (SDAI), and routine assessment of patient index data (RAPID) are valuable tools and should be used in routine care to achieve disease control.

Abeles AM, Marjanovic N, Park J, Attur M, Chan ES, Al-Mussawir HE, Al-Mussawir H, Dave M, Fisher MC, Stuchin SA, Abramson SB, Pillinger MH. · New York University Hospital for Joint Diseases, and New York University School of Medicine, New York, New York 10003, USA. · Arthritis Rheum. · Pubmed #17763406 links to  free full text

Abstract: OBJECTIVE: To determine whether protein prenylation (farnesyl/geranylgeranylation) regulates matrix metalloproteinase (MMP) secretion from rheumatoid arthritis (RA) synovial fibroblasts (RASFs), and whether MMP-1 secretion can be regulated by statins or prenyltransferase inhibitors via effects mediated by ERK, JNK, and NF-kappaB. METHODS: RASFs obtained from patients during elective knee replacement surgery were assessed by immunoblotting and/or enzyme-linked immunosorbent assay for secretion of MMP-1 and MMP-13 in the presence of tumor necrosis factor alpha (TNFalpha), interleukin-1beta (IL-1beta), statins, the farnesyl transferase (FT) inhibitor FTI-276 and geranylgeranyl transferase inhibitor GGTI-298, and prenyl substrates (farnesyl pyrophosphate [FPP] and geranylgeranyl pyrophosphate [GGPP]). Activities of JNK and ERK were determined by phosphoimmunoblotting, and NF-kappaB activation was determined by nuclear translocation of the p65 component. RESULTS: FTI-276, but not statins, inhibited RASF secretion of MMP-1, but not MMP-13, following induction with TNFalpha (P = 0.0007) or IL-1beta (P = 0.006). Loading RASFs with FPP to promote farnesylation enhanced MMP-1 secretion. FTI-276 inhibited activation of JNK (P < 0.05) and NF-kappaB (P = 0.02), but not ERK. In contrast, GGTI-298 enhanced, while GGPP inhibited, MMP-1 secretion. FTI-276 and GGTI-298 together had no effect on MMP-1 secretion. Stimulation of RASFs with TNFalpha or IL-1beta led to increased expression and activity of FT. CONCLUSION: Protein farnesylation is required for expression and secretion of MMP-1 from RASFs, via effects on JNK and NF-kappaB. The ability of cytokines to stimulate the expression and activity of FT suggests that FT may be increased in the rheumatoid joint. In contrast, geranylgeranylation down-regulates MMP-1 expression. Statins simultaneously inhibit farnesylation and geranylgeranylation, and in consequence do not inhibit MMP-1 secretion. The ability of FTI-276 to inhibit MMP-1 secretion suggests a potential therapeutic strategy in RA.

Greenberg JD, Bingham CO, Abramson SB, Reed G, Kishimoto M, Hinkle K, Kremer J. · New York University Hospital for Joint Diseases, New York 10003, USA. · Arthritis Rheum. · Pubmed #16874798 links to  free full text

Abstract: OBJECTIVE: To examine cyclooxygenase 2 inhibitor (coxib) utilization by rheumatologists for patients receiving nonsteroidal antiinflammatory drugs (NSAIDs) prior to the coxib market withdrawals. METHODS: A prospective study of patients with rheumatoid arthritis enrolled in the Consortium of Rheumatology Researchers of North America registry was performed. RESULTS: Of 1,833 patients receiving prescription NSAIDs, 1,380 (75.3%) received gastroprotection, defined as either coxib monotherapy and/or gastroprotective agent (GPA) cotherapy, and 1,207 (65.8%) received coxibs. The distribution of gastroprotective strategies included 860 (46.9%) patients who were prescribed coxib monotherapy, 347 (18.9%) prescribed dual coxib plus GPA cotherapy, 173 (9.4%) prescribed a nonselective NSAID (NS-NSAID) plus GPA cotherapy, and 453 (24.7%) prescribed an NS-NSAID without GPA cotherapy. For patients with 0, 1, and > or =2 identifiable gastrointestinal (GI) risk factors, coxib prescribing rates as a proportion of NSAID agents were 64.1%, 66.4%, and 68.6%, respectively; among dual aspirin/NSAID users, coxib prescribing rates were 66.2%, 78.3%, and 68.5% of NSAID prescriptions, respectively. CONCLUSION: The majority of NSAID users were prescribed a gastroprotective strategy, primarily attributable to coxib utilization. Coxib utilization rates were consistently high across all levels of GI risk, including patients without identifiable risk factors. These data indicate that rheumatologists broadly adopted the coxib class of NSAIDs in a nonselective manner with respect to underlying GI risk and concomitant aspirin use. As novel therapeutic classes are introduced, early evaluation of prescribing patterns using arthritis registries can determine the appropriateness of prescribing patterns and may improve patient outcomes.

Gomez PF, Pillinger MH, Attur M, Marjanovic N, Dave M, Park J, Bingham CO, Al-Mussawir H, Abramson SB. · Department of Rheumatology, Hospital for Joint Diseases and Department of Medicine, New York University School of Medicine, New York, NY 10003, USA. · J Immunol. · Pubmed #16272352 links to  free full text

Abstract: NF-kappaB transcription factors regulate inflammatory responses to cytokines such as IL-1beta and TNF-alpha. We tested whether PGE2 regulated nuclear localization of individual NF-kappaB subunits, p65 and p50, in synovial fibroblasts harvested from patients with rheumatoid arthritis (RA). IL-1beta/TNF-alpha stimulated the translocation of p65 and p50 from the cytosol to the nucleus of human RA synovial fibroblasts, as well as NF-kappaB activation measured by luciferase reporter assay. PGE2 (10 nM, 6 h) enhanced p50, but inhibited p65 translocation and NF-kappaB activation. In contrast, depletion of endogenous PGE2 by ibuprofen (100 microM) and celecoxib (5 microM) enhanced p65, but inhibited p50 nuclear translocation as well as binding to NF-kappaB DNA binding sites. PGE2 also blocked IL-1beta/TNF-alpha-stimulated ERK activation, and the ERK inhibitor, PD98059, mimicked PGE2 in blocking p65, but enhancing p50 nuclear translocation, suggesting that the effects of PGE2 on p65 and p50 are mediated via effects on ERK. PGE2 also enhanced the expression of IkappaBalpha in an ERK-independent manner, suggesting that PGE2 inhibits NF-kappaB activation by both ERK-dependent and -independent mechanisms. Our data indicate that PGE2 may act to attenuate cytokine-induced inflammatory responses in RA synovial fibroblasts via regulation of the localization of specific NF-kappaB family dimers.

Greenberg JD, Bingham CO, Abramson SB, Reed G, Sebaldt RJ, Kremer J. · New York University-Hospital for Joint Diseases, New York, New York, USA. · Arthritis Rheum. · Pubmed #15696570 links to  free full text

Abstract: OBJECTIVE: To evaluate the effects of cardiovascular comorbidities and aspirin coprescription on cyclooxygenase (COX)-2 inhibitor (coxib) prescribing patterns among rheumatologists. METHODS: A prospective cohort study was carried out with rheumatoid arthritis and osteoarthritis patients in the Consortium of Rheumatology Researchers of North America registry. Medication and comorbidity data were obtained prospectively from physician and patient questionnaires between March 2002 and September 2003. Multivariate adjusted associations between coxib use and specific cardiovascular variables, including aspirin use, were examined. RESULTS: A total of 3,522 arthritis patients were included. COX inhibitors, including coxibs, nonselective nonsteroidal antiinflammatory drugs (NSAIDs), and meloxicam, were prescribed to a larger proportion of osteoarthritis patients (68.4%) than rheumatoid arthritis patients (47.1%) in our study (P < 0.001). COX inhibitors were prescribed to the majority of aspirin users (51.5%) and a similar proportion of nonusers (49.8%). In multivariate analyses, independent predictors of coxib use versus nonselective NSAID use included diagnoses of osteoarthritis (odds ratio [OR] 2.52, 95% confidence interval [95% CI] 1.81-3.52) and diabetes (OR 1.63, 95% CI 1.06-2.51). Conversely, aspirin use independently predicted selection of a nonselective NSAID rather than a coxib (OR 0.73, 95% CI 0.55-0.98). Neither a history of myocardial infarction nor stroke predicted utilization of a coxib. Similarly, cardiovascular variables did not predict the use of rofecoxib versus celecoxib. CONCLUSION: Our data indicate that COX inhibitor coprescription among aspirin users is frequent. Despite cardiovascular concerns regarding the coxibs, our data suggest that aspirin use, but not cardiovascular comorbidities, predicted the selection of nonselective NSAIDs over coxibs.