Rheumatoid Arthritis: Taylor PC

Feldmann M, Brennan FM, Foxwell BM, Taylor PC, Williams RO, Maini RN. · Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College, 1 Aspenlea Road, London W6 8LH, UK. · J Autoimmun. · Pubmed #16260118 No free full text.

Abstract: The blockade of TNF has had significant impact on the therapy of a number of chronic autoimmune diseases. In this chapter we review the concepts leading up to this therapy in rheumatoid arthritis (RA), how it spreads into other autoimmune diseases, and how greater understanding of its use has led to augmented therapeutic benefit. There are still many limitations, but the prospects for the future are intriguing.

Taylor PC, Sivakumar B. · The Kennedy Institute of Rheumatology, Division Imperial College Faculty of Medicine, London, UK. · Curr Opin Rheumatol. · Pubmed #15838239 No free full text.

Abstract: PURPOSE OF REVIEW: Angiogenesis is a prominent feature of rheumatoid synovitis. Although new blood vessels deliver oxygen to the augmented inflammatory cell mass, the neovascular network is dysfunctional and fails to restore tissue oxygen homeostasis, so that the rheumatoid joint remains a markedly hypoxic environment. The purpose of this review is to discuss the role of hypoxia and angiogenesis in the pathogenesis of rheumatoid arthritis. RECENT FINDINGS: Vascular pathologic change, in the form of angiogenesis, is important in the perpetuation of rheumatoid arthritis and, in the form of endothelial dysfunction, contributes to associated cardiovascular comorbidity. Recent data suggest that tumor necrosis factor-alpha blockade may modify the vascular pathologic changes in rheumatoid arthritis. Angiogenesis is a prominent feature of rheumatoid synovitis. Emerging evidence based on ultrasonographic vascular imaging and angiogenic biomarkers implicates angiogenesis in the active phase of erosive disease. Many factors contribute to the profoundly hypoxic environment that can arise within the joint affected by rheumatoid arthritis. At a cellular level, hypoxia is detected by a mechanism that regulates cytoplasmic concentrations of hypoxia-inducible factor-1alpha. After translocation to the nucleus, hypoxia-inducible factor-1alpha binds its partner hypoxia-inducible factor-1beta to form a heterodimeric, functional transcription factor, hypoxia-inducible factor-1, which activates a gene program associated with angiogenesis, glycolysis, and adaptation to pH. SUMMARY: Despite the luxuriant vasculature associated with rheumatoid arthritis synovitis, the joint affected by rheumatoid arthritis is hypoxic. Repetitive cycles of hypoxia and reoxygenation together with oxidants produced by phagocytic cells promote chronic oxidative stress within the microenvironment of the affected joint, leading to the generation of reactive oxygen species with the potential to contribute to tissue damage.

Taylor PC. · Kennedy Institute of Rheumatology Division, Imperial College Faculty of Medicine, 1 Aspenlea Road, London W6 8LH, U.K. · Rheumatology (Oxford). · Pubmed #15644394 links to  free full text

Abstract: Vascular pathology, in the form of angiogenesis, is important in the perpetuation of rheumatoid arthritis (RA) and, in the form of endothelial dysfunction, contributes to associated cardiovascular co-morbidity. Emerging evidence suggests that TNFalpha blockade may modify vascular pathology in RA. Serum concentrations of vascular endothelial growth factor (VEGF), a potent endothelial cell-specific growth factor that is up-regulated by pro-inflammatory cytokines and by hypoxia, are elevated in RA and correlate with disease activity. Serum levels of VEGF at first presentation in RA predict radiographic progression of the disease over the subsequent year. Power Doppler ultrasonography is a sensitive method for demonstrating the presence of blood flow in small vessels and the vascular signal correlates with histopathological quantification of the vascular density of synovial tissue. Recent data indicate that high-frequency ultrasound and power Doppler are sensitive tools for evaluation of disease activity and assessment of response to therapy. Power Doppler imaging may also have the potential to predict those patients most at risk of accelerated joint destruction. However, much work has yet to be done to standardize the use of these imaging technologies.

Taylor PC, Williams RO, Feldmann M. · The Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College London, 1 Aspenlea Road, London W68LH, UK. · Curr Opin Biotechnol. · Pubmed #15560982 No free full text.

Abstract: Preclinical studies have identified and validated tumour necrosis factor alpha (TNFalpha) as a key disease molecule and therapeutic target for immunotherapeutic intervention in many immune-mediated inflammatory diseases. Clinical indications include rheumatoid arthritis, Crohn's disease, ankylosing spondylitis and psoriasis. Recent clinical findings indicate that many chronic inflammatory disorders share certain pathogenic pathways, whereas others are limited to particular disease phenotypes. Better understanding of these pathogenic pathways will inform the development of new therapeutic approaches leading to more complete and sustained disease remissions.

Taylor PC. · The Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College London, UK. · Arthritis Res Ther. · Pubmed #12932279 links to  free full text

Abstract: X-ray evaluation of rheumatoid joints is relatively inexpensive, is widely available and has standardised methods for interpretation. It also has limitations, including the inability to reliably determine structural change in less than 6-12 months, the need for experienced readers to interpret images and the limited acceptance of this technique in routine clinical practice. High-frequency ultrasound, with or without power Doppler, and magnetic resonance imaging of rheumatoid joints permit an increasingly refined analysis of anatomic detail. However, further research using these sensitive imaging technologies is required to delineate pathophysiological correlates of imaging abnormalities and to standardise methods for assessment.

Taylor PC. · The Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College London, 1 Aspenlea Road, London W6 8LH, UK. · Curr Opin Pharmacol. · Pubmed #12810200 No free full text.

Abstract: High-quality monoclonal antibodies (mAbs) with specificity for relevant disease molecules can now be produced in abundance. Anti-tumour necrosis factor-alpha therapies have set a new standard for symptom control in rheumatoid arthritis, and blockade of tumour necrosis factor has the potential to protect joints from structural damage. Other targets for therapeutic antibodies include the cytokines interleukin (IL)-1, IL-6, IL-8, IL-15, IL-17 and IL-18. In addition, there is preliminary evidence for the clinical efficacy of both keliximab, a mAb targeting the T cell antigen CD4, and rituximab, a chimeric mAb against the B cell antigen CD20 and CTLA4-Ig, which blocks the CD28/B7 interaction. Phase III studies have yet to be undertaken for these novel biological agents, and it is unclear whether any of these agents will have true disease-modifying capabilities.

Taylor PC. · The Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College London, 1 Aspenlea Road, London, W6 8LH. · Curr Pharm Des. · Pubmed #12769749 No free full text.

Abstract: The treatment approach to rheumatoid arthritis has undergone a major evolutionary change in recent years in part as a consequence of growing appreciation of the severity of this condition and in part due to very considerable progress in understanding the important role of cytokines in the immunopathogenesis of this disease. The major focus of this review is on the rationale for targeting TNFalpha and IL-1 in rheumatoid arthritis and the results of clinical studies designed to assess the validity of this therapeutic approach. Recently published studies confirm that the long term use of a several biological agents targeting TNFalpha give rise to sustained improvements in symptoms and signs of rheumatoid disease and, furthermore, that TNFalpha blockade protects joints from structural damage. Although these drugs are well tolerated and have a good overall safety profile, pitfalls to the use of anti-TNFalpha agents apparent with increasing clinical experience include rare cases of tuberculosis. The mechanism of action of anti-TNFalpha therapy is discussed. Clinical trials of interleukin-1 receptor antagonist show relatively modest anti-inflammatory efficacy and an effect on X-ray indicative of retardation of joint damage. Other pro-inflammatory cytokines representing potential therapeutic targets include interferon-beta, interferon-alpha, IL-6, IL-15, IL-17 and IL-18. I will consider preliminary data, where available, arising from clinical trials designed to inhibit the activity of such molecules. In this review I will also discuss the rationale and preliminary data for other potential therapeutic strategies designed to augment the activity of anti-inflammatory cytokines such as IL-4, IL-10, and IL-11 in rheumatoid disease.

Taylor PC. · Kennedy Institute Division, Faculty of Medicine, Imperial College School of Science, Technology and Medicine, 1 Aspenlea Road, London W6 8LH. · Intern Med. · Pubmed #12583612 links to  free full text

Abstract: Many studies have confirmed that the long term use of biological agents targeting TNFalpha in therapy for rheumatoid arthritis give rise to sustained improvement in symptoms and signs of disease provided the anti-TNF agent is efficacious and of low immunogenicity. The current regimes for infliximab 3 or 10 mg/kg infusion in combination with weekly oral methotrexate, or of subcutaneous etanercept 25 mg twice per week fulfil these criteria. D2E7, a 'human' antibody produced by phage display, has also demonstrated efficacy in clinical trials. It has recently emerged that anti-TNF therapy protects joints from structural damage. One year data for infliximab and methotrexate combination therapy suggest that this regime reduces disability. In early RA, etanercept acts more rapidly than methotrexate to decrease symptoms and retard progression of erosions. In conclusion, for patients with established and early RA, anti-TNF therapies set a new standard for symptom control and joint protection.

Andreakos E, Taylor PC, Feldmann M. · Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College of Science, Technology and Medicine, 1 Aspenlea Road, Hammersmith, W6 8LH, London, UK. · Curr Opin Biotechnol. · Pubmed #12482523 No free full text.

Abstract: The era of monoclonal antibody-based therapeutics has arrived. Monoclonal antibodies of high quality targeting almost any antigen can now be engineered and manufactured in large quantities. In the clinic, monoclonal antibodies are proving to be safe and effective for the treatment of a wide range of diseases including rheumatoid arthritis, Crohn's disease, spondyloarthropathies, psoriasis and allograft rejection.

Taylor PC. · The Kennedy Institute Division, Imperial College School of Medicine, London, UK. · Arthritis Res. · Pubmed #12110128 No free full text.

Abstract: Angiogenesis is a prominent feature of rheumatoid synovitis. Formation of new blood vessels permits a supply of nutrients and oxygen to the augmented inflammatory cell mass and so contributes to perpetuation of joint disease. Vascular endothelial growth factor (VEGF) is a potent endothelial cell-specific growth factor that is upregulated by proinflammatory cytokines and by hypoxia. Serum VEGF concentrations are elevated in rheumatoid arthritis (RA) and correlate with disease activity. Furthermore, serum VEGF measured at first presentation in RA is highly significantly correlated with radiographic progression of disease over the subsequent year. Power Doppler ultrasonography is a sensitive method for demonstrating the presence of blood flow in small vessels and there is a very close relation between the presence or absence of vascular flow signal on power Doppler imaging and the rate of early synovial enhancement on dynamic gadolinium-enhanced magnetic resonance imaging (MRI) of joints with RA. Images obtained by both dynamic enhanced MRI and power Doppler ultrasonography correlate with vascularity of synovial tissue as assessed histologically. In early RA, there is a striking association between joint erosions assessed on high-resolution ultrasonography and vascular signal in power Doppler mode. Collectively, these findings implicate vascular pannus in the erosive phase of disease and strongly suggest that proangiogenic molecules such as VEGF are targets for novel therapies in RA. Animal model data supports this concept. It seems likely that serological and imaging measures of vascularity in RA will become useful tools in the assessment of disease activity and response to therapy.

Taylor PC, Williams RO, Maini RN. · Kennedy Institute of Rheumatology, London, UK. · Curr Dir Autoimmun. · Pubmed #11791460 No free full text.

This publication has no abstract.

Taylor PC. · Kennedy Institute Division, Imperial College School of Medicine, 1 Aspenlea Road, London, W6 8LH. · Mol Biotechnol. · Pubmed #11725485 No free full text.

Abstract: The availability of agents that block the biological activity of tumor necrosis factor alpha (TNF alpha) in rheumatoid arthritis (RA) has permitted studies that confirm the key role of this cytokine in the pathogenesis of this disease. To date, two anti-TNF agents, infliximab and etanercept, have been approved for use in treatment. Clinical trials of these agents demonstrate efficacy for the control of symptoms and signs and acceptable safety in patients who have failed to respond adequately to conventional therapy. Combination with methotrexate appears to be particularly effective and may provide the main initial indication for clinical application in the first instance. Repeated administration of anti-TNF therapies over a one year period results in sustained reduction in symptoms and signs of RA in the majority of patients. It has recently become apparent that anti-TNF therapy protects joints from structural damage. These findings imply that TNF alpha has a critical role in the bone and cartilage damage associated with RA. Evidence to date support the hypothesis that there are 2 particularly important mechanisms of action; deactivation of the proinflammatory cytokine cascade at the site of inflammation and diminished recruitment of inflammatory cells from blood to the rheumatoid joint.

Taylor PC, Williams RO, Maini RN. · The Kennedy Institute Division, Imperial College School of Medicine, 1 Aspenlea Road, W6 8LH, London, UK. · Curr Opin Immunol. · Pubmed #11544014 No free full text.

Abstract: Recently published studies confirm that the long-term use of biological agents targeting TNF-alpha in therapy for rheumatoid arthritis (RA) gives rise to sustained improvement in symptoms and signs of disease, and in the quality of life. Furthermore, it has emerged that anti-TNF therapy protects joints from structural damage, which unexpectedly is also observed in the patient population showing no apparent benefit in control of signs and symptoms. Therapeutic benefit is observed in established disease that is unresponsive to conventional DMARDS and in early DMARDS-naïve RA patients. Thus, for patients with RA, anti-TNF therapies set a new standard for symptom control and joint protection.

Taylor PC. · The Kennedy Institute Division, Imperial College School of Medicine, London, UK. · Curr Opin Rheumatol. · Pubmed #11333343 No free full text.

Abstract: Recently published studies confirm that the long-term use of biologicals targeting tumor necrosis factor-alpha (TNF-alpha) in therapy for rheumatoid arthritis (RA) gives rise to sustained improvement in symptoms and signs of disease provided the anti-TNF agent is efficacious and of low immunogenicity. The current regimens for infliximab 3 or 10 mg/kg infusion in combination with weekly oral methotrexate, or of etanercept 25 mg subcutaneously twice per week, appear to fulfill these criteria. D2E7, a "human" antibody produced by phage display, has also been used for over a year. It has recently emerged that anti-TNF therapy protects joints from structural damage. The 1-year data for infliximab and methotrexate combination therapy suggest that this regimen reduces disability. In early RA, etanercept acts more rapidly than methotrexate to decrease symptoms and retard the progression of erosions. In conclusion, for patients with established and early RA, anti-TNF therapies set a new standard for symptom control and joint protection.

Maini RN, Taylor PC. · Kennedy Institute of Rheumatology, London, UK. · Annu Rev Med. · Pubmed #10774461 No free full text.

Abstract: Tumor necrosis factor alpha (TNF alpha) and interleukin-1 (IL-1) are important in mediating inflammation in rheumatoid arthritis (RA). Randomized phase II and III clinical trials of anti-TNF reagents (infliximab and etanercept) have demonstrated an acceptable safety profile and marked clinical efficacy in cases of RA that have not responded adequately to conventional therapy. Combination therapy with methotrexate (MTX) appears to be particularly effective in patients whose disease activity persists despite prior disease-modifying antirheumatic drugs (DMARDs) and ongoing MTX monotherapy. DMARD-recalcitrant disease may become the main indication for the use of anti-TNF drugs in patients with RA. Trials of IL-1 receptor antagonist show a relatively modest anti-inflammatory effect and a possible retardation of joint damage. Whether anti-TNF therapy protects joints from structural damage is under investigation. One anti-TNF reagent has already been approved in the United States for the treatment of RA, and other cytokine antagonists or agonists are under development.

Maini RN, Taylor PC, Paleolog E, Charles P, Ballara S, Brennan FM, Feldmann M. · The Kennedy Institute of Rheumatology and Imperial College School of Medicine, London. · Ann Rheum Dis. · Pubmed #10577974 links to  free full text

This publication has no abstract.

Taylor PC, Steuer A, Gruber J, Cosgrove DO, Blomley MJ, Marsters PA, Wagner CL, McClinton C, Maini RN. · Kennedy Institute of Rheumatology Division, Imperial College School of Medicine, London, UK. · Arthritis Rheum. · Pubmed #15077292 links to  free full text

Abstract: OBJECTIVE: To investigate sensitive ultrasonographic imaging methods for detection of synovial thickness and vascularity to discriminate between patients with early rheumatoid arthritis (RA) receiving infliximab + methotrexate (MTX) versus placebo + MTX over 18 weeks, and to compare the relationship between synovial thickening and vascularity at baseline and radiologic damage to joints of the hands and feet at 54 weeks. METHODS: Patients with early RA (duration <3 years) receiving stable dosages of MTX were randomly assigned to receive blinded infusions of 5 mg/kg infliximab (n = 12) or placebo (n = 12) at weeks 0, 2, 6, and then every 8 weeks until week 46. At baseline and week 18, clinical assessments were performed, and metacarpophalangeal joints were assessed by high-frequency ultrasonography and power Doppler ultrasonography measurements. Radiographs of the hands and feet taken at baseline and at 54 weeks were evaluated using the van der Heijde modification of the Sharp method (vdH-Sharp score). RESULTS: Using changes in the total vdH-Sharp score over 54 weeks and changes in synovial thickening and joint vascularity at 18 weeks, we were able to distinguish those patients receiving infusions of infliximab + MTX from those receiving placebo + MTX. Sonographic measurements of synovial thickening and vascularity at baseline in the placebo + MTX group demonstrated clear relationships with the magnitude of radiologic joint damage at week 54. Infliximab + MTX treatment abolished these relationships. CONCLUSION: The delay or reversal of inflammatory and joint-destructive mechanisms in patients with early RA was already apparent following 18 weeks of treatment with infliximab + MTX and was reflected in radiologic changes at 54 weeks.

Kiely PD, Brown AK, Edwards CJ, O'Reilly DT, Ostör AJ, Quinn M, Taggart A, Taylor PC, Wakefield RJ, Conaghan PG. · Department of Rheumatology, St Georges Healthcare NHS Trust, London, UK. · Rheumatology (Oxford). · Pubmed #19401359 No free full text.

Abstract: OBJECTIVE: RA has a substantial impact on both patients and healthcare systems. Our objective is to advance the understanding of modern management principles in light of recent evidence concerning the condition's diagnosis and treatment. METHODS: A group of practicing UK rheumatologists formulated contemporary management principles and clinical practice recommendations concerning both diagnosis and treatment. Areas of clinical uncertainty were documented, leading to research recommendations. RESULTS: A fundamental concept governing treatment of RA is minimization of cumulative inflammation, referred to as the inflammation-time area under the curve (AUC). To achieve this, four core principles of management were identified: (i) detect and refer patients early, even if the diagnosis is uncertain: patients should be referred at the first suspicion of persistent inflammatory polyarthritis and rheumatology departments should provide rapid access to a diagnostic and prognostic service; (ii) treat RA immediately: optimizing outcomes with conventional DMARDs and biologics requires that effective treatment be started early-ideally within 3 months of symptom onset; (iii) tight control of inflammation in RA improves outcome: frequent assessments and an objective protocol should be used to make treatment changes that maintain low-disease activity/remission at an agreed target; (iv) consider the risk-benefit ratio and tailor treatment to each patient: differing patient, disease and drug characteristics require long-term monitoring of risks and benefits with adaptations of treatments to suit individual circumstances. CONCLUSION: These principles focus on effective control of the inflammatory process in RA, but optimal uptake may require changes in service provision to accommodate appropriate care pathways.

Taylor PC. · Experimental Rheumatology at Kennedy Institute of Rheumatology Division, Imperial College, London, UK. · Nat Clin Pract Rheumatol. · Pubmed #19252515 No free full text.

Abstract: Since the introduction of biologic therapies that target tumor necrosis factor (TNF), short-term and long-term outlooks for many patients with rheumatoid arthritis have greatly improved. Not all patients, however, respond to therapy with these agents. Furthermore, despite favorable overall profiles for safety and tolerability, some concerns remain in this regard. Following the emergence of next-generation biologic agents with new targets, a key question for clinicians concerns the relative efficacy and safety of the different biologic therapies. A study by Schiff et al. directly compared the biologic T-cell costimulation blocker abatacept and the anti-TNF agent infliximab. The results of the 6-month, placebo-controlled trial demonstrated a similar efficacy for both drugs; however, in the 6-month treatment extension period, outcomes of efficacy differed in favor of abatacept. Overall, abatacept had a relatively more-acceptable safety and tolerability profile compared to infliximab.

Fisher BA, Dolan K, Hastings L, McClinton C, Taylor PC. · Kennedy Institute of Rheumatology, Imperial College London, London, UK. · Clin Rheumatol. · Pubmed #18716729 No free full text.

Abstract: Rheumatoid arthritis (RA) might lead to voice impairment through several mechanisms but its prevalence has been little investigated. RA patients attending a rheumatology outpatient clinic had joint assessments and completed the Voice Handicap Index-10 (VHI-10). A comparator group consisted of patients attending the department with other diseases. Seventy-three patients with RA and 73 comparators were recruited. Four patients with RA (5%) and one comparator (1%) had significantly abnormal VHI-10 scores. RA patients with a Disease Activity Score 28 >3.2, indicating more active disease, had significantly higher VHI-10 scores. A low prevalence of self-reported voice handicap occurs in RA and associates with more active disease.

Taylor PC. · Kennedy Institute of Rheumatology Division, Imperial College, London, UK. · Nat Clin Pract Rheumatol. · Pubmed #18711419 No free full text.

This publication has no abstract.

Sivakumar B, Akhavani MA, Winlove CP, Taylor PC, Paleolog EM, Kang N. · Kennedy Institute of Rheumatology, Faculty of Medicine, Imperial College London, London, United Kingdom. · J Hand Surg Am. · Pubmed #18261665 No free full text.

Abstract: PURPOSE: Hypoxia and angiogenesis are now recognized as being important events in the perpetuation of joint destruction in rheumatoid arthritis (RA). In 50% of patients with RA, however, the disease also involves inflammation of the synovial tissue surrounding the tendons, which is associated with multiple ruptures and poor prognosis for long-term hand function. The aim of this study was to determine whether hypoxia and angiogenesis may also play a role in RA tendon disease. METHODS: Matched in vivo synovial oxygen measurements (invasive and encapsulating tenosynovium and joint synovium) were taken intraoperatively using a microelectrode technique in patients having elective hand surgery for RA. Patients having elective hand surgery for indications other than inflammatory synovitis were recruited as controls. In parallel, RA synovial tissue was harvested and stained for vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-2alpha. Tissue was also cultured under either hypoxic (1% O(2)) or normoxic (21% O(2)) conditions to investigate the effect of hypoxia on the expression of VEGF and its soluble receptor, as well as on the key cytokines interleukin (IL)-6, IL-8, IL-10 and the chemokine monocyte chemoattractant protein-1. RESULTS: Invasive tenosynovium was observed to be significantly more hypoxic than either noninvasive tenosynovium or joint synovium in the same patients. Furthermore, RA tenosynovium was shown to be more hypoxic than tenosynovium in patients without RA. This hypoxia was accompanied by expression of VEGF and hypoxia-inducible factor-2alpha. Using in vitro joint synovial cell cultures, upregulation of VEGF expression was shown to be a consequence of this in vivo hypoxia. Furthermore, hypoxia downregulated release of monocyte chemoattractant protein-1 and the immunoregulatory cytokine IL-10. CONCLUSIONS: These data demonstrate that hypoxia is a feature of rheumatoid tendon disease and differentially regulates angiogenesis and the inflammatory cascade in RA.

Fisher BA, Taylor PC. · Kennedy Institute of Rheumatology Division, Imperial College Faculty of Medicine, London, UK. · Nat Clin Pract Rheumatol. · Pubmed #17228310 No free full text.

This publication has no abstract.

Maini RN, Taylor PC, Szechinski J, Pavelka K, Bröll J, Balint G, Emery P, Raemen F, Petersen J, Smolen J, Thomson D, Kishimoto T, Anonymous00119. · Kennedy Institute of Rheumatology Division, Imperial College, London, UK. · Arthritis Rheum. · Pubmed #16947782 links to  free full text

Abstract: OBJECTIVE: To establish the safety and efficacy of repeat infusions of tocilizumab (previously known as MRA), a humanized anti-interleukin-6 (IL-6) receptor antibody, alone and in combination with methotrexate (MTX), for the treatment of rheumatoid arthritis (RA). METHODS: The study group comprised 359 patients with active RA in whom the response to MTX was inadequate. During a stabilization period, these patients received their current dose of MTX for at least 4 weeks. Following stabilization, they were randomized to 1 of 7 treatment arms, as follows: tocilizumab at doses of 2 mg/kg, 4 mg/kg, or 8 mg/kg either as monotherapy or in combination with MTX, or MTX plus placebo. RESULTS: A 20% response (improvement) according to the American College of Rheumatology criteria (ACR20 response) was achieved by 61% and 63% of patients receiving 4 mg/kg and 8 mg/kg of tocilizumab as monotherapy, respectively, and by 63% and 74% of patients receiving those doses of tocilizumab plus MTX, respectively, compared with 41% of patients receiving placebo plus MTX. Statistically significant ACR50 and ACR70 responses were observed in patients receiving combination therapy with either 4 mg/kg or 8 mg/kg of tocilizumab plus MTX (P < 0.05). A dose-related reduction in the Disease Activity Score in 28 joints was observed from week 4 onward, in all patients except those receiving monotherapy with 2 mg/kg of tocilizumab. In the majority of patients who received 8 mg/kg of tocilizumab, the C-reactive protein level/erythrocyte sedimentation rate normalized, while placebo plus MTX had little effect on these laboratory parameters. Tocilizumab was mostly well tolerated, with a safety profile similar to that of other biologic and immunosuppressive therapies. Alanine transaminase and aspartate transaminase levels followed a sawtooth pattern (rising and falling between infusions). There were moderate but reversible increases in the nonfasting total cholesterol and triglyceride levels and reversible reductions in the high-density lipoprotein cholesterol and neutrophil levels. There were 2 cases of sepsis, both of which occurred in patients who were receiving combination therapy with 8 mg/kg of tocilizumab plus MTX. CONCLUSION: These results indicate that targeted blockade of IL-6 signaling is a highly efficacious and promising means of decreasing disease activity in RA.

Taylor PC. · Kennedy Institute of Rheumatology Division, Imperial College Faculty of Medicine, London, UK. · Nat Clin Pract Rheumatol. · Pubmed #16932670 No free full text.

This publication has no abstract.