Biological agents in monotherapy for the treatment of rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory disease, which results in joint destruction and permanent disability. The advent of disease-modifying antirheumatic drugs (DMARDs) has made a profound impact on the outcome and prognosis of RA. Methotrexate (MTX) is a central agent in RA therapy, and is used either alone or in combination with biological DMARDs. However, a large proportion of RA patients (20%–40%) either do not respond to or are unable to tolerate MTX or the alternative agents used in place of MTX (including leflunomide, sulfasalazine, azathioprine, hydroxycholoquine and combination DMARDs). For these patients, monotherapy with biological DMARDs is a key treatment option that balances tolerability with improved clinical outcomes. This article reviews the data for four biological agents approved for use as monotherapy in Switzerland (adalimumab, certolizumab pegol, etanercept and tocilizumab) in order to formulate a consensus statement on their roles in biologic monotherapy of RA.


Introduction and current therapy recommendations
Rheumatoid arthritis (RA) is one of the most frequently occurring autoimmune rheumatic diseases, affecting an estimated 1% of the global population [1,2].Deregulation of the pro-and anti-inflammatory homeostasis is the cornerstone of pathogenesis, triggering the induction of autoimmunity [3].The chronic inflammation that underpins this disease leads to synovial inflammation and effusion, the cardinal signs of which are joint pain, stiffness and swelling, ultimately followed by joint destruction and permanent disability.The synthetic disease-modifying antirheumatic drug (sDMARD) methotrexate (MTX) is a central agent in the treatment of RA, and can be used either alone or in combination with other sDMARDs or biological DMARDs [4][5][6].However, an estimated 20%-40% of patients either fail to achieve remission or are unable to tolerate MTX or standard combination therapy [5,7,8].The use of MTX is associated with significant variability in response, with respect to both efficacy and toxicity [9,10], and often patients with severe disease exhibit only a partial response to MTX therapy [11].According to the latest European League Against Rheumatism (EULAR) recommendations, if the treatment goal is not achieved using the first DMARD and there are no poor prognostic factors, then the patient should be switched to another sDMARD (such as leflunomide or sulfasalazine) [12].If, however, there are poor prognostic factors, the addition of a biological DMARD is recommended [12].For those patients with insufficient response to MTX or other conventional DMARDs (with or without accompanying glucocorticoids), the EULAR recommends the inclusion of a biological DMARD, such as tumour necrosis factor (TNF) inhibitors, abatacept or tocilizumab, and, in certain conditions, rituximab [12].In the case of failure of the biologic therapy, tofacitinib may be considered [12].Although the efficacy of combination therapy is well documented, it is associated with side effects that may limit its application in certain settings, such as in patients with significant comorbidities [13].Monotherapy with biological DMARDs is indicated in the case of intolerance to MTX and other sDMARDs alongside persistent active disease [8,14].In many cases, however, patients themselves choose to forego the sDMARD (usually MTX) and continue only with the biological agent [15].The resulting clinical reality is that roughly one-third of RA patients are undergoing treatment with biological DMARD monotherapy [16].There is thus an urgent need for clear guidance on the application of biological agents in this setting.Currently, four biological agents are licensed for use as monotherapy in Switzerland: adalimumab, certolizumab pegol, etanercept, and tocilizumab.This review considers the available evidence for these agents, and also provides a brief overview of the nonapproved agents abatacept, golimumab and rituximab in monotherapy.We performed a PubMed literature search for clinical trial data on biologic monotherapy in RA published until May 2013.Included studies were limited to prospective, randomised clinical trials.Owing to the limitations of space, we present the main findings from pivotal trials, and the section on safety will focus on the key issues relevant to therapy with these biological agents.The appendix provides an overview of the main clinical trial data.

Key messages -biologic monotherapy in rheumatoid arthritis
Efficacy: • Monotherapy with biological DMARDs provides a critical line of therapy for patients who cannot tolerate MTX and other conventional DMARDs.

Adalimumab
Adalimumab is a recombinant, fully human monoclonal anti-TNFα antibody that specifically binds to the cytokine and removes it from the circulation.The standard dosage of adalimumab is 40 mg every other week, administered subcutaneously [17].An initial randomised, double-blind, phase III study showed that adalimumab monotherapy achieved significant improvements in disease activity compared with placebo [18].Following these findings, the PREMIER trial compared the combination of adalimumab plus MTX versus both agents as monotherapy in MTXnaïve patients with early RA [19].Results from the PREMIER study demonstrated that combination therapy yielded superior outcomes to either agent alone.After 2 years of treatment, 49% of patients receiving combination therapy achieved a state of clinical remission defined as a Disease Activity Score using 28 joints (DAS28 score) <2.6 and 49% had a major clinical response (defined as American College of Rheumatology [ACR] 70 response for at least 6 consecutive months).These rates were around twice those observed in the patients who received monotherapy with either MTX or adalimumab [19].Of note, there was significantly less radiographic disease progression with adalimumab monotherapy compared with MTX monotherapy [19].
Recommendations: Adalimumab appears to be most effective when used in combination with MTX, but may be used alone in order to slow radiographic progression.
Certolizumab pegol monotherapy has been shown to be superior to placebo, as demonstrated by the FAST4WARD study [21].After 6 months, a significantly higher proportion of the certolizumab pegol group (45.5%) achieved the primary endpoint of ACR20 response, compared with 9.3% of the placebo group.Significant improvements were also seen across the other study endpoints.In the phase IIIb REALISTIC study, certolizumab pegol was compared against placebo plus the patient's current therapy [22].The study included patients who had inadequate response to at least one DMARD.Treatment with certolizumab pegol resulted in significant improvements in ACR20 across all patient subgroups, irrespective of concomitant DMARD use at baseline.ACR50, health assessment questionnaire disability index (HAQ-DI) and DAS28 also showed significant improvements from baseline with the benefits becoming apparent as early as 2 weeks after treatment initiation [22].The findings from these two trials demonstrate that certolizumab pegol can yield consistent responses in RA patients with diverse disease characteristics, including those who had failed prior DMARD treatment.Recommendations: At present, there are no comparative data against MTX for certolizumab pegol monotherapy.

Etanercept
Etanercept is a dimeric fusion protein consisting of the extracellular region of two human p75 TNF receptors plus

Review article
Swiss Med Wkly.2014;144:w13950 the Fc region of human IgG1 [23].The main data supporting the use of etanercept as monotherapy come from the ERA trial, which compared etanercept with MTX in 632 patients with early RA [24].At 6 months, the ACR70 response was significantly higher in patients treated with etanercept than in those receiving MTX, though ACR20 or ACR50 response rates were no different in the two treatment arms.Mean increases in bone erosion scores during the first 6 months were significantly lower in the etanercept group than in the MTX group [24].
Results from a more recent randomised, double-blind clinical trial (the TEMPO study), which included MTX-naïve patients, demonstrated that etanercept is more efficacious when used in combination with MTX [25].As monotherapy, etanercept was not significantly superior to MTX [25,26].The COMET study, which also included MTX-naïve patients, compared the etanercept-MTX combination versus MTX monotherapy in the first year, while the second year of the study evaluated etanercept as monotherapy [27].The findings from the main study as well as from a post-hoc analysis demonstrated that the main clinical benefits were derived from the combination of etanercept and MTX [27,28].At week 104, the removal of MTX resulted in a worsening of clinical and radiographic responses compared with continuous etanercept-MTX combination therapy.These findings indicate that MTX needs to be administered alongside etanercept in order to achieve optimal clinical and radiographic outcomes for patients with early RA [28].
In patients with inadequate response to MTX, the accepted indication for etanercept therapy, published data have been conflicting, with etanercept monotherapy yielding either similar or inferior results to MTX.The ADORE study compared etanercept added to patients' baseline MTX dose versus etanercept monotherapy.Both arms of this study had similar outcomes with respect to ACR and DAS responses [29].In contrast, the JESMR study showed that patients treated with etanercept plus MTX exhibited significantly better ACR responses than those treated with etanercept alone.Furthermore, the combination regimen resulted in better prevention of structural damage [30].The CAMEO study examined the effect of MTX withdrawal in patients treated with a combination of etanercept and MTX for 6 months and who were randomised to pursue the combination of MTX plus etanercept or switched to etanercept alone [31].After 6 months, DAS28 levels remained stable in patients treated with etanercept plus MTX but increased in those treated with etanercept alone.Notably, this difference was observed in patients with DAS28 levels ≥3.2 at the time of randomisation, indicating that the use of MTX is necessary if low disease activity is not achieved [31].These findings have been supported by registry data, which showed a longer maintenance of drug efficacy when etanercept was combined with MTX, in comparison with etanercept monotherapy [32].Of note, results from the ETA study indicated that etanercept could also be used in combination with sulfasalazine in patients who had active RA despite ongoing sulfasalazine treatment [33].
Recommendations: The bulk of the data from the above studies supports the use of etanercept in combination with MTX.
The first study to demonstrate the safety and efficacy of tocilizumab monotherapy was a Japanese phase I/II study in 162 patients with DMARD-resistant active disease [35].
The patients received treatment with either placebo or tocilizumab.After 3 months, there were significant benefits with respect to ACR20 response in the 8 mg/kg and 4 mg/ kg tocilizumab groups (78%, and 57%, respectively).Similar benefits were observed for ACR50 and ACR70 [35].
Both the Japanese SATORI and SAMURAI studies demonstrated the superiority of tocilizumab compared with the control treatment (MTX or other conventional DMARDs) [36,37].The primary endpoint of the SATORI study, an ACR20 response at week 24, was achieved in 80.3% of the tocilizumab group compared with 25.0% of the MTX control group [37].The aim of the SAMURAI study was to assess the ability of tocilizumab monotherapy to reduce progressive structural joint damage in RA patients at risk of disease progression [36].Results showed that treatment with tocilizumab monotherapy suppressed bone erosion more efficiently than conventional DMARD treatment.
Results from both SAMURAI and SATORI underscored the clinical benefits of tocilizumab monotherapy in RA patients who do not respond to treatment with other DMARDs, including MTX.However, the use of low-dose MTX in Japan limits the extrapolation of these data to Western populations.The AMBITION study also compared tocilizumab monotherapy with MTX, but in patients who were either MTXnaïve or who had not used it in the 6 months prior to the study and were not considered refractory to MTX or TNF inhibitors [38].Patients were randomised to three treatment arms: tocilizumab, MTX, or placebo for 8 weeks followed by tocilizumab.Significantly more patients on tocilizumab monotherapy (70.6%) achieved an ACR20 response, in contrast to 52.1% of the MTX arm.The benefits of tocilizumab treatment were maintained regardless of whether patients were MTX-naïve or had received prior MTX treatment.Together with the positive results from the SATORI and SAMURAI studies, the findings from AMBITION establish tocilizumab as the first biological agent to show statistically superior clinical efficacy compared with standard MTX monotherapy [38].
The benefits of tocilizumab monotherapy demonstrated in the above trials raised the question of whether tocilizumab can be given in combination with MTX, or whether MTX therapy can be stopped and the patient switched to tocilizumab monotherapy.The ACT-RAY study, although not designed to evaluate tocilizumab monotherapy per se, aimed to evaluate the efficacy of switching from MTX to tocilizumab monotherapy in patients with active RA despite MTX treatment [39].There were no clinically significant benefits of the tocilizumab + MTX combination compared with the switch to tocilizumab monotherapy [39,40,41].
The SURPRISE study compared the switch to tocilizumab monotherapy ("switch") versus addition of tocilizumab to an existing MTX regimen ("add-on"), in patients with inadequate response to MTX [42].Results showed that the add-on strategy was superior compared with the switch to tocilizumab monotherapy in terms of DAS28 remission.However, results across all other criteria were similar in both groups.Recent data from the FUNCTION study revealed statistically significant improvements in DAS28 remission after 24 weeks of treatment with either the combination of tocilizumab plus MTX, or tocilizumab monotherapy [43].Taken together, these results support the feasibility of tocilizumab as monotherapy as well as in combination with MTX.
The ADACTA study was the first head-to-head comparative trial to explore the efficacy of two monotherapy agents (tocilizumab vs adalimumab) [44].The mean change in DAS28 score as the primary endpoint was significantly better in the tocilizumab arm than in the adalimumab arm; these findings were similar across all other endpoints.These data corroborate the data from previously published studies on both agents [18,[36][37][38][39], further supporting the conclusion that more patients may benefit from tocilizumab monotherapy compared with adalimumab monotherapy.
Recommendations: Tocilizumab is the first biological agent to show statistically superior clinical efficacy compared with standard MTX monotherapy.In addition, clinical data suggest a comparable efficacy when used as monotherapy as in combination with MTX.

Nonapproved biological agents used in monotherapy
An overview of the agents that have not received formal approval in Switzerland for use as monotherapy in RA is given in table 1.As these biologicals have significant offlabel use, the reader should be aware of the available evidence for each of these agents as monotherapy in the treatment of RA.
The T-cell inhibitor abatacept is currently approved only in the USA for use as monotherapy.In a phase II study, abatacept yielded numerically superior responses compared with placebo in patients with inadequate response to DMARDs [45].Data from the open-label ARRIVE study, however, showed that abatacept was more efficacious when used in combination with a DMARD [46].Recently, the efficacy of abatacept monotherapy was shown to be equivalent to that of abatacept with concomitant MTX in the 4-month openlabel ACCOMPANY trial [47].
Golimumab is a human anti-TNFα monoclonal antibody with demonstrated efficacy in combination with MTX.However, results from both the GO-BEFORE and GO-FORWARD studies indicated that golimumab monotherapy was not superior to MTX monotherapy [48,49].The use of golimumab in combination with MTX yielded consistently better outcomes compared to MTX alone; however, when used alone golimumab yielded similar results to MTX monotherapy [48].Data for the anti-CD20 monoclonal antibody rituximab were derived from a phase II study, which included RA patients who had inadequate response to MTX.A higher percentage of patients achieved ACR50 and ACR70 responses when treated with a combination of rituximab plus MTX compared with rituximab monotherapy [50].However, DAS28 scores and the number of patients achieving good or moderate EULAR responses were not significantly different between the two treatment arms [50].Similar results were observed in a small study which compared rituximab monotherapy with the combination of rituximab plus MTX [51].

Safety and tolerability
In general, the safety and tolerability issues for biologic monotherapy are similar to those for combination therapy, with the exception of the formation of anti-drug antibodies.Table 2 summarises the recommended safety monitoring procedures for each agent.

Infection
Compared with the general population, RA patients have an increased risk of infection, due to the pathobiology of the disease, the impact of age, chronic comorbidities, and the sequelae of immunosuppressive therapy [52,53].An increased risk of serious bacterial infections has been associated with TNF inhibitors [54,55], although conflicting data have been reported [56][57][58].Infection rates in patients treated with tocilizumab monotherapy were reported at 4.5 per 100 patient-years [59].It has been reported that tocilizumab suppressed fever and the increase in C-reactive protein (CRP) levels after joint surgery [60].This finding is in line with the role of IL-6 in the regulation of the acutephase response [61], and suggests that CRP cannot be used as a marker of tissue damage and infection during tocilizumab treatment.In general, safety findings suggest that careful monitoring for infections is important during treatment with all biological agents.Special attention should be given when monitoring patients with a history of chronic infections [62].

Malignancies
Compared with the general population, patients with RA have a higher risk of developing certain malignancies [63].Despite initial concern with the use of TNF inhibitors, meta-analysis of registry data and observational published Phase II study [45]; subanalysis of the ARRIVE open-label study [46].

Review article
Swiss Med Wkly.2014;144:w13950 Swiss Medical Weekly • PDF of the online version • www.smw.chreports did not identify any increase in malignancies [62].
The exception is the incidence of nonmelanoma skin cancer, which has been shown to increase with infliximab, etanercept and adalimumab treatment [64].In addition, recent data from the Swedish registry showed that the incidence of melanoma is increased with TNF antagonists [65].
There are only limited data on the risk of malignancy with tocilizumab use.Safety data from the STREAM study indicated that the rates of malignancy with tocilizumab treatment were not significantly elevated from those seen in the general population [66], although these results are limited by the relatively short timeframe of the follow-up.Similarly, no increase in rates of malignancies have been detected with rituximab or abatacept [64].

Antibody development
The development of anti-drug antibodies is the most important issue that affects drug efficacy, and is associated with the use of biological agents as monotherapy.However, the long-term clinical relevance of these antibodies is not clear.A prospective cohort study in RA outpatients showed that the presence of anti-adalimumab antibodies was associated with lower circulating drug concentrations and decreased likelihood of minimal disease activity or clinical remission [67].Interestingly, the concomitant use of MTX has been shown to have a favourable effect on the development of anti-adalimumab antibodies, an effect that was dose dependent [68].Anti-drug antibodies against certolizumab pegol have been reported in approximately 12% of patients, but the clinical significance of this is unknown [69].The development of anti-tocilizumab antibodies is relatively rare; a meta-analysis of four clinical trials showed that treatment efficacy was maintained even in the few (18 out of 1,747 patients) who developed neutralising antibodies against the drug [6].Furthermore, the levels of antitocilizumab antibodies were not affected by concomitant MTX treatment [40].Use of etanercept is not associated with the formation of neutralising antibodies [70].

Injection-site reactions
Meta-analysis of clinical trial data for adalimumab and etanercept indicated that injection-site reactions occurred more frequently compared with placebo [71].A similar meta-analysis for certolizumab pegol, however, reported rates of injection-site reactions that were similar to placebo controls [64].Product information sheets report rates of infusion reactions of 8% with tocilizumab (vs 5% in control groups) when used at the approved dose [72].Treatment with TNF inhibitors and tocilizumab has been associated with allergic skin reactions [73,74].Although rare, anaphylactic hypersensitivity reactions have been associated with tocilizumab, adalimumab and etanercept, indicating the need for careful monitoring for this side effect [6,[75][76][77][78].

Other adverse events
Minor elevations in the levels of transaminases have been observed in patients treated with tocilizumab.Clinical trial data revealed that these occurred at a similar rate seen with MTX monotherapy, with a higher incidence associ- ated with the combination of tocilizumab plus DMARD therapy [64,79].Other liver function parameters, however, were not affected, and there have been no reports of severe liver injury or liver failure thus far.Patients treated with tocilizumab often exhibit abnormal lipid profiles, including elevations in cholesterol levels, which increase during the first 6 weeks of treatment and remain relatively stable thereafter [59].Although RA in itself is known to alter the lipid profile [80], the long-term cardiovascular effects of the cholesterol elevations observed with tocilizumab are unknown [64] and coadministration of a cholesterol-lowering agent must be considered.Demyelinating conditions are rare events that appear to be specific to TNF inhibitors [81].Cases of multiple sclerosis have been observed in TNF inhibitor trials as well as in surveillance reports; therefore, previous history of multiple sclerosis or optic neuritis is a contraindication for treatment with inhibitors of TNF [63].

Pregnancy
In general, the administration of all biological agents is not recommended during pregnancy and lactation [82].

Conclusions
This review summarises the key clinical data for the four biological DMARDs licensed for use in Switzerland as monotherapy, namely adalimumab, certolizumab pegol, etanercept and tocilizumab.For various reasons, such as intolerance to MTX or patient compliance issues, biologic monotherapy is used in roughly one-third of RA patients [16].Data from the Swiss Clinical Quality Management registry for RA patients show that biological agents are prescribed as monotherapy in up to 39% of treatment courses, and that 27% of treatment courses with biological agents are begun as monotherapy (Gabay et al., unpublished observations).
For patients who are nonresponders or intolerant to maximal doses of MTX, the choice consists of either introducing DMARD combination therapy or initiating treatment with a biological agent.The available data indicate that TNF antagonists show less efficacy as monotherapy than when used in combination with MTX, whereas tocilizumab is the only biological agent that has demonstrated greater efficacy than MTX and other conventional DMARDs when used as monotherapy.Taken together, the bulk of clinical data supports tocilizumab as a good choice of monotherapy for the subpopulation of RA patients who are not eligible for biological agent combination therapy due to their inability to tolerate MTX or its alternatives.

Table 1 :
Biological agents without monotherapy approval in Switzerland.