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1.  Rheumatoid arthritis 
Clinical Evidence  2007;2007:1124.
Rheumatoid arthritis usually starts as a symmetrical polyarthritis, and its course is marked by flares and remissions. The aims of treatment are to relieve pain and swelling, and to improve function. In addition, disease-modifying antirheumatic drugs (DMARDs) may reduce disease progression.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of drug treatments in people with rheumatoid arthritis who have not previously received any disease-modifying antirheumatic drug treatment? How do different drug treatments compare in people with rheumatoid arthritis who have either not responded to or are intolerant of first-line disease-modifying antirheumatic drugs? We searched: Medline, Embase, The Cochrane Library and other important databases up to June 2005 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
We found 62 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
In this systematic review we present information relating to the effectiveness and safety of the following interventions: adalimumab, anakinra, antimalarial drugs, azathioprine, ciclosporin, corticosteroids, cyclophosphamide, etanercept, infliximab plus methotrexate, leflunomide, methotrexate (alone; or plus sulfasalazine plus hydroxychloroquine), oral gold, parenteral gold, penicillamine, sulfasalazine.
Key Points
Rheumatoid arthritis is a chronic inflammatory disorder that mainly affects the peripheral joints and surrounding tissue. It usually starts as a symmetrical polyarthritis, and its course is marked by flares and remissions.The aims of treatment are to relieve pain and swelling, and to improve function. In addition, disease-modifying antirheumatic drugs (DMARDs) may reduce disease progression.
The DMARD methotrexate is widely used as first-line treatment in people with rheumatoid arthritis because of consensus about its effectiveness in practice. Sulfasalazine and combined treatment with methotrexate and sulfasalazine are as effective as methotrexate in improving pain, joint swelling, and function in people with early rheumatoid arthritis who have not previously received DMARDs. Antimalarials may improve symptoms and function in DMARD-naïve people, and are reasonably well tolerated, but radiological evidence of erosion is more marked with antimalarials than with sulfasalazine.
There is a variety of DMARDs available for second-line treatment of rheumatoid arthritis, and we found no clear evidence that one is superior. Methotrexate, sulfasalazine, penicillamine , and leflunomide cause similar improvements in symptoms and function when given to people as second-line DMARD treatment, although methotrexate causes fewer adverse effects.The combination of methotrexate plus sulfasalazine plus hydroxychloroquine is more effective in reducing measures of disease activity in people receiving second-line treatment than any of the drugs used alone. Adding the cytokine inhibitors infliximab or etanercept to methotrexate is more effective than using methotrexate alone.Although antimalarials and oral gold seem to improve clinical disease activity when given as second-line treatment, they are not as effective as methotrexate or sulfasalazine. Although parenteral gold is more effective than oral gold, it leads to higher levels of toxicity than most of the other commonly used DMARDs. Ciclosporin offers short-term control of rheumatoid arthritis when used as second-line treatment, but is associated with nephrotoxicity.We don′t know whether cyclophosphamide is as effective as other DMARDs for second-line treatment.Cytokine inhibitors may offer an alternative to traditional DMARDs for second line treatment of rheumatoid arthritis, but more research is needed. Etanercept may be as effective as methotrexate in improving symptoms, function, and radiological evidence of progression, but more evidence for its effect is needed Azathioprine is less effective and is less well tolerated than methotrexate.We don't know whether anakinra or adalimumab are as effective as other DMARDs for second-line treatment.Although widely used for the initial short-term relief of clinical disease activity in rheumatoid arthritis, we don't know how corticosteroids compare with other drugs for first or second-line treatment.
PMCID: PMC2943775  PMID: 19454108
2.  Disease-modifying antirheumatic drugs are associated with a reduced risk for cardiovascular disease in patients with rheumatoid arthritis: a case control study 
Rheumatoid arthritis (RA) is characterized by inflammation and an increased risk for cardiovascular disease (CVD). This study investigates possible associations between CVD and the use of conventional disease-modifying antirheumatic drugs (DMARDs) in RA. Using a case control design, 613 RA patients (5,649 patient-years) were studied, 72 with CVD and 541 without CVD. Data on RA, CVD and drug treatment were evaluated from time of RA diagnosis up to the first cardiovascular event or the end of the follow-up period. The dataset was categorized according to DMARD use: sulfasalazine (SSZ), hydroxychloroquine (HCQ) or methotrexate (MTX). Odds ratios (ORs) for CVD, corrected for age, gender, smoking and RA duration, were calculated per DMARD group. Patients who never used SSZ, HCQ or MTX were used as a reference group. MTX treatment was associated with a significant CVD risk reduction, with ORs (95% CI): 'MTX only', 0.16 (0.04 to 0.66); 'MTX and SSZ ever', 0.20 (0.08 to 0.51); and 'MTX, SSZ and HCQ ever', 0.20 (0.08 to 0.54). The risk reductions remained significant after additional correction for the presence of rheumatoid factor and erosions. After correction for hypertension, diabetes and hypercholesterolemia, 'MTX or SSZ ever' and 'MTX, SSZ and HCQ ever' showed significant CVD risk reduction. Rheumatoid factor positivity and erosions both increased CVD risk, with ORs of 2.04 (1.02 to 4.07) and 2.36 (0.92 to 6.08), respectively. MTX and, to a lesser extent, SSZ were associated with significantly lower CVD risk compared to RA patients who never used SSZ, HCQ or MTX. We hypothesize that DMARD use, in particular MTX use, results in powerful suppression of inflammation, thereby reducing the development of atherosclerosis and subsequently clinically overt CVD.
PMCID: PMC1779436  PMID: 16984661
3.  Adherence to disease modifying anti-rheumatic drugs and the effects of exposure misclassification on the risk of hospital admission 
Arthritis care & research  2010;62(5):730-734.
Describe the effect of different exposure classification strategies for disease modifying anti-rheumatic drugs (DMARDs) on drug-outcome associations.
We studied the association between DMARD initiation and all-cause hospitalizations in rheumatoid arthritis (RA) patients (1995-2005). Initiators of DMARDs and oral glucocorticoids were followed a maximum of 180 days. We compared two strategies for exposure classification: 1) A persistent exposure required (PER) approach, in which follow-up stopped when the regimen changed; and, 2) A persistent exposure ignored (PEI) approach, in which follow-up continued despite regimen changes. For PEI, adherence was assessed using the medication possession ratio. All-cause hospitalization risk was compared among RA regimen initiators using Cox models and methotrexate as the reference.
We identified 28906 episodes of medication initiation. In PER analyses, TNFα-antagonists did not increase hospitalization risk compared with methotrexate, whereas leflunomide did (hazard ratio [HR]: 1.36, 95% CI: 1.1-1.67). Glucocorticoids increased hospitalization risk (HR: 1.29, 1.54 and 2.03 for low, medium and high doses, respectively). PEI results were similar to PER except that infliximab initiation increased the risk of hospitalization compared with methotrexate (HR: 1.46, 95% CI: 1.19-1.8), and most other effects were closer to the null. In PEI, adherence ranged from 73% for etanercept to 6% for glucocorticoids. Adherence to methotrexate was 59%.
Compared with methotrexate initiation, initiation of leflunomide or glucocorticoids consistently increased all-cause hospitalizations in the first 180 days of use. Most PER and PEI estimates were similar; observed differences in risk between these methods were likely due to differences in adherence.
PMCID: PMC2945370  PMID: 20191470
rheumatoid arthritis; Anti-TNF Drugs; DMARD; pharmacoepidemiology
4.  Clinical practice decision tree for the choice of the first disease modifying antirheumatic drug for very early rheumatoid arthritis: a 2004 proposal of the French Society of Rheumatology 
To elaborate a clinical practice decision tree for the choice of the first disease modifying antirheumatic drug (DMARD) for untreated rheumatoid arthritis of less than six months' duration.
Four steps were employed: (1) review of published reports on DMARD efficacy against rheumatoid arthritis; (2) inventory of the information available to guide DMARD choice; (3) selection of the most pertinent information by 12 experts using a Delphi method; and (4) choice of DMARDs in 12 clinical situations defined by items selected in step 3 (28 joint disease activity score (DAS 28): ⩽3.2; >3.2 and ⩽5.1; >5.1; rheumatoid factor status (positive/negative); structural damage (with/without)—that is, 3×2×2). Thus, multiplied by all the possible treatment pairs, 180 scenarios were obtained and presented to 36 experts, who ranked treatment choices according to the Thurstone pairwise method.
Among the 77 items identified, 41 were selected as pertinent to guide the DMARD choice. They were reorganised into five domains: rheumatoid arthritis activity, factors predictive of structural damage; patient characteristics; DMARD characteristics; physician characteristics. In the majority of situations, the two top ranking DMARD choices were methotrexate and leflunomide. Etanercept was an alternative for these agents when high disease activity was associated with poor structural prognosis and rheumatoid factor positivity.
Starting with simple scenarios and using the pairwise method, a clinical decision tree could be devised for the choice of the first DMARD to treat very early rheumatoid arthritis.
PMCID: PMC1797976  PMID: 15994280
decision tree; early rheumatoid arthritis; DMARD choice
5.  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.
PMCID: PMC3747998  PMID: 23997576
rheumatoid arthritis; pharmacotherapy and biologic drugs
6.  Methotrexate: Optimizing the Efficacy in Rheumatoid Arthritis 
Methotrexate (MTX) is currently the most frequently used drugs in the treatment of rheumatoid arthritis (RA). The drug had been synthesized in 1948 and first tests to treat patients with psoriasis and RA were published in 1951. However, until the 1980s there was only limited use of MTX in the treatment of RA. Since the 1990s MTX is the disease-modifying antirheumatic drug (DMARD) of first choice for the treatment of RA in most countries worldwide. By definition, DMARDs in RA are those compounds for which an inhibiting effect on radiographic progression has been demonstrated. Several combinations of DMARDs have been tested, most commonly with MTX as the anchor drug. Regarding the route of administration of MTX there is some evidence that the parenteral route, most often performed subcutaneously, has some additional benefits over the oral route. In MTX monotherapy, dosages up to 30 mg/week are now used. There are now three main combinations that are playing an important role: MTX + sulfasalazine (SSZ) + hydroxychloroquine, MTX + leflunomide (LEF), and MTX + biologics such as antitumour necrosis factor (anti-TNF) and other new compounds which block the interleukin 6 (IL6) receptor or T-cell activation and delete B cells. Regarding clinical efficacy, MTX monotherapy has performed almost similarly well in comparison with biologic mono-therapy, both usually combined with glucocorticoids. However, structural damage is usually inhibited to a significantly greater degree with the biologics. The combination of MTX with biologics has proven superior to either agent alone in all aspects. Current strategic regimens which concentrate on systematic ways to bring patients into remission all include MTX as first choice.
PMCID: PMC3389391  PMID: 22870474
combination therapy; DMARDs; methotrexate; monotherapy; rheumatoid arthritis; therapeutic strategies
7.  The Effect of Tobacco Control Measures during a Period of Rising Cardiovascular Disease Risk in India: A Mathematical Model of Myocardial Infarction and Stroke 
PLoS Medicine  2013;10(7):e1001480.
In this paper from Basu and colleagues, a simulation of tobacco control and pharmacological interventions to prevent cardiovascular disease mortality in India predicted that Smokefree laws and increased tobacco taxation are likely to be the most effective measures to avert future cardiovascular deaths in India.
Please see later in the article for the Editors' Summary
We simulated tobacco control and pharmacological strategies for preventing cardiovascular deaths in India, the country that is expected to experience more cardiovascular deaths than any other over the next decade.
Methods and Findings
A microsimulation model was developed to quantify the differential effects of various tobacco control measures and pharmacological therapies on myocardial infarction and stroke deaths stratified by age, gender, and urban/rural status for 2013 to 2022. The model incorporated population-representative data from India on multiple risk factors that affect myocardial infarction and stroke mortality, including hypertension, hyperlipidemia, diabetes, coronary heart disease, and cerebrovascular disease. We also included data from India on cigarette smoking, bidi smoking, chewing tobacco, and secondhand smoke. According to the model's results, smoke-free legislation and tobacco taxation would likely be the most effective strategy among a menu of tobacco control strategies (including, as well, brief cessation advice by health care providers, mass media campaigns, and an advertising ban) for reducing myocardial infarction and stroke deaths over the next decade, while cessation advice would be expected to be the least effective strategy at the population level. In combination, these tobacco control interventions could avert 25% of myocardial infarctions and strokes (95% CI: 17%–34%) if the effects of the interventions are additive. These effects are substantially larger than would be achieved through aspirin, antihypertensive, and statin therapy under most scenarios, because of limited treatment access and adherence; nevertheless, the impacts of tobacco control policies and pharmacological interventions appear to be markedly synergistic, averting up to one-third of deaths from myocardial infarction and stroke among 20- to 79-y-olds over the next 10 y. Pharmacological therapies could also be considerably more potent with further health system improvements.
Smoke-free laws and substantially increased tobacco taxation appear to be markedly potent population measures to avert future cardiovascular deaths in India. Despite the rise in co-morbid cardiovascular disease risk factors like hyperlipidemia and hypertension in low- and middle-income countries, tobacco control is likely to remain a highly effective strategy to reduce cardiovascular deaths.
Please see later in the article for the Editors' Summary
Editors' Summary
Cardiovascular diseases (CVDs) are conditions that affect the heart and/or the circulation. In coronary heart disease, for example, narrowing of the heart's blood vessels by fatty deposits slows the blood supply to the heart and may eventually cause a heart attack (myocardial infarction). Stroke, by contrast, is a CVD in which the blood supply to the brain is interrupted. CVD has been a major cause of illness and death in high-income countries for many years, but the burden of CVD is now rapidly rising in low- and middle-income countries. Indeed, worldwide, three-quarters of all deaths from heart disease and stroke occur in low- and middle-income countries. Smoking, high blood pressure (hypertension), high blood cholesterol (hyperlipidemia), diabetes, obesity, and physical inactivity all increase an individual's risk of developing CVD. Prevention strategies and treatments for CVD include lifestyle changes (for example, smoking cessation) and taking drugs that lower blood pressure (antihypertensive drugs) or blood cholesterol levels (statins) or thin the blood (aspirin).
Why Was This Study Done?
Because tobacco use is a key risk factor for CVD and for several other noncommunicable diseases, the World Health Organization has developed an international instrument for tobacco control called the Framework Convention on Tobacco Control (FCTC). Parties to the FCTC (currently 176 countries) agree to implement a set of core tobacco control provisions including legislation to ban tobacco advertising and to increase tobacco taxes. But will tobacco control measures reduce the burden of CVD effectively in low- and middle-income countries as other risk factors for CVD are becoming more common? In this mathematical modeling study, the researchers investigated this question by simulating the effects of tobacco control measures and pharmacological strategies for preventing CVD on CVD deaths in India. Notably, many of the core FCTC provisions remain poorly implemented or unenforced in India even though it became a party to the convention in 2005. Moreover, experts predict that, over the next decade, this middle-income country will contribute more than any other nation to the global increase in CVD deaths.
What Did the Researchers Do and Find?
The researchers developed a microsimulation model (a computer model that operates at the level of individuals) to quantify the likely effects of various tobacco control measures and pharmacological therapies on deaths from myocardial infarction and stroke in India between 2013 and 2022. They incorporated population-representative data from India on risk factors that affect myocardial infarction and stroke mortality and on tobacco use and exposure to secondhand smoke into their model. They then simulated the effects of five tobacco control measures—smoke-free legislation, tobacco taxation, provision of brief cessation advice by health care providers, mass media campaigns, and advertising bans—and increased access to aspirin, antihypertensive drugs, and statins on deaths from myocardial infarction and stroke. Smoke-free legislation and tobacco taxation are likely to be the most effective strategies for reducing myocardial infarction and stroke deaths over the next decade, according to the model, and the effects of these strategies are likely to be substantially larger than those achieved by drug therapies under current health system conditions. If the effects of smoke-free legislation and tobacco taxation are additive, the model predicts that these two measures alone could avert about 9 million deaths, that is, a quarter of the expected deaths from myocardial infarction and stroke in India over the next 10 years, and that a combination of tobacco control policies and pharmacological interventions could avert up to a third of these deaths.
What Do These Findings Mean?
These findings suggest that the implementation of smoke-free laws and the introduction of increased tobacco taxes in India would yield substantial and rapid health benefits by averting future CVD deaths. The accuracy of these findings is likely to be affected by the many assumptions included in the mathematical model and by the quality of the data fed into it. Importantly, however, these finding suggest that, despite the rise in other CVD risk factors such as hypertension and hyperlipidemia, tobacco control is likely to be a highly effective strategy for the reduction of CVD deaths over the next decade in India and probably in other low- and middle-income countries. Policymakers in these countries should, therefore, work towards fuller and faster implementation of the core FCTC provisions to boost their efforts to reduce deaths from CVD.
Additional Information
Please access these websites via the online version of this summary at
The American Heart Association provides information on all aspects of cardiovascular disease; its website includes personal stories about heart attacks and stroke
The US Centers for Disease Control and Prevention has information on heart disease and on stroke (in English and Spanish
The UK National Health Service Choices website provides information about cardiovascular disease and stroke
MedlinePlus provides links to other sources of information on heart diseases, vascular diseases, and stroke (in English and Spanish)
The World Health Organization provides information (in several languages) about the dangers of tobacco, about the Framework Convention on Tobacco Control, and about noncommunicable diseases; its Global Noncommunicable Disease Network (NCDnet) aims to help low- and middle- income countries reduce illness and death caused by CVD and other noncommunicable diseases
SmokeFree, a website provided by the UK National Health Service, offers advice on quitting smoking and includes personal stories from people who have stopped smoking, supported by the US National Cancer Institute and other US agencies, offers online tools and resources to help people quit smoking
PMCID: PMC3706364  PMID: 23874160
8.  Impact of concomitant use of DMARDs on the persistence with anti-TNF therapies in patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register 
Annals of the Rheumatic Diseases  2011;70(4):583-589.
To evaluate the effect of different concomitant disease modifying antirheumatic drugs (DMARDs) on the persistence with antitumour necrosis factor (anti-TNF) therapies in patients with rheumatoid arthritis (RA).
This analysis included 10 396 patients with RA registered with the British Society for Rheumatology Biologics Register, a prospective observational cohort study, who were starting their first anti-TNF therapy and were receiving one of the following DMARD treatments at baseline: no DMARD (n=3339), methotrexate (MTX) (n=4418), leflunomide (LEF) (n=610), sulfasalazine (SSZ) (n=308), MTX+SSZ (n=902), MTX+ hydroxychloroquine (HCQ) (n=401) or MTX+SSZ+HCQ (n=418). Kaplan–Meier survival analysis was used to study the persistence with anti-TNF therapy in each DMARD subgroup up to 5 years. Multivariate Cox proportional hazard models, stratified by anti-TNF used and start year and adjusted for a number of potential confounders, were used to compare treatment persistence overall and according to the reason for discontinuation between each of the DMARD subgroups, using MTX as reference.
One-year drug survival (95% CI) for the first anti-TNF therapy was 71% (71% to 72%) but this dropped to 42% (41% to 43%) at 5 years. Compared with MTX, patients receiving no DMARD, LEF or SSZ were more likely to discontinue their first anti-TNF therapy while patients receiving MTX in combination with other DMARDs showed better treatment persistence.
These results support the continued use of background DMARD combinations which include MTX. Consideration should be given to the discontinuation of LEF and SSZ monotherapy at the time anti-TNF therapies are started, with the possible exception of the SSZ+ETN combination.
PMCID: PMC3048625  PMID: 21330639
9.  Methotrexate in rheumatoid arthritis is frequently effective, even if re-employed after a previous failure 
Effectiveness of therapy with individual disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis (RA) is limited, and the number of available DMARDs is finite. Therefore, at some stage during the lengthy course of RA, institution of traditional DMARDs that have previously been applied may have to be reconsidered. In the present study we investigated the effectiveness of re-employed methotrexate in patients with a history of previous methotrexate failure (original course). A total of 1,490 RA patients (80% female, 59% rheumatoid factor positive) were followed from their first presentation, yielding a total of 6,470 patient-years of observation. We identified patients in whom methotrexate was re-employed after at least one intermittent course of a different DMARD. We compared reasons for discontinuation, improvement in acute phase reactants, and cumulative retention rates of methotrexate therapy between the original course of methotrexate and its re-employment. Similar analyses were peformed for other DMARDs. Methotrexate was re-employed in 86 patients. Compared with the original courses, re-employment was associated with a reduced risk for treatment termination because of ineffectiveness (P = 0.02, by McNemar test), especially if the maximum methotrexate dose of the original course had been low (<12.5 mg/week; P = 0.02, by logistic regression). In a Cox regression model, re-employed MTX was associated with a significantly reduced hazard of treatment termination compared with the original course of methotrexate, adjusting for dose and year of employment (hazard ratio 0.64, 95% confidence interval 0.42–0.97; P = 0.04). These findings were not recapitulated in analyses of re-employment of other DMARDs. Re-employment of MTX despite prior inefficacy, but not re-employment of other DMARDs, is an effective therapeutic option, especially in those patients in whom the methotrexate dose of the original course was low.
PMCID: PMC1526609  PMID: 16507172
10.  Psoriatic arthritis therapy: NSAIDs and traditional DMARDs 
Annals of the Rheumatic Diseases  2005;64(Suppl 2):ii74-ii77.
Non-steroidal anti-inflammatory drugs (NSAIDs) and traditional disease modifying antirheumatic drugs (DMARDs) are widely used in the treatment of psoriatic arthritis (PsA), but this is based more upon clinical experience than adequate evidence from clinical trials. This report summarises the results from available trials highlighting evidence of efficacy and deficiencies with respect to effect on joints and to a lesser degree cutaneous disease. The available published data on efficacy of NSAIDs, glucocorticoids, antimalarials, sulfasalazine, gold, methotrexate, azathioprine, and ciclosporin are detailed, as well as new data on leflunomide and other novel agents. The conclusions of this review are that evidence supports marginal efficacy of sulfasalazine and perhaps gold in the treatment of peripheral psoriatic arthropathy, and methotrexate and ciclosporin are effective for treating the skin disease although evidence for improvement of the arthropathy is empirical at best. New trials with standardised and validated outcome measures are required to better assess efficacy. Evaluating newer agents, against and in combination with traditional DMARDS, may further clarify the latter's role in the future management of this condition.
PMCID: PMC1766880  PMID: 15708943
11.  Treatment of psoriatic arthritis in a phase 3 randomised, placebo-controlled trial with apremilast, an oral phosphodiesterase 4 inhibitor 
Annals of the Rheumatic Diseases  2014;73(6):1020-1026.
Apremilast, an oral phosphodiesterase 4 inhibitor, regulates inflammatory mediators. Psoriatic Arthritis Long-term Assessment of Clinical Efficacy 1 (PALACE 1) compared apremilast with placebo in patients with active psoriatic arthritis despite prior traditional disease-modifying antirheumatic drug (DMARD) and/or biologic therapy.
In the 24-week, placebo-controlled phase of PALACE 1, patients (N=504) were randomised (1:1:1) to placebo, apremilast 20 mg twice a day (BID) or apremilast 30 mg BID. At week 16, patients without ≥20% reduction in swollen and tender joint counts were required to be re-randomised equally to either apremilast dose if initially randomised to placebo or remained on their initial apremilast dose. Patients on background concurrent DMARDs continued stable doses (methotrexate, leflunomide and/or sulfasalazine). Primary outcome was the proportion of patients achieving 20% improvement in modified American College of Rheumatology response criteria (ACR20) at week 16.
At week 16, significantly more apremilast 20 mg BID (31%) and 30 mg BID (40%) patients achieved ACR20 versus placebo (19%) (p<0.001). Significant improvements in key secondary measures (physical function, psoriasis) were evident with both apremilast doses versus placebo. Across outcome measures, the 30-mg group generally had higher and more consistent response rates, although statistical comparison was not conducted. The most common adverse events were gastrointestinal and generally occurred early, were self-limiting and infrequently led to discontinuation. No imbalance in major adverse cardiac events, serious or opportunistic infections, malignancies or laboratory abnormalities was observed.
Apremilast was effective in the treatment of psoriatic arthritis, improving signs and symptoms and physical function. Apremilast demonstrated an acceptable safety profile and was generally well tolerated.
Clinical trial registration number
PMCID: PMC4033106  PMID: 24595547
Spondyloarthritis; Psoriatic Arthritis; Treatment
12.  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.
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.
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.
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.
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.
PMCID: PMC2689526  PMID: 19054823
13.  Cardiovascular events in early RA are a result of inflammatory burden and traditional risk factors: a five year prospective study 
Arthritis Research & Therapy  2011;13(4):R131.
Co-morbidity and mortality due to cardiovascular disease (CVD) are increased in patients with rheumatoid arthritis (RA). Most published studies in this field are retrospective or cross sectional. We investigated the presence of traditional and disease related risk factors for CVD at the onset of RA and during the first five years following diagnosis. We also evaluated their potential for predicting a new cardiovascular event (CVE) during the five-year follow-up period and the modulatory effect of pharmacological treatment.
All patients from the four northern-most counties of Sweden with early RA are, since December 1995, consecutively recruited at diagnosis (T0) into a large survey on the progress of the disease. Information regarding cardiovascular co-morbidity and related predictors was collected from clinical records and supplemented with questionnaires. By April 2008, 700 patients had been included of whom 442 patients had reached the five-year follow-up (T5).
Among the 442 patients who reached T5 during the follow-up period, treatment for hypertension increased from 24.5 to 37.4% (P < 0.001)), diagnosis of diabetes mellitus (DM) from 7.1 to 9.5% (P < 0.01) whilst smoking decreased from 29.8 to 22.4% (P < 0.001) and the BMI from 26.3 to 25.8 (P < 0.05), respectively. By T5, 48 patients had suffered a new CVE of which 12 were fatal. A total of 23 patients died during the follow-up period. Age at disease onset, male sex, a previous CVE, DM, treatment for hypertension, triglyceride level, cumulative disease activity (area under the curve (AUC) disease activity score (DAS28)), extra-articular disease, corticosteroid use, shorter duration of treatment with disease modifying anti-rheumatic drugs (DMARDs) and use of COX-2 inhibitors increased the hazard rate for a new CVE. A raised erythrocyte sedimentation rate (ESR) at inclusion and AUC DAS28 at six months increased the hazard rate of CVE independently whilst DMARD treatment was protective in multiple Cox extended models adjusted for sex and CV risk factors. The risk of a CVE due to inflammation was potentiated by traditional CV risk factors.
The occurrence of new CV events in very early RA was explained by traditional CV risk factors and was potentiated by high disease activity. Treatment with DMARDs decreased the risk. The results may have implications for cardio-protective strategies in RA.
PMCID: PMC3239373  PMID: 21843325
14.  Step‐up combination versus switching of non‐biological disease‐modifying antirheumatic drugs in rheumatoid arthritis: results from a retrospective observational study 
Annals of the Rheumatic Diseases  2007;66(8):1059-1065.
In rheumatoid arthritis (RA), treatment with disease‐modifying antirheumatic drugs (DMARDs) frequently needs to be changed because of insufficient effectiveness.
To compare the clinical outcomes of two potential strategies for patients experiencing DMARD discontinuations related to ineffectiveness: switching to another DMARD or step‐up combination therapy of the present DMARD with a new one.
In a large observational database of 4585 DMARD courses in 1214 patients with RA, all patients who had experienced a change in treatment regimen were identified, and retention, effectiveness and safety of these subsequent treatment courses between the two strategies (switching vs step‐up combination). All analyses were stratified according to the type of the new DMARD into methotrexate (MTX), sulphasalazine (SSZ) or leflunomide (LEF); all other DMARDs were excluded.
Kaplan–Meier analysis for MTX courses showed no significant difference in overall retention rates between the strategies of adding MTX and switching to MTX (p = 0.49 by log rank test). Likewise, switching or adding did not result in significantly different retention rates for SSZ and LEF (p = 0.61 and 0.74, respectively). This similarity between strategies remained after adjusting for several confounding variables. The frequencies of treatment terminations related to ineffectiveness or toxicity were likewise similar between the two strategies for the MTX, SSZ and LEF groups. This was also confirmed by the similarity of erythrocyte sedimentation rates that were reached at the end of the two therapeutic strategies for all three drugs, in adjusted analysis.
Given all limitations of observational studies, the present data indicate that in situations of ineffective DMARD treatments, step‐up combination therapy using traditional DMARDs, such as MTX, SSZ or LEF, bears no clear clinical advantage over switching to the new DMARD. Our results do not implicate any predication about step‐up design including biologicals, where the benefit of combination therapy has been suggested convincingly.
PMCID: PMC1954688  PMID: 17307765
15.  Limited efficacy of conventional DMARDs after initial methotrexate failure in patients with recent onset rheumatoid arthritis treated according to the disease activity score 
Annals of the Rheumatic Diseases  2007;66(10):1356-1362.
To determine the efficacy of subsequent disease modifying antirheumatic drug (DMARD) therapies after initial methotrexate (MTX) failure in patients with recent onset rheumatoid arthritis (RA), treated according to the DAS for 2 years.
In groups 1 and 2 of the BeSt study, 244 RA patients were initially treated with MTX 15–25 mg/week. Patients who discontinued MTX because of insufficient clinical response (disease activity score, DAS >2.4) or toxicity were classified as “MTX failures.” In group 1, these patients switched to sulfasalazine (SSA), then leflunomide and finally to MTX + infliximab (IFX). In group 2, “MTX failures” added SSA to MTX, then hydroxychloroquine (HCQ), then prednisone, and eventually switched to MTX + IFX. “MTX successes” were patients who achieved a DAS ⩽2.4 after 2 years while still on MTX monotherapy. Total Sharp/van der Heijde score (TSS) progression from 0–2 years was assessed in “MTX failures” versus “MTX successes.”
After 2 years, 162/244 patients (66%) had discontinued MTX because of insufficient response or toxicity. Of these, 78% also failed on SSA (adding or switching), 87% subsequently failed on leflunomide (in group 1), and 64% on MTX + SSA + HCQ (in group 2). 34 of 48 patients (71%) in groups 1 and 2 were successfully treated with MTX + IFX. After 2 years, regardless of the “success” on subsequent DMARDs, “ MTX failures” had a median TSS progression of 3 units (mean 9) versus 1 unit (mean 3) in “MTX successes” (p = 0.007).
After failure on initial MTX, treatment with subsequent conventional DMARDs is unlikely to result in a DAS ⩽2.4 and allows progression of joint damage.
PMCID: PMC1994290  PMID: 17293364
rheumatoid arthritis; methotrexate; DMARDs; joint damage
16.  Rheumatologists, take heart! We may be doing something right 
In the present issue of Arthritis Research & Therapy data are presented suggesting that antirheumatic therapies decrease the risk of cardiovascular disease in patients with rheumatoid arthritis. The QUEST-RA group, a large international collaboration, analyzed data on 4,363 patients in a cross-sectional manner. Traditional risk factors were all significantly associated with cardiovascular events, and the presence of extraarticular disease significantly increased the risk, confirming a previous publication. The most interesting analysis in this study suggests that effective antirheumatic treatment, with traditional disease-modifying antirheumatic drugs (DMARDs), glucocorticoids, or anti-TNF biologics, reduces the risk of cardiovascular disease in rheumatoid arthritis. Some methodological issues are discussed, however, and confirmatory studies are suggested.
PMCID: PMC2453770  PMID: 18341711
17.  Reduction in the incidence of myocardial infarction in patients with rheumatoid arthritis who respond to anti–tumor necrosis factor α therapy: Results from the British Society for Rheumatology Biologics Register 
Arthritis and Rheumatism  2007;56(9):2905-2912.
Rheumatoid arthritis (RA) is associated with an increased risk of coronary artery disease, possibly acting via shared mechanisms of inflammation. This study was undertaken to test the hypothesis that the powerful antiinflammatory effect of anti–tumor necrosis α (anti-TNFα) therapy might lead to a reduction in the incidence of myocardial infarction (MI) in patients with RA.
Using data from the British Society for Rheumatology Biologics Register, a national prospective observational study, we compared MI rates in 8,670 patients with RA treated with anti-TNFα and 2,170 patients with active RA treated with traditional disease-modifying antirheumatic drugs (DMARDs).
Through July 2006, 63 MIs occurred in the anti-TNFα cohort during 13,233 person-years of followup and 17 MIs occurred in the DMARD cohort during 2,893 person-years of followup, equivalent to a rate of 4.8 events per 1,000 person-years and 5.9 events per 1,000 person-years, respectively. After adjustment for baseline risk factors, there was no reduction in the rate of MI in the anti-TNFα cohort compared with the DMARD cohort (incidence rate ratio 1.44 [95% confidence interval 0.56–3.67]). In an analysis of anti-TNFα–treated patients who responded to the treatment within 6 months versus those who did not, MI rates were found to be 3.5 events per 1,000 person-years in responders and 9.4 events per 1,000 person-years in nonresponders. The adjusted incidence rate ratio (95% confidence interval) for responders compared with nonresponders was 0.36 (0.19–0.69).
These results indicate that RA patients treated with anti-TNFα do not have a lower incidence of MI compared with RA patients treated with traditional DMARDs. However, the risk of MI is markedly reduced in those who respond to anti-TNFα therapy by 6 months compared with nonresponders. This finding supports the notion that inflammation plays a pivotal role in MI.
PMCID: PMC2435427  PMID: 17763428
18.  Attitudes to early rheumatoid arthritis: changing patterns. Results of a survey 
Annals of the Rheumatic Diseases  2004;63(10):1269-1275.
Objective: To determine if rheumatologists have changed their views on diagnosis and treatment of early rheumatoid arthritis (RA).
Methods: Three consecutive questionnaires were sent out to international rheumatologists in 1997, 2000, and 2003. The following aspects of early RA were covered: definition; patient referral time; diagnostic means; follow up intervals; and treatment strategies. All initial participants who responded to at least one of the follow up surveys were included in the analysis.
Results: RA is now defined by a smaller number of affected joints (monarthritis: 9.8% respondents in 1997 v 17.4% in 2003), and shorter symptom duration (<3 months: 65.5% in 1997 v 85.8% in 2003). Early referrals (<6 weeks) increased (8.9% in 1997 v 17.4% in 2003). Serological test for diagnosis was mostly rheumatoid factor (100% in 2003), but anti-CCP was already used by 17.4% in 2003. Follow up of patients with early RA intensified (every 2 weeks: 16.1% in 1997 v 30.4% in 2003; every month: 47.8% in 2003 v 64.3% in 1997). Treatment with disease modifying antirheumatic drugs (DMARDs) mainly comprised methotrexate, sulfasalazine, and antimalarial drugs. Leflunomide was among the two favourite DMARDs of 10.9% in 2003, whereas no biological agent was so. In 2003, 46.7% respondents started treatment with DMARDs if RA was suspected (30.9% in 1997); no one waited for erosions to occur (7.3% in 1997).
Conclusion: The data obtained in this study suggest that the concept of diagnosing and treating RA early is accepted by a large proportion of the rheumatological community.
PMCID: PMC1754776  PMID: 15361385
19.  Cardiovascular Events Are Not Associated with MTHFR Polymorphisms, But Are Associated with Methotrexate Use and Traditional Risk Factors in US Veterans with Rheumatoid Arthritis 
The Journal of rheumatology  2013;40(6):809-817.
C677T and A1298C polymorphisms in the enzyme methylenetetrahydrofolate reductase (MTHFR) have been associated with increased cardiovascular (CV) events in non-rheumatoid arthritis (RA) populations. We investigated potential associations of MTHFR polymorphisms and use of methotrexate (MTX) with time-to-CV event in data from the Veterans Affairs Rheumatoid Arthritis (VARA) registry.
VARA participants were genotyped for MTHFR polymorphisms. Variables included demographic information, baseline comorbidities, RA duration, autoantibody status, and disease activity. Patients’ comorbidities and outcome variables were defined using International Classification of Diseases-9 and Current Procedural Terminology codes. The combined CV event outcome included myocardial infarction (MI), percutaneous coronary intervention, coronary artery bypass graft surgery, and stroke. Cox proportional hazards regression was used to model the time-to-CV event.
Data were available for 1047 subjects. Post-enrollment CV events occurred in 97 patients (9.26%). Although there was a trend toward reduced risk of CV events, MTHFR polymorphisms were not significantly associated with time-to-CV event. Time-to-CV event was associated with prior stroke (HR 2.01, 95% CI 1.03–3.90), prior MI (HR 1.70, 95% CI 1.06–2.71), hyperlipidemia (HR 1.57, 95% CI 1.01–2.43), and increased modified Charlson-Deyo index (HR 1.23, 95% CI 1.13–1.34). MTX use (HR 0.66, 95% CI 0.44–0.99) and increasing education (HR 0.87, 95% CI 0.80–0.95) were associated with a lower risk for CV events.
Although MTHFR polymorphisms were previously associated with CV events in non-RA populations, we found only a trend toward decreased association with CV events in RA. Traditional risk factors conferred substantial CV risk, while MTX use and increasing years of education were protective. (First Release April 1 2013; J Rheumatol 2013;40:809–17; doi:10.3899/ jrheum.121012)
PMCID: PMC4097095  PMID: 23547211
20.  Can clinical factors at presentation be used to predict outcome of treatment with methotrexate in patients with early inflammatory polyarthritis? 
Methotrexate (MTX) is the first choice conventional disease-modifying antirheumatic drug (DMARD) for rheumatoid arthritis. It is not universally effective, however; although to date it is not possible to predict with any accuracy which patients will respond to treatment. The aim of this analysis was to examine whether clinical and genetic variables could be used to predict response to MTX.
Patients recruited to the Norfolk Arthritis Register (NOAR), a primary care based inception cohort of patients with inflammatory polyarthritis, were eligible for this analysis if they were commenced on MTX as their first DMARD within 3 months of their baseline visit and had at least 2 years of follow-up data. Outcome on MTX was defined as: (1) stopped for adverse events; (2) stopped for inefficacy or second DMARD added; (3) stopped for other reasons; or (4) remained on MTX monotherapy. Multiple logistic regression was used to establish which variables (including demographics, disease activity and Health Assessment Questionnaire score) predicted stopping monotherapy for inefficacy or adverse event (with those remaining on treatment taken as the referent category). The area under the Receiver Operating Characteristic curves (AUC ROC), were used to determine how accurate the model was at predicting outcome.
309 patients were included in this analysis. At 1 year (2 years), 34 (46) patients had stopped for adverse events and 25 (49) had either stopped monotherapy for inefficacy or had a second DMARD added. 231 (188) patients remained on MTX monotherapy. The strongest predictor of inefficacy at both time points was shared epitope positivity: odds ratios (OR) 5.8 (95% confidence intervals (CI) 1.3 to 25.6) at 1 year, OR 3.0 (95% CI 1.3 to 7.3) at 2 years. High Health Assessment Questionnaire score (OR 1.84 95% CI 1.12 to 3.01) and female gender (OR 2.2, 95% CI 0.92 to 5.28) were associated with adverse events on MTX at 1 year. However, even the most optimal combinations of the factors analysed were only weakly predictive of treatment outcome: AUC ROC for adverse events 0.68 (95% CI 0.58 to 0.78) and for inefficacy AUC ROC 0.71 (95% CI 0.6 to 0.81).
Within this cohort, routine clinical and laboratory factors were poor at predicting outcome of treatment with MTX. Given the major therapeutic advantage to be derived from accurate prediction of treatment outcome, further studies will need to investigate novel biological and other markers.
PMCID: PMC2596302  PMID: 18292102
21.  The Trends of DMARDS prescribed in Rheumatoid Arthritis Patients in Malaysia 
Oman Medical Journal  2009;24(4):260-206.
To evaluate the trends of disease-modifying anti-rheumatic drugs (DMARDs) used in the treatment of rheumatoid arthritis (RA).
Patients who fulfilled the ACR criteria for RA from 1995 to 2006 and who attended the Rheumatology clinic at Ipoh Hospital were selected and their records were evaluated to determine the changing trends in the use of DMARDs.
128 patients with RA were identified. The most commonly prescribed DMARD as monotherapy was sulphasalazine (47.7%), followed by methotrexate (35.9%) and hydroxychloroquine. Methotrexate and sulphasalazine were the most frequently prescribed DMARDs, of which the use of methotrexate has increased 6 folds from 1997 to 2007 and the use of sulphasalazine remains around 30% to 50%. The combination of methotrexate with leflunomide has significantly increased in usage by 4 folds during the study period whilst methotrexate with sulphasalazine combination usage had slightly declined.
DMARDs are still the cornerstone in the treatment of RA. Changes in the trend and aggressive use of DMARDs has been markedly influenced by the patient’s awareness of early treatment, the incapacitating damage, availability of recently introduced leflunomide and the advancement of current recommended treatment protocol.
PMCID: PMC3243867  PMID: 22216379
22.  Changes in co-therapies after initiation of disease-modifying anti-rheumatic drugs (DMARDs) therapy in patients with rheumatoid arthritis 
Arthritis care & research  2011;63(10):1415-1424.
We hypothesized that initiation of a new disease modifying anti-rheumatic drug DMARD) for rheumatoid arthritis (RA) treatment would decrease use of corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs) and narcotics.
Using administrative databases we assembled 4 retrospective cohorts of RA patients (1998-2005), and identified 5 groups initiating DMARD regimens: methotrexate with (new MTX) or without (first MTX) use of other non-biologic DMARDs in the previous year; new hydroxychloroquine and/or sulfasalazine (new HCQ/SSZ) and new leflunomide (new LEF), both with previous use of MTX; and new TNF-α antagonists (new anti-TNF). We compared within-person differences in any use of co-therapies (≥1 prescription) between the 6 months before and the 6-12 months after DMARD initiation.
Among 32476 DMARD initiators, the prevalence of corticosteroids, NSAIDs and narcotics use increased by 15%, 5% and 6% respectively in the 6 months before initiation compared to the previous 6 months suggesting worsening of the disease. In the 6 to 12 months after initiation for most initiator groups, more patients stopped using corticosteroids and NSAIDs than started, with overall decreases of 8.9% [95%CI 8.4-9.4%] for corticosteroids and 12.9% [95%CI 12.3-13.4%] for NSAIDs. The proportion of narcotic users changed little (overall decrease of 2.5% [95%CI 1.9-3.0%]).
Use of all three co-therapies increased in the 6 months before initiation of new DMARD regimens for RA. Use of corticosteroids and NSAIDs decreased modestly 6-12 months fter initiation, but there was only a very small decrease in narcotic use. These differential changes require further study.
PMCID: PMC3227007  PMID: 22121511
23.  Treatment of active rheumatoid arthritis with leflunomide: two year follow up of a double blind, placebo controlled trial versus sulfasalazine 
Annals of the Rheumatic Diseases  2001;60(10):913-923.
OBJECTIVE—Recent studies have demonstrated the short term efficacy of leflunomide. This study evaluates the efficacy and safety of leflunomide and sulfasalazine in rheumatoid arthritis over a two year follow up period.
METHODS—358 patients with rheumatoid arthritis in a double blind trial were randomly allocated to receive either leflunomide 20 mg/day, placebo, or sulfasalazine 2 g/day. Those completing six months of treatment (n=230) were given the option to continue in 12 (n=168) and 24 (n=146) month double blinded extensions; the placebo group switched to sulfasalazine. This report compares efficacy and safety of leflunomide with sulfasalazine in the 6, 12, and 24 month patient cohorts.
RESULTS—The efficacy seen at six months was maintained at 12 and 24 months. Twenty four month cohorts on leflunomide showed significant improvement compared with sulfasalazine in doctor (−1.46 v −1.11, p=0.03) and patient (−1.61 v −1.04, p<0.001) global assessments, ACR20% response (82% v 60%, p<0.01), and functional ability (Δmean HAQ −0.65 v −0.36, p=0.0149; ΔHAQ disability index −0.89 v −0.60, p=0.059). Improvement in other variables was comparable for the two drugs, including slowing of disease progression. Improved HAQ scores in 6, 12, and 24 month leflunomide cohorts were seen in both non-responders (24%, 29%, 35%, respectively v sulfasalazine 8%, 10%, 27%) and ACR20% responders (leflunomide 63%, 62%, 66% v sulfasalazine 50%, 64%, 44%). Leflunomide is well tolerated at doses of 20 mg. No unexpected adverse events or late toxicity were noted during the two year period. Diarrhoea, nausea, and alopecia were less frequent with continued treatment.
CONCLUSION—These long term data confirm that leflunomide is an efficacious and safe disease modifying antirheumatic drug.

PMCID: PMC1753377  PMID: 11557646
24.  Methotrexate therapy associates with reduced prevalence of the metabolic syndrome in rheumatoid arthritis patients over the age of 60- more than just an anti-inflammatory effect? A cross sectional study 
Arthritis Research & Therapy  2009;11(4):R110.
The metabolic syndrome (MetS) may contribute to the excess cardiovascular burden observed in rheumatoid arthritis (RA). The prevalence and associations of the MetS in RA remain uncertain: systemic inflammation and anti-rheumatic therapy may contribute. Methotrexate (MTX) use has recently been linked to a reduced presence of MetS, via an assumed generic anti-inflammatory mechanism. We aimed to: assess the prevalence of the MetS in RA; identify factors that associate with its presence; and assess their interaction with the potential influence of MTX.
MetS prevalence was assessed cross-sectionally in 400 RA patients, using five MetS definitions (National Cholesterol Education Programme 2004 and 2001, International Diabetes Federation, World Health Organisation and European Group for Study of Insulin Resistance). Logistic regression was used to identify independent predictors of the MetS. Further analysis established the nature of the association between MTX and the MetS.
MetS prevalence rates varied from 12.1% to 45.3% in RA according to the definition used. Older age and higher HAQ scores associated with the presence of the MetS. MTX use, but not other disease modifying anti-rheumatic drugs (DMARDs) or glucocorticoids, associated with significantly reduced chance of having the MetS in RA (OR = 0.517, CI 0.33–0.81, P = 0.004).
The prevalence of the MetS in RA varies according to the definition used. MTX therapy, unlike other DMARDs or glucocorticoids, independently associates with a reduced propensity to MetS, suggesting a drug-specific mechanism, and makes MTX a good first-line DMARD in RA patients at high risk of developing the MetS, particularly those aged over 60 years.
PMCID: PMC2745792  PMID: 19607680
25.  No Evidence of Association Between Anti–Tumor Necrosis Factor Treatment and Mortality in Patients With Rheumatoid Arthritis: Results From the British Society for Rheumatology Biologics Register 
Arthritis and Rheumatism  2010;62(11):3145-3153.
To study the association between anti–tumor necrosis factor (anti-TNF) therapy and mortality in a national cohort of patients with rheumatoid arthritis.
We prospectively followed up 12,672 patients who were beginning anti-TNF therapy and 3,522 biologic-naive patients receiving disease-modifying antirheumatic drugs (DMARDs) until either July 31, 2008, or death, whichever occurred first. Notification of death and cause of death was received from the UK National Death Register. Mortality was compared using Cox proportional hazards models. Inverse probability of treatment weighting was used to adjust for the confounding effects of baseline differences between groups, including age, sex, disease severity, disability, and comorbidity. Missing baseline data were accounted for using multiple imputation.
When compared with the DMARD cohort, the anti-TNF cohort was younger (median age 57 years versus 61 years), had greater disease activity (median Disease Activity Score in 28 joints 6.6 versus 5.1), and had greater disability (median Health Assessment Questionnaire score 2.1 versus 1.6). Patients in the DMARD cohort were more likely to have a history of myocardial infarction (4.8% versus 3.1%) and chronic obstructive pulmonary disease (8.1% versus 4.8%) but were less likely to have had depression (16.5% versus 18.9%). There were 9,445 and 50,803 person-years of followup in the DMARD and anti-TNF cohorts, respectively, during which time 204 DMARD-treated and 856 anti-TNF–treated patients died. The weighted mortality hazard ratios in the anti-TNF cohort were as follows: all-cause 0.86 (95% confidence interval [95% CI] 0.64–1.16), circulatory disease 0.73 (95% CI 0.44–1.23), neoplasm 0.65 (95% CI 0.39–1.09), and respiratory disease 0.81 (95% CI 0.36–1.83).
Our results indicate that, compared with standard DMARD therapy, treatment with anti-TNF therapies was not associated with an increase in mortality.
PMCID: PMC3061010  PMID: 20662063

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