When to initiate and discontinue biologic treatments for rheumatoid arthritis?

Review doi: 10.1111/j.1365-2796.2011.02355.x When to initiate and discontinue biologic treatments for rheumatoid arthritis? K. Chatzidionysiou & R. F. van Vollenhoven FromtheUnitforClinicalTherapy Research, Inflammatory Diseases, KarolinskaInstitutet, Stockholm, Sweden Abstract. Chatzidionysiou K, van Vollenhoven RF (Karolinska Institutet, Stockholm, Sweden). When to initiate and discontinue biologic treatments for rheumatoid arthritis (Review). JInternMed2011; 269:614 625. The introduction of biologic therapies heralded a new era in the treatment for chronic inflammatory autoimmune diseases of which rheumatoid arthritis is one of the most prevalent. From a scientific point of view, these therapies demonstrated that the targeting of individual cytokines or cell-surface markers is a very effective approach. For the physician, the appropriate selection of patients in whom these therapies should be initiated is critical, as is the even more contentious issue of whether these therapies can or should be discontinued in selected patients with excellent clinical responses. Whereas the former issue has been addressed in a large number of clinical trials and observational studies, the latter remains poorly investigated and is currently the subject of further study. Keywords: clinical trials, rheumatoid arthritis, therapeutics, treatments. Introduction Rheumatoid arthritis (RA) is a chronic inflammatory disease of unknown aetiology, which is generally considered to be autoimmune in nature, and is characterized by inflammation in the synovial tissues of the joints, primarily the small joints of the hands and feet but also larger joints such as the shoulders, elbows, knees and ankles. The disease affects around 0.8% of the adult population in Western societies, and although the incidence peaks during the fifth decade of life, it can affect individuals in all age groups. RA is generally chronic, although spontaneous remissions are seen in a minority of patients. When left unchecked, the disease causes severe symptoms in the form of pain, stiffness, malaise, and fatigue and progressive destruction of the cartilage and bone in the inflamed joints in the majority of patients. The aim of the treatment for RA must therefore be both to control the symptoms in the short term and to prevent the accrual of damage in the long term. Traditionally, treatment for RA has been based on the use of a small group of disease-modifying antirheumatic drugs (DMARDs), of which methotrexate (MTX) is the most widely used. The subsequent development of biologic DMARDs, known as biologics, as an alternative to conventional DMARDs is the subject of this review. Because of its relatively frequent occurrence in the population and the tendency of RA to cause progressive functional deterioration, leading to unemployment and exclusion of individuals from many societal roles, the disease has a large socio-economic impact, and this has become increasingly more important as expensive new therapies have been developed. Moreover, RA might serve as the prototype for a large number of chronic inflammatory diseases within rheumatology and the wider field of internal medicine. The landscape of RA treatment has unquestionably changed dramatically during the last decade. A deeper understanding of the pathophysiological and immunological mechanisms in RA has led to the development and introduction into daily clinical practice of biologic disease-modifying agents with, in some cases, tremendous effects in patients with severe RA whose disease was difficult to control with conventional DMARDs. To date, nine biologic agents have been approved for the treatment for RA: five inhibitors of tumour necrosis factor (TNF: i.e. infliximab, etanercept, adalimumab, golimumab and certolizumab pegol), the interleukin (IL)-1 blocker anakinra, the IL-6 blocker tocilizumab, the B-celldepleting agent rituximab and the T-cell co-stimulation inhibitor abatacept. In addition, more molecules with distinct mechanisms of action are currently being tested in laboratories and in clinical trials. In all cases, very good clinical efficacy and safety were documented in trials that led to regulatory approval. Some of these data will be discussed below. The 614 ª 2011The Association for the Publication ofthe Journalof InternalMedicine

biologics available for the treatment for RA are summarized in Table 1. Despite the advances in the field of biologic treatment, we still lack definitive treatment algorithms to guide the rheumatologist through the medical management of the individual patient with RA. Many issues remain unclear today, and therapeutic decisions are based mainly on the experience of the treating physician and local or national guidance documents. For example, in some situations, it might still be unclear whether the rheumatologist should consider the introduction of a biologic agent at all, and there remains much greater uncertainty as to which drug this should be and when whether it is appropriate to discontinue treatment. The importance of these clinical decisions is clear, especially considering the proven benefit of early aggressive Table 1 (a) Anti-TNF biologics approved for use in rheumatoid arthritis (RA) and (b) biologics approved for use in RA with mode of action other than TNF blockade Biologic (generic name) Adalimumab Certolizumab pegol Etanercept Golimumab Infliximab (a) Brand name Humira Cimzia Enbrel Simponi Remicade Molecule Human anti-tnf monoclonal antibody PEGylated Fab fragment of humanized anti-tnf monoclonal antibody Dimerized soluble TNF receptor Human anti-tnf monoclonal antibody Chimeric anti-tnf monoclonal antibody Mode of action Usual dosage Route of administration Binds TNF Binds TNF Binds TNF Binds TNF Binds TNF 40 mg every 2weeks 200 mg every 2weeks 50 mg once weekly 50 mg once monthly 3mgkg )1 every 8weeks Subcutaneous Subcutaneous Subcutaneous Subcutaneous Intravenous Biologic (generic name) Abatacept Anakinra Rituximab Tocilizumab (b) Brand name Orencia Kineret MabThera (Rituxan) RoActemra (Actemra) Molecule Mode of action Usual dosage Route of administration Dimerized CTLA4 molecule Inhibits T-cell activation 500 1000 mg once monthly Recombinant IL-1 receptor antagonist Binds IL-1 receptor Chimeric anti-cd20 monoclonal antibody Binds and eliminates B cells 100 mg daily 1000 mg 2 given every 6 12 months Humanized anti-il-6 receptor antibody Binds IL-6 receptor 8mgkg )1 once monthly Intravenous Subcutaneous Intravenous Intravenous ª 2011TheAssociationfor the Publication ofthe JournalofInternal Medicine Journal ofinternal Medicine 269; 614 625 615

management of RA but also the high cost of biologic drugs and their possible long-term side effects. Fortunately, there is emerging evidence from clinical and observational studies that will increasingly provide an understanding of these crucial issues. When to introduce a biologic treatment Two important principles in RA treatment have increasingly been recognized during the last few years. First, the goal of treatment should be clinical remission or at least low disease activity where remission is not achievable; this target should be achieved as soon as possible to attain the best results [1]. Second, tighter control of the patient is necessary, with assessments every 1 3 months, and treatment adjustments after 3 6 months according to the treating physician s assessment if the aim (remission) is not achieved. It has been highlighted that strict monitoring is associated with better clinical, functional and radiological outcomes [2 5]. These principles and the plethora of synthetic and biologic DMARDs that are available today form the background of current RA treatment. There is no doubt that DMARDs should be initiated as soon as a definite diagnosis of active RA is made, as a long delay can lead to significant structural damage with detrimental effects on physical function. MTX is the usual choice in the absence of contraindications, and various other synthetic DMARDs and DMARD combinations can be employed as initial treatment. The principles guiding RA treatment are summarized in Table 2. ately upon diagnosis, that is, whether biologics should be the first line of treatment for RA. Various clinical trials have investigated this issue, usually by referring to MTX-naïve patients who in practical terms often equate to newly diagnosed patients. These trials have generally provided clear evidence of the superiority of the combination of biologics with MTX over MTX alone in such patients. In a small (20 patients), randomized, double-blind, placebo-controlled trial, Quinn et al. [6] showed significantly greater clinical, functional and radiological benefit of combination treatment with MTX plus infliximab in early RA compared to MTX alone. It is interesting that 1 year after stopping induction therapy with infliximab, 70% of patients had a sustained response. In a much larger study by St. Clair et al. [7], patients with RA of 3 years of duration achieved significantly better clinical efficacy with infliximab plus MTX than with MTX monotherapy. Similar results were shown in large, randomized, controlled trials for etanercept and adalimumab, as well as for abatacept and the new TNF inhibitor golimumab; the data are summarized in Fig. 1 [8 11]. All of the above-mentioned studies were based on a population of patients with early RA (disease duration from 6.5 to 10.8 months) who 90% 80% 70% 60% 50% 40% ACR20 ACR50 ACR70 Biologic treatment in MTX-naïve patients It is questionable whether biologic agents should be considered at the earliest stage of the disease immedi- 30% 20% 10% 0% INF + MTX MTX ADA + MTX MTX ETA + MTX MTX ABT + MTX MTX GMB + MTX MTX Table 2 Principles of rheumatoid arthritis treatment Rheumatoid arthritis should be treated with one or more specific antirheumatic medications (disease-modifying antirheumatic drugs) The goals of treatment should be both alleviation of symptoms and prevention of damage Treatment should be aimed at achieving remission or, at least, low disease activity Therapy results should be assessed regularly and therapy adjusted if the results are not optimal Fig. 1 Efficacy of the biologic agents infliximab (INF), adalimumab (ADA), etanercept (ETN), abatacept (ABT) and golimumab (GLM) in combination with methotrexate (MTX) versus MTX monotherapy in MTX-naïve RA patients. These patients can for practical purposes be thought of as newly diagnosed patients in whom the first line of therapy is being investigated. The data demonstrate that the combination is superior to MTX monotherapy for all of the biologic agents but also clearly show that a considerable proportion of patients respond to the simpler and far less expensive monotherapy. The American College of Rheumatology (ACR) 20, 50 and 70 response criteria are standardized clinical trial outcomes that are based on the interval changes in seven parameters. They roughly correspond to the following levels of improvement: ACR20, modest; ACR50, good; ACR70, excellent. 616 ª 2011The Association for thepublication of the Journal of InternalMedicine Journalof Internal Medicine 269; 614 625

had not received prior MTX, and they all demonstrated that the combination of a biologic agent and MTX can yield better clinical, functional and radiographic outcome than MTX alone. However, it is worth noting that a substantial proportion of patients in these trials responded well to MTX monotherapy. Thus, one should keep in mind that in the combination groups, there are patients who would have responded to MTX monotherapy as well. Biologic treatment after MTX failure The most clearly established and best documented role for biologics in the treatment for RA is in those patients who have failed to respond adequately to one or more conventional DMARD, usually including MTX. Double-blind, placebo-controlled, randomized trials for all nine biologic agents available today have been conducted and have established the efficacy of these drugs in patients with RA with inadequate response to MTX [12 20]. In Fig. 2, the clinical responses after 6 months of therapy with biologic agent plus MTX versus placebo plus MTX are summarized. All these biologic agents, apart from anakinra, seem to have comparable efficacy in the MTX-nonresponder population and significantly greater efficacy than placebo. These results do not, however, answer the question of whether a combination of biologic drugs with MTX is also superior to a combination of synthetic DMARDs. Fig. 2 Efficacy of the biologic agents anakinra (ANA), abatacept (ABT), rituximab (RTX) and tocilizumab (TCZ), and the five TNF inhibitors certolizumab pegol (CZP), golimumab (GLM), adalimumab (ADA), etanercept (ETN) and infliximab (INF) in combination with methotrexate (MTX) versus MTX monotherapy in MTX-nonresponders. These trials represent the most common trial design for demonstrating the efficacy of a new antirheumatic agent (biologic or synthetic), including patients who have responded inadequately to MTX, the most commonly used disease-modifying antirheumatic drug. For an explanation of the ACR20, ACR50 and ACR70 response criteria, see legend to Fig. 1. So far, only a few clinical trials have made a direct comparison of these two treatment options, by adding a biologic agent or adding switching to another synthetic DMARD. In the SWEFOT trial, patients with early RA with an inadequate response to MTX after 3 months, defined as lack of achievement of low disease activity, were randomly allocated to addition of either sulfasalazine and hydroxychloroquine or infliximab. The latter group had significantly greater responses after 12 months of therapy, with 39% of patients achieving the primary end-point (European League Against Rheumatism (EULAR) good response, which is a widely used validated outcome) compared to 25% in the former group (P =0.016) [21]. Similar results were established in the BeSt trial, in which it was shown that initial combination therapy with initial high-dose prednisone followed by a gradual prednisone-dose reduction or with infliximab provided earlier clinical improvement than sequential monotherapy and conventional combination therapy [5]. After 2 years, patients in all four treatment groups had approximately the same improvement in disease activity and functional status irrespective of initial treatment, probably because of tight control and frequent treatment adjustments. However, the more aggressively treated patients had less radiological progression of joint damage, and during the second year, more of them could be treated successfully with monotherapy, suggesting that the initial aggressive therapy did result in some longterm gains. Thus, if the first DMARD fails to lead to remission, there are two main treatment alternatives: (i) switch or add a second synthetic DMARD (with or without low-dose glucocorticoids) or (ii) add a biologic agent. According to EULAR recommendations for the management of RA, the choice should be based on the presence or absence of poor prognostic markers, such as seropositivity for rheumatoid factor (RF) and or anticyclic citrullinated peptide (anti-ccp), high disease activity and early radiographic damage [22]. Such factors can be predictive of rapid radiographic progression and subsequent poor clinical and functional outcome [23]. Thus, the failure of an initial DMARD in a patient with unfavourable prognostic factors should be an indication for adding a biologic regimen (Fig. 3). Subjects with generally favourable prognostic factors could reasonably be treated with additional DMARDs alone or in combination but might be candidates for biologic treatment after the failure of additional DMARDs. Even if the aforementioned approach is rational, further proof from clinical trials supporting guided treatment by risk factors ª 2011TheAssociationfor the Publication ofthe JournalofInternal Medicine Journal ofinternal Medicine 269; 614 625 617

Table 3 Principles for initiation of biologic treatment in rheumatoid arthritis (RA) Failure*: primary or secondary loss of efficacy, intolerance or a partial, inadequate response. (After optimizing DMARD dose and/or trying combination of DMARDs). Fig. 3 Algorithm for biologic treatment for rheumatoid arthritis. for more aggressive disease is needed. Table 3 summarizes the principles guiding initiation of biologic treatment in RA. Which biologic to start with According to most guidelines, TNF inhibitors are the first-line biologic agents of choice. Unless contraindicated, a candidate for biologic treatment will most often receive initial treatment with one of the three classical TNF inhibitors, i.e. infliximab, adalimumab or etanercept. This is mainly because of the fact that a large amount of efficacy and safety data from numerous clinical trials and epidemiological studies has been gathered over the past 10 years. If possible, TNF inhibitors should be combined with MTX; the clinical efficacy particularly the radiological efficacy of the combination is clearly superior to TNF inhibitor monotherapy. In case of a contraindication to TNF inhibitor therapy, a biologic agent with a different mechanism of action (rituximab, abatacept or tocilizumab) can be chosen. Note, however, that there is evidence regarding the efficacy of each of these agents in TNF-naïve patients. The reason that TNF inhibitor therapy is considered first has much to do with the order in which the biologic drugs came to the clinic, so that with time, a shift in the agent of choice could be conceivable, if supported by new data. Although direct, head-to-head comparisons of biologic treatments would be of interest, only a few such trials have been conducted. The ATTEST trial, in In patients with highly active disease despite all attempts to control disease with conventional disease-modifying antirheumatic drug (DMARDs) Uncontroversial In patients with active RA and who have failed two or more DMARDs Widely accepted In patients with active RA and who have failed one DMARD Generally accepted for patients with multiple negative prognostic factors More controversial for patients without negative prognostic factors May opt for attempts with other DMARDs In patients with active RA who have not yet been treated with DMARDs Strong evidence that biologics provide better results at the group level, but not widely used in practice based on various considerations Many patients do respond to conventional treatment Safety Health economics which Schiff et al. randomly assigned patients to receive placebo, infliximab or abatacept, demonstrated that the two biologics had similar efficacy after 6 months of therapy, but that after 12 months, abatacept yielded slightly better clinical results and had a better safety and tolerability profile than infliximab [24]. The main safety issues, risks and contraindications for the biologics are listed in Table 4. Need for prognostic factors It has become clear from clinical observation as well as from studies that not all patients respond to all biologic drugs; some patients have moderate responses, and some do not respond at all. Even with tight control over 3 months, significant time can be lost trying various biologics, one after another, until the optimal one is eventually found, especially for patients who are partial responders; in this case, the time to switch agents could be 6 months or even longer, because the time to response can vary between individuals. As rapid control of inflammation has been proven to be of utmost importance for the long-term outcome of patients, finding prognostic factors for response to each 618 ª 2011The Association for thepublication of the Journal of InternalMedicine Journalof Internal Medicine 269; 614 625

Table 4 Adverse events and contraindications for biologic treatment for rheumatoid arthritis Biologic Adverse events and risk Contraindications (absolute and relative) Abatacept Infusion reactions (uncommon) Increased frequency of infections (measureable but small increase) Reactivation of tuberculosis (not clear if this risk is increased with abatacept) Malignancy? (no clear evidence) before starting abatacept) Adalimumab Injection site reactions (common) Increased frequency of infections (measureable but small increase) Reactivation of tuberculosis (marked increase in risk but still uncommon) Psoriasis (not uncommon) SLE-like syndrome (uncommon) Demyelinating disease (rare) Malignancy? (no clear evidence) before starting anti-tnf) Heart failure (absolute for moderate-severe, although no good data) Anakinra Injection site reactions (common) Increased frequency of infections (measureable but small increase) Malignancy (increased incidence, unknown clinical importance) Renal failure (absolute for severe) Certolizumab pegol Injection site reactions (uncommon) Increased frequency of infections (measureable but small increase) Reactivation of tuberculosis (marked increase in risk but still uncommon) SLE-like syndrome (rare) Demyelinating disease (rare) Malignancy? (no clear evidence) before starting anti-tnf) Heart failure (absolute for moderate-severe, although no good data) Etanercept Injection site reactions (common) Increased frequency of infections (measureable but small increase) Reactivation of tuberculosis (marked increase in risk but still uncommon) Psoriasis (not uncommon) SLE-like syndrome (uncommon) Demyelinating disease (rare) Malignancy? (no clear evidence) before starting anti-tnf) Heart failure (absolute for moderate-severe, although no good data) ª 2011TheAssociationfor the Publication ofthe JournalofInternal Medicine Journal ofinternal Medicine 269; 614 625 619

Table 4 (Continued ) Biologic Adverse events and risk Contraindications (absolute and relative) Golimumab Injection site reactions (common) Increased frequency of infections (uncommon) Reactivation of tuberculosis (uncommon) SLE-like syndrome (rare) Demyelinating disease (rare) Malignancy? (no clear evidence) before starting anti-tnf) Heartfailure (absolute for moderate-severe, although no good data) Infliximab Infusion reactions (common) Increased frequency of infections (measureable but small increase) Reactivation of tuberculosis (marked increase in risk but still uncommon) Psoriasis (not uncommon) SLE-like syndrome (uncommon) Demyelinating disease (rare) Malignancy? (no clear evidence) before starting anti-tnf) Heartfailure (absolute for moderate-severe, although no good data) Rituximab Infusion reactions (common with the first infusion) Infections (increase in risk, tendency to decrease over time) Reactivation of viral infections (including hepatitis B), (uncommon) Few reported cases of progressive multifocal leukoencephalopathy (PML) before starting rituximab) Heartfailure (absolute for moderate-severe) Tocilizumab Infusion reactions (uncommon) Infections (measureable but small increase) Increases in transaminases, other liver enzymes (common) Increases in lipids (common) Thrombocytopenia (common, usually mild) Neutropenia (common, usually mild) Gastrointestinal perforations (rare; seen in patients with other risk factors) before starting tocilizumab) Heartfailure (absolute for moderate-severe) a Listed as contraindication in product information, but based on the clinical situation, this might nonetheless be considered in some patients. biologic treatment is one of the next big challenges for modern rheumatology. To date, the progress made in this field has not been impressive. In general, male seronegative patients with low inflammatory burden tend to respond better to all treatments than female seropositive patients with high levels of inflammation, and low disability at baseline has been associated with higher remission rates. Useful prognostic indicators, however, would 620 ª 2011The Association for thepublication of the Journal of InternalMedicine Journalof Internal Medicine 269; 614 625

be biomarkers related to response to a certain biologic agent. A good example of this comes from a case report by Buch et al. [25] in which a patient with no improvement with infliximab, and the presence of lymphotoxin (LT) in the synovium, responded extremely well to subsequent treatment with etanercept which differs from infliximab by its ability also to block LT. This suggests that pathophysiology can vary amongst individuals with RA, and identification of potential biomarkers such as LT could lead the path to targeted treatment. Another example of a potential biomarker is seropositivity and response to rituximab [26, 27, 28]. As might be expected, RF- and anti-ccp-positive patients, in whom B cells might play an important role in the pathogenesis of arthritis, respond better to the B-celldepleting agent rituximab than seronegative patients. The extent to which seronegative patients can respond to rituximab is currently unclear, with responses in some clinical trials being no better than with placebo, and other data suggesting responses. Choice of biologic after failure of the first Data from randomized trials and cohort studies suggest that about one-third of patients discontinue therapy with a first biologic within a year because of primary ineffectiveness, loss of efficacy after a period of time or intolerance. Of course, the goal for these patients remains remission. Even patients with moderate responses ( partial responders ) should eventually be candidates for an alternative treatment, taking into account that even smouldering disease activity might lead to structural damage. After the failure of one biologic agent for the reasons described above, and after having perhaps tried to modify the dose of the concomitant DMARDs with no effect, three main treatment options are available: (i) optimize the dose of biologic drug; (ii) switch between TNF inhibitors; or (iii) switch to a biologic agent with a different mechanism of action. Controversial data are available concerning the optimization of the infliximab dose. In the ATTRACT trial, four different treatment regimens (i.e. infliximab 3mgkg )1 every 4 and 8 weeks, and 10 mg kg )1 every 4 and 8 weeks) yielded similar American College of Rheumatology (ACR) responses at 24 weeks [16]. At 48 weeks, however, there was a tendency for the lowest dosage of infliximab to be less effective than the higher ones, but this difference was only significant with respect to the ACR50 responses [29]. Results from uncontrolled observational studies have suggested that in patients with secondary loss of efficacy to infliximab, a higher dosage of infliximab could provide better efficacy [30]. On the other hand, in a double-blind randomized trial, Pavelka et al. showed no significant difference in efficacy of two dosages of infliximab (3 and 5 mg kg )1 ) after initial failure of the lower dosage to lead to remission [31]. Moreover, the higher dosage had a poorer safety profile. Another large trial of infliximab showed similar results, with no significant superiority of the higher dosage of 6 mg kg )1 [7]. In an observational study conducted in our centre, patients in whom the dose of infliximab was increased in clinical practice appeared to have a benefit, as defined by reduction in the disease activity score (DAS28) [32]. However, patients in the control groups (i.e. patients with no change in infliximab dose and those receiving a stable dose of etanercept) also showed an improvement in DAS28. This observation suggests that the improvements were most probably attributable to regression to the mean and that no important benefit is gained from dose increases of infliximab. Finally, van den Bemt et al. [33] found that 17 of 18 patients who were in clinical practice treated with infliximab at dosages higher than 3 mg kg )1 showed no deterioration of their RA if the dosage was reduced to 3 mg kg )1.In conclusion, the evidence suggests that increasing the dose of infliximab might result in loss of time, higher cost and potentially more side effects with no significant efficacy gain in most patients. Therefore, it would clearly be useful to be able to identify, using relevant biomarkers, a smaller subset of patients who might truly benefit from dose increases. Studies to investigate this possibility are currently underway. Different TNF inhibitors might target the same cytokine but differ substantially in their molecular structure and immunological actions. This is the rationale behind switching between different TNF inhibitors. Because of differences in pharmacokinetics between these inhibitors, it is possible that a patient will respond to an alternative agent after the failure of the first. This issue was investigated in the randomized double-blinded GO-AFTER study, in which after failure of a prior TNF inhibitor, patients who received golimumab showed significantly greater responses than those who received placebo [34]. In addition, results from many observational studies support switching between TNF inhibitors, as a substantial proportion of patients can benefit from this strategy [35 39]. Cohort study data also suggest a gradual loss of efficacy after a greater number of switches. Thus, a first switch might provide significant ª 2011TheAssociationfor the Publication ofthe JournalofInternal Medicine Journal ofinternal Medicine 269; 614 625 621

improvement, whereas the effect is much less profound at the second or third switch. After the failure of TNF inhibition (with a single or multiple agents), the next step is change of mechanism, which might be more logical than trying different regimens of the same drug class. Large trials have proved the efficacy of rituximab, abatacept and tocilizumab versus placebo after TNF treatment [40 42]. Superiority of rituximab over placebo was observed in the REFLEX trial. Abatacept demonstrated acceptable safety and clinically meaningful efficacy in patients who failed TNF inhibitor treatment in the ATTAIN trial. Additionally, in the RADI- ATE trial, tocilizumab-treated patients achieved significantly better results than those who received placebo during the first 6 months of therapy. But are these biologic agents with a different mechanism of action better than an alternative TNF inhibitor? Again, no randomized clinical trial has provided us with hard evidence to answer this question. On the other hand, observational studies have compared the two treatment options (Fig. 3). In the Swiss Clinical Quality Management program for RA (SCQM- RA) registry, patients with inadequate response to TNF inhibitor treatment achieved greater reductions in DAS28 when switching to rituximab than to an alternative TNF blocker [43]. In a subanalysis of the same population, it was shown that the superiority of rituximab over an alternative TNF inhibitor was observed for the subgroup of patients who discontinued previous TNF inhibitor therapy because of primary or secondary inefficacy [44]. A small observational study by Venkatachalam et al. provided similar results, whilst a study reported by Buch et al. also demonstrated comparable results of rituximab and alternative TNF inhibitors [45, 46]. In our centre, we observed slightly better overall results for patients who had failed TNF inhibitor therapy when treated with rituximab than with another TNF blocker, but both options provided clinical benefits [Chatzidionysiou K, Camara H, van Vollenhoven R, submitted]. These results are summarized in Fig. 3. Discontinuation of biologics As discussed earlier, the goal of treatment for RA is clinical remission. An additional refinement of that goal is biologic-free remission, which is important with respect to long-term safety issues, patient comfort and health economics (Fig. 4).In various settings, the possibility has been investigated of discontinuing the biologic agent whilst maintaining the patient in remission on a conventional DMARD. As part of the ATTRACT study [29], 17 patients in a single centre in the United Kingdom received infliximab and all 17 experienced flare-ups after discontinuation of the biologic therapy after 2 years, with a mean time of 13.5 15.0 weeks after the end of therapy. Of importance, reintroduction of infliximab after disease flare was associated with comparable responses without any safety issues. Whereas patients included in the ATTRACT study had longstanding disease (mean disease duration, 11 years), Quinn et al. [6] addressed the same question in a randomized, double-blind, placebo-controlled trial in a population of patients with early RA, with symptom duration of <12 months. These authors showed that induction of remission with infliximab plus MTX in early, poor prognosis RA provided not only significant reduction in synovitis and erosions at 1 year (shown by magnetic resonance imaging) but also sustained functional and quality-of-life benefits for 70% of the patients at 2 years despite infliximab withdrawal. More recently, Tanaka et al. [47] determined the possibility of discontinuing infliximab after attaining DAS-guided low disease activity in patients with RA in the remission induction by Remicade in RA (RRR) study. Of 102 patients, 56 (55%) maintained DAS28 < 3.2 and 44 (43%) reached remission (DAS28 < 2.6) 1 year after the discontinuation of infliximab. The mean disease duration in this study was 5.9 years, which suggests that discontinuation of infliximab would be possible not only in patients with early RA but also in patients with more established disease. In a post hoc analysis from the BeSt study, it was shown that significantly more patients who received initial combination therapy with infliximab and MTX achieved sustained DAS 2.4 and were able to discontinue infliximab, compared with those with delayed introduction of the biologic agent (56% vs. 29%, P = 0.008) [48]. It was also shown in the BeSt study that the shorter the symptom duration, the higher the likelihood of a biologic-free, and even a drugfree, remission [49]. The results of a systematic review and meta-analysis showed that patients with established RA who stopped treatment with synthetic DMARDs had a significantly higher risk of disease flare or deterioration than those who continued treatment [50]. In this analysis, however, patients had RA of more than 2 years of duration. 622 ª 2011The Association for thepublication of the Journal of InternalMedicine Journalof Internal Medicine 269; 614 625

Table 5 Current viewpoints on discontinuation (dose reduction) of biologics in patients with well-controlled disease Fig. 4 Comparison of switchingbetweentnf inhibitors with switching to rituximab, based on reductions in DAS28. The results from four observational studies (not randomized trials) are shown, demonstrating the improvements in DAS28 that occurred in patients who had failed one or more prior TNF inhibitors and who were subsequently given another TNF inhibitor (blue) or rituximab (red). A DAS28 improvement of 1.2 is considered clinically relevant. From the results of the above studies, one can draw several conclusions. First, biologic-free remission might be possible after achieving remission or low disease activity in a considerable proportion of patients. Second, the duration of disease until the introduction of the biologic treatment might be negatively associated with the risk of deterioration after discontinuation of treatment (Fig. 5), thus suggesting that earlier initiation of biologic treatment not only leads to better results but also increases the possibility of withdrawal of biologic agents with maintenance of remission. Third, if a patient has had a remission for a long time, it is more likely that the patient will remain in remission. The current view of discontinuation and dose reduction with biologics is summarized in Table 5. Few controlled data Biologic-free remission might be a reasonable long-term therapeutic goal Some evidence to suggest that attempts at dose reduction or discontinuation of biologics might be successful in a considerable proportion of patients Usually whilstmaintaining a conventional disease-modifying antirheumatic drug Some hope that early treatment with biologic drugs might yield a higher likelihood of achieving biologic-free and even disease-free remission Two large, multi-centre, randomized trials are currently being conducted to address the question of discontinuation of the TNF inhibitors adalimumab and etanercept in patients who are in remission and in remission have low disease activity, respectively. Conclusions Biologics have dramatically improved our ability to control RA and other inflammatory diseases, but many important practical questions and challenges remain. The early introduction of biologic treatment for RA is undeniably associated with the best clinical and functional outcomes, but hitherto they remain the second step in RA management, mainly for socioeconomic and safety reasons. Emerging data indicate the possibility that discontinuing the biologic agent or even all antirheumatic drugs after achieving and maintaining remission is more likely to be possible with very early initiation of biologic treatment; if confirmed, this possibility would have a tremendous impact, both medically and with regard to health economics. Furthermore, the need for more individually targeted treatment is becoming increasingly apparent with each new biologic agent that is approved. Fortunately, it is very likely that epidemiological, clinical and basic research will increasingly supply rheumatologists with the evidence necessary to address the remaining practical questions. Fig. 5 Positive correlation between disease duration before the introduction of infliximab (INF) and proportion of patients who experienced flare-up after discontinuation of the biologic agent. Data from three studies (ATTRACT [16], RRR and the randomized controlled study conducted by Quinn et al. [47]). Ethical considerations None. Conflicts of interest statement KC has none to declare. RvV has received research support and or honoraria from Abbott, Bristol-Myers ª 2011TheAssociationfor the Publication ofthe JournalofInternal Medicine Journal ofinternal Medicine 269; 614 625 623

Squibb, Roche, Schering-Plough (now MSD), Wyeth (now Pfizer) and UCB Pharma. Acknowledgements None. References 1 Smolen JS, Han C, van der Heijde DM et al. 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 factorblockade. Ann Rheum Dis 2009; 68: 823 7. 2 GrigorC,CapellH,Stirling A et al. Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial. Lancet 2004; 364: 263 9. 3 Fransen J, Moens HB, Speyer I, van Riel PL et al. Effectiveness of systematic monitoring of rheumatoid arthritis disease activity in daily practice: a multicentre, cluster randomised controlled trial. Ann Rheum Dis 2005; 64: 1294 8. 4 Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF et al. Comparison of treatment strategies in early rheumatoid arthritis: a randomized trial. Ann Intern Med 2007; 146: 406 15. 5 Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF et al. Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial. Arthritis Rheum 2005; 52: 3381 90. 6 Quinn MA, Conaghan PG, O Connor PJ et al. Very early treatment with infliximab inadditionto methotrexate in early, poor-prognosis rheumatoid arthritis reduces magnetic resonance imaging evidence of synovitis and damage, with sustained benefit after infliximab withdrawal: results from a twelve-month randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2005; 52: 27 35. 7 St Clair EW, van der Heijde DM, Smolen JS et al. Combination of infliximab and methotrexate therapyfor early rheumatoid arthritis: a randomized, controlled trial. Arthritis Rheum 2004; 50: 3432 43. 8 Emery P, Breedveld FC, Hall S et al. Comparison of methotrexate monotherapywithacombinationofmethotrexate andetanercept in active, early, moderate to severe rheumatoid arthritis (CO- MET): a randomised, double-blind, parallel treatment trial. Lancet 2008; 372: 375 82. 9 Emery P, Fleischmann RM, Moreland LW et al. Golimumab, a human anti-tumor necrosis factor alpha monoclonal antibody, injected subcutaneously every four weeks in methotrexate-naive patients with active rheumatoid arthritis: twenty-four-week results of a phase III, multicenter, randomized, double-blind, placebo-controlled study of golimumabbefore methotrexate as firstline therapyfor early-onset rheumatoid arthritis. Arthritis Rheum 2009; 60: 2272 83. 10 Breedveld FC, Weisman MH, Kavanaugh AF et al. 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. ArthritisRheum 2006; 54: 26 37. 11 Westhovens R, Robles M, Ximenes AC et al. Clinical efficacy and safety of abatacept in methotrexate-naive patients with early rheumatoid arthritis and poor prognostic factors. Ann Rheum Dis 2009; 68: 1870 7. 12 Smolen JS, Beaulieu A, Rubbert-Roth A et al. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial. Lancet 2008; 371: 987 97. 13 Emery P, Deodhar A, Rigby WF et al. Efficacy and safety of different doses and retreatment of rituximab: a randomised, placebo-controlled trial in patients who are biological naive with active rheumatoid arthritis and an inadequate response to methotrexate (Study Evaluating Rituximab s Efficacy in MTX inadequate responders (SERENE)). Ann Rheum Dis 2010; 69: 1629 35. 14 Kremer JM, Genant HK, Moreland LW et al. Effects of abatacept in patients with methotrexate-resistant active rheumatoid arthritis: a randomized trial. Ann Intern Med 2006; 144: 865 76. 15 Cohen S.B, Moreland LW, Cush JJ et al. A multicentre, double blind, randomised, placebo controlled trial of anakinra (Kineret), a recombinant interleukin 1 receptor antagonist, in patients with rheumatoid arthritis treated with background methotrexate. Ann Rheum Dis 2004; 63: 1062 8. 16 Maini R, St Clair EW, Breedveld F et al. Infliximab (chimeric antitumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group. Lancet 1999; 354: 1932 9. 17 Weinblatt ME, Keystone EC, Furst DE et al. Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADAtrial. Arthritis Rheum 2003; 48: 35 45. 18 Weinblatt ME, Kremer JM, Bankhurst AD et al. A trial of etanercept, a recombinant tumor necrosis factor receptor:fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N EnglJ Med 1999; 340: 253 9. 19 Keystone E, Genovese MC, Klareskog L et al. Golimumab in patients with active rheumatoid arthritis despite methotrexate therapy: 52-week results of the GO-FORWARD study. Ann Rheum Dis 2010; 69: 1129 35. 20 Smolen J, LandeweRB, Mease P et al. Efficacy and safetyof certolizumab pegol plus methotrexate in active rheumatoid arthritis: the RAPID 2 study. A randomised controlled trial. Ann Rheum Dis 2009; 68: 797 804. 21 van Vollenhoven RF, Ernestam S, Geborek P et al. Addition of infliximab compared with addition of sulfasalazine and hydroxychloroquine to methotrexate in patients with early rheumatoid arthritis (Swefot trial): 1-yearresults ofarandomisedtrial. Lancet 2009; 374: 459 66. 22 Smolen JS, Landewe R, Breedveld FC et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. Ann Rheum Dis 2010; 69: 964 75. 23 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 21. 24 Schiff M, Keiserman M, Codding C et al. Efficacy and safety of abatacept or infliximab vs placebo in ATTEST: a phase III, multicentre, randomised, double-blind, placebo-controlled study in patients with rheumatoid arthritis and an inadequate response to methotrexate. Ann Rheum Dis 2008; 67: 1096 103. 624 ª 2011The Association for thepublication of the Journal of InternalMedicine Journalof Internal Medicine 269; 614 625

25 Buch MH, Conaghan PG, Quinn MA, Bingham SJ, Veale D, Emery P. True infliximab resistance in rheumatoid arthritis: a role for lymphotoxinalpha? Ann Rheum Dis 2004; 63: 1344 6. 26 Cambridge G, Leandro MJ, Edwards JC et al. Serologic changes following B lymphocyte depletion therapy for rheumatoid arthritis. ArthritisRheum 2003; 48: 2146 54. 27 Quartuccio L, Fabris M, Salvin S et al. Rheumatoid factor positivity rather than anti-ccp positivity, a lower disability and a lower number of anti-tnf agents failed are associated with response to rituximab in rheumatoid arthritis. Rheumatology (Oxford) 2009; 48: 1557 9. 28 Quartuccio L, Fabris M, Salvin S et al. Controversies on rituximab therapy in sjogren syndrome-associated lymphoproliferation. Int J Rheumatol2009; 2009: 424935. 29 Lipsky PE, van der Heijde DM, St Clair EW et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N Engl J Med 2000; 343: 1594 602. 30 Durez P, Van den Bosch F, Corluy L et al. A dose adjustment in patients with rheumatoid arthritis not optimally responding to a standard dose of infliximab of 3 mg kg every 8 weeks can be effective: a Belgian prospective study. Rheumatology (Oxford) 2005; 44: 465 8. 31 Pavelka K, Jarosova K, Suchy D et al. Increasing the infliximab dose in rheumatoid arthritis patients: a randomised, double blind study failed to confirm its efficacy. Ann Rheum Dis 2009; 68: 1285 9. 32 vanvollenhoven RF, BrannemarkS, KlareskogL et al. Doseescalation of infliximab in clinical practice: improvements seen may beexplained bya regression-likeeffect. Ann Rheum Dis 2004; 63: 426 30. 33 van den BemtBJ, den Broeder AA, SnijdersGFetal. Sustained effect after lowering high-dose infliximab in patients with rheumatoid arthritis: a prospective dose titration study. Ann Rheum Dis 2008; 67: 1697 701. 34 Smolen JS, Kay J, Doyle MKet al. Golimumab in patients with active rheumatoid arthritis after treatment with tumour necrosis factor alpha inhibitors (GO-AFTER study): a multicentre, randomised, double-blind, placebo-controlled, phase III trial. Lancet 2009; 374: 210 21. 35 Haraoui B, KeystoneEC, ThorneJC etal. Clinicaloutcomes ofpatients with rheumatoid arthritis after switching from infliximab to etanercept. JRheumatol2004; 31: 2356 9. 36 Bingham CO 3rd, Ince A, Haraoui B, Keystone EC, Chon Y, Baumgartner S. Effectiveness and safety of etanercept in subjects with RA who have failed infliximab therapy: 16-week, openlabel, observational study. Curr Med Res Opin 2009; 25: 1131 42. 37 Buch MH, Bingham SJ, Bejarano V et al. Therapyof patients with rheumatoid arthritis: outcome of infliximab failures switched to etanercept. Arthritis Rheum 2007; 57: 448 53. 38 Furst DE, Gaylis N, Bray V et al. Open-label, pilot protocol of patients with rheumatoid arthritis who switch to infliximab after an incomplete response to etanercept: the opposite study. Ann Rheum Dis 2007; 66: 893 9. 39 Bombardieri S, Ruiz AA, Fardellone P et al. Effectiveness of adalimumab for rheumatoid arthritis in patients with a history of TNF-antagonist therapy in clinical practice. Rheumatology (Oxford) 2007; 46: 1191 9. 40 Cohen SB, Emery P, Greenwald MW et al. 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. ArthritisRheum 2006; 54: 2793 806. 41 Genovese MC, Becker JC, Schiff M et al. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition. NEnglJMed2005; 353: 1114 23. 42 Emery P, Keystone E, Tony HP et al. 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 placebocontrolled trial. Ann Rheum Dis2008; 67: 1516 23. 43 Finckh A, Ciurea A, Brulhart L et al. B cell depletion may be more effectivethanswitchingto analternative anti-tumornecrosis factor agent in rheumatoid arthritis patients with inadequate response to anti-tumor necrosis factor agents. Arthritis Rheum 2007; 56: 1417 23. 44 Finckh A, Ciurea A, Brulhart L et al. Which subgroup of patients with rheumatoid arthritis benefits from switching to rituximab versus alternative anti-tumour necrosis factor (TNF) agents after previous failure of an anti-tnf agent? Ann Rheum Dis 2010; 69: 387 93. 45 Venkatachalam S, Roskell S, Suchitra R, Price T, Mulherin D, Sheeran T et al. Rituximab may be more effective than switching to an alternative TNF inhibitor in rheumatoid arthritis patients who have failed other tnf inhibitors. Rheumatology 2008; 47: Ii31. 46 Buch MH, English A, Cunnane G et al. Does tumour necrosis factor (TNF)-alpha blockade differentially reduce synovial TNF-alpha expression in patients with rheumatoid arthritis? Arthritis Rheum 2003; 48: S146. 47 Tanaka Y, Takeuchi T, Mimori T et al. Discontinuation of infliximab after attaining low disease activity in patients with rheumatoid arthritis: RRR (remission induction by Remicade in RA) study. Ann RheumDis 2010; 69: 1286 91. 48 vander KooijSM, le CessieS, Goekoop-RuitermanYP, et al. Clinical and radiological efficacy of initial vs delayed treatment with infliximab plus methotrexate in patients with early rheumatoid arthritis. Ann Rheum Dis 2009; 68: 1153 8. 49 van der Kooij SM, Goekoop-Ruiterman YP, de Vries-Bouwstra JK et al. Drug-free remission, functioning and radiographic damage after 4 years of response-driven treatment in patients with recent-onset rheumatoid arthritis. Ann Rheum Dis 2009; 68: 914 21. 50 O Mahony R, Richards A, Deighton C, Scott D et al. Withdrawal of DMARDs in patients with Rheumatoid Arthritis: a systematic review and meta-analysis. Ann Rheum Dis 2010; 69: 1823 6. Correspondence: KaterinaChatzidionysiou, Unit for Clinical Therapy Research, Inflammatory Diseases, KarolinskaInstitutet, Stockholm, Sweden. (fax: 0046851773080; e-mail: aikaterini.chatzidionysiou@ karolinska.se). ª 2011TheAssociationfor the Publication ofthe JournalofInternal Medicine Journal ofinternal Medicine 269; 614 625 625