Volume 13 Supplement 1
Infliximab: 12 years of experience
© BioMed Central Ltd. 2011
Published: 25 May 2011
Rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) are immune-mediated conditions that share an inflammatory mechanism fuelled by excessive cytokines, particularly TNF. Control of inflammation and rapid suppression of cytokines are important in treating these diseases. With this understanding and the corresponding advent of TNF inhibitors, RA patients, AS patients and PsA patients have found more choices than ever before and have greater hope of sustained relief. As a widely used TNF inhibitor, infliximab has a deep and established record of efficacy and safety data. Extensive evidence - from randomised controlled clinical trials, large registries and postmarketing surveillance studies - shows that infliximab effectively treats the signs and symptoms, provides rapid and prolonged suppression of inflammation, prevents radiologically observable disease progression and offers an acceptable safety profile in RA, AS and PsA. In very recent studies, investigators have observed drug-free remission in some patients. Additionally, infliximab may interfere with rapidly progressing disease in RA by early addition to methotrexate in patients with signs of an aggressive course. Finally, infliximab has been shown to reduce PsA clinical manifestations such as nail involvement. With our current understanding, substantial data and increasing confidence regarding use in practice, infliximab can be considered a well-known drug in our continued campaign against inflammatory rheumatic diseases.
Insights into mechanisms
Rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) are all associated with a probably distinct immune-mediated pathogenesis that is central to the pathophysiology of each disease but ultimately leads to a chronic inflammatory response as a final common pathway. This fundamental inflammatory response is characterised by an overproduction of pro inflammatory cytokines, particularly TNF, IL-1 and IL-6 .
TNF is a dominant proinflammatory cytokine in RA, AS and PsA. The cytokine has both a direct effect and an indirect effect on the inflammatory events in these conditions [2–4]. TNF induces macrophages and other cells to secrete other proinflammatory cytokines (for example, IL-1, IL-6, IL-8), leads to T-cell activation and induces endothelial cells to express both adhesion molecules that increase T-cell infiltration and vascular growth factors that promote angiogenesis and keratinocyte proliferation. TNF is also involved in the differentiation and maturation of osteoclasts, the pivotal cells engaged in bone destruction in arthritis , and stimulates fibroblasts, osteoclasts and chondrocytes to release proteinases, which destroy articular cartilage and bone [1, 3, 6, 7].
Typical inflammatory symptoms in RA include joint swelling and pain, systemic malaise and morning joint stiffness. As RA progresses, continued inflammation leads to permanent damage to the cartilage, bone, tendons and ligaments and, subsequently, to joint destruction and disability .
AS is primarily a disease of the axial skeleton that involves the sacroiliac joints and spine . Inflammatory back pain with stiffness is the main clinical symptom . Nonaxial involvement may include peripheral joint arthritis (most commonly of the knees), enthesitis and dactylitis [10, 11]. Extra-articular manifestations are fairly common in AS patients [12–14] and can affect the eyes, gastrointestinal tract, lungs, heart and bones.
PsA is characterised by joint damage with associated pain and swelling. The disorder is similar to RA but with less severe symptoms. Nail abnormalities, psoriatic skin lesions, enthesitis and dactylitis are common in PsA . Nail psoriasis is associated with a higher prevalence of joint involvement and a more progressive form of the disease [16, 17]. The skin lesions usually manifest before arthritic symptoms .
Targeting underlying inflammation
Disease control differs among RA, AS and PsA. In AS, nonsteroidal anti-inflammatory drugs can slow or inter fere with the associated radiographic changes  and are the cornerstone of symptom control, even though not all patients benefit . In mild PsA, nonsteroidal anti-inflammatory drugs may also be sufficient to control symptoms and joint damage, since the disease’s propensity to destroy joints is frequently not high. In RA, however, nonbiologic (synthetic) disease-modifying anti-rheumatic drugs (DMARDs) (for example, sulphasalazine, methotrexate (MTX), leflunomide) are the mainstay of treatment, since they interfere not only with the signs and symptoms but also with progression of joint damage in many patients. These drugs also are effective in PsA; they have limited or no efficacy in axial AS, however, despite being effective in the other chronic inflammatory joint diseases and in peripheral arthritis of patients with AS [21, 22].
Corticosteroids also have DMARD properties . In RA, they are used in combination with synthetic DMARDs such as MTX (bridging therapy) to induce more rapid reduction of disease activity, and then are rapidly tapered. Corticosteroids are also used to treat oligoarthritis in PsA, although reactivation of psoriasis may occur upon steroid tapering. In AS, local corticosteroids can relieve site-specific inflammation, but systemic use in axial AS is not supported by available evidence . Long-term use of these drugs is limited by their side-effect profile [24, 25].
Although synthetic DMARDs are effective in many patients with RA and PsA, a considerable number require a different approach. Until the advent of biologic therapies, alternative medications did not exist and treatments often did not sufficiently control symptoms, joint damage and impairment of physical function. Consequently, confinement to a wheelchair and rapid loss of work ability were not infrequent. As understanding of the central inflammatory mechanism has improved and the role of TNF has been elucidated, however, therapies have shifted from mere interference with the magnitude of the inflammatory response to its abrogation and thus toward halting progression of joint damage and restoring physical function and work ability. Interference with the proinflammatory cytokine cascade using TNF inhibitors, but also interfering with other biological targets, may rapidly suppress and control inflammation and thereby prevent irreversible tissue damage and disability .
For a long time, only three TNF inhibitors were available for the treatment of RA, AS and PsA: adalimumab, etanercept and infliximab. Etanercept and infliximab were approved for the treatment of RA within a year of each other (1998 and 1999, respectively) in the United States and in the same year (2000) in Europe. Worldwide patient exposures for these three agents total almost 2 million patients [27–29].
Infliximab was the first biologic agent shown to be efficacious in RA, AS and PsA . Later studies revealed that combination infliximab plus MTX tended to be superior to monotherapy , dramatically affected joint damage  and inhibited joint damage even in the absence of a clinical response, thus fostering the dissociation hypothesis (see Early rheumatoid arthritis, below) . That these infliximab data were paradigmatic for the new class of TNF inhibitors has been shown in studies of other agents that fully confirmed the infliximab results [34–37]. An examination of the wealth of clinical data amassed over 12 years of experience with infliximab from its first licensing in Crohn’s disease (1998 in the United States) can thus tell us much about the state – and future – of TNF inhibitor therapy in RA, AS and PsA.
Whilst etanercept is not sufficiently efficacious in Crohn’s disease, the three TNF inhibitors appear to have similar efficacy in RA, PsA and AS. In the present review, we focus on infliximab as a prototypical example for these effects.
Long-term infliximab use
The available data reveal that infliximab provides rapid and prolonged suppression of inflammation and inhibits progression of joint damage in many patients with RA and PsA [38–41]. In addition, TNF inhibition – such as that with infliximab – induces almost complete and sustained resolution of spinal inflammation in many patients with AS [42, 43].
Efficacy in rheumatoid arthritis
Early rheumatoid arthritis
Efficacy in patients with early RA is critically important, since it is now understood that progression in inflam-mation severity and joint damage is slow in some patients and more rapid in others [46, 47]. Rapidly progressing patients should be identified early in their disease course because they may benefit from more intensive therapy. The best predictors of rapidly progressing RA are currently the number of swollen joints, the presence of autoantibodies (high-titre rheumatoid factor and anti-citrullinated peptide antibodies) and elevated acute-phase response (as measured by the erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) level) [47–50].
Another report from the ASPIRE trial investigated the prognostic value of disease activity markers (laboratory, clinical and radiographic) in relation to progression of joint damage . In patients receiving MTX alone, a higher swollen joint count, higher ESR and CRP levels and higher rheumatoid factor levels at baseline were significantly correlated with greater joint damage at week 54. This correlation was abrogated in patients treated with infliximab plus MTX because of the marked effects on joint damage irrespective of the underlying disease activity or auto antibody state. An additional analysis that adjusted for baseline demographic and other clinical characteristics still found an increased ESR and increased swollen joint counts to be significantly associated with greater joint damage at week 54 in the MTX-alone group. Neither of these markers, however, was predictive of greater joint damage in the infliximab-plus-MTX group. The Disease Activity Score in 28 joints (DAS28) was mostly high at baseline in all patients; decreases were seen after 12 weeks. At 14 weeks, patients in the MTX-alone group who had higher DAS28 scores showed greater progression of joint damage at week 54 than those in the group with lower scores. Again, no such correlation was noted in the infliximab-plus-MTX group.
Radiographic progression, as determined by van der Heijde–Sharp scores, was also greatest in the portion of the MTX-only group that had the highest baseline CRP level and ESR: at 54 weeks, the score changed by 1.81 points (± 7.27) in patients with normal CRP levels and ESR, and by 4.71 points (± 10.69) in patients with high CRP levels (≥0.8 mg/dl) and high ESR (>15 to 20 mm/ hour) . In the infliximab-plus-MTX group, however, the baseline CRP level and ESR had little association with radiographic progression; infliximab plus MTX inhibited radiographic progression regardless of baseline disease activity or joint damage. In fact, all anti-TNF agents, when combined with MTX, are very effective in preventing radiological damage.
Rapidly progressing disease in rheumatoid arthritis
Although the efficacy of MTX is appreciable, patients with rapidly progressing disease (RPD) may obtain additional benefit from more intensive therapy. The CRP level and ESR may serve as predictors of future joint damage in patients with early RA who are treated with MTX monotherapy and may allow potentially optimal management with the earlier addition of a TNF inhibitor. Although few studies have been performed in patients with RPD despite MTX therapy, analyses of subsets of these patients have demonstrated improved long-term benefits with the early addition of infliximab [33, 52, 53]. Infliximab has been evaluated in this regard in both early and long-term disease with similar results. Likewise, starting these patients on etanercept monotherapy or adalimumab plus MTX has shown similar efficacy [54, 55]. The GUEPARD trial, however, showed that rapid addition of a TNF inhibitor to a DMARD – if the latter has not been sufficiently effective within 3 to 6 months – provides clear-cut benefit similar to that derived from starting with combination anti-TNF and DMARD therapy .
The prediction of RPD in patients with RA represents an intriguing challenge for tailoring biologic therapy and an exciting development in the field. Two pilot risk models for predicting RPD in RA patients were recently proposed . ASPIRE data were used to define RPD and to identify baseline risk factors; in line with previous data , these risk factors were swollen joint counts, rheumatoid factor levels, CRP levels and the ESR. The results were then combined with initiated treatments and arranged in matrices that allow prediction of risk in 1 year (Figure 3). One model incorporated all risk factors except the CRP level, and the other model incorporated all risk factors except the ESR, to enable interchangeable use depending on clinical availability. Both models identified subpopulations of RA patients at higher predicted risk of RPD, particularly those who were MTX-naïve with early disease. Additional development plus testing of the models in other RA populations is needed (and currently in progress) to produce a single tool that would be practical and validated for use in everyday practice.
The BeST study, a randomised trial that assessed four different treatment strategies in 508 patients with recent-onset RA, showed similar results. Over year 1, patients receiving initial combination therapy with tapered high-dose prednisone plus MTX plus sulphasalazine (group 3, 133 patients) or infliximab plus MTX (group 4, 128 patients) had more rapid functional improvement and less progression of radiographic joint damage than patients treated with sequential monotherapy (group 1, 126 patients) or step-up combination therapy (group 2, 121 patients), and the differences at most time points were significant . The BeST study also demonstrated that clinical and functional benefits of infliximab plus MTX were maintained over 4 years [58, 59]. In addition, the study provided important information about remission in RA. After 2 years of infliximab combination therapy, 67 out of 120 patients in group 4 (56%) were able to discontinue treatment, and 40 out of the 67 (33% of the total group 4 population) achieved clinical remission . Moreover, significantly more patients in this group (16%) maintained clinical remission off infliximab than in groups 2 and 3, who received infliximab later in the course of their treatment (6% and 7%, respectively; P <0.05 for all) . (The difference between groups 1 and 4 was not significant.) After 3 years of combination therapy, 31% of patients in group 3 and 48% of patients in group 4 were able to taper their medication to DMARD monotherapy or no DMARD. Finally, at year 4 – when 61 out of 120 patients (51%) were off infliximab – 20 out of the 61 (17%) were in complete remission, which lasted on average 1 year .
Six-year BeST data were presented at the October 2009 ACR scientific meeting. Of the original 508-patient study population, 99 patients (19%) withdrew over 6 years. Of the remaining 409 patients, 51% were in clinical remission at 6 years, and 17% (36 patients) of those in remission were in prolonged drug-free remission .
Established rheumatoid arthritis
Infliximab has also demonstrated efficacy in patients with established RA. The ATTRACT study evaluated the efficacy of infliximab in 428 patients with active RA of 7.2-year to 9-year duration, despite 3 months or more of MTX therapy [32, 40, 44]. Patients received 3 mg/kg or 10 mg/kg infusions of infliximab at weeks 0, 2 and 6 and then at 4 or 8 weeks thereafter in combination with MTX. This randomised, double-blind, placebo-controlled phase III study showed that infliximab plus MTX is effective in controlling the signs and symptoms of established RA. After 30 weeks of assessment, 51.8% of patients receiving any dose of infliximab plus MTX demon strated a clinical response (≥20% improvement from baseline using ACR assessment criteria (ACR20)) compared with only 17% of patients receiving placebo plus MTX [32, 44]. Furthermore, approximately 30% of infliximab-plus-MTX patients achieved a 50% improvement from baseline compared with only 5% of placebo-plus-MTX patients .
Studies of long-term infliximab therapy have demonstrated that the positive effects on joint damage are sustained. For example, at the end of ATTRACT year 2, the data showed significant improvements in clinical response and inhibition of progressive joint damage with infliximab plus MTX compared with placebo (plus insufficiently effective MTX) . Indeed, patients receiving infliximab plus MTX not only continued to have good clinical responses and inhibition of progressive joint damage during that 2-year period, but also experienced significant improvements in physical function (as determined by the self-administered Health Assessment Questionnaire) and health-related QoL (as determined by the Short-form 36 Health Survey) com pared with patients receiving placebo (plus insufficiently effective MTX) .
Another study of 511 patients with longstanding, refractory RA found that long-term maintenance therapy with infliximab continues to reduce disease activity . The researchers also examined 4-year compliance rates and found that a majority of patients continued treatment. Infliximab was well tolerated, and 61.6% of patients were still receiving this treatment at the 4-year point . The main reasons for discontinuing therapy were lack of efficacy (13.6%) and safety issues (16.9%). This study is in line with smaller studies demonstrating 3-year infliximab continuation rates of 58 to 75% [63–68].
Efficacy in ankylosing spondylitis
The reduction in spinal inflammation with infliximab was sustained over the long term. At week 24 of the ASSERT study, placebo patients crossed over to receive infliximab (5 mg/kg) as part of an open-label extension . Short-tau inversion recovery MRI images were taken at baseline and at weeks 24 and 102. Patients in the infliximab group showed improvement in the Ankylosing Spondylitis MRI Spinal Score for Activity at week 24 (mean, –4.4; median, –2.00) compared with no change in the placebo group (mean, 0.38; median, 0.25), and this improvement was sustained through 102 weeks . Patients in the placebo group improved after crossing over to receive infliximab at week 24, and subsequently achieved similar levels of spinal inflammation reduction by week 102 as patients receiving infliximab from the start. Interestingly, however, and contrasting with results in RA, infliximab does not appear to halt progression of radiographic changes; likewise, structural changes also progressed on etanercept treatment, contrasting the clinical effects [75, 76].
In another study, 40 patients in whom early sacroiliitis had been determined by MRI were randomised in a double-blind manner to infliximab 5 mg/kg or placebo at 0, 2, 6 and 12 weeks. Both MRI and clinical assessment at 16 weeks showed significantly reduced disease activity. For example, significantly more lesions resolved in the infliximab group (P <0.001), while significantly more new lesions developed in the placebo group (P = 0.004) .
Infliximab was also found to mitigate extra-articular manifestations of AS, which can reduce QoL and signal worse outcomes. For example, patients with AS have a 20 to 30% risk of uveitis , and a meta-analysis showed that infliximab significantly reduced the incidence of uveitis compared with placebo (P = 0.005) . Sub-clinical inflammation of the gut is present in up to 60% of AS patients, and this inflammation can evolve into fullblown inflammatory bowel disease . Another meta-analysis showed that infliximab significantly reduced incidence rates of flares or new-onset inflammatory bowel disease compared with etanercept (P = 0.001) and adalimumab (P = 0.02) . Similarly, a subanalysis of the ASSERT trial’s 24-week phase demonstrated significant increases in mean spinal bone density in AS patients treated with infliximab compared with placebo (P <0.001) . The effects on vertebral fracture, however, are not yet known.
Efficacy in psoriatic arthritis
Infliximab is effective in treating various aspects of PsA, including joint symptoms and extra-articular manifestations such as dactylitis, enthesitis and nail disease, as well as psoriatic skin involvement. The efficacy of infliximab in PsA was assessed in the IMPACT 1 and IMPACT 2 studies [82, 83]. These studies were similar in design, with a 16-week to 24-week, randomised, placebo-controlled phase, after which all patients received infliximab for up to 1 year. Both studies measured articular and composite disease assessment, skin symptoms, enthesitis, dactylitis and QoL. Enrolled patients had active PsA that was unresponsive to at least one DMARD.
Infliximab also inhibits the radiological progression of joint damage in PsA [41, 85]. During the placebo-controlled phase (weeks 1 to 24) of the IMPACT 2 study, radiographs of the hands and feet showed significantly less progression of structural damage in infliximab patients compared with placebo patients (mean change from baseline in modified van der Heijde–Sharp score, –0.70 and 0.82, respectively) . The mean annual progression rate at baseline was equivalent to 5.8 modified van der Heijde–Sharp points/year for the overall study population, but the projected rate for the overall population post infliximab was –1.79 . In fact, 84.3% of the total patient population did not have radiographic progression after a year of infliximab treatment .
Infliximab also improved physical function in PsA regard less of baseline radiographic damage. After 54 weeks of treatment, the percentage improvement in the Health Assessment Questionnaire was strikingly better than at baseline in both treatment groups . Importantly, those patients with less radiological damage regained function more quickly, suggesting that therapeutic intervention early in the disease course may limit the amount of joint damage.
The IMPACT 2 study also evaluated the effect of infliximab on the incidence of other typical features of PsA. Dactylitis was less frequent in infliximab-treated patients than placebo patients at both week 14 (18% vs. 30%, P = 0.025) and week 24 (12% vs. 34%, P <0.001). Enthesopathy was also less frequent in infliximab-treated patients than in placebo patients at both week 14 (22% vs. 34%, P = 0.016) and week 24 (20% vs. 37%, P = 0.002) .
The EXPRESS trial was the first large, controlled, phase III clinical study to use the Nail Psoriasis Severity Index tool in patients with psoriasis . Of the 378 patients randomised, 114 (30.2%) had a history of PsA. Among the 373 patients evaluated for nail disease, it was found to be present at baseline in 87.5% of patients (98 out of 112) with a history of PsA and in 79.3% of patients without a history of PsA. At week 24, the mean percentage improve ments in nail bed scores in patients receiving infliximab versus those receiving placebo were 69.2% and 18.4%, respectively; the percentage improvements in nail matrix scores were 52.9% and –1.9%, respectively (P <0.001). Significant and comparable degrees of improvement were observed, regardless of baseline history of PsA. The Nail Psoriasis Severity Index values persevered in both groups at weeks 38 and 50 (placebo crossover to infliximab occurred at week 24), also regardless of PsA history.
The recently concluded RESPOND trial investigated an aggressive strategy in early, severe polyarticular PsA . This study compared the efficacy and safety of infliximab 5 mg/kg plus MTX with MTX alone in MTX-naïve subjects who had an inadequate response to steroids and nonsteroidal anti-inflammatory drug therapy. The primary end point (ACR20 at week 16) was achieved in 44 out of 51 patients (86.3%) in the infliximab-plus-MTX group compared with 32 out of 48 patients (66.7%) in the MTX-alone group (P = 0.021). The ACR50 and ACR70 response rates at week 16 were also significantly greater in the infliximab-plus-MTX group, with 37 out of 51 patients (72.5%) achieving ACR50 (compared with 19 out of 48 patients (39.6%) in the MTX-alone group; P = 0.0009) and 25 out of 51 patients (49%) achieving ACR70 (compared with nine out of 48 patients (18.8%) in the MTX-alone group; P = 0.0015). Overall, patients receiving infliximab plus MTX showed more profound levels of disease suppression, as illustrated by DAS28 remission rates, an absence of swollen or tender joints, a normal CRP level and PASI 90 responses.
With 12 years of clinical use and the availability of national disease registries, the safety profile of TNF inhibitors is well characterised. Serious adverse events (SAEs) with infliximab include: the development of viral, fungal or bacterial infectious diseases (for example, tuberculosis (TB), listeriosis, sepsis, opportunistic infections due to Cryptococcus, Aspergillus and Pneumocystis); reactivation of hepatitis B virus; hepatobiliary disorders (for example, worsening of hepatitis C, chole cystitis and cholelithiasis, very rare jaundice and non-infectious hepatitis); allergic/ infusion-related reactions (for example, anaphylaxis); malignancies (for example, lymphoma, nonmelanoma skin cancer); autoantibody formation (for example, lupus-like syndrome); haematological reactions (for example, pancytopaenia, aplastic anaemia); neurological disorders (for example, optic neuritis, seizure, demyelinating disorders such as multiple sclerosis); and worsening of congestive heart failure . In general, as with efficacy, the safety aspects of TNF inhibitors are similar [90, 91], and registries compile data on all of the biologics. The risks are thus recognised and are increasingly understood.
In an assessment of safety profiles for DMARDs and biologic agents in more than 10,000 patients with RA, no unexpected safety signals and no trends of concern were noted compared with data seen during earlier trials and in the early days of TNF-inhibiting therapies . The assessment was based on the RADIUS trial, and also showed that rates of SAEs and and serious infections across multiple therapies were comparable with the rates observed with MTX treatment. Similar conclusions were drawn from an observational cohort of the Consortium of Rheumatology Researchers of North America registry, which included 18,305 RA patients . There was no significant increase in the adjusted risk for overall infections associated with anti-TNF therapy compared with MTX, and the infection-related safety profiles of the various biologic agents appeared to be similar.
Serious infection rates were calculated in a prospective, observational study of 7,664 patients treated with TNF inhibitors and 1,354 patients treated with DMARDs from the British Society for Rheumatology Biologics Register . All patients had severe RA. The crude rates of serious infections were found to be similar among TNF inhibitors: 51.3 events/1,000 person-years for etanercept, 55.2 events/1,000 person-years for infliximab and 51.9 events/1,000 person-years for adalimumab. During the study period, however, there were 525 serious infections in the TNF-inhibitor cohort and 56 in the DMARD cohort (9,868 and 1,352 person-years of follow-up, respectively). The incidence rate ratio, adjusted for baseline risk, for the TNF-inhibitor cohort compared with the DMARD cohort was 1.03 (95% confidence interval, 0.68 to 1.57), suggesting similar risk levels between the two treatment groups. The types of serious infections were different between the groups, however, with 19 serious bacterial intracellular infections occurring exclusively in patients in the TNF-inhibitor cohort. After adjustment for baseline risk, anti-TNF therapy was not associated with an increased risk of overall serious infections compared with DMARD treatment in patients with active RA . Nevertheless, the data did show an increased risk of TB infection in patients treated with infliximab and other anti-TNF therapies, although this risk might be lower with etanercept .
A large randomised, placebo-controlled trial assessed the risk of serious infections following infliximab-plus-MTX therapy in patients with active RA . The risk of serious infections in patients receiving infliximab 3 mg/kg plus MTX was similar to that in patients receiving MTX monotherapy. Furthermore, most infections reported in clinical trials of TNF inhibitors were minor and were treated with either outpatient antibiotic therapy and/or temporary withdrawal of the drug .
A prospective cohort study of the German RA registry RABBIT compared the rates of infections in patients treated with the biologic agents infliximab, etanercept and anakinra with the rates of infections in patients receiving conventional DMARDs. Among patients receiving infliximab, 21% experienced a serious infection compared with 6% of control patients. In addition, the incidence of adverse events in general was 3.3 to 4.1 times higher in patients receiving biologic agents than in the control group .
The immunosuppressive activity of TNF inhibitors conveys a theoretical risk of malignancy development. Postmarketing surveillance, however, reported lymphoma rates (mostly non-Hodgkin’s lymphoma) of between 0.01 and 0.03 events/100 patient-years in patients receiving TNF inhibitors . The expected rate was 0.07 events/100 patient-years in a normal population aged 65 years. Further more, the potential rate of lymphoma was com plicated by the association of some immune-mediated diseases, especially RA, with an inherent lymphoma risk . Currently, no clear association between infliximab and lymphoma has been established . Cumulatively, 565 cases of lymphoma development have been reported among more than 1 million patients since the launch of infliximab. The cumulative rate for lymphoma per 100 patient-years since first exposure is 0.017 . Although a definitive conclusion regarding lymphoma risk with TNF inhibitors in general – and infliximab in particular – cannot be reached at present, postmarketing pharmaco vigilance continues to track lymphoma incidence.
Injection site or infusion reactions occur with all TNF inhibitors – but because infliximab is a human-plus-mouse (that is, chimeric) antibody, anaphylaxis is possible. Anaphylactic reactions are uncommon in patients receiving infliximab . In clinical trials, 5,706 patients received 36,485 infliximab infusions, for a mean of 6.4 infusions/patient, and 3,722 patients received 15,379 placebo infusions, for a mean of 4.1 infusions/ patient. Overall, the frequency of infusion reactions was 4% for infliximab compared with 1.6% for placebo. The majority of infusion reactions were mild to moderate (for example, nausea, headache, sweating, flushing). The rate of serious infusion reactions was 0.2% for infliximab and zero for placebo [102, 103]. Immunogenicity can also arise (incidence, 9 to 17%). Although the effect of immuno genicity on efficacy is unclear, patients who develop immunogenicity may be at higher risk for infusion reactions .
Long-term safety data for infliximab
The benefit:risk profile should be considered when selecting patients for infliximab therapy. The safety profile for infliximab is well established, and the labelling explains all risks (the following excerpts address TB, hepatitis and pregnancy):
Before starting treatment, all patients must be evaluated for active and inactive (‘latent’) tuberculosis [TB] according to local standards. In case of latent (or active) TB appropriate prophylactic (or therapeutic) measures have to be taken. Reactivation of hepatitis B has occurred in patients receiving a TNF-inhibitor including infliximab, who are chronic carriers of this virus. Some cases have had fatal outcome. Risk for HBV [hepatitis B virus] infection has to be evaluated before initiating Remicade therapy. Carriers of HBV who require treatment with Remicade need to be closely monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy. Effective anti-viral therapy may be needed. Post-marketing reports from approximately 300 pregnancies exposed to infliximab, did not indicate unexpected effects on pregnancy out come.
Due to its inhibition of TNFα, infliximab administered during pregnancy could affect normal immune responses in the newborn. […] Since the available clinical experience is too limited to exclude a risk, infliximab should not be administered during pregnancy.
Remicade Summary of Product Characteristics, 2009
In RA, a meta-analysis of seven randomised controlled trials (n = 2,100 patients) of duration ≤1 year in patients receiving either infliximab plus MTX or placebo plus MTX demonstrated that between-group differences for SAEs, serious infections, malignancy or death were not significant. The between-group difference for infections was close to significance (P = 0.06) . The infliximab group had significantly more infusion reactions than the placebo group (P = 0.02). The number of withdrawals due to adverse events was also significantly higher in the infliximab group compared with the control group (P = 0.001). A network meta-analysis of six Cochrane reviews, all of which were updated to 2009 (31 randomised controlled trials, n = 17,668), confirmed that efficacy is similar among the TNF inhibitors . Adverse reactions are thought to be related to TNF blockade, and to represent class effects of these agents .
In AS, a recent head-to-head, 2-year trial of infliximab and etanercept in 50 patients with late disease (mean 15.4 and 15.7 years, respectively) found that adverse events were mostly mild to moderate in both groups. There were no discontinuations for safety reasons and no opportunistic infections, TB, congestive heart disease, demyelinating disorders, lupus-like syndrome or malignancy . In an open-label, 5-year (except for a short discontinuation at 3 years) randomised controlled trial of 69 patients with AS who received either infliximab or placebo, most early adverse events were mild to moderate, except one case of TB and one case of allergic bronchiocentric granulomatosis at 1 year . At 3 years (n = 43), none of the six SAEs were considered causally related to infliximab . At 5 years (n = 38) there were no safety concerns, and about one-half of the initial patient cohort was still being successfully treated . These safety results are consistent with data from a large registry .
In PsA, the IMPACT 1 and IMPACT 2 studies demonstrated that infliximab was generally well tolerated. In the IMPACT 1 study (n = 104), the treatment groups had a similar incidence of all adverse events, treatment-related adverse events, infusion-related adverse events and both SAEs and severe adverse events during the placebo-controlled phase (weeks 0 to 16) and the crossover phase (weeks 16 to 50) . In the IMPACT 2 study (n = 200), 67 out of 100 infliximab patients (67%) experienced an adverse event through week 24 (prior to crossover) and 147 out of 173 combined-infliximab patients (85%) experienced an adverse event through week 54 . Through week 54, 22 out of 173 patients (12.5%) in the combined group also experienced an SAE. Importantly, adverse event incidence in the combined-infliximab group was similar between patients receiving MTX (87.5%) and patients not receiving MTX (82.5%) at baseline. When balanced with the improvement in signs and symptoms of PsA, QoL and physical function, and with the high degree of ACR and PASI response through 1 year of infliximab treatment, the authors concluded that the beneft:risk ratio was positive.
Determining the benefit:risk profile of TNF inhibitors can be challenging, for reasons that include the lack of head-to-head clinical trials between drugs and the wide variability in the reported rates of SAEs by different studies. Infliximab, the drug of focus in the present review, has demonstrated efficacy in all rheumatological conditions (RA, AS and PsA) as well as other inflammatory disorders (Crohn’s disease, ulcerative colitis and psoriasis), and no new or unexpected safety signals have arisen over the years. Potential risks exist, but infliximab is generally well tolerated when clinicians appropriately select patients and adhere to indications and contraindications. Vigilance regarding important safety considerations continues to be necessary, as is the need for adequate patient screening and monitoring.
Few questions remain
Research since 1990 has revealed that an immune-mediated inflammatory mechanism leading to the activation of proinflammatory cytokines underlies RA, AS and PsA. This knowledge has driven the development of anti-TNF agents. Today, TNF inhibitors effectively suppress and control the inflammation that drives these diseases. Suppression and control are critical to the prevention of irreversible tissue damage and disability. TNF inhibitors have therefore radically changed the entire therapeutic approach, which has shifted from mitigation of symptoms to blockade of progression.
As with any drug, patient response varies. A proportion of patients do not respond, insufficiently respond or lose an initial good response to classic TNF inhibitors. In such patients, other TNF inhibitors, including golimumab , or other agents, such as the B-cell-depleting chimeric antibody rituximab [110–112], the T-cell co-stimulation inhibitor abatacept , or the IL-6 receptor inhibitor tocilizumab , may be effective.
Studies of the TNF inhibitor infliximab stimulated most of the developments recognised today as pertinent for TNF inhibitors and also set the stage for other biologic agents. The first randomised controlled study in a rheumatic disease reported the efficacy of a single infusion of infliximab in RA patients 16 years ago . Over the 12 years that followed licensing of the first TNF inhibitor for an inflammatory disease, research has shown that, for most patients, infliximab effectively treats signs and symptoms, provides rapid and prolonged suppression of inflammation and may prevent long-term disease progression in RA, AS and PsA. In RA, infliximab, like other TNF blockers, is highly effective for both early and established disease, and can induce clinical remission. Importantly, initial analysis shows that infliximab can even maintain remission for approximately 1 year drug free in patients with early RA. In AS, infliximab induces a rapid reduction in disease activity; and in PsA, infliximab treats not only joint symptoms, but also extra-articular manifestations, including skin disorders, dactylitis, enthesitis and nail disease.
More recently, as we have learned that some patients with RA experience RPD despite MTX therapy, an aggressive approach early in the disease course has been tried. Data are not yet widely available, but subset analyses have demonstrated reductions in potential markers of RPD (for example, CRP levels, ESR, swollen joint count, rheumatoid factor levels) and improved long-term benefits with the early addition of infliximab. Infliximab has been shown to halt joint destruction even in these patients, and predicting RPD may allow tailoring of biologic therapy in the disease course.
American College of Rheumatology
Assessment of the SpondyloArthritis International Society
Active-Controlled Study of Patients Receiving Infliximab for the Treatment of RA of Early Onset
Ankylosing Spondylitis Study for Evaluation of Recombinant Infliximab Therapy
Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy
Bath Ankylosing Spondylitis Disease Activity Index
Disease Activity Score in 28 joints
disease-modifying anti-rheumatic drug
erythrocyte sedimentation rate
European Infliximab for Psoriasis (Remicade) Efficacy and Safety Study
GUerir la PolyArthrite Rhumatoide Debutante [cure early RA]
Infliximab Multinational Psoriatic Arthritis Controlled Trial
magnetic resonance imaging
Psoriasis Area and Severity Index
Rheumatoid Arthritis DMARD Intervention and Utilization Study
Remicade Study in Psoriatic Arthritis Patients of Methotrexate-Naïve Disease
rapidly progressing disease
quality of life
serious adverse event
tumour necrosis factor.
Merck, Sharp & Dohme Corporation (Whitehouse Station, NJ, USA) provided financial support for this article. Synergy Medical Education (Conshohocken, PA, USA) assisted in the preparation of the manuscript.
This article is part of Arthritis Research & Therapy Volume 13 Supplement 1: The evolution on anti-TNF therapy in rheumatic disease: experience, insights and advances. The full contents of the supplement are available online at http://arthritis-research.com/supplements/13/S1. Publication of this supplement is sponsored by Merck, Sharp & Dohme Corporation, Whitehouse Station, New Jersey, USA.
- Smolen JS, Steiner G: Therapeutic strategies for rheumatoid arthritis. Nat Rev Drug Discov. 2003, 2: 473-488. 10.1038/nrd1109.PubMedGoogle Scholar
- Mielants H, Sieper J, Antoni CE, Van den Bosch F, van Vollenhoven RF: A new treatment approach paradigm in the management of spondyloarthropathies. Rheumatol News. 2005, 1-11. Suppl
- Choy EH, Panayi GS: Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med. 2001, 344: 907-916. 10.1056/NEJM200103223441207.PubMedGoogle Scholar
- Chen S, Gill MA, Luu CH, Takami S: Pain and rheumatoid arthritis: an update. Drug Topics. 2000, 144: 47-55.Google Scholar
- Redlich K, Hayer S, Ricci R, David J-P, Tohidast-Akrad M, Kollias G, Steiner G, Smolen JS, Erwin Wagner EF, Schett G: Osteoclasts are essential for TNF-α-mediated joint destruction. J Clin Invest. 2002, 110: 1419-1427.PubMed CentralPubMedGoogle Scholar
- Butler DM, Maini RN, Feldmann M, Brennan FM: Modulation of proinflammatory cytokine release in rheumatoid synovial membrane cell cultures: comparison of monoclonal anti TNF-α antibody with interleukin-1 receptor antagonist. Eur Cytokine Netw. 1995, 6: 225-230.PubMedGoogle Scholar
- Lizzul PF, Aphale A, Malaviya R, Sun Y, Masud S, Dombrovskiy V, Gottlieb AB: Differential expression of phosphorylated NF-κB/RelA in normal and psoriatic epidermis and downregulation of NF-κB in response to treatment with etanercept. J Invest Dermatol. 2005, 124: 1275-1283. 10.1111/j.0022-202X.2005.23735.x.PubMedGoogle Scholar
- Gladman DD: Established criteria for disease controlling drugs in ankylosing spondylitis. Ann Rheum Dis. 2003, 62: 793-794. 10.1136/ard.62.9.793.PubMed CentralPubMedGoogle Scholar
- Rudwaleit M, Baeten D: Ankylosing spondylitis and bowel disease. Best Pract Res Clin Rheumatol. 2006, 20: 451-471. 10.1016/j.berh.2006.03.010.PubMedGoogle Scholar
- Lee JH, Jun JB, Jung S, Bae SC, Yoo DH, Kim TY, Kim SY, Kim TH: Higher prevalence of peripheral arthritis among ankylosing spondylitis patients. J Korean Med Sci. 2002, 17: 669-673.PubMed CentralPubMedGoogle Scholar
- Braun J, Sieper J: The sacroiliac joint in the spondyloarthropathies. Curr Opin Rheumatol. 1996, 8: 275-287. 10.1097/00002281-199607000-00003.PubMedGoogle Scholar
- Brophy S, Calin A: Ankylosing spondylitis: interaction between genes, joints, age at onset, and disease expression. J Rheumatol. 2001, 28: 2283-2288.PubMedGoogle Scholar
- Peters MJ, van der Horst-Bruinsma IE, Dijkmans BA, Nurmohamed MT: Cardiovascular risk profile of patients with spondylarthropathies, particularly ankylosing spondylitis and psoriatic arthritis. Semin Arthritis Rheum. 2004, 34: 585-592. 10.1016/j.semarthrit.2004.07.010.PubMedGoogle Scholar
- Vander Cruyssen B, Ribbens C, Boonen A, Mielants H, de Vlam K, Lenaerts J, Steinfeld S, Van den Bosch F, Dewulf L, Vastesaeger N: The epidemiology of ankylosing spondylitis and the commencement of anti-TNF therapy in daily rheumatology practice. Ann Rheum Dis. 2007, 66: 1072-1077. 10.1136/ard.2006.064543.Google Scholar
- McGonagle D, Tan AL, Benjamin M: The nail as a musculoskeletal appendage – implications for an improved understanding of the link between psoriasis and arthritis. Dermatology. 2009, 218: 97-102. 10.1159/000182250.PubMedGoogle Scholar
- Serarslan G, Güler H, Karazincir S: The relationship between nail and distal phalangeal bone involvement severity in patients with psoriasis. Clin Rheumatol. 2007, 26: 1245-1247. 10.1007/s10067-006-0476-y.PubMedGoogle Scholar
- Williamson L, Dalbeth N, Dockerty JL, Gee BC, Weatherall R, Wordsworth BP: Extended report: nail disease in psoriatic arthritis – clinically important, potentially treatable and often overlooked. Rheumatology (Oxford). 2004, 43: 790-794. 10.1093/rheumatology/keh198.Google Scholar
- Mease PJ: Tumour necrosis factor (TNF) in psoriatic arthritis: pathophysiology and treatment with TNF inhibitors. Ann Rheum Dis. 2002, 61: 298-304. 10.1136/ard.61.4.298.PubMed CentralPubMedGoogle Scholar
- Wanders A, van der Heijde D, Landewe R, Behier J-M, Calin A, Olivieri I, Zeidler H, Dougados M: Nonsteroidal anti-inflammatory drugs reduce radiographic progression in patients with ankylosing spondylitis: a randomized clinical trial. Arthritis Rheum. 2005, 52: 1756-1765. 10.1002/art.21054.PubMedGoogle Scholar
- Miceli-Richard C, Dougado M: NSAIDs in ankylosing spondylitis. Clin Exp Rheumatol. 2002, 20 (Suppl 28): S65-S66.PubMedGoogle Scholar
- Rudwaleit M, Khan MA, Sieper J: The challenge of diagnosis and classification in early ankylosing spondylitis: do we need new criteria?. Arthritis Rheum. 2005, 52: 1000-1008. 10.1002/art.20990.PubMedGoogle Scholar
- Zochling J, van der Heijde D, Burgos-Vargas R, Collantes E, Davis JC, Dijkmans B, Dougados M, Géher P, Inman RD, Khan MA, Kvien TK, Leirisalo-Repo M, Olivieri I, Pavelka K, Sieper J, Stucki G, Sturrock RD, van der Linden S, Wendling D, Böhm H, van Royen BJ, Braun J: ‘ASsessment in AS’ International Working Group; European League Against Rheumatism: ASAS/EULAR recommendations for the management of ankylosing spondylitis. Ann Rheum Dis. 2006, 65: 442-452. 10.1136/ard.2005.041137.PubMed CentralPubMedGoogle Scholar
- Kirwan JR, Arthritis and Rheumatism Council Low-Dose Glucocorticoid Study Group: The effect of glucocorticoids on joint destruction in rheumatoid arthritis. N Engl J Med. 1995, 333: 142-146. 10.1056/NEJM199507203330302.PubMedGoogle Scholar
- Mitka M: Early rheumatoid arthritis treatments weighed. JAMA. 2005, 294: 3073-3074. 10.1001/jama.294.24.3073.PubMedGoogle Scholar
- Kyle S, Chandler D, Griffiths CEM, Helliwell P, Lewis J, McInnes I, Oliver S, Symmons D, McHugh N, British Society for Rheumatology Standards Guidelines Audit Working Group (SGAWG): Guidelines for anti-TNF-α therapy in psoriatic arthritis. Rheumatology (Oxford). 2005, 44: 390-397. 10.1093/rheumatology/keh514.Google Scholar
- Smolen JS, Aletaha D, Koeller M, Weisman MH, Emery P: New therapies for treatment of rheumatoid arthritis. Lancet. 2007, 370: 1861-1874. 10.1016/S0140-6736(07)60784-3.PubMedGoogle Scholar
- Amgen/Wyeth Pharmaceuticals. [http://www.enbrel.com]
- Abbott Laboratories: Five-year Data Demonstrate Initial Use of Abbott’s Humira (Adalimumab) plus Methotrexate may Prevent Further Joint Damage in Early Rheumatoid Arthritis Patients. [http://www.abbott.com/global/url/pressRelease/en_US/60.5:5/Press_Release_0737.htm]
- Centocor, Inc. Remicade becomes First Anti-TNF Biologic Therapy to Treat One Million Patients Worldwide. [http://www.merck.com/newsroom/news-release-archive/schering-plough-news-archive/all/releaseid=1077200.html]
- Elliott MJ, Maini RN, Feldmann M, Kalden JR, Antoni C, Smolen JS, Leeb B, Breedveld FC, Macfarlane JD, Bijl H, Woody JN: Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis. Lancet. 1994, 344: 1105-1110. 10.1016/S0140-6736(94)90628-9.PubMedGoogle Scholar
- Maini RN, Breedveld FC, Kalden JR, Smolen JS, Davis D, Macfarlane JD, Antoni C, Leeb B, Elliott MJ, Woody JN, Schaible TF, Feldmann M: Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor α monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum. 1998, 41: 1552-1563. 10.1002/1529-0131(199809)41:9<1552::AID-ART5>3.0.CO;2-W.PubMedGoogle Scholar
- Lipsky PE, van der Heijde DMFM, St Clair EW, Furst DE, Breedveld FC, Kalden JR, Smolen JS, Weisman M, Emery P, Feldmann M, Harriman GR, Maini RN, Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group: Infliximab and methotrexate in the treatment of rheumatoid arthritis. N Engl J Med. 2000, 343: 1594-1602. 10.1056/NEJM200011303432202.PubMedGoogle Scholar
- Smolen JS, Han C, Bala M, Maini RN, Kalden JR, van der Heijde D, Breedveld FC, Furst DE, Lipsky PE, ATTRACT Study Group: Evidence of radiographic benefit of treatment with infliximab plus methotrexate in rheumatoid arthritis patients who had no clinical response. Arthritis Rheum. 2005, 52: 1020-1030. 10.1002/art.20982.PubMedGoogle Scholar
- Keystone EC, Kavanaugh AF, Sharp JT, Tannenbaum H, Hua Y, Teoh LS, Fischkoff SA, Chartash EK: Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti–tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy. Arthritis Rheum. 2004, 50: 1400-1411. 10.1002/art.20217.PubMedGoogle Scholar
- Landewé R, van der Heijde D, Klareskog L, van Vollenhoven R, Fatenejad S: Disconnect between inflammation and joint destruction after treatment with etanercept plus methotrexate: results from the trial of etanercept and methotrexate with radiographic and patient outcomes. Arthritis Rheum. 2006, 54: 3119-3125. 10.1002/art.22143.PubMedGoogle Scholar
- van der Heijde D, Klareskog L, Boers M, Landewé R, Codreanu C, Bolosiu HD, Pedersen R, Fatenejad S, TEMPO Investigators: Comparison of different definitions to classify remission and sustained remission: 1 year TEMPO results. Ann Rheum Dis. 2005, 64: 1582-1587. 10.1136/ard.2004.034371.PubMed CentralPubMedGoogle Scholar
- Weinblatt ME, Kremer JM, Bankhurst AD, Bulpit KJ, Fleischmann RM, Fox RI, Jackson CG, Lange M, Burge DJ: A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med. 1999, 340: 253-259. 10.1056/NEJM199901283400401.PubMedGoogle Scholar
- Conaghan PG, Quinn MA, O’Connor P, Wakefield RJ, Karim Z, Emery P: Can very high-dose anti-tumor necrosis factor blockade at onset of rheumatoid arthritis produce long-term remission?. Arthritis Rheum. 2002, 46: 1971-1972. 10.1002/art.10274.PubMedGoogle Scholar
- Shergy WJ, Isern RA, Cooley DA, Harshbarger JL, Huffstutter JE, Hughes GM, Spencer-Smith EA, Goldman AL, Roth SH, Toder JS, Warner D, Quinn A, Keenan GF, Schaible TF, PROMPT Study Group. Profiling Remicade Onset with MTX in a Prospective Trial: Open label study to assess infliximab safety and timing of onset of clinical benefit among patients with rheumatoid arthritis. J Rheumatol. 2002, 29: 667-677.PubMedGoogle Scholar
- Maini RN, Breedveld FC, Kalden JR, Smolen JS, Furst D, Weisman MH, St Clair EW, Keenan GF, van der Heijde D, Marsters PA, Lipsky PE, Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group: Sustained improvement over two years in physical function, structural damage, and signs and symptoms among patients with rheumatoid arthritis treated with infliximab and methotrexate. Arthritis Rheum. 2004, 50: 1051-1065. 10.1002/art.20159.PubMedGoogle Scholar
- van der Heijde D, Kavanaugh A, Gladman DD, Antoni C, Krueger GG, Guzzo C, Zhou B, Dooley LT, de Vlam K, Geusens P, Birbara C, Halter D, Beutler A: Infliximab inhibits progression of radiographic damage in patients with active psoriatic arthritis through one year of treatment: results from the induction and maintenance psoriatic arthritis clinical trial 2. Arthritis Rheum. 2007, 56: 2698-2707. 10.1002/art.22805.PubMedGoogle Scholar
- Braun J, Landewé R, Hermann K-G, Han J, Yan S, Williamson P, van der Heijde D, ASSERT Study Group: Major reduction in spinal inflammation in patients with ankylosing spondylitis after treatment with infliximab: results of a multicenter, randomized, double-blind, placebo-controlled magnetic resonance imaging study. Arthritis Rheum. 2006, 54: 1646-1652. 10.1002/art.21790.PubMedGoogle Scholar
- Braun J, Landewé R, Hermann KG, Deodhar A, Baker D, Han J, Xu W, Williamson P, van der Heijde D: Sustained reduction in spinal inflammation in patients with ankylosing spondylitis after treatment with infliximab [abstract]. Ann Rheum Dis. 2007, 66 (Suppl II): 64-Google Scholar
- Maini R, St Clair W, Breedveld FC, Furst D, Kalden J, Weisman M, Smolen J, Emery P, Harriman G, Feldmann M, Lipsky P: Infliximab (chimeric anti-tumour necrosis factor α monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. Lancet. 1999, 354: 1932-1939. 10.1016/S0140-6736(99)05246-0.PubMedGoogle Scholar
- St Clair EW, van de Heijde D, Smolen JS, Maini RN, Bathon JM, Emery P, Keystone E, Schiff M, Kalden JR, Wang B, Dewoody K, Weiss R, Baker D, Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset Study Group: Combination of infliximab and methotrexate therapy for early rheumatoid arthritis. Arthritis Rheum. 2004, 50: 3432-3443. 10.1002/art.20568.PubMedGoogle Scholar
- Verstappen SMM, Poole AR, Ionescu M, King LE, Abrahamowicz M, Hofman DM, Bijlsma JWJ, Lafeber FPJG, Utrecht Rheumatoid Arthritis Cohort Study Group (SRU), Utrecht Rheumatoid Arthritis Cohort Study Group (SRU): Radiographic joint damage in rheumatoid arthritis is associated with differences in cartilage turnover and can be detected by serum biomarkers: an evaluation from 1 to 4 years after diagnosis. Arthritis Res Ther. 2006, 8: 1-9. 10.1186/ar1882.Google Scholar
- Vastesaeger N, Xu S, Aletaha D, St Clair EW, Smolen JS: A pilot risk model for the prediction of rapid radiographic progression in rheumatoid arthritis. Rheumatology (Oxford). 2009, 48: 1114-1121. 10.1093/rheumatology/kep155.Google Scholar
- Emery P, McInnes IB, van Vollenhoven R, Kraan MC: Clinical identification and treatment of a rapidly progressing disease state in patients with rheumatoid arthritis. Rheumatology (Oxford). 2008, 47: 392-398. 10.1093/rheumatology/kem257.Google Scholar
- van Gaalen FA, Linn-Rasker SP, van Venrooij WJ, de Jong BA, Breedveld FC, Verweij CL, Toes RE, Huizinga TW: Autoantibodies to cyclic citrullinated peptides predict progression to rheumatoid arthritis in patients with undifferentiated arthritis: a prospective cohort study. Arthritis Rheum. 2004, 50: 709-715. 10.1002/art.20044.PubMedGoogle Scholar
- Smolen JS, van der Heijde D, St Clair EW, Emery P, Bathon JM, Keystone E, Maini RN, Kalden JR, Schif M, Baker D, Han C, Han J, Bala M, Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset (ASPIRE) Study Group: Predictors of joint damage in patients with early rheumatoid arthritis treated with high-dose methotrexate with or without concomitant infliximab. Results from the ASPIRE trial. Arthritis Rheum. 2006, 54: 702-710. 10.1002/art.21678.PubMedGoogle Scholar
- Smolen JS, Han C, van der Heijde DM, Emery P, Bathon JM, Keystone E, Maini RN, Kalden JR, Aletaha D, Baker D, Han J, Bala M, St Clair EW, Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset (ASPIRE) Study Group: Radiographic changes in rheumatoid arthritis patients attaining different disease activity states with methotrexate monotherapy and infliximab plus methotrexate: the impacts of remission and tumour necrosis factor blockade. Ann Rheum Dis. 2009, 68: 823-827. 10.1136/ard.2008.090019.PubMedGoogle Scholar
- Breedveld FC, Emery P, Keystone E, Patel K, Furst DE, Kalden JR, St Clair EW, Weisman M, Smolen J, Lipsky PE, Maini RN: Infliximab in active early rheumatoid arthritis. Ann Rheum Dis. 2004, 63: 149-155. 10.1136/ard.2003.013961.PubMed CentralPubMedGoogle Scholar
- Quinn MA, Conaghan PG, O’Connor PJ, Karim Z, Greenstein A, Brown A, Brown C, Fraser A, Jarret S, Emery P: Very early treatment with infliximab in addition to methotrexate in early, poor-prognosis rheumatoid arthritis reduces magnetic resonance imaging evidence of synovitis and damage, with sustained benefit after infliximab withdrawal. Arthritis Rheum. 2005, 52: 27-35. 10.1002/art.20712.PubMedGoogle Scholar
- Breedveld FC, Weisman MH, Kavanaugh AF, Cohen SB, Pavelka K, van Vollenhoven R, Sharp J, Perez JL, Spencer-Green GT: The PREMIER study: a multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum. 2006, 54: 26-37. 10.1002/art.21519.PubMedGoogle Scholar
- Genovese MC, Bathon JM, Martin RW, Fleischmann RM, Tesser JR, Schiff MH, Keystone EC, Wasko MC, Moreland LW, Weaver AL, Markenson J, Cannon GW, Spencer-Green G, Finck BK: Etanercept versus methotrexate in patients with early rheumatoid arthritis: two-year radiographic and clinical outcomes. Arthritis Rheum. 2002, 46: 1443-1450. 10.1002/art.10308.PubMedGoogle Scholar
- Soubrier M, Puéchal X, Sibilia J, Mariette X, Meyer O, Combe B, Flipo RM, Mulleman D, Berenbaum F, Zarnitsky C, Schaeverbeke T, Fardellone P, Dougados M: Evaluation of two strategies (initial methotrexate monotherapy vs its combination with adalimumab) in management of early active rheumatoid arthritis: data from the GUEPARD trial. Rheumatology (Oxford). 2009, 48: 1429-1434. 10.1093/rheumatology/kep261.Google Scholar
- Goekoop-Ruiterman YPM, de Vries-Bouwstra JK, Allaart CF, van Zeben D, Kerstens PJ, Hazes JM, Zwinderman AH, Ronday HK, Han KH, Westedt ML, Gerards AH, van Groenendael JH, Lems WF, van Krugten MV, Breedveld FC, Dijkmans BA: Clinical and radiographic outcomes of four diferent treatment strategies in patients with early rheumatoid arthritis (the BeST study). Arthritis Rheum. 2005, 52: 3381-3390. 10.1002/art.21405.PubMedGoogle Scholar
- Van Der Kooij SM, Goekoop-Ruiterman YPM, De Vries-Bouwstra JK, Guler-Yuksel M, Zwinderman AH, Kerstens PJSM, Van Der Lubbe PAHM, De Beus WM, Grillet BAM, Ronday K, Huizinga TWJ, Breedveld FC, Dijkmans BAC, Allaart CF: Drug-free remission, functioning, and radiographic damage after 4 years of response-driven treatment in patients with recent onset rheumatoid arthritis. Ann Rheum Disease. 2009, 68: 914-921. 10.1136/ard.2008.092254.Google Scholar
- van der Bijl AE, Goekoop-Ruiterman YPM, de Vries-Bouwstra JK, ten Wolde S, Han KH, van Krugten MV, Allaart CF, Breedveld FC, Dijkmans BAC: Infliximab and methotrexate as induction therapy in patients with early rheumatoid arthritis. Arth Rheum. 2007, 56: 2129-2134. 10.1002/art.22718.Google Scholar
- Klarenbeek NB, Dirven L, Guler-Yuksel M, Gerards AH, Kerstens PJSM, Molenaar THE, Huizinga TWJ, Dijkmans BAC, Allaart CF: Clinical and radiological outcomes of four DAS-driven treatment strategies: 6-year results of the BeSt study. Presented at: American College of Rheumatology/Association of Rheumatology Health Professionals (ACR/ ARHP) Scientific Meeting, October 16–21, 2009, Philadelphia, Pennsylvania, USA [abstract]. Arthritis Rheum. 2009, 60 (Suppl 10):
- Vander Cruyssen B, Van Looy S, Wyns B, Westhovens R, Durez P, Van den Bosch F, Mielants H, De Clerck L, Peretz A, Malaise M, Verbruggen L, Vastesaeger N, Geldhof A, Boullart L, De Keyser F: Four-year follow-up of infliximab therapy in rheumatoid arthritis patients with long-standing refractory disease: attrition and long-term evolution of disease activity. Arthritis Res Ther. 2006, 8: R112-10.1186/ar2001.Google Scholar
- Voulgari PV, Alamanos Y, Nikas SN, Bougias DV, Temekonidis TI, Drosos AA: Infliximab therapy in established rheumatoid arthritis: an observational study. Am J Med. 2005, 118: 515-520. 10.1016/j.amjmed.2005.01.029.PubMedGoogle Scholar
- Geborek P, Crnkic M, Petersson IF, Saxne T, South Swedish Arthritis Treatment Group: Etanercept, infliximab, and leflunomide in established rheumatoid arthritis: clinical experience using a structured follow up programme in southern Sweden. Ann Rheum Dis. 2002, 61: 793-798. 10.1136/ard.61.9.793.PubMed CentralPubMedGoogle Scholar
- Wendling D, Materne GE, Michel F, Lohse A, Lehuede G, Toussirot E, Massol J, Woronoff-Lemsi MC: Infliximab continuation rates in patients with rheumatoid arthritis in everyday practice. Joint Bone Spine. 2005, 72: 309-312. 10.1016/j.jbspin.2004.08.008.PubMedGoogle Scholar
- Flendrie M, Creemers MC, Welsing PM, den Broeder AA, van Riel PL: Survival during treatment with tumour necrosis factor blocking agents in rheumatoid arthritis. Ann Rheum Dis. 2003, 62 (Suppl 2): ii30-ii33.PubMed CentralPubMedGoogle Scholar
- Zink A, Listing J, Kary S, Ramlau P, Stoyanova-Scholz M, Babinsky K, von Hinueber U, Gromnica-Ihle E, Wassenberg S, Antoni C, Herzer P, Kekow J, Schneider M, Rau R: Treatment continuation in patients receiving biological agents or conventional DMARD therapy. Ann Rheum Dis. 2005, 64: 1274-1279. 10.1136/ard.2004.031476.PubMed CentralPubMedGoogle Scholar
- Chevillotte-Maillard H, Ornetti P, Mistrih R, Sidot C, Dupuis J, Dellas JA, Tavernier C, Maillefert JF: Survival and safety of treatment with infliximab in the elderly population. Rheumatology (Oxford). 2005, 44: 695-696. 10.1093/rheumatology/keh562.Google Scholar
- Baeten D, De Keyser F, Mielants H, Veys EM: Ankylosing spondylitis and bowel disease. Best Pract Res Clin Rheumatol. 2002, 16: 537-549. 10.1053/berh.2002.0249.PubMedGoogle Scholar
- Braun J, Baraliakos X, Listing J, Sieper J: Decreased incidence of anterior uveitis in patients with ankylosing spondylitis treated with the anti-tumor necrosis factor agents infliximab and etanercept. Arthritis Rheum. 2005, 52: 2447-2451. 10.1002/art.21197.PubMedGoogle Scholar
- Braun J, Brandt J, Listing J, Zink A, Alten R, Golder W, Gromnica-Ihle E, Kellner H, Krause A, Schneider M, Sörensen H, Zeidler H, Thriene W, Sieper J: Treatment of active ankylosing spondylitis with infliximab: a randomised controlled multicentre trial. Lancet. 2002, 359: 1187-1193. 10.1016/S0140-6736(02)08215-6.PubMedGoogle Scholar
- Braun J, Brandt J, Listing A, Zink A, Alten R, Burmester G, Gromnica-Ihle E, Kellner H, Schneider M, Sörensen H, Zeidler H, Sieper J: Two year maintenance of efficacy and safety of infliximab in the treatment of ankylosing spondylitis. Ann Rheum Dis. 2005, 64: 229-234. 10.1136/ard.2004.025130.PubMed CentralPubMedGoogle Scholar
- Braun J, Baraliakos X, Brandt J, Listing J, Zink A, Alten R, Burmester G, Gromnica-Ihle E, Kellner H, Schneider M, Sörensen H, Zeidler H, Sieper J: Persistent clinical response to anti-TNF antibody infliximab in patients with ankylosing spondylitis over 3 years. Rheumatology (Oxford). 2005, 44: 670-676. 10.1093/rheumatology/keh584.Google Scholar
- Braun J, Baraliakos X, Listing J, Fritz C, Alten R, Burmester G, Krause A, Schewe S, Schneider M, Sörensen H, Zeidler H, Sieper J: Persistent clinical efficacy and safety of anti-tumour necrosis factor-α therapy with infliximab in patients with ankylosing spondylitis over 5 years: evidence for different types of response. Ann Rheum Dis. 2008, 67: 340-345. 10.1136/ard.2007.075879.PubMedGoogle Scholar
- van der Heijde D, Dijkmans B, Geusens P, Sieper J, DeWoody K, Williamson P, Braun J, Ankylosing Spondylitis Study for the Evaluation of Recombinant Infliximab Therapy Study Group: Efficacy and safety of infliximab in patients with ankylosing spondylitis. Results of a randomized, placebo-controlled trial (ASSERT). Arthritis Rheum. 2005, 52: 582-591. 10.1002/art.20852.PubMedGoogle Scholar
- Baraliakos X, Listing J, Brandt J, Haibel H, Rudwaleit M, Sieper J, Braun J: Radiographic progression in patients with ankylosing spondylitis after 4 yrs of treatment with the anti-TNF-alpha antibody infliximab. Rheumatology (Oxford). 2007, 46: 1450-1453. 10.1093/rheumatology/kem166.Google Scholar
- van der Heijde D, Landewé R, Einstein S, Ory P, Vosse D, Ni L, Lin SL, Tsuji W, Davis JC: Radiographic progression of ankylosing spondylitis after up to two years of treatment with etanercept. Arthritis Rheum. 2008, 58: 1324-1331. 10.1002/art.23471.PubMedGoogle Scholar
- Barkham N, Keen HI, Coates LC, O’Connor P, Hensor E, Fraser AD, Cawkwell LS, Bennett A, McGonagle D, Emery P: Clinical and imaging efficacy of infliximab in HLA-B27–positive patients with magnetic resonance imaging-determined early sacroiliitis. Arthritis Rheum. 2009, 60: 946-954. 10.1002/art.24408.PubMedGoogle Scholar
- Rosenbaum JT: Acute anterior uveitis and spondyloarthropathies. Rheum Dis Clin North Am. 1992, 18: 143-151.PubMedGoogle Scholar
- Mielants H, Veys EM, Cuvelier C, de Vos M: Course of gut inflammation in spondylarthropathies and therapeutic consequences. Baillière Clin Rheumatol. 1996, 10: 147-164. 10.1016/S0950-3579(96)80010-0.Google Scholar
- Braun J, Baraliakos X, Listing J, Davis J, van der Heijde D, Haibel H, Rudwaleit M, Sieper J: Differences in the incidence of flares or new onset of inflammatory bowel diseases in patients with ankylosing spondylitis exposed to therapy with anti-tumor necrosis factor alpha agents. Arthritis Rheum. 2007, 57: 639-647. 10.1002/art.22669.PubMedGoogle Scholar
- Visvanathan S, van der Heijde D, Deodhar A, Wagner C, Baker DG, Han J, Braun J: Effects of infliximab on markers of inflammation and bone turnover and associations with bone mineral density in patients with ankylosing spondylitis. Ann Rheum Dis. 2009, 68: 175-182. 10.1136/ard.2007.084426.PubMed CentralPubMedGoogle Scholar
- Antoni CE, Kavanaugh A, Kirkham B, Tutuncu Z, Burmester GR, Schneider U, Furst DE, Molitor J, Keystone E, Gladman D, Manger B, Wassenberg S, Weier R, Wallace DJ, Weisman MH, Kalden JR, Smolen J: Sustained benefits of infliximab therapy for dermatologic and articular manifestations of psoriatic arthritis: results from the infliximab multinational psoriatic arthritis controlled trial (IMPACT). Arthritis Rheum. 2005, 52: 1227-1236. 10.1002/art.20967.PubMedGoogle Scholar
- Antoni C, Krueger GG, de Vlam K, Birbara C, Beutler A, Guzzo C, Zhou B, Dooley LT, Kavanaugh A, IMPACT 2 Trial Investigators: Infliximab improves signs and symptoms of psoriatic arthritis: results of the IMPACT 2 trial. Ann Rheum Dis. 2005, 64: 1150-1157. 10.1136/ard.2004.032268.PubMed CentralPubMedGoogle Scholar
- Kavanaugh A, Krueger GG, Beutler A, Guzzo C, Zhou B, Dooley LT, Mease PJ, Gladman DD, de Vlam K, Geusens PP, Birbara C, Halter DG, Antoni C, IMPACT 2 Study Group: Infliximab maintains a high degree of clinical response in patients with active psoriatic arthritis through 1 year of treatment: results from the IMPACT 2 trial. Ann Rheum Dis. 2007, 66: 498-505. 10.1136/ard.2006.058339.PubMed CentralPubMedGoogle Scholar
- Kavanaugh A, Antoni CE, Gladman DD, Wassenberg S, Zhou B, Beutler A, Keenan G, Burmester G, Furst DE, Weisman MH, Kalden JR, Smolen J, van der Heijde D: The infliximab multinational psoriatic arthritis controlled trial (IMPACT): results of radiographic analyses after 1 year. Ann Rheum Dis. 2006, 65: 1038-1043. 10.1136/ard.2005.045658.PubMed CentralPubMedGoogle Scholar
- Krueger GG, Antoni C, Bala M, Yan S, Zhao N, Beutler A, Guzzo C, Kavanaugh A: The correlation of skin and joint response in patients with psoriatic arthritis treated with infliximab [abstract]. Ann Rheum Dis. 2005, 64 (Suppl III): 319-Google Scholar
- Rich P, Griffiths CEM, Reich K, Nestle FO, Scher RK, Li S, Xu S, Hsu MC, Guzzo C: Baseline nail disease in patients with moderate to severe psoriasis and response to treatment with infliximab during 1 year. J Am Acad Dermatol. 2008, 58: 224-231. 10.1016/j.jaad.2007.07.042.PubMedGoogle Scholar
- Raffayova H, Kungurov N, Kubanova A, Baranauskaite A, Venalis A, Helmle L, Srinivasan S, Nasonov E: A randomized, multicenter, international, open-label study of infliximab plus methotrexate versus methotrexate alone for the treatment of methotrexate-naïve subjects with early, severe psoriatic arthritis (RESPOND trial). Presented at: American College of Rheumatology/Association of Rheumatology Health Professionals (ACR/ ARHP) Scientific Meeting, October 16–21, 2009, Philadelphia, Pennsylvania, USA [abstract]. Arthritis Rheum. 2009, 60 (Suppl 10):
- Remicade (Infliximab) Summary of Product Characteristics, November 2009. European Medicines Agency. [http://emc.medicines.org.uk/]
- Enbrel (Etanercept) Summary of Product Characteristics, July 2009. European Medicines Agency. [http://emc.medicines.org.uk/]
- Humira (Adalimumab) Summary of Product Characteristics, September 2009. European Medicines Agency. [http://emc.medicines.org.uk/]
- Gibofsky A, Palmer W, Keystone EC, Schiff MH, Feng JY, Baumgartner S, Markenson JA: Safety profiles of disease-modifying anti-rheumatic drugs and biologics in patients with rheumatoid arthritis: observations from the RADIUS registry. Presented at: American College of Rheumatology/ Association of Rheumatology Health Professionals (ACR/ARHP) Scientific Meeting, October 16–21, 2009, Philadelphia, Pennsylvania, USA [abstract]. Arthritis Rheum. 2009, 60 (Suppl 10):
- Curtis JR, Chen L, Cush JJ, Dao KH, Delzell E, Furst DE, Greenberg J, Hochberg MC, Jain A, Kremer JM, Patkar N, Solomon DH: The risk for hospitalized and outpatient infections related to anti-TNF therapy and newer biologics. Presented at: American College of Rheumatology/Association of Rheumatology Health Professionals (ACR/ARHP) Scientific Meeting, October 16–21, 2009, Philadelphia, Pennsylvania, USA [abstract]. Arthritis Rheum. 2009, 60 (Suppl 10):
- Dixon WG, Watson K, Lunt M, Hyrich KL, Silman AJ, Symmons DP: British Society for Rheumatology Biologics Register: Rates of serious infection, including site-specif c and bacterial intracellular infection, in rheumatoid arthritis patients receiving anti-tumor necrosis factor therapy: results from the British Society for Rheumatology Biologics Register. Arthritis Rheum. 2006, 54: 2368-2376. 10.1002/art.21978.PubMedGoogle Scholar
- Tubach F, Salmon D, Ravaud P, Allanore Y, Goupille P, Bréban M, Pallot-Prades B, Pouplin S, Sacchi A, Chichemanian RM, Bretagne S, Emilie D, Lemann M, Lortholary O, Mariette X, Research Axed on Tolerance of Biotherapies Group: Risk of tuberculosis is higher with anti-tumor necrosis factor monoclonal antibody therapy than with soluble tumor necrosis factor receptor therapy: the three-year prospective French Research Axed on Tolerance of Biotherapies registry. Arthritis Rheum. 2009, 60: 1884-1894. 10.1002/art.24632. erratum Arthritis Rheum 2009, 60:2540PubMed CentralPubMedGoogle Scholar
- Westhovens R, Yocum D, Han J, Berman A, Strusberg I, Geusens P, Rahman MU, START Study Group: The safety of infliximab, compared with background treatments, among patients with rheumatoid arthritis and various comorbidities. Arthritis Rheum. 2006, 54: 1075-1086. 10.1002/art.21734.PubMedGoogle Scholar
- Keystone E: Advances in targeted therapy: safety of biological agents. Ann Rheum Dis. 2003, 62 (Suppl II): S34-S36.Google Scholar
- Listing J, Strangfeld A, Kary S, Rau R, von Hinueber U, Stoyanova-Scholz M, Gromnica-Ihle E, Antoni C, Herzer P, Kekow J, Schneider M, Zink A: Infections in patients with rheumatoid arthritis treated with biologic agents. Arthritis Rheum. 2005, 52: 3403-3412. 10.1002/art.21386.PubMedGoogle Scholar
- Keystone E: Safety of biologic therapies – an update. J Rheumatol. 2005, 32 (Suppl 74): 8-12.Google Scholar
- Khanna D, McMahon M, Furst DE: Safety of tumour necrosis factor-α antagonists. Drug Safe. 2004, 27: 307-324. 10.2165/00002018-200427050-00003.Google Scholar
- Baecklund E, Iliadou A, Askling J, Ekbom A, Backlin C, Granath F, Catrina AI, Rosenquist R, Feltelius N, Sundström C, Klareskog L: Association of chronic inflammation, not its treatment, with increased lymphoma risk in rheumatoid arthritis. Arthritis Rheum. 2006, 54: 692-701. 10.1002/art.21675.PubMedGoogle Scholar
- Periodic Safety Update Report (PSUR) 18. 2008, Horsham, PA: Centocor, Inc.
- Remicade (infliximab) Summary of Clinical Safety. Module 2.7.4. Horsham, PA: Centocor, Inc., 244-254. July 2004 and August 2005
- Wiens A, Correr CJ, Venson R, Grochocki MC, Otuki MF, Pontarolo R: A meta-analysis of the efficacy and safety of using infliximab for the treatment of rheumatoid arthritis. Clin Rheumatol. 2009, 28: 1365-1373. 10.1007/s10067-009-1233-9.PubMedGoogle Scholar
- Singh JA, Christensen R, Wells GA, Suarez-Almazor ME, Buchbinder R, Lopez-Olivo MA, Ghogomu ET, Tugwell P: A network meta-analysis of randomized controlled trials of biologics for rheumatoid arthritis: a Cochrane overview. CMAJ. 2009, 181: 787-796. 10.1503/cmaj.091391.PubMed CentralPubMedGoogle Scholar
- Bradley JR: TNF-mediated inflammatory disease. J Pathol. 2008, 214: 149-160. 10.1002/path.2287.PubMedGoogle Scholar
- Giardina AR, Ferrante A, Ciccia F, Impastato R, Miceli MC, Principato A, Triolo G: A 2-year comparative open label randomized study of efficacy and safety of etanercept and infliximab in patients with ankylosing spondylitis. Rheumatol Int. 2010, 30: 1437-1440. 10.1007/s00296-009-1157-3.PubMedGoogle Scholar
- Braun J, Brandt J, Listing J, Zink A, Alten R, Burmester G, Golder W, Gromnica-Ihle E, Kellner H, Schneider M, Sörensen H, Zeidler H, Reddig J, Sieper J: Long-term efficacy and safety of infliximab in the treatment of ankylosing spondylitis: an open, observational, extension study of a 3-month, randomized, placebo-controlled trial. Arthritis Rheum. 2003, 48: 2224-2233. 10.1002/art.11104.PubMedGoogle Scholar
- Smolen JS, Kay J, Doyle MK, Landewé R, Matteson EL, Wollenhaupt J, Gaylis N, Murphy FT, Neal JS, Zhou Y, Visvanathan S, Hsia EC, Rahman MU: GO-AFTER Study Investigators: Golimumab in patients with active rheumatoid arthritis after treatment with TNF-α inhibitors (GO-AFTER study): a multicentre, randomized, double-blind, placebo-controlled, phase III trial. Lancet. 2009, 374: 210-221. 10.1016/S0140-6736(09)60506-7.PubMedGoogle Scholar
- Cohen SB, Emery P, Greenwald MW, Dougados M, Furie RA, Genovese MC, Keystone EC, Loveless JE, Burmester GR, Cravets MW, Hessey EW, Shaw T, Totoritis MC, REFLEX Trial Group, REFLEX Trial Group: Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum. 2006, 54: 2793-2806. 10.1002/art.22025.PubMedGoogle Scholar
- Emery P, Fleischmann R, Filipowicz-Sosnowska A, Schechtman J, Szczepanski L, Kavanaugh A, Racewicz AJ, van Vollenhoven RF, Li NF, Agarwal S, Hessey EW, Shaw TM: DANCER Study Group; DANCER Study Group: The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment. Arthritis Rheum. 2006, 54: 1390-1400. 10.1002/art.21778.PubMedGoogle Scholar
- Keystone E, Emery P, Peterfy CG, Tak PP, Cohen S, Genovese MC, Dougados M, Burmester GR, Greenwald M, Kvien TK, Williams S, Hagerty D, Cravets MW, Shaw T: Rituximab inhibits structural joint damage in patients with rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitor therapies. Ann Rheum Dis. 2009, 68: 216-221. 10.1136/ard.2007.085787.PubMedGoogle Scholar
- Genovese MC, Schiff M, Luggen M, Becker JC, Aranda R, Teng J, Li T, Schmidely N, Le Bars M, Dougados M: Efficacy and safety of the selective co-stimulation modulator abatacept following 2 years of treatment in patients with rheumatoid arthritis and an inadequate response to anti-tumour necrosis factor therapy. Ann Rheum Dis. 2008, 67: 547-554. 10.1136/ard.2007.074773.PubMedGoogle Scholar
- Emery P, Keystone E, Tony HP, Cantagrel A, van Vollenhoven R, Sanchez A, Alecock E, Lee J, Kremer J: IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial [RADIATE study]. Ann Rheum Dis. 2008, 67: 1516-1523. 10.1136/ard.2008.092932.PubMed CentralPubMedGoogle Scholar