Rheumatoid Arthritis: Lin J

Lin J, Ziring D, Desai S, Kim S, Wong M, Korin Y, Braun J, Reed E, Gjertson D, Singh RR. · UCLA David Geffen School of Medicine, Los Angeles, CA 90095, USA. · Clin Immunol. · Pubmed #17916445 links to  free full text

Abstract: Tumor necrosis factor-alpha (TNFalpha) antagonists including antibodies and soluble receptors have shown remarkable efficacy in various immune-mediated inflammatory diseases (IMID). As experience with these agents has matured, there is an emerging need to integrate and critically assess the utility of these agents across disease states and clinical sub-specialties. Their remarkable efficacy in reducing chronic damage in Crohn's disease and rheumatoid arthritis has led many investigators to propose a new, 'top down' paradigm for treating patients initially with aggressive regimens to quickly control disease. Intriguingly, in diseases such as rheumatoid arthritis and asthma, anti-TNFalpha agents appear to more profoundly benefit patients with more chronic stages of disease but have a relatively weaker or little effect in early disease. While the spectrum of therapeutic efficacy of TNFalpha antagonists widens to include diseases such as recalcitrant uveitis and vasculitis, these agents have failed or even exacerbated diseases such as heart failure and multiple sclerosis. Increasing use of these agents has also led to recognition of new toxicities as well as to understanding of their excellent long-term tolerability. Disconcertingly, new cases of active tuberculosis still occur in patients treated with all TNFalpha antagonists due to lack of compliance with recommendations to prevent reactivation of latent tuberculosis infection. These safety issues as well as guidelines to prevent treatment-associated complications are reviewed in detail in this article. New data on mechanisms of action and development of newer TNFalpha antagonists are discussed in a subsequent article in the Journal. It is hoped that these two review articles will stimulate a fresh assessment of the priorities for research and clinical innovation to improve and extend therapeutic use and safety of TNFalpha antagonism.

Wong M, Ziring D, Korin Y, Desai S, Kim S, Lin J, Gjertson D, Braun J, Reed E, Singh RR. · UCLA David Geffen School of Medicine, Los Angeles, CA 90095, USA. · Clin Immunol. · Pubmed #17916444 links to  free full text

Abstract: Tumor necrosis factor-alpha (TNFalpha) antagonists have shown remarkable efficacy in a variety of immune-mediated inflammatory diseases (IMIDs). Therapeutic scope and limitations of these agents are reviewed in a recently published article in the Journal. In spite of their therapeutic popularity, little is known about their modes of action in vivo and factors that limit their scope of therapeutic use. Intriguingly, while all TNFalpha antagonists including blocking antibodies and soluble receptors are effective in certain IMIDs, only anti-TNFalpha antibodies are effective in other IMIDs. Early efforts at understanding how TNFalpha antagonists act in IMIDs centered on their ability to neutralize soluble TNFalpha or to block TNF receptors from binding to their ligands. Subsequent studies suggested a role of complement-mediated lysis or antibody-dependent cell cytotoxicity in their therapeutic effects. More recent models postulate that TNFalpha blockers may act by affecting intracellular signaling, with the end result being a hastened cell cycle arrest, apoptosis, suppression of cytokine production, or improved Treg cell function. TNFalpha antagonists can also modulate the functions of myofibroblasts and osteoclasts, which might explain how TNFalpha antagonists reduce tissue damage in chronic IMIDs. Focusing on the human therapeutic experience, this analytical review will review the biology of mechanisms of action, the limiting factors contributing to disease restriction in therapeutic efficacy, and the mechanism and frequency of treatment-limiting adverse responses of TNFalpha antagonists. It is hoped that the overview will address the needs of clinicians to decide on optimal use, spur clinical innovation, and incite translational researchers to set priorities for in vivo human investigations.

Chen J, Liu C, Lin J. · TheFirst Affiliated Hospital of Fujian Medical University, Department of Hematology and Rheumatology, Fuzhou, Fujian Province, China. · Cochrane Database Syst Rev. · Pubmed #17054209 No free full text.

Abstract: BACKGROUND: Ankylosing spondylitis (AS) is a chronic inflammatory disease of unknown cause, characterised by sacroiliitis and spondylitis. Generally, treatment is limited to the alleviation of symptoms using non-steroidal anti-inflammatory drugs (NSAIDs). Recently, disease-modifying antirheumatic drugs (DMARDs) have been used for patients for whom NSAIDs do not work. Methotrexate (MTX), a widely used DMARD, is effective for rheumatoid arthritis (RA), and so might work for AS too. OBJECTIVES: To evaluate the efficacy and toxicity of MTX for treating AS. SEARCH STRATEGY: We conducted searches in any language in: CENTRAL (The Cochrane Library Issue 4, 2005); MEDLINE (1966 to November 20, 2005); EMBASE (1980 to November 20, 2005); CINAHL (1982 to November 20, 2005), and the reference sections of retrieved articles. SELECTION CRITERIA: Randomised and quasi-randomised trials examining the efficacy of MTX versus placebo, other medication, or no medication, for AS. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed unblinded trial reports for inclusion, assessed methodological quality and entered trial data into RevMan 4.2 using the double-entry facility. Disagreements were resolved by a third reviewer. In the absence of significant heterogeneity, results for continuous data were combined using weighted mean difference or standardised mean difference. Relative risk was used for dichotomous data. MAIN RESULTS: Three trials, involving 116 patients, were included. One 12-month trial compared naproxen plus MTX with naproxen alone. Two 24-week trials compared different doses of MTX with placebo. No statistically significant differences were found for the primary outcome measures of physical function, pain, spinal mobility, peripheral joints/entheses pain, swelling and tenderness, changes in spine radiographs and patient and physician global assessment. Only the response rate in one trial showed a statistically significant benefit of 36% in the MTX group compared to the placebo group (RR 3.18, 95% CI 1.03 to 9.79). This response rate was a composite index that included assessments of morning stiffness, physical well-being, Bath ankylosing spondylitis disease activity index (BASDAI), Bath ankylosing spondylitis functional index (BASFI), health assessment questionnaire for spondyloarthropathies (HAQ-S), and physician and patient global assessment. However, no single outcome showed a statistically significant difference between the MTX and placebo groups when endpoint results were compared. Therefore, this benefit of MTX is questionable. No serious side effects were reported in these trials. AUTHORS' CONCLUSIONS: There is not enough evidence to support any benefit of MTX in the treatment of AS. High-quality randomised controlled trials of longer durations and with larger sample sizes are needed to clarify the effect(s) of MTX on AS.

Zeng RM, Zou YC, Lin J, Zhao ZJ, Liu MZ, Li WM. · Department of Orthopedics, First Clinical College of Shantou University, Shantou 515041, China. · Nan Fang Yi Ke Da Xue Xue Bao. · Pubmed #16793624 links to  free full text

Abstract: OBJECTIVE: To continuously observe the long-term effects of synovectomy for improving joint damage and quality-of-life in patients with the rheumatoid knee. METHODS: Twenty-one consecutive patients with rheumatoid arthritis (RA) involving 24 knees underwent open synovectomy from November 1988 to January 1997 between November 1988 and January 1997. The changes in radiographic damage were assessed with Larsen score on plain films before and 6 months after surgery with subsequent annual assessment for 8 years, and the functional recovery of the patients was also evaluated with Health Assessment Questionnaire (HAQ) at the same time. RESULTS: The radiographic joint damage and juxta-articular osteoporosis or bone erosion was ameliorated after surgery in all the patients. Larsen score began to decrease 6 months after the operation, and the best effects were achieved at one year and maintained for at least 5 years after the operation, but then followed by recurrence of joint lesions. HAQ scores were improved after the surgery with the best effects observed 6 months after the operation lasting for over 2 years. HAQ score gradually decreased 4 years after the operation till reaching the preoperative scores. CONCLUSION: Synovectomy in the patients with rheumatoid knee not only reverses progressive joint damage, but also improves juxta-articular bone erosions and the patients' quality of life. However, radiographic joint damage and functional deterioration may recur due to hyperplasia of the inflammatory synovium in the long term after operation, suggesting that the inflammatory synovium participates in local joint damage with bone erosions and systemic pathologic process of RA.

Yin H, Yu M, Cheng H, Zhang F, Gao Y, Lin J, Han B, Zhu L. · Department of Rheumatology & Clinical Immunology, Peking Union Medical College Hospital, 1 Shuaifuyuan,Wangfujing, Beijing, 100730 PR China. · Neuro Endocrinol Lett. · Pubmed #16380673 No free full text.

Abstract: OBJECTIVE: To observe the effects and mechanisms of beta-endorphin (beta-END) preventing collagen induced arthritis (CIA) by neuroimmuno-regulating pathway. METHODS: Female wistar (Ws) rats were used in this study. CIA was induced by Native bovine type II collagen emulsified with complete Freund's adjuvant (CFA). Beta-END was administered i.p. to CIA rats every other day from the 14th day (secondary immunization) to the 35th day after primary immunization. Clinical assessments were performed by two independent, blinded examiners every other day. Pathological and radiological observations were taken on the 35th day after the primary immunization. Tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), interleukin-6 (IL-6), regulated upon activation, normal T-cell expressed and secreted (RANTES), inducible NO syntheses (iNOS), matrix metalloproteinase-2 (MMP-2) and MMP-9 mRNA expression of synovium tissues of CIA rats was estimated by quantitative RT-PCR. The frequency of spleen Th1 and Th2 cells were assessed by fluorescence activated cell sorter (FACS) assay. RESULTS: Clinical manifestation of rats with CIA were significantly abrogated or ameliorated by treatment with beta-END. Beta-END treatment in vivo could down-regulate mRNA expression of several pro-inflammatory cytokines, chemokines and MMPs in CIA synovial, and polarize Th1/Th2 balance to Th2. CONCLUSION: Beta-END alleviates CIA through both depressing Th1 responses and down-regulating proinflammatory and other rheumatic factors, suggesting beta-END is a promising anti-inflammatory and anti-rheumatic agent in treating CIA.

Jin J, Li QY, Lin J, Li JY, Qiu GX. · Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Beijing 100730, China. · Zhonghua Yi Xue Za Zhi. · Pubmed #16313800 No free full text.

Abstract: OBJECTIVE: To evaluate the curative effectiveness of Swanson double-stem silicone implant arthroplasty on the reconstruction of first metatarsophalangeal joint. METHODS: Swanson double-stem silicone implant arthroplasty was performed on 10 patients, 2 males and 8 females, aged 60 (57-75), suffering from diseases of first metatarsophalangeal joint with 13 diseased joints, including hallux valgus with geriatric osteoarthritis (8 cases, 10 joints), rheumatoid arthritis (1 case, 2 joints), and traumatic arthritis (1 case, 1 joint). All patients were followed up for an average of 25 months (12-38 months). RESULTS: Eight patients felt complete satisfaction with the operation, 1 patient showed satisfaction to some extent, and 1 patient was not satisfied because of pain of the first matatarsophalangeal joint due to severe hyperosteogeny surrounding the cut bone face 3 years after the operation. Osteolysis around the silicone implant occurred in 2 cases without clinical symptoms, and no special treatment was given. CONCLUSION: With the advantages of alleviating pain, preserving the length and alignment of great toe, improving the function of walking, and correcting the deformity, Swanson double-stem silicone implant arthroplasty is effective on reconstruction of the first metatarsophalangeal joint.

Xiong M, Song C, Lin J, Song L. · Sun Yat-sen Medical College, Sun Yat-sen University, Guangzhou 510080. · Zhong Yao Cai. · Pubmed #15562720 No free full text.

Abstract: OBJECTIVE: To study the effect of tongbiling, a complex preparation of Chinese traditional medicine, on the expression of MCP-1 mRNA of synovial cells in rats with adjuvant arthritis. METHOD: The expression level of MCP-1 mRNA in synoviocytes from rats with adjuvant arthritis was assayed by the method of RT-PCR. RESULT: The amounts of MCP-1 mRNA expression in synoviocytes from rats with adjuvant arthritis were distinctly decreased by tongbiling. It suggested that tongbiling had inhibition effect on rheumatoid arthritis by a down regulation for the expression of MCP-1 mRNA in the inflamed synoviocytes.

Guan Z, Lu H, Kou B, Yuan Y, Lin J, Yang G. · Arthritis and Clinic Research Center, People's Hospital, Beijing Medical Univercity, Beijing 100044. · Zhonghua Wai Ke Za Zhi. · Pubmed #11829791 No free full text.

Abstract: OBJECTIVE: To evaluate the results of reinfusion of autologous shed blood after joint replacement. METHODS: From February 1996 to March 1998, we selected 36 patients for 56 joint replacements. Apart from preoperative donation of autologous blood, all patients received transfusion of unwashed autologous drained blood from hips and knees after arthroplasty. The CBCIIConstaVac blood conservation system was used to salvage shed blood. Among the patients, 8 hips and 48 knees were involved. 12 patients had rheumatoid arthritis, 16 osteoarthritis, 5 ankylosing spondylitis, and 3 other arthritis. RESULTS: 36 patients received 24 260 ml (50%) autologous shed blood, 9 700 ml (20%) reserved autologous blood, and 14 600 ml (30%) allogenic blood. 15 patients experienced transient febrile reaction at the time of reinfusion, no other clinic abnormalities were discovered after reinfusion. CONCLUSIONS: Reinfusion of autologous shed blood is a safe and effective to decrease the use of allogenic blood and avoid the complications of its transfusion.

Lu H, Mow CS, Lin J. · Department of Orthopaedic Surgery, Beijing Medical University and Beijing People's Hospital, PR China. · J Arthroplasty. · Pubmed #10537249 No free full text.

Abstract: From 1987 to 1994, 37 total knee arthroplasties were performed in 23 patients with severe, fixed flexion contractures averaging 78 degrees (range, 60 degrees -100 degrees). Fourteen of the knees had flexion contractures of greater than 90 degrees and 7 were fused at 90 degrees. There were 19 women and 4 men. The average age at surgery was 42 years (range, 20-57 years). The diagnoses were rheumatoid arthritis in 17 patients, juvenile rheumatoid arthritis in 3, and ankylosing spondylitis in 3. Preoperatively, all patients were Knee Society Category C, with 14 being nonambulatory and 9 minimally ambulatory. Follow-up averaged 4.3 years (range, 2-8 years). Postoperatively, patients were immobilized in extension when not in continuous passive motion or physical therapy. Flexion contractures were corrected to an average of 7 degrees postoperatively (range, 0 degrees -15 degrees). Arc of motion improved from 25 degrees preoperatively to 82 degrees postoperatively. The average Knee Society knee scores improved from 25 points preoperatively to 78 points postoperatively, and the functional scores improved from 0 points preoperatively to 71 points postoperatively. Five knees were manipulated under anesthesia postoperatively. Complications included 3 transient peroneal nerve palsies, 1 transient episode of vascular insufficiency, 6 delayed wound healings, and 1 deep infection. There were no aseptic loosenings. We conclude that although technically difficult, total knee arthroplasty can be performed successfully in this challenging and highly debilitated subset of patients, giving them marked improvement in quality of life.

Liverton NJ, Butcher JW, Claiborne CF, Claremon DA, Libby BE, Nguyen KT, Pitzenberger SM, Selnick HG, Smith GR, Tebben A, Vacca JP, Varga SL, Agarwal L, Dancheck K, Forsyth AJ, Fletcher DS, Frantz B, Hanlon WA, Harper CF, Hofsess SJ, Kostura M, Lin J, Luell S, O'Neill EA, O'Keefe SJ. · Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. · J Med Chem. · Pubmed #10377223 No free full text.

Abstract: Novel potent and selective diarylimidazole inhibitors of p38 MAP (mitogen-activated protein) kinase are described which have activity in both cell-based assays of tumor necrosis factor-alpha (TNF-alpha) release and an animal model of rheumatoid arthritis. The SAR leading to the development of selectivity against c-Raf and JNK2alpha1 kinases is presented, with key features being substitution of the 4-aryl ring with m-trifluoromethyl and substitution of the 5-heteroaryl ring with a 2-amino substituent. Cell-based activity was significantly enhanced by incorporation of a 4-piperidinyl moiety at the 2-position of the imidazole which also enhanced aqueous solubility. In general, oral bioavailability of this class of compounds was found to be poor unless the imidazole was methylated on nitrogen. This work led to identification of 48, a potent (p38 MAP kinase inhibition IC50 0.24 nM) and selective p38 MAP kinase inhibitor which inhibits lipopolysaccharide-stimulated release of TNF-alpha from human blood with an IC50 2.2 nM, shows good oral bioavailability in rat and rhesus monkey, and demonstrates significant improvement in measures of disease progression in a rat adjuvant-induced arthritis model.