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1.  TNF inhibitor therapy for rheumatoid arthritis 
Biomedical Reports  2012;1(2):177-184.
Immunotherapy has markedly improved treatment outcomes in rheumatoid arthritis (RA). Tumor necrosis factor (TNF)-α antagonists, such as infliximab (IFX), etanercept (ETN), adalimumab (ADA), golimumab (GOLI) and certolizumab pegol (CZP) have been widely used for the treatment of RA. IFX provides significant, clinically relevant improvement in physical function and the quality of life, inhibits progressive joint damage and sustains improvement in the signs and symptoms of patients with RA. ETN is effective and safe for patients with RA. Combination therapy with ETN plus methotrexate (MTX) reduces disease activity, decreases total joint score progression, slows the pace of joint destruction and improves function more effectively compared to any of the monotherapies. ADA with or without MTX also relieves the signs and symptoms of RA. CZP and GOLI expand the therapeutic schedule for patients with RA. The TNF-α inhibitors have similar efficacy, but distinct clinical pharmacokinetic and -dynamic properties. The common adverse events of these TNF-α antagonists include adverse reactions, infections and injection-site reaction. Additionally, these adverse events are mostly mild or moderate and their incidence is low. Certain patients exhibit a lack of response to anti-TNF-α therapies. Some patients may discontinue the initial drug and switch to a second anti-TNF-α agent. The shortage of clinical response to one agent may not predict deficiency of response to another. This review mainly addresses the latest developments of these biological agents in the treatment of RA.
doi:10.3892/br.2012.42
PMCID: PMC3956207  PMID: 24648915
rheumatoid arthritis; immunotherapy; biological agent
2.  Advances in rheumatology: new targeted therapeutics 
Arthritis Research & Therapy  2011;13(Suppl 1):S5.
Treatment of inflammatory arthritides - including rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis - has seen much progress in recent years, partially due to increased understanding of the pathogenesis of these diseases at the cellular and molecular levels. These conditions share some common mechanisms. Biologic therapies have provided a clear advance in the treatment of rheumatological conditions. Currently available TNF-targeting biologic agents that are licensed for at east one of the above-named diseases are etanercept, infliximab, adalimumab, golimumab, and certolizumab. Biologic agents with a different mechanism of action have also been approved in rheumatoid arthritis (rituximab, abatacept, and tocilizumab). Although these biologic agents are highly effective, there is a need for improved management strategies. There is also a need for education of family physicians and other healthcare professionals in the identification of early symptoms of inflammatory arthritides and the importance of early referral to rheumatologists for diagnosis and treatment. Also, researchers are developing molecules - for example, the Janus kinase inhibitor CP-690550 (tofacitinib) and the spleen tyrosine kinase inhibitor R788 (fostamatinib) - to target other aspects of the inflammatory cascade. Initial trial results with new agents are promising, and, in time, head-to-head trials will establish the best treatment options for patients. The key challenge is identifying how best to integrate these new, advanced therapies into daily practice.
doi:10.1186/1478-6354-13-S1-S5
PMCID: PMC3123966  PMID: 21624184
3.  Abatacept with methotrexate versus other biologic agents in treatment of patients with active rheumatoid arthritis despite methotrexate: a network meta-analysis 
Arthritis Research & Therapy  2011;13(6):R204.
Introduction
The goal of this study was to compare the efficacy in terms of Health Assessment Questionnaire change from baseline (HAQ CFB), 50% improvement in American College of Rheumatology criterion (ACR-50) and Disease Activity Score in 28 joints (DAS28) defined remission (< 2.6) between abatacept and other biologic disease modifying anti-rheumatic drugs (DMARDs) in patients with rheumatoid arthritis (RA) who have inadequate response to methotrexate (MTX-IR).
Methods
A systematic literature review identified controlled trials investigating the efficacy of abatacept (three studies), etanercept (two studies), infliximab (two), adalimumab (two), certolizumab pegol (two) ritixumab (three), and tocilizumab (two) in MTX-IR patients with RA. The clinical trials included in this analysis were similar with respect to trial design, baseline patient characteristics and background therapy (MTX). The key clinical endpoints of interest were HAQ CFB, ACR-50 and DAS28 < 2.6 measured at 24 and 52 weeks. The results were analysed using network meta-analysis methods that enabled calculation of an estimate for expected relative effect of comparative treatments. Analysis results were expressed as the difference in HAQ CFB score and odds ratio (OR) of achieving an ACR-50 and DAS28 response and associated 95% credible intervals (CrI).
Results
The analysis of HAQ CFB at 24 weeks and 52 weeks showed that abatacept in combination with MTX is expected to be more efficacious than MTX monotherapy and is expected to show a comparable efficacy relative to other biologic DMARDs in combination with MTX. Further, abatacept showed comparable ACR-50 and DAS28 < 2.6 response rates with other biologic DMARDs at 24 and 52 weeks, except for ACR-50 compared to certolizumab pegol at 52 weeks and for DAS28 < 2.6 compared to tocilizumab at 24 weeks. Sensitivity analyses confirmed the robustness of the findings.
Conclusions
Abatacept in combination with MTX is expected to result in a comparable change from baseline in HAQ score and comparable ACR-50 and DAS28 < 2.6 response rates in MTX-IR patients compared to other approved biologic agents.
doi:10.1186/ar3537
PMCID: PMC3334657  PMID: 22151924
abatacept; rheumatoid arthritis; biologic DMARDs; network meta-analysis; health assessment questionnaire
4.  Review of tocilizumab in the treatment of rheumatoid arthritis 
Biologics : Targets & Therapy  2008;2(1):75-82.
Constitutively overproduced in proliferating synovial tissues, interleukin-6 (IL-6) is deeply involved in the pathology of rheumatoid arthritis (RA). Tocilizumab is a humanized anti-human IL-6 receptor antibody that binds to soluble and membrane-bound IL-6 receptor, and at detectable levels in blood, tocilizumab is capable of almost completely blocking the transmembrane signaling of IL-6. In clinical trials for patients with RA in Japan, tocilizumab monotherapy has shown clinical efficacy equaling that of tumor necrosis factor (TNF) inhibitor in combination with methotrexate, and in an extension study in patients who responded to tocilizumab, almost no patients showed a decrease in the efficacy of tocilizumab. Evidence obtained in a phase III study in Japan demonstrated that tocilizumab monotherapy had a sig-nificant inhibitory effect on the progression of structural joint damage compared with that of conventional disease modifying antirheumatic drugs (DMARDs). Furthermore it has been shown that tocilizumab has an excellent ability to suppress serum amyloid A levels and could therefore be an important therapeutic strategy in amyloid A amyloidosis secondary to rheumatic diseases. The safety profile of tocilizumab appears to be satisfactory. However, several serious infections were also reported, and careful monitoring is therefore important during use.
PMCID: PMC2727785  PMID: 19707430
tocilizumab; rheumatoid arthritis; interleukin-6; treatment; amyloidosis; biologics
5.  Systematic review of disease-modifying antirheumatic drugs for juvenile idiopathic arthritis 
BMC Pediatrics  2012;12:29.
Background
Treatment of juvenile idiopathic arthritis (JIA) with disease-modifying antirheumatic drugs (DMARDs) may improve outcomes compared to conventional therapy (e.g., non-steroidal anti-inflammatory drugs, intra-articular corticosteroids). The purpose of this systematic review was to evaluate the comparative effectiveness and safety of DMARDs versus conventional therapy and versus other DMARDs.
Results
A systematic evidence review of 156 reports identified in MEDLINE®, EMBASE®, and by hand searches. There is some evidence that methotrexate is superior to conventional therapy. Among children who have responded to a biologic DMARD, randomized discontinuation trials suggest that continued treatment decreases the risk of having a flare. However, these studies evaluated DMARDs with different mechanisms of action (abatacept, adalimumab, anakinra, etanercept, intravenous immunoglobulin, tocilizumab) and used varying comparators and follow-up periods. Rates of serious adverse events are similar between DMARDs and placebo in published trials. This review identified 11 incident cases of cancer among several thousand children treated with one or more DMARD.
Conclusions
Few data are available to evaluate the comparative effectiveness of either specific DMARDs or general classes of DMARDs. However, based on the overall number, quality, and consistency of studies, there is moderate strength of evidence to support that DMARDs improve JIA-associated symptoms. Limited data suggest that short-term risk of cancer is low.
doi:10.1186/1471-2431-12-29
PMCID: PMC3340294  PMID: 22420649
Juvenile rheumatoid arthritis; Disease-modifying antirheumatic drugs; Comparative effectiveness research; Systematic review
6.  Pharmacotherapy Options in Rheumatoid Arthritis 
Drugs form the mainstay of therapy in rheumatoid arthritis (RA). Five main classes of drugs are currently used: analgesics, non-steroidal anti-inflammatories (NSAIDs), glucocorticoids, nonbiologic and biologic disease-modifying antirheumatic drugs. Current clinical practice guidelines recommend that clinicians start biologic agents if patients have suboptimal response or intolerant to one or two traditional disease modifying agents (DMARDs). Methotrexate, sulfasalazine, leflunomide and hydroxychloroquine are the commonly used DMARDs. Currently, anti-TNF is the commonly used first line biologic worldwide followed by abatacept and it is usually combined with MTX. There is some evidence that tocilizumab is the most effective biologic as a monotherapy agent. Rituximab is generally not used as a first line biologic therapy due to safety issues but still as effective as anti-TNF. The long term data for the newer oral small molecule biologics such as tofacitinib is not available and hence used only as a last resort.
doi:10.4137/CMAMD.S5558
PMCID: PMC3747998  PMID: 23997576
rheumatoid arthritis; pharmacotherapy and biologic drugs
7.  Choice of Biologic Therapy for Patients with Rheumatoid Arthritis: The Infection Perspective 
Current Rheumatology Reviews  2011;7(1):77-87.
Biologicals revolutionized the treatment of Rheumatoid Arthritis (RA). The targeted suppression of key inflammatory pathways involved in joint inflammation and destruction allows better disease control, which, however, comes at the price of an elevated infection risk due to relative immunosuppression. The disease-related infection risk and the infection risk associated with the use of TNF-α inhibitors (infliximab, adalimumab, etanercept, golimumab and certolizumab pegol), rituximab, abatacept and tocilizumab are discussed. Risk factors clinicians need to take into account when selecting the most appropriate biologic therapy for RA patients, as well as precautions and screening concerning a number of specific infections, such as tuberculosis, intracellular bacterial infections, reactivation of chronic viral infections and HIV are reviewed.
doi:10.2174/157339711794474620
PMCID: PMC3182090  PMID: 22081766
Rheumatoid arthritis; infection; biologicals; targeted therapies; TNF inhibitors.
8.  Do anti-TNF agents have equal efficacy in patients with rheumatoid arthritis? 
Arthritis Research & Therapy  2004;6(Suppl 2):S3-S11.
Tumor necrosis factor (TNF) antagonists have dramatically improved the outcomes of rheumatoid arthritis (RA). Three agents currently available in the USA – infliximab, etanercept, and adalimumab – have been designed to modify the biologic effects of TNF. Infliximab and adalimumab are monoclonal antibodies, and etanercept is a soluble protein. The pharmacokinetic and pharmacodynamic properties of each differs significantly from those of the others. All three agents are effective and safe, and can improve the quality of life in patients with RA. Although no direct comparisons are available, clinical trials provide evidence that can be used to evaluate the comparative efficacy of these agents. Infliximab, in combination with methotrexate, has been shown to relieve the signs and symptoms of RA, decrease total joint score progression, prevent joint erosions and joint-space narrowing, and improve physical function for up to 2 years. Etanercept has been shown to relieve the signs and symptoms of RA, decrease total joint score progression, and slow the rate of joint destruction, and might improve physical function. Etanercept is approved with and without methotrexate for patients who have demonstrated an incomplete response to therapy with methotrexate and other disease-modifying anti-rheumatic drugs (DMARDs), as well as for first-line therapy in early RA, psoriatic arthritis, and juvenile RA. Adalimumab relieves the signs and symptoms of RA with and without methotrexate and other DMARDs, decreases total joint score progression, prevents joint erosions and joint-space narrowing in combination with methotrexate, and might improve physical function. When selecting a TNF antagonist, rheumatologists should weigh evidence and experience with specific agents before a decision is made for use in therapy.
doi:10.1186/ar1013
PMCID: PMC2833457  PMID: 15228615
adalimumab; efficacy; etanercept; infliximab; rheumatoid arthritis
9.  Adding tocilizumab or switching to tocilizumab monotherapy in methotrexate inadequate responders: 24-week symptomatic and structural results of a 2-year randomised controlled strategy trial in rheumatoid arthritis (ACT-RAY) 
Objective
In patients with active rheumatoid arthritis (RA) despite methotrexate, to compare the efficacy of adding tocilizumab to that of switching to tocilizumab monotherapy.
Methods
Double-blind, 2-year study in which adults with active RA (DAS28 >4.4) despite methotrexate were randomly assigned either to continue methotrexate with the addition of tocilizumab (MTX+TCZ) 8 mg/kg every 4 weeks or switch to tocilizumab and placebo (TCZ+PBO). The primary endpoint was the DAS28–erythrocyte sedimentation rate (ESR) remission rate at week 24. Secondary objectives included other symptomatic outcomes, quality of life and progression of structural damage.
Results
Of 556 randomly assigned patients, 512 (92%) completed 24 weeks. DAS28–ESR remission rates were 40.4% for TCZ+MTX and 34.8% for TCZ+PBO (p=0.19); American College of Rheumatology 20/50/70/90 rates were 71.5%/45.5%/24.5%/5.8% (TCZ+MTX) and 70.3%/40.2%/25.4%/5.1% (TCZ+PBO; differences not significant). A significant difference between groups was seen for low DAS28 (61.7% vs 51.4%). Radiographic progression was small and not different between groups (Genant–Sharp score progression ≤ smallest detectable change in 91% (TCZ+MTX) and 87% (TCZ+PBO)). Rates per 100 patient-years of serious adverse events and serious infections were 21 and six, respectively, for TCZ+MTX and 18 and six, respectively, for TCZ+PBO. Alanine aminotransferase elevations greater than threefold the upper limit of normal occurred in 7.8% and 1.2% of TCZ+MTX and TCZ+PBO patients, respectively.
Conclusion
No clinically relevant superiority of the TCZ+MTX add-on strategy over the switch to tocilizumab monotherapy strategy was observed. The combination was more commonly associated with transaminase increases. Meaningful clinical and radiographic responses were achieved with both strategies, suggesting that tocilizumab monotherapy might be a valuable treatment strategy in suitable RA patients.
doi:10.1136/annrheumdis-2011-201282
PMCID: PMC3551223  PMID: 22562983
10.  Improved health outcomes with Etanercept versus usual DMARD therapy in an Asian population with established rheumatoid arthritis 
Background
Patient reported outcomes (PROs) are especially useful in assessing treatments for rheumatoid arthritis (RA) since they measure dimensions of health-related quality of life that cannot be captured using strictly objective physiological measures. The aim of this study was to compare the effects of combination etanercept and methotrexate (ETN + MTX) versus combination synthetic disease modifying antirheumatic drugs (DMARDs) and methotrexate (DMARD + MTX) on PRO measures among RA patients from the Asia-Pacific region, a population not widely studied to date. Patients with established moderate to severe rheumatoid arthritis who had an inadequate response to methotrexate were studied.
Methods
Patients were randomized to either ETN + MTX (N = 197) or DMARD + MTX (N = 103) in an open-label, active-comparator, multicenter study, with PRO measures designed as prospective secondary endpoints. The Health Assessment Questionnaire (HAQ), Functional Assessment of Chronic Illness Therapy Fatigue Scale (FACIT-Fatigue), Medical Outcomes Short Form-36 Health Survey (SF-36), Hospital Anxiety and Depression Scale (HADS) and the Work Productivity and Activity Impairment Questionnaire: General Health (WPAI:GH) were used.
Results
Significantly greater improvements were noted for the ETN + MTX group at week16 for HAQ mean scores and for proportion of patients achieving HAQ score ≤ 0.5, compared to patients in the DMARD + MTX group. SF-36 Summary Scores for physical and mental components and for 6 of 8 health domains showed significantly greater improvements at week16 for the ETN + MTX group; only scores for physical functioning and role-emotional domains did not differ significantly between the two treatment arms. Greater improvements at week16 were noted for the ETN + MTX group for FACIT-Fatigue, HADS, and WPAI:GH mean scores.
Conclusion
Combination therapy using ETN + MTX demonstrated superior improvements using a comprehensive set of PRO measures, compared to combination therapy with usual standard of care DMARDs plus MTX in patients with established rheumatoid arthritis from the Asia-Pacific region.
Trial registration
clintrials.gov # NCT00422227
doi:10.1186/1471-2474-14-13
PMCID: PMC3606371  PMID: 23294908
Patient reported outcomes; Etanercept; Rheumatoid arthritis; Asia-Pacific; Health outcomes assessments
11.  Description of the Efficacy and Safety of Three New Biologics in the Treatment of Rheumatoid Arthritis 
English articles on abatacept, golimumab, and tocilizumab in rheumatoid arthritis published between 2002 and 2009 were reviewed systematically. All randomized clinical trials, open-label extensions, meta-analyses, and reviews were examined. There were thirteen articles on abatacept, four on golimumab, and seven on tocilizumab. All three drugs were effective in methotrexate-naïve, methotrexate-incomplete responders, and tumor-necrosis-factor-failure rheumatoid arthritis patients. Of the three, only abatacept has been tested in a head-to-head trial with infliximab, in which it was found to be equivalent to infliximab. Golimumab resulted in a more modest improvement than the others in methotrexate-naïve patients, although no direct comparisons among the three drugs were possible or appropriate. Descriptive analysis of adverse events showed that patients receiving abatacept, golimumab, and tocilizumab were subject to more adverse events than controls overall, as expected. In the abatacept studies, a few cases of tuberculosis, more cardiovascular events and gastrointestinal bleedings and more basal cell carcinoma were seen. Golimumab was associated with more skin rashes and pneumonia, while tocilizumab was associated with increased lipids, more liver-function abnormalities, and neutropenia. These new medications are useful additions to the rheumatologic armamentarium and represent greater convenience (golimumab) or different mechanisms of action (abatacept and tocilizumab) than tumor-necrosis-factor inhibitors for treating rheumatoid arthritis. As expected, some adverse events occur when using these drugs and patients need to be watched carefully.
doi:10.3904/kjim.2010.25.1.1
PMCID: PMC2829405  PMID: 20195397
Arthritis, rheumatoid; Biological products; Abatacept; Golimumab; Tocilizumab
12.  Patient preferences for treatment of rheumatoid arthritis 
Annals of the Rheumatic Diseases  2004;63(11):1372-1378.
Objective: To elicit treatment preferences of patients with rheumatoid arthritis (RA) for disease modifying antirheumatic drugs (DMARDs) with varying risk profiles.
Methods: Patient values for 16 DMARD characteristics were ascertained using published data about side effects, effectiveness, and cost. Patient preferences were determined by Adaptive Conjoint Analysis, an interactive computer program that predicts preferences by asking patients to make trade-offs between specific treatment characteristics. Simulations were run to derive preferences for four drugs: methotrexate, gold, leflunomide, and etanercept, under different risk-benefit scenarios. Infliximab was not included because it is given with methotrexate, and we did not include preferences for combination therapy. Based on each patient's expressed preferences, and the characteristics of the treatments available at the time of the study, the option that best fitted each patient's perspective was identified.
Results: 120 patients (mean age 70 years) were interviewed. For the base case scenario (which assumed the maximum benefits reported in the literature, a low probability of adverse effects, and low equal monthly "co-pays" (out of pocket costs)), 95% of the respondents preferred etanercept over the other treatment options. When all four options were described as being equally effective, 88% continued to prefer etanercept owing to its safer short term adverse effect profile. Increasing etanercept's co-pay to $30.00 decreased the percentage of patients preferring this option to 80%.
Conclusions: In this study, older patients with RA, when asked to consider trade-offs between specific risk and benefits, preferred etanercept over other treatment options. Preference for etanercept is explained by older patients' risk aversion for drug toxicity.
doi:10.1136/ard.2003.019422
PMCID: PMC1754807  PMID: 15020312
13.  Tocilizumab: A Review of Its Safety and Efficacy in Rheumatoid Arthritis 
Recent years have seen many exciting developments in the treatment of rheumatoid arthritis. Tocilizumab (TCZ) is a monoclonal antibody which inhibits the interleukin-6 receptor. After initial studies in Japan, it has been extensively studied in five multicentre clinical trials. This report summarises the key efficacy and toxicity findings from the major clinical trials. TCZ works quickly and effectively in rheumatoid arthritis either as monotherapy or in combination with other agents in early disease, DMARD inadequate responders, seronegative disease and after anti-TNF failure. The toxicity profile is manageable but includes infections (most notably skin and soft tissue), increases in serum cholesterol, transient decreases in neutrophil count and abnormal liver function tests (especially in combination with methotrexate). In summary, there is sufficient evidence to make TCZ a first line biologic therapy for rheumatoid arthritis especially for those who are unable to take methotrexate or who fail anti-TNF therapy.
doi:10.4137/CMAMD.S4864
PMCID: PMC3018893  PMID: 21234291
clinical trials; rheumatoid; therapy; interleukin-6
14.  Systematic Review and Meta-Analysis of the Efficacy and Safety of Existing TNF Blocking Agents in Treatment of Rheumatoid Arthritis 
PLoS ONE  2012;7(1):e30275.
Background and Objectives
Five-tumour necrosis factor (TNF)-blockers (infliximab, etanercept, adalimumab, certolizumab pegol and golimumab) are available for treatment of rheumatoid arthritis. Only few clinical trials compare one TNF-blocker to another. Hence, a systematic review is required to indirectly compare the substances. The aim of our study is to estimate the efficacy and the safety of TNF-blockers in the treatment of rheumatoid arthritis (RA) and indirectly compare all five currently available blockers by combining the results from included randomized clinical trials (RCT).
Methods
A systematic literature review was conducted using databases including: MEDLINE, SCOPUS (including EMBASE), Cochrane library and electronic search alerts. Only articles reporting double-blind RCTs of TNF-blockers vs. placebo, with or without concomitant methotrexate (MTX), in treatment of RA were selected. Data collected were information of patients, interventions, controls, outcomes, study methods and eventual sources of bias.
Results
Forty-one articles reporting on 26 RCTs were included in the systematic review and meta-analysis. Five RCTs studied infliximab, seven etanercept, eight adalimumab, three golimumab and three certolizumab. TNF-blockers were more efficacious than placebo at all time points but were comparable to MTX. TNF-blocker and MTX combination was superior to either MTX or TNF-blocker alone. Increasing doses did not improve the efficacy. TNF-blockers were relatively safe compared to either MTX or placebo.
Conclusions
No single substance clearly rose above others in efficacy, but the results of the safety analyses suggest that etanercept might be the safest alternative. Interestingly, MTX performs nearly identically considering both efficacy and safety aspects with a margin of costs.
doi:10.1371/journal.pone.0030275
PMCID: PMC3260264  PMID: 22272322
15.  Impact of concomitant DMARD therapy on adherence to treatment with etanercept and infliximab in rheumatoid arthritis. Results from a six-year observational study in southern Sweden 
The objective of this work is to compare the adherence to therapy of patients receiving etanercept and infliximab during first tumour necrosis factor (TNF)-blocking treatment course in rheumatoid arthritis. Special emphasis is placed on potential predictors for treatment termination and the impact of concomitant methotrexate (MTX) or other disease-modifying antirheumatic drugs (DMARDs). Patients (n = 1,161) with active rheumatoid arthritis, not responding to at least two DMARDs including MTX starting etanercept or infliximab therapy for the first time, were included in a structured clinical follow-up protocol. Information on diagnosis, disease duration, previous and ongoing DMARDs, treatment start and termination, as well as cause of withdrawal was prospectively collected during the period of March 1999 through December 2004. Patients were divided into six groups according to TNF-blocking drugs and concomitant DMARDs. Five-year level (one-year) of adherence to therapy was 36% (69%) for patients receiving infliximab in combination with MTX compared with 65% (89%) for patients treated with etanercept and MTX (p < 0.001). Cox regression models showed that the risk for premature treatment termination of patients treated with infliximab was threefold higher than for etanercept (p < 0.001). Also, the regression analysis showed that patients receiving concomitant MTX had better treatment continuation than patients treated solely with TNF blockers (p < 0.001). Moreover, patients receiving concomitant MTX had superior drug survival than patients receiving other concomitant DMARDs (p < 0.010). The superior effect of MTX was associated primarily with fewer treatment terminations because of adverse events. In addition, the study identifies low C-reactive protein level, high age, elevated health assessment questionnaire score, and higher previous number of DMARDs as predictors of premature treatment termination. In summary, treatment with etanercept has higher adherence to therapy than treatment with infliximab. Concomitant MTX is associated with improved treatment continuation of biologics when compared with both TNF blockers as monotherapy and TNF blockers combined with other DMARDs.
doi:10.1186/ar2084
PMCID: PMC1794519  PMID: 17121678
16.  Tocilizumab inhibits progression of joint damage in rheumatoid arthritis irrespective of its anti-inflammatory effects: disassociation of the link between inflammation and destruction 
Annals of the Rheumatic Diseases  2011;71(5):687-693.
Background
Treatment with tumour necrosis factor inhibitors (TNF-i) plus methotrexate (MTX), but not MTX monotherapy alone, inhibits joint damage progression even at higher levels of disease activity. Such disassociation of disease activity and structural damage has not been shown for biological agents other than TNF-i.
Objectives
To evaluate whether interleukin 6 (IL-6) inhibition with tocilizumab (TCZ) interferes with joint destruction beyond its effects on disease activity.
Methods
A random 90% sample of data from the (The Tocilizumab Safety and the Prevention of Structural Joint Damage Study) LITHEtrial on active rheumatoid arthritis (RA) despite MTX was used, which compared addition of placebo (n=117) with addition of TCZ (n=414) every 4 weeks. Baseline and 1-year values of clinical and serological variables were correlated with changes to 1 year of the total Genant-modified Sharp score (TGSS) using a Spearman test, and the progression of TGSS, erosion and joint space narrowing (JSN) scores in groups with low and high disease activity were compared for placebo and TCZ (Kruskal–Wallis).
Results
Baseline variables were similar among the groups. Change of TGSS was lower in patients receiving TCZ than placebo (TCZ: 0.29±0.96; placebo: 0.90±1.92; p=0.0007). In patients receiving placebo, the correlation with TGSS change was significant for baseline scores of the simplified disease activity index (SDAI; r=0.18, p=0.047) and swollen joint count 28 (r=0.22, p=0.019), with similar trends for C-reactive protein. Similar correlations were seen for SDAI, clinical disease activity index, disease activity score 28 at 1 year with x-ray change during that year (r=0.26–0.28, p=0.002–0.006). In contrast, none of the baseline or 1-year variables showed significant correlation with x-ray changes in patients receiving TCZ+MTX, suggesting a disassociation of the link between disease activity and damage by TCZ. Finally, for patients in remission or with low disease activity, progression of TGSS, erosion and JSN was similar among treatment groups (TGSS: placebo, 0.4±1.1; TCZ, 0.2±0.7; p=NS), while for patients with moderate or high disease activity placebo-treated patients progression was significantly greater (TGSS: 1.2±2.2 vs 0.4±1.2; p=0.0009).
Conclusions
IL-6 inhibition with TCZ plus MTX retards joint damage progression independently of its impact on disease activity. Similar effects have hitherto been reported only for TNF-i. This indicates that the effects of IL-6 inhibition on progression of joint damage in RA are among the most profound currently attainable.
doi:10.1136/annrheumdis-2011-200395
PMCID: PMC3329225  PMID: 22121130
17.  The efficacy and safety of tacrolimus in rheumatoid arthritis 
The crucial role of T cells in the pathogenesis of rheumatoid arthritis (RA) is well recognized. Tacrolimus is an immunomodulator that acts by the inhibition of T-cell activation. There have been numerous studies examining the use of tacrolimus in RA, including four randomized controlled trials. This article reviews these data with respect to the efficacy of the use of tacrolimus in RA as monotherapy and as part of combination therapy. The safety of tacrolimus use in RA is then evaluated. Tacrolimus is shown to be an effective and safe therapeutic option for RA patients intolerant of or resistant to previous disease-modifying antirheumatic drugs (DMARDs). In addition to monotherapy, tacrolimus has been successfully used as part of combination RA therapy, in particular in conjunction with methotrexate. Further assessment of combination approaches involving tacrolimus use alongside other DMARDs or biologics would be helpful. More studies are required to examine the effects of tacrolimus on the radiographic progression of RA.
doi:10.1177/1759720X11419038
PMCID: PMC3383498  PMID: 22870486
efficacy; rheumatoid arthritis; safety; tacrolimus
18.  Efficacy and toxicity of methotrexate (MTX) monotherapy versus MTX combination therapy with non-biological disease-modifying antirheumatic drugs in rheumatoid arthritis: a systematic review and meta-analysis 
Annals of the Rheumatic Diseases  2008;68(7):1105-1112.
Objective:
To evaluate the efficacy and toxicity of methotrexate (MTX) monotherapy compared with MTX combination with non-biological disease-modifying antirheumatic drugs (DMARDs) in adults with rheumatoid arthritis.
Method:
A systematic review of randomised trials comparing MTX alone and in combination with other non-biological DMARDs was carried out. Trials were identified in Medline, EMBASE, the Cochrane Library and ACR/EULAR meeting abstracts. Primary outcomes were withdrawals for adverse events or lack of efficacy.
Results:
A total of 19 trials (2025 patients) from 6938 citations were grouped by the type of patients randomised. Trials in DMARD naive patients showed no significant advantage of the MTX combination versus monotherapy; withdrawals for lack of efficacy or toxicity were similar in both groups (relative risk (RR) = 1.16; 95% CI 0.70 to 1.93). Trials in MTX or non-MTX DMARD inadequate responder patients also showed no difference in withdrawal rates between the MTX combo versus mono groups (RR = 0.86; 95% CI 0.49 to 1.51 and RR = 0.75; 95% CI 0.41 to 1.35), but in one study the specific combination of MTX with sulfasalazine and hydroxychloroquine showed a better efficacy/toxicity ratio than MTX alone with RR = 0.3 (95% CI 0.14 to 0.65). Adding leflunomide to MTX non-responders improved efficacy but increased the risk of gastrointestinal side effects and liver toxicity. Withdrawals for toxicity were most significant with ciclosporin and azathioprine combinations.
Conclusion:
In DMARD naive patients the balance of efficacy/toxicity favours MTX monotherapy. In DMARD inadequate responders the evidence is inconclusive. Trials are needed that compare currently used MTX doses and combination therapies.
doi:10.1136/ard.2008.099861
PMCID: PMC2689526  PMID: 19054823
19.  Does route of administration affect the outcome of TNF antagonist therapy? 
Arthritis Research & Therapy  2004;6(Suppl 2):S19-S23.
The tumor necrosis factor (TNF) antagonists are parenterally administered biologic response modifiers indicated for the management of rheumatoid arthritis. Although infliximab, etanercept, and adalimumab are all members of this class, they differ in route of administration and dosing regimen. In the USA and in Europe, infliximab, in combination with oral methotrexate, is administered intravenously, initially at a dose of 3 mg/kg at weeks 0, 2, and 6, then every 8 weeks thereafter. The US Food and Drug Administration (FDA) has further approved that the dosage can be increased to 10 mg/kg and the doses can be given as often as every 4 weeks to optimize patient outcome (information based on the US package insert dated June 2002). Etanercept and adalimumab are given subcutaneously and can be self-injected. The FDA-approved dose of etanercept is 25 mg twice weekly, and of adalimumab is 40 mg every 2 weeks with methotrexate, or 40 mg alone. Medication adherence, possibly the most important factor in maintaining the benefits of anti-TNF therapy, is influenced by the interaction between the patient and his or her healthcare team, the patient's attitude toward the disease and medication regimen, and the choice of therapy.
doi:10.1186/ar996
PMCID: PMC2833461  PMID: 15228617
adherence; efficacy; intravenous; rheumatoid arthritis; subcutaneous; tumor necrosis factor
20.  Adalimumab therapy reduces hand bone loss in early rheumatoid arthritis: explorative analyses from the PREMIER study 
Annals of the Rheumatic Diseases  2008;68(7):1171-1176.
Objective:
The effect of adalimumab on hand osteoporosis was examined and related to radiographic joint damage in the three treatment arms of the PREMIER study: adalimumab plus methotrexate, adalimumab and methotrexate monotherapy. Predictors of hand bone loss were also searched for.
Methods:
768 patients (537 fulfilled 2 years) with rheumatoid arthritis (RA) for less than 3 years, never treated with methotrexate, were included. Hand bone loss was assessed by digital x ray radiogrammetry (DXR) on the same hand radiographs scored with modified Sharp score at baseline, 26, 52 and 104 weeks. For DXR, metacarpal cortical index (MCI) was the primary bone measure.
Results:
At all time points the rate of percentage DXR–MCI loss was lowest in the combination group (−1.15; −2.16; −3.03) and greatest in the methotrexate monotherapy group (−1.42; −2.87; −4.62), with figures in between for the adalimumab monotherapy group (−1.33; −2.45; −4.03). Significant differences between the combination group and the methotrexate group were seen at 52 (p = 0.009) and 104 weeks (p<0.001). The order of hand bone loss across the three treatment arms was similar to the order of radiographic progression. Older age, elevated C-reactive protein and non-use of adalimumab were predictors of hand bone loss.
Conclusion:
This study supports a similar pathogenic mechanism for hand bone loss and erosions in RA. The combination of adalimumab and methotrexate seems to arrest hand bone loss less effectively than radiographic joint damage. Quantitative measures of osteoporosis may thus be a more sensitive tool for assessment of inflammatory bone involvement in RA.
doi:10.1136/ard.2008.091264
PMCID: PMC2689520  PMID: 18801760
21.  Combination therapy with sulfasalazine and methotrexate is more effective than either drug alone in patients with rheumatoid arthritis with a suboptimal response to sulfasalazine: results from the double‐blind placebo‐controlled MASCOT study 
Annals of the Rheumatic Diseases  2006;66(2):235-241.
Background
Optimal use of disease‐modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis is vital if progression of disease is to be reduced. Methotrexate (MTX) and sulfasalazine (SASP) are widely used inexpensive DMARDs, recently often combined despite no firm evidence of benefit from previous studies.
Aim
To establish whether a combination of SASP and MTX is superior to either drug alone in patients with rheumatoid arthritis with a suboptimal response to 6 months of SASP.
Methods
A randomised controlled study of step‐up DMARD treatment in early rheumatoid arthritis. In phase I, 687 patients received SASP for 6 months. Those with a disease activity score (DAS) ⩾2.4 were offered additional treatment in phase II (SASP alone, MTX alone or a combination of the two). The primary outcome measure was change in DAS.
Results
At 6 months, 191 (28%) patients had a DAS <2.4, 123 (18%) were eligible but did not wish to enter phase II, 130 (19%) stopped SASP because of reversible adverse events and 165 (24%) entered phase II. DAS at 18 months was significantly lower in those who received combination treatment compared with those who received either SASP or MTX: monotherapy arms did not differ. Improvement in European League Against Rheumatism and American College of Rheumatology 20, 50 and 70 scores favoured combination therapy.
Conclusions
In this “true‐to‐life” study, an inexpensive combination of DMARDs proved more effective than monotherapy in patients with rheumatoid arthritis with a suboptimal response to SASP. There was no increase in toxicity. These results provide an evidence base for the use of this combination as a component of tight control strategies.
doi:10.1136/ard.2006.057133
PMCID: PMC1798490  PMID: 16926184
22.  A randomised, double-blind, parallel-group study of the safety and efficacy of subcutaneous tocilizumab versus intravenous tocilizumab in combination with traditional disease-modifying antirheumatic drugs in patients with moderate to severe rheumatoid arthritis (SUMMACTA study) 
Objectives
This study compared the efficacy and safety of subcutaneous (SC) versus intravenous (IV) formulations of tocilizumab in patients with rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs (DMARD).
Methods
Patients (n=1262) were randomly assigned to receive tocilizumab-SC 162 mg weekly+placebo-IV every 4 weeks or tocilizumab-IV 8 mg/kg every 4 weeks+placebo-SC weekly in combination with traditional DMARD. The primary outcome was to demonstrate the non-inferiority of tocilizumab-SC to tocilizumab-IV with regard to the proportion of patients in each group achieving an American College of Rheumatology (ACR) 20 response at week 24 using a 12% non-inferiority margin (NIM). Secondary outcomes were disease activity score using 28 joints (DAS28), ACR responses, health assessment questionnaire scores and safety assessments.
Results
At week 24, 69.4% (95% CI 65.5 to 73.2) of tocilizumab-SC-treated patients versus 73.4% (95% CI 69.6 to 77.1) of tocilizumab-IV-treated patients achieved an ACR20 response (weighted difference between groups −4.0%, 95% CI −9.2 to 1.2); the 12% NIM was met. ACR50/70 responses, DAS28 and physical function improvements were comparable between the tocilizumab-SC and tocilizumab-IV groups. The safety profiles of tocilizumab-SC and tocilizumab-IV were similar, and the most common adverse event was infection. Injection-site reactions (ISR) occurred more frequently in the tocilizumab-SC group than in the tocilizumab-IV (placebo-SC) group. No anaphylaxis was reported over the 24 weeks.
Conclusions
Tocilizumab-SC 162 mg weekly demonstrated comparable efficacy to tocilizumab-IV 8 mg/kg. The safety profile of tocilizumab-SC is consistent with the known and well-established safety profile of tocilizumab-IV, with the exception of a higher incidence of ISR, which were more common with tocilizumab-SC administration.
doi:10.1136/annrheumdis-2013-203523
PMCID: PMC3888614  PMID: 23904473
Rheumatoid Arthritis; DMARDs (biologic); Disease Activity
23.  Tocilizumab: A Novel Humanized Anti-Interleukin 6 Receptor Antibody for the Treatment of Patients with Rheumatoid Arthritis 
Tocilizumab (TCZ; RoActemra® or Actemra®) is a recombinant humanized monoclonal antibody that acts as an interleukin 6 (IL-6) receptor antagonist. For rheumatoid arthritis (RA), intravenous (IV) TCZ 8 mg/kg every 4 weeks has been approved since 2008 in Japan (where it is also approved for polyarticular juvenile idiopathic arthritis, systemic-onset juvenile idiopathic arthritis and Castleman's disease), and since 2009 in Europe in combination with methotrexate (MTX) for the treatment of moderate to severe active RA in adult patients with inadequate response to, or intolerance of, disease-modifying antirheumatic drug (DMARD) or tumor necrosis factor (TNF) antagonist therapy. It may also be administered as monotherapy in the same dose regimen in patients with methotrexate intolerance or with inadequate response to MTX. Since January 2011 in the United States, the indication for treatment with TCZ for RA patients with an inadequate response to one or more TNF antagonists was extended to patients with moderately to severely active RA, and the recommended starting dose is 4 mg/kg every 4 weeks, with an increase to 8 mg/kg based on clinical response. All of these approvals are based on the effectiveness and safety of the 8 mg/kg dose regimen when administered either as monotherapy or in combination with conventional DMARDs in well-designed clinical studies in adult patients with moderate to severe RA. TCZ at this dose is more effective than placebo, MTX or other DMARDs in reducing disease activity and improving health-related quality of life (HR-QoL). Although there were fewer responses with the 4 mg/kg dose, this dose every 4 weeks was not statistically different to 8 mg/kg when administered in combination with MTX, and this dose is the recommended starting dose in the US. Both doses have also been shown to inhibit structural joint damage in patients with an inadequate response to MTX. Thus, TCZ is an important new treatment option in patients with moderate to severe RA.
doi:10.1177/1759720X11407540
PMCID: PMC3389389  PMID: 22870473
interleukin 6; monoclonal antibody; rheumatoid arthritis; tocilizumab
24.  Evidence for differential acquired drug resistance to anti‐tumour necrosis factor agents in rheumatoid arthritis 
Annals of the Rheumatic Diseases  2005;65(6):746-752.
Background
Acquired drug resistance or gradual drug failure has been described with most disease modifying antirheumatic drugs (DMARDs) and is also starting to be recognised with anti‐tumour necrosis factor (anti‐TNF) agents.
Objective
To study acquired drug resistance to anti‐TNF agents in rheumatoid arthritis (RA).
Methods
Swiss health authorities requested continuous monitoring of patients receiving biological agents. Intensification of co‐therapy with traditional DMARDs, gradual dose escalation, and drug discontinuation rates in all patients receiving infliximab, etanercept, or adalimumab, adjusting for potential confounders, were analysed. Intensification of DMARD co‐therapy and time to discontinuation of the three anti‐TNF agents were analysed using a proportional hazards models. Dose escalation and evolution of RA disease activity (DAS28) were analysed using a longitudinal regression model.
Results
1198 patients contributing 1450 patient‐years of anti‐TNF treatment met the inclusion criteria. The rate of intensification of traditional DMARD co‐therapy over time was significantly higher with infliximab (hazards ratio = 1.73 (99% confidence interval (CI) 1.19 to 2.51)) than with the two other agents. Infliximab also showed significant dose escalation over time, with an average dose increase of +12% (99% CI 8% to 16%) after 1 year, and +18% (99% CI 11% to 25%) after 2 years. No significant differences in discontinuation rates were seen between the three anti‐TNF agents (ANOVA, p = 0.67). Evolution of disease activity over time indicated a lower therapeutic response to infliximab (DAS28, p<0.001) compared with etanercept, after 6 months' treatment.
Conclusions
In this population, infliximab was associated with a higher risk of requiring intensification of DMARD co‐therapy than the other anti‐TNF agents and a significant dose escalation over time. Analysis of RA disease activity indicated a reduced therapeutic response to infliximab after the first 6 months of treatment, suggestive of acquired drug resistance.
doi:10.1136/ard.2005.045062
PMCID: PMC1798167  PMID: 16339288
rheumatoid arthritis; antirheumatic therapy; anti‐tumour necrosis factor agents; drug resistance
25.  Adalimumab in the treatment of arthritis 
Tumor necrosis factor (TNF) has been implicated in a number of arthritic disease states, including rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. Adalimumab is the first fully human, high-affinity, recombinant immunoglobulin G1 (IgG1) anti-TNF monoclonal antibody. Adalimumab in combination with methotrexate or standard antirheumatic therapies, or as monotherapy, is effective in the treatment of adults with active rheumatoid arthritis who have had an inadequate response to disease-modifying antirheumatic drugs. Adalimumab is also effective in the treatment of patients with moderately to severely active psoriatic arthritis, improving both joint and skin manifestations of the disease as well as disability due to joint damage. In the Adalimumab Trial Evaluating Long-term Efficacy and Safety in Ankylosing Spondylitis (ATLAS), adalimumab significantly reduced the signs and symptoms of active ankylosing spondylitis and established a sustained clinical response in patients who had an inadequate response or intolerance to nonsteroidal antiinflammatory drug therapy. Overall, across these indications, adalimumab demonstrated a rapid onset of action, sustained efficacy with long-term treatment, and was well-tolerated, with few patients discontinuing treatment because of adverse events. The safety profile was similar to other TNF antagonists. Inhibition of TNF activity by adalimumab also significantly improved physical functioning and quality of life measures.
PMCID: PMC1936294  PMID: 18360621
Adalimumab; TNF antagonists; rheumatoid arthritis; psoriatic arthritis; ankylosing spondylitis

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