Infliximab: 12 years of experience

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.

inter fere with the associated radiographic changes [19] and are the cornerstone of symptom control, even though not all patients benefi t [20]. In mild PsA, nonsteroidal anti-infl ammatory drugs may also be suffi cient 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 antirheumatic drugs (DMARDs) (for example, sulphasalazine, methotrexate (MTX), lefl unomide) 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. Th ese drugs also are eff ective in PsA; they have limited or no effi cacy in axial AS, however, despite being eff ective in the other chronic infl ammatory joint diseases and in peripheral arthritis of patients with AS [21,22].
Corticosteroids also have DMARD properties [23]. 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-specifi c infl ammation, but systemic use in axial AS is not supported by available evidence [22]. Long-term use of these drugs is limited by their side-eff ect profi le [24,25].
Although synthetic DMARDs are eff ective in many patients with RA and PsA, a considerable number require a diff erent approach. Until the advent of biologic therapies, alternative medications did not exist and treatments often did not suffi ciently control symptoms, joint damage and impairment of physical function. Consequently, confi ne ment to a wheelchair and rapid loss of work ability were not infrequent. As understanding of the central infl am matory mechanism has improved and the role of TNF has been elucidated, however, therapies have shifted from mere interference with the magnitude of the infl am ma tory response to its abrogation and thus toward halting progression of joint damage and restoring physical function and work ability. Interference with the pro infl ammatory cytokine cascade using TNF inhibitors, but also interfering with other biological targets, may rapidly suppress and control infl ammation and thereby prevent irreversible tissue damage and disability [26].
For a long time, only three TNF inhibitors were available for the treatment of RA, AS and PsA: adalimumab, etanercept and infl iximab. Etanercept and infl iximab 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][28][29].
Infl iximab was the fi rst biologic agent shown to be effi cacious in RA, AS and PsA [30]. Later studies revealed that combination infl iximab plus MTX tended to be superior to monotherapy [31], dramatically aff ected joint damage [32] and inhibited joint damage even in the absence of a clinical response, thus fostering the dissociation hypothesis (see Early rheumatoid arthritis, below) [33]. Th at these infl iximab data were paradigmatic for the new class of TNF inhibitors has been shown in studies of other agents that fully confi rmed the infl iximab results [34][35][36][37]. An examination of the wealth of clinical data amassed over 12 years of experience with infl iximab from its fi rst licensing in Crohn's disease (1998 in the United States) can thus tell us much about the state -and futureof TNF inhibitor therapy in RA, AS and PsA.
Whilst etanercept is not suffi ciently effi cacious in Crohn's disease, the three TNF inhibitors appear to have similar effi cacy in RA, PsA and AS. In the present review, we focus on infl iximab as a prototypical example for these eff ects.

Long-term infl iximab use
Th e available data reveal that infl iximab provides rapid and prolonged suppression of infl ammation and inhibits progression of joint damage in many patients with RA and PsA [38][39][40][41]. In addition, TNF inhibition -such as that with infl iximab -induces almost complete and sustained resolution of spinal infl ammation in many patients with AS [42,43].

Effi cacy in rheumatoid arthritis
Infl iximab has emerged as a highly eff ective treatment in both early and established RA [32,40,44,45].

Early rheumatoid arthritis
Effi cacy in patients with early RA is critically important, since it is now understood that progression in infl ammation severity and joint damage is slow in some patients and more rapid in others [46,47]. Rapidly progressing patients should be identifi ed early in their disease course because they may benefi t from more intensive therapy. Th e best predictors of rapidly progressing RA are currently the number of swollen joints, the presence of autoantibodies (high-titre rheumatoid factor and anticitrullinated peptide antibodies) and elevated acute-phase response (as measured by the erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) level) [47][48][49][50].
In the ASPIRE trial, the effi cacy of infl iximab (3 or 6 mg/kg infusions at weeks 0, 2 and 6 and every 8 weeks thereafter) plus MTX (titrated up to 20 mg/week by week 4) was assessed in 1,004 MTX-naïve patients with early (≥3 months, ≤3 years), moderate-to-severe active RA over a 54-week period [45]. Infl iximab plus MTX provided signifi cantly greater clinical, radiological and func tional benefi ts than MTX alone in patients with early RA. At week 54 there were no signifi cant diff erences in clinical effi cacy between the infl iximab groups -but compared with MTX alone, the American College of Rheumatology (ACR)-N, ACR20, ACR50 and ACR70 response rates were signifi cantly higher with infl iximab. From baseline to week 54, the change in radiological progression was signifi cantly less in patients receiving infl iximab 3 mg/kg plus MTX and infl iximab 6 mg/kg plus MTX than in those receiving MTX alone (van der Heijde-Sharp scores, 0.4 ± 5.8, 0.5 ± 5.6 and 3.7 ± 9.6, respectively; Figure 1). In addition, improvements in physical function (Health Assessment Questionnaire) were signifi cantly greater in both infl iximab treatment groups compared with the MTX-alone group [45].
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 [50]. In patients receiving MTX alone, a higher swollen joint count, higher ESR and CRP levels and higher rheumatoid factor levels at baseline were signifi cantly correlated with greater joint damage at week 54. Th is corre lation was abrogated in patients treated with infl iximab plus MTX because of the marked eff ects on joint damage irrespective of the underlying disease activity or auto antibody state. An additional analysis that adjusted for baseline demographic and other clinical charac ter istics still found an increased ESR and increased swollen joint counts to be signifi cantly 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 infl iximab-plus-MTX group. Th e 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 MTXalone 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 infl iximab-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) [50]. In the infl iximab-plus-MTX group, however, the baseline CRP level and ESR had little association with radiographic progression; infl iximab 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 eff ective in preventing radiological damage.
Importantly, only patients attaining stringent remission by the criteria of the simplifi ed disease activity index at week 14 did not progress radiologically irrespective of therapy; while those on MTX, when attaining low or higher categories of disease activity at week 14, progressed with increasing disease activity state. In contrast, infl iximab plus MTX halted radiologic progression even if patients had achieved low or moderate disease activity at week 14 [51], confi rming previous notions that this treatment dissociates the traditional link between infl ammation and destruction [33]. According to this dissociation hypothesis, treatment reduces the impact of infl ammation on destruction to the extent that some progression of damage is seen only in patients with very high levels of un suppressed infl ammation ( Figure 2). Whether stringent remission was achieved at 3 months or 1 year, there was an almost linear increase in progression of joint damage with MTX, reaching approximately 6 radiographic score points with high disease activity ( Figure 2). Th e radiographic progres sion was not only fully or mostly abrogated with infl iximab plus MTX in remission, but also in low and even moderate disease activity [51]. Nevertheless, even with combination therapy there was a link between disease activity and progression of joint damage, although the slope was dramatically diverted. Th erefore, although there is still a connection between infl ammation and destruction, TNF-inhibitor-plus-MTX treatment reduces the impact of infl ammation on destruction to the extent that progressive damage is seen only in cases with high levels of unsuppressed infl ammation -but even then to a lesser degree than upon treatment with MTX alone.

Rapidly progressing disease in rheumatoid arthritis
Although the effi cacy of MTX is appreciable, patients with rapidly progressing disease (RPD) may obtain additional benefi t from more intensive therapy. Th e 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 benefi ts with the early addition of infl iximab [33,52,53]. Infl iximab 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 effi cacy [54,55]. Th e GUEPARD trial, however, showed that rapid addition of a TNF inhibitor to a DMARD -if the latter has not been suffi ciently eff ective within 3 to 6 monthsprovides clear-cut benefi t similar to that derived from starting with combination anti-TNF and DMARD therapy [56].
Th e prediction of RPD in patients with RA represents an intriguing challenge for tailoring biologic therapy and an exciting development in the fi eld. Two pilot risk models for predicting RPD in RA patients were recently proposed [47]. ASPIRE data were used to defi ne RPD and to identify baseline risk factors; in line with previous data [50], these risk factors were swollen joint counts, rheumatoid factor levels, CRP levels and the ESR. Th e 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 identifi ed subpopulations of RA patients at higher predicted risk of RPD, particularly those who were MTXnaïve with early disease. Additional develop ment 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.
Very early transient treatment with infl iximab has been shown to be eff ective in early, poor-prognosis RA. In a randomised, double-blind study, 20 previously untreated patients with early (<12 months), poor-prognosis RA (defi ned by the Persistent Infl ammatory Symmetrical Arthritis scoring system) were randomised to receive infl iximab plus MTX (3 mg/kg) or placebo plus MTX for 12 months [53]. After 1 year of treatment, magnetic resonance imaging (MRI) evidence of synovitis and joint damage was reduced (with signifi cantly fewer new erosions) in infl iximab-treated patients compared with MTX-alone patients. Signifi cantly more patients receiving infl iximab plus MTX than those receiving MTX alone were ACR50 responders (78% and 40%, respectively) and ACR70 responders (67% and 30%, respectively). Furthermore, greater improvements in physical function (Health Assessment Questionnaire) and quality of life (QoL) (determined by the Rheumatoid Arthritis Quality of Life questionnaire) were seen throughout the 12 months of treatment in the infl iximab-plus-MTX group. Treatment was stopped after 1 year, and the patients were then followed for another 12 months. One year post infl iximab-plus-MTX therapy, clinical response was sustained in 70% of the patients in this group, with a median DAS28 of 2.05. Signifi cant improvements in function and QoL were also sustained [53].
Th e BeST study, a randomised trial that assessed four diff erent treatment strategies in 508 patients with recentonset RA, showed similar results. Over year 1, patients receiving initial combination therapy with tapered highdose prednisone plus MTX plus sulphasalazine (group 3, 133 patients) or infl iximab 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 diff erences at most time points were signifi cant [57]. Th e BeST study also demonstrated that clinical and functional benefi ts of infl iximab plus MTX were maintained over 4 years [58,59]. In addition, the study provided important information about remission in RA. After 2 years of infl iximab 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 [60]. Moreover, signifi cantly more patients in this group (16%) maintained clinical remission off infl iximab than in groups 2 and 3, who received infl iximab later in the course of their treatment (6% and 7%, respectively; P <0.05 for all) [58]. (Th e diff erence between groups 1 and 4 was not signifi cant.) 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 infl iximab -20 out of year, including all selected baseline risk factors, except (a) erythrocyte sedimentation rate (ESR) or (b) C-reactive protein (CRP), generated from the ASPIRE early rheumatoid arthritis dataset. Numbers in each cell represent the percentage (95% confi dence interval) of patients who had RRP out of all patients who have the baseline characteristics and receive the initiated treatment as indicated. Predicted probability of RRP: blue, 0 to 9%; green, 10 to 19%; yellow, 20 to 29%; orange, 30 to 39%; red, 40 to 100%. A higher percentage indicates more severe radiographic progression of joint damage. IFX, infl iximab; mono, monotherapy; MTX, methotrexate; RF, rheumatoid factor; SJC, swollen joint count. Reprinted with permission from [47].
Six-year BeST data were presented at the October 2009 ACR scientifi c 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 [61].

Established rheumatoid arthritis
Infl iximab has also demonstrated effi cacy in patients with established RA. Th e ATTRACT study evaluated the effi cacy of infl iximab 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 infl iximab at weeks 0, 2 and 6 and then at 4 or 8 weeks thereafter in combination with MTX. Th is randomised, double-blind, placebo-controlled phase III study showed that infl iximab plus MTX is eff ective in controlling the signs and symptoms of established RA. After 30 weeks of assessment, 51.8% of patients receiving any dose of infl iximab 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 infl iximab-plus-MTX patients achieved a 50% improvement from baseline compared with only 5% of placeboplus-MTX patients [44].
Th e ATTRACT study also showed that infl iximab plus MTX signifi cantly reduced progression of structural joint damage in RA compared with MTX alone [32]. After 1 year of treatment, infl iximab plus MTX prevented the progressive joint damage associated with infl ammation and resulted in a signifi cant reduction in progression of radiological changes, using the modifi ed van der Heijde-Sharp score, in a signifi cant proportion of patients compared with placebo plus MTX (van der Heijde-Sharp scores, 1.63 and 6.95, respectively; Figure 4). Interestingly, the ATTRACT study also assessed the relationship between infl ammation and joint destruction in patients not suffi ciently responding clinically to infl iximab plus MTX (ACR20 nonresponders), and found that infl iximab plus MTX still provided inhibition of structural damage compared with placebo (plus insuffi ciently eff ective MTX) [32]. Th ese results suggest that these two disease measures, which are usually tightly linked, are dissociated under this treatment ( Figure 5) [33]. Th is suggestion was confi rmed when it was shown that joint damage was retarded even in patients who had no improvement in disease activity measures [33], and similar fi ndings were made in early RA [51], as discussed above (see Figure 2).
Studies of long-term infl iximab therapy have demonstrated that the positive eff ects on joint damage are sustained. For example, at the end of ATTRACT year 2, the data showed signifi cant improvements in clinical response and inhibition of progressive joint damage with infl iximab plus MTX compared with placebo (plus insuffi ciently eff ective MTX) [40]. Indeed, patients receiv ing infl iximab plus MTX not only continued to have good clinical responses and inhibition of progressive joint damage during that 2-year period, but also experienced signifi cant improvements in physi cal 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 insuffi ciently eff ective MTX) [40].
Another study of 511 patients with longstanding, refractory RA found that long-term maintenance therapy with infl iximab continues to reduce disease activity [62]. Th e researchers also examined 4-year compliance rates and found that a majority of patients continued treatment. Infl iximab was well tolerated, and 61.6% of patients were still receiving this treatment at the 4-year point [62]. Th e main reasons for discontinuing therapy were lack of effi cacy (13.6%) and safety issues (16.9%). Th is study is in line with smaller studies demonstrating 3-year infl iximab continuation rates of 58 to 75% [63][64][65][66][67][68].

Effi cacy in ankylosing spondylitis
Infl iximab induces a rapid reduction in disease activity in patients with AS. Th e TNF-inhibitor aff ects the underlying infl ammation of both articular and extra-articular mani fes tations of AS [2,12,69,70]. Signifi cant effi cacy compared with placebo was fi rst reported by Braun and colleagues in a random ised, double-blind study of 69 patients with active AS [71]. After 12 weeks of treatment, 53% of patients receiving infl iximab (5 mg/kg) had ≥50% reduction in disease activity, as measured by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), compared with 9% of patients receiving placebo ( Figure 6). Th e physical function, as measured by the Bath Ankylosing Spondylitis Functional Index, and QoL (Short-form 36 Health Survey) also signifi cantly improved in infl iximab-treated patients compared with placebo-treated patients (both P <0.0001).
After the 12-week, placebo-controlled phase of this study, all patients entered a 3-year open-label extension. Sixty-two per cent (43 out of 69 patients) completed 3 years of infl iximab treatment and then discontinued to allow assessment of the time to fl are. Most patients relapsed within 18 to 24 weeks, and 42 out of 43 patients restarted infl iximab, with most regaining effi cacy. Good clinical response was sustained for 5 years, with 63%, 58%, 61% and 63% of patients achieving at least a 50% reduction in disease activity (BASDAI) from baseline after 1, 2, 3 and 5 years of treatment, respectively (Figure 7) [72][73][74]. Th e Assessment of the Spondylo-Arthritis International Society (ASAS) ASAS40 response was seen in 75% and 63% of patients at the end of years 3 and 5, respectively. Similarly, an ASAS5/6 response was achieved in 76% and 71% of patients at the end of years 3 and 5, respectively (see Figure 7). Low disease activity (BASDAI value <3 units) was attained in 57.9% of patients after 5 years; the mean BASDAI was 2.5 ± 1.9 (baseline, 6.4; at 3 years, 2.5) [74]. Partial clinical remission (score ≤2 in each of the four ASAS domains) was reached by 37% and 34% of patients at the end of years 3 and 5, respectively [74]. Th e time to fl are during discontinuation suggested that continuous therapy is necessary to achieve a lasting eff ect in patients with severe, active AS.
Th e ASSERT trial also provided evidence for the effi cacy and safety of infl iximab (5 mg/kg) in patients with AS [75]. In this randomised, placebo-controlled study of 279 patients, the clinical response was rapid, as early as 2 weeks, and was sustained over 24 weeks, with 61.2% of infl iximab patients achieving ASAS20 compared with 19.2% of placebo patients at week 24 (P <0.001). In addition, 47% of patients in the infl iximab group were ASAS40 responders compared with 12% of patients in the placebo group at week 24 ( Figure 8). Signifi cant improvements in the BASDAI and the Bath Ankylosing Spondylitis Functional Index were also seen in the patients receiving infl iximab.
Infl iximab induced a pronounced reduction in spinal infl ammation in MRI examinations of patients in the ASSERT study. Th e MRI activity score improved significantly more in infl iximab-treated patients (mean, 5.02; median, 2.72) compared with placebo patients (mean, 0.60; median, 0.0) from baseline to week 24 [42]. Most infl iximab-treated patients achieved complete resolution of spinal infl ammation (Figure 9).
Th e reduction in spinal infl ammation with infl iximab was sustained over the long term. At week 24 of the ASSERT study, placebo patients crossed over to receive infl iximab (5 mg/kg) as part of an open-label extension [43]. Short-tau inversion recovery MRI images were taken at baseline and at weeks 24 and 102. Patients in the infl iximab 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 [43]. Patients in the placebo group improved after crossing over to receive infl iximab at week 24, and subsequently achieved similar levels of spinal infl ammation reduction by week 102 as patients receiving infl iximab from the start. Interestingly, however, and contrasting with results in RA, infl iximab does not appear to halt progression of radiographic changes; likewise, structural changes also progressed on etanercept treatment, contrasting the clinical eff ects [75,76].
In another study, 40 patients in whom early sacroiliitis had been determined by MRI were randomised in a double-blind manner to infl iximab 5 mg/kg or placebo at 0, 2, 6 and 12 weeks. Both MRI and clinical assessment at 16 weeks showed signifi cantly reduced disease activity. For example, signifi cantly more lesions resolved in the infl iximab group (P <0.001), while signifi cantly more new lesions developed in the placebo group (P = 0.004) [77].
Infl iximab 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 [78], and a meta-analysis showed that infl iximab signifi cantly reduced the incidence of uveitis compared with placebo (P = 0.005) [70]. Subclinical infl ammation of the gut is present in up to 60% of AS patients, and this infl ammation can evolve into fullblown infl ammatory bowel disease [79]. Another metaanalysis showed that infl iximab signifi cantly reduced incidence rates of fl ares or new-onset infl ammatory bowel disease compared with etanercept (P = 0.001) and adalimumab (P = 0.02) [80]. Similarly, a subanalysis of the ASSERT trial's 24-week phase demonstrated signifi cant increases in mean spinal bone density in AS patients treated with infl iximab compared with placebo (P <0.001) [81]. Th e eff ects on vertebral fracture, however, are not yet known.

Effi cacy in psoriatic arthritis
Infl iximab is eff ective in treating various aspects of PsA, including joint symptoms and extra-articular manifestations such as dactylitis, enthesitis and nail disease, as well  Smolen and Emery Arthritis Research & Therapy 2011, 13(Suppl 1):S2 http://arthritis-research.com/supplements/13/S1/S2 as psoriatic skin involvement. Th e effi cacy of infl iximab in PsA was assessed in the IMPACT 1 and IMPACT 2 studies [82,83]. Th ese studies were similar in design, with a 16-week to 24-week, randomised, placebo-controlled phase, after which all patients received infl iximab 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.
Signifi cant improvements were observed in the signs and symptoms of articular disease. In the IMPACT 1 study (n = 104), 65.4% of patients treated with infl iximab were ACR20 responders at week 16 compared with only 9.6% of placebo patients (Figure 10a) [82]. Furthermore, 46.2% and 28.8% of infl iximab-treated patients were ACR50 and ACR70 responders, respectively, compared with none of the placebo patients at week 16. Similar improvements were seen in the IMPACT 2 study (n = 200): 58% of infl iximab-treated patients and 11% of placebo patients achieved an ACR20 response at week 14 (P <0.001) [83]. Forty-one per cent and 27% of patients in the infl iximab group were ACR50 and ACR70 responders, respectively, compared with 4% and 2% of placebo patients, respectively, at week 24. Th e improvement in joint symptoms was sustained throughout both studies (up to 54 weeks) [82,84]. In IMPACT 1, for example, the proportion of ACR20 responders in the group of placebo patients who crossed over to infl iximab treatment was similar to the proportion of ACR20 responders in the group of patients who received infl iximab from day 1: 68% and 69%, respectively (Figure 10b) [82].
Infl iximab also inhibits the radiological progression of joint damage in PsA [41,85]. During the placebocontrolled phase (weeks 1 to 24) of the IMPACT 2 study, radiographs of the hands and feet showed signifi cantly less progression of structural damage in infl iximab patients compared with placebo patients (mean change from baseline in modifi ed van der Heijde-Sharp score, -0.70 and 0.82, respectively) [41]. Th e mean annual progression rate at baseline was equivalent to 5.8 modifi ed van der Heijde-Sharp points/year for the overall study population, but the projected rate for the overall population post infl iximab was -1.79 [85]. In fact, 84.3% of the total patient population did not have radiographic progression after a year of infl iximab treatment [85].
Infl iximab 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 [84]. 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.
Additionally, infl iximab was eff ective in treating psoriatic skin symptoms. In the IMPACT 1 study, infl iximab-treated patients with a Psoriasis Area and Severity Index (PASI) score ≥2.5 at baseline had a mean improvement from baseline in PASI score of 86% compared with a 12% deterioration in placebo patients (P <0.001) [82]. Of these, 68% of infl iximab-treated patients achieved an improvement in PASI score ≥75% compared with none of the placebo patients (P <0.001). Improvements were maintained over 50 weeks (Figure 11). Similar fi ndings were observed in the IMPACT 2 study; 64% of patients with skin involvement treated with infl iximab achieved an improvement in PASI ≥75% compared with 2% of placebo patients (P <0.001) [83]. Interest ingly, another study observed a correlation between skin response and improvement in joint symptoms in PsA patients treated with infl iximab. Patients with a good skin response had a greater joint response than those with no skin response [86].
Th e EXPRESS trial was the fi rst large, controlled, phase III clinical study to use the Nail Psoriasis Severity Index tool in patients with psoriasis [87]. 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 Smolen and Emery Arthritis Research & Therapy 2011, 13(Suppl 1):S2 http://arthritis-research.com/supplements/13/S1/S2 history of PsA. At week 24, the mean percentage improve ments in nail bed scores in patients receiving infl iximab versus those receiving placebo were 69.2% and 18.4%, respectively; the percentage improve ments in nail matrix scores were 52.9% and -1.9%, respec tively (P <0.001). Signifi cant and comparable degrees of improvement were observed, regardless of baseline history of PsA. Th e Nail Psoriasis Severity Index values persevered in both groups at weeks 38 and 50 (placebo crossover to infl iximab occurred at week 24), also regardless of PsA history.
Th e recently concluded RESPOND trial investigated an aggressive strategy in early, severe polyarticular PsA [88]. Th is study compared the effi cacy and safety of infl iximab 5 mg/kg plus MTX with MTX alone in MTX-naïve subjects who had an inadequate response to steroids and nonsteroidal anti-infl ammatory drug therapy. Th e primary end point (ACR20 at week 16) was achieved in 44 out of 51 patients (86.3%) in the infl iximab-plus-MTX group compared with 32 out of 48 patients (66.7%) in the MTXalone group (P = 0.021). Th e ACR50 and ACR70 response rates at week 16 were also signifi cantly greater in the infl iximab-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 MTXalone group; P = 0.0015). Overall, patients receiving infl iximab 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.

Safety considerations
With 12 years of clinical use and the availability of national disease registries, the safety profi le of TNF inhibitors is well characterised. Serious adverse events (SAEs) with infl iximab include: the development of viral, fungal or bacterial infectious diseases (for example, tuberculosis (TB), listeriosis, sepsis, opportunistic infections due to Cryptococcus, Aspergillus and Pneumo cystis); 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); haemato logical 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 [89]. In general, as with effi cacy, the safety aspects of TNF inhibitors are similar [90,91], and registries compile data on all of the biologics. Th e risks are thus recognised and are increasingly understood.
In an assessment of safety profi les 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 [92]. Th e http://arthritis-research.com/supplements/13/S1/S2 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 [93]. Th ere was no signifi cant increase in the adjusted risk for overall infections associated with anti-TNF therapy compared with MTX, and the infection-related safety profi les 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 [94]. All patients had severe RA. Th e 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 infl iximab 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, respec tively). Th e incidence rate ratio, adjusted for baseline risk, for the TNF-inhibitor cohort compared with the DMARD cohort was 1.03 (95% confi dence interval, 0.68 to 1.57), suggesting similar risk levels between the two treatment groups. Th e types of serious infections were diff erent 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 [94]. Nevertheless, the data did show an increased risk of TB infection in patients treated with infl iximab and other anti-TNF therapies, although this risk might be lower with etanercept [95].
A large randomised, placebo-controlled trial assessed the risk of serious infections following infl iximab-plus-MTX therapy in patients with active RA [96]. Th e risk of serious infections in patients receiving infl iximab 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 [97].
A prospective cohort study of the German RA registry RABBIT compared the rates of infections in patients treated with the biologic agents infl iximab, etanercept and anakinra with the rates of infections in patients receiving conventional DMARDs. Among patients receiving infl iximab, 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 [98].
Th e 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 [99]. Th e 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 [100]. Currently, no clear association between infl iximab and lymphoma has been established [101]. Cumulatively, 565 cases of lymphoma development have been reported among more than 1 million patients since the launch of infl iximab. Th e cumulative rate for lymphoma per 100 patient-years since fi rst exposure is 0.017 [101]. Although a defi nitive conclusion regarding lymphoma risk with TNF inhibitors in general -and infl iximab 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 infl iximab is a human-plusmouse (that is, chimeric) antibody, anaphylaxis is possible. Anaphylactic reactions are uncommon in patients receiving infl iximab [89]. In clinical trials, 5,706 patients received 36,485 infl iximab 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 infl iximab compared with 1.6% for placebo. Th e majority of infusion reactions were mild to moderate (for example, nausea, headache, sweating, fl ushing). Th e rate of serious infusion reactions was 0.2% for infl iximab and zero for placebo [102,103]. Immunogenicity can also arise (incidence, 9 to 17%). Although the eff ect of immuno genicity on effi cacy is unclear, patients who develop immunogenicity may be at higher risk for infusion reactions [100].

Long-term safety data for infl iximab
Th e benefi t:risk profi le should be considered when selecting patients for infl iximab therapy. Th e safety profi le for infl iximab is well established, and the labelling explains all risks (the following excerpts address TB, hepatitis and pregnancy): Before starting treatment, all patients must be evalu ated for active and inactive ('latent') tuber-  [89] In RA, a meta-analysis of seven randomised controlled trials (n = 2,100 patients) of duration ≤1 year in patients receiving either infl iximab plus MTX or placebo plus MTX demonstrated that between-group diff erences for SAEs, serious infections, malignancy or death were not signifi cant. Th e between-group diff erence for infections was close to signifi cance (P = 0.06) [104]. Th e infl iximab group had signifi cantly more infusion reactions than the placebo group (P = 0.02). Th e number of withdrawals due to adverse events was also signifi cantly higher in the infl iximab 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), confi rmed that effi cacy is similar among the TNF inhibitors [105]. Adverse reactions are thought to be related to TNF blockade, and to represent class eff ects of these agents [106].
In AS, a recent head-to-head, 2-year trial of infl iximab 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. Th ere were no discontinuations for safety reasons and no opportunistic infections, TB, congestive heart disease, demyelina ting disorders, lupus-like syndrome or malignancy [107]. 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 infl iximab or placebo, most early adverse events were mild to moderate, except one case of TB and one case of allergic bronchio centric granulomatosis at 1 year [108]. At 3 years (n = 43), none of the six SAEs were considered causally related to infl iximab [73]. At 5 years (n = 38) there were no safety concerns, and about one-half of the initial patient cohort was still being successfully treated [74]. Th ese safety results are consistent with data from a large registry [94].
In PsA, the IMPACT 1 and IMPACT 2 studies demonstrated that infl iximab 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 placebocontrolled phase (weeks 0 to 16) and the crossover phase (weeks 16 to 50) [82]. In the IMPACT 2 study (n = 200), 67 out of 100 infl iximab patients (67%) experienced an adverse event through week 24 (prior to crossover) and 147 out of 173 combined-infl iximab patients (85%) experi enced an adverse event through week 54 [84]. Th rough week 54, 22 out of 173 patients (12.5%) in the combined group also experienced an SAE. Importantly, adverse event incidence in the combined-infl iximab 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 infl iximab treatment, the authors concluded that the beneft:risk ratio was positive.

Benefi t:risk profi le
Determining the benefi t:risk profi le 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 diff erent studies. Infl iximab, the drug of focus in the present review, has demonstrated effi cacy in all rheumatological conditions (RA, AS and PsA) as well as other infl ammatory disorders (Crohn's disease, ulcerative colitis and psoriasis), and no new or unexpected safety signals have arisen over the years. Potential risks exist, but infl iximab is generally well tolerated when clinicians appropriately select patients and adhere to indications and contraindications. Vigilance regarding important safety considera tions continues to be necessary, as is the need for adequate patient screening and monitoring.

Few questions remain
Research since 1990 has revealed that an immunemediated infl ammatory mechanism leading to the activation of proinfl ammatory cytokines underlies RA, AS and PsA. Th is knowledge has driven the development of anti-TNF agents. Today, TNF inhibitors eff ectively suppress and control the infl ammation 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, insuffi ciently respond or lose an initial good response to classic TNF inhibitors. In such patients, other TNF inhibitors, including golimumab [109], or other agents, such as the B-cell-depleting chimeric antibody rituximab [110][111][112], the T-cell costimulation inhibitor abatacept [113], or the IL-6 receptor inhibitor tocilizumab [114], may be eff ective.
Studies of the TNF inhibitor infl iximab stimulated most of the developments recognised today as pertinent for TNF inhibitors and also set the stage for other biologic agents. Th e fi rst randomised controlled study in a rheumatic disease reported the effi cacy of a single infusion of infl iximab in RA patients 16 years ago [30]. Over the 12 years that followed licensing of the fi rst TNF inhibitor for an infl ammatory disease, research has shown that, for most patients, infl iximab eff ectively treats signs and symptoms, provides rapid and prolonged suppression of infl ammation and may prevent long-term disease progression in RA, AS and PsA. In RA, infl iximab, like other TNF blockers, is highly eff ective for both early and established disease, and can induce clinical remission. Importantly, initial analysis shows that infl iximab can even maintain remission for approximately 1 year drug free in patients with early RA. In AS, infl iximab induces a rapid reduction in disease activity; and in PsA, infl iximab 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 longterm benefi ts with the early addition of infl iximab. Infl iximab has been shown to halt joint destruction even in these patients, and predicting RPD may allow tailoring of biologic therapy in the disease course.