REVIEW/CME ARTICLE

Treatment with Biologicals in Rheumatoid Arthritis:An Overview

Philipp Rein . Ruediger B. Mueller

Received: May 22, 2017 / Published online: August 22, 2017� The Author(s) 2017. This article is an open access publication

ABSTRACT

Management and therapy of rheumatoidarthritis (RA) has been revolutionized by thedevelopment and approval of the first biologicaldisease-modifying antirheumatic drugs(bDMARDs) targeting tumor necrosis factor(TNF) a at the end of the last century. Today,numerous efficacious agents with differentmodes of action are available and achievementof clinical remission or, at least, low diseaseactivity is the target of therapy. Early thera-peutic interventions aiming at a defined goal oftherapy (treat to target) are supposed to haltinflammation, improving symptoms and signs,and preserving structural integrity of the jointsin RA. Up to now, bDMARDs approved fortherapy in RA include agents with five differentmodes of action: TNF inhibition, T cellco-stimulation blockade, IL-6 receptor

inhibition, B cell depletion, and interleukin 1inhibition. Furthermore, targeted syntheticDMARDs (tsDMARDs) inhibiting Janus kinase(JAK) and biosimilars also are approved for RA.The present review focuses on bDMARDs andtsDMARDS regarding similarities and possibledrug-specific advantages in the treatment of RA.Furthermore, compounds not yet approved inRA and biosimilars are discussed. Following theAmerican College of Rheumatology (ACR) andEuropean League Against Rheumatism (EULAR)recommendations, specific treatment of thedisease will be discussed with respect to safetyand efficacy. In particular, we discuss the ques-tion of favoring specific bDMARDs ortsDMARDs in the two settings of insufficientresponse to methotrexate and to the firstbDMARD, respectively.

Keywords: B cell depletion; BiologicalDMARDs; IL-6 receptor inhibition; Januskinase inhibitors; Review; Rheumatoidarthritis; T cell co-stimulation blockade;Targeted synthetic DMARDs; Therapy; TNFinhibitors

INTRODUCTION

Rheumatoid Arthritis (RA) is a chronic inflam-matory systemic disease affecting approximately1% of the population with a higher frequency in

CME content This article has associated CMEaccreditation, valid until August 2018. Please follow thislink to access the activity: https://rheumatology.medicinematters.com/mmr1703/14216360.

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P. Rein (&) � R. B. MuellerDivision of Rheumatology, Immunology andRehabilitation, Kantonsspital St. Gallen, St. Gallen,Switzerlande-mail: philipp.rein@kssg.ch

Rheumatol Ther (2017) 4:247–261

DOI 10.1007/s40744-017-0073-3

women than in men [1]. Inflammation in RAprimarily affects the small joints and is charac-terized by pain and swelling, thereby leading tochronic progressive joint destruction causing adecline in quality of life, physical function, andworking ability. Cytokines such as tumornecrosis factor a (TNF) and interleukin 6 (IL-6)play a specific role in the inflammatory processesin RA [2]. As inflammation drives symptoms(pain and swelling of joints) and sequentiallydamage (loss of function leading to work dis-ability), suppression of inflammation is the maintarget in RA. As a result of its systemic nature, theindividual burden of the disease is not necessar-ily limited to the joints but also results fromfatigue, depression, osteoporosis, and anincreased risk for cardiovascular disease [3].

Management of RA has dramaticallyimproved in the last few decades: In formertimes, the disease was diagnosed late and relief ofsymptoms or prevention of adverse events wasthe main goal of therapy. For much of the lastcentury, available compounds for therapy in RAhad limited efficacy but significant toxicity.Management and therapy of RA has been revo-lutionized by the development and approval ofthe first biological disease-modifying antirheu-matic drugs (bDMARDs) targeting TNF at the endof the last century. Today, numerous efficaciousagents with different modes of action are avail-able and achievement of clinical remission or, atleast, low disease activity is the target of therapy.Earlier treatment in the course of RA leads to ahigher clinical efficacy [4] and, consequently,the 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria focus on enablingdiagnosis of RA in early stages of the disease [5].Within this phase of the disease, active inflam-mation instead of irretrievable structural damageis the key driver of symptoms and disability.Early therapeutic interventions aiming at adefined goal of therapy (treat to target) are sup-posed to halt inflammation, improving symp-toms and signs, and preserving structuralintegrity of the joints in RA [6].

Up to now, biological DMARDs approved fortherapy in RA include agents with five differentmodes of action: TNF inhibition, T cell co-stimu-lation blockade, IL-6 receptor inhibition, B cell

depletion, and interleukin 1 inhibition. Further-more, targeted synthetic DMARDs (tsDMARDs)inhibiting Janus kinase (JAK) and biosimilars alsoare approved for RA. Currently, five TNF inhibi-tors (adalimumab, certolizumab pegol, etaner-cept, golimumab, and infliximab) and twotsDMARDs inhibiting JAK (tofacitinib and barici-tinib) are approved for therapy in RA. The presentreview focuses on bDMARDs and tsDMARDsregarding similarities and possible drug-specificadvantages in the treatment of RA. Furthermore,compounds not yet approved in RA and biosimi-lars are discussed. Following the ACR and EULARrecommendations, specific treatment of the dis-ease will be discussed with respect to the firstbiologic intervention and management after fail-ure of the first bDMARD, respectively. This articleis based on previous studies and does not involveany new studies on human or animal subjectsperformed by the authors.

MANAGEMENT OF MTXINSUFFICIENT RESPONDERS

Efficacy of Approved Biological DMARDs

According to the recently updated EULAR rec-ommendations on RA [7], therapy with con-ventional synthetic DMARDs (csDMARDs)should be started immediately after havingdiagnosed RA and methotrexate (MTX) shouldbe part of the first treatment strategy. UsingMTX, however, a large proportion of patients donot achieve remission or low disease activity[8, 9]. In general, bDMARDs or tsDMARDsshould be considered if the first csDMARD doesnot achieve treatment target in the presence ofnegative prognostic factors or if response to twocsDMARDs is insufficient in the absence ofnegative prognostic factors.

In the setting of MTX-IR (MTX incompleteresponders), neither the EULAR nor the ACRrecommendations favor the use of one specificbDMARD or tsDMARD or suggest a certainsequence of its use [7, 10]: This strategy of rec-ommending all agents without hierarchicalpositioning is a novelty compared to the 2013version of the EULAR recommendations [11]and is well in line with the published evidence

248 Rheumatol Ther (2017) 4:247–261

Table1

Resultsof

rand

omized

controlledtrials(RCTs)of

biologicalsandsm

allmoleculeJAK

inhibitorscomparedto

placeboin

MTX

insufficientresponders

Intervention

Trial

Follo

w-up(weeks)

ACR20

(%)

ACR50

(%)

ACR70

(%)

Intervention

Placebo

Intervention

Placebo

Intervention

Placebo

Adalim

umab

Weinblatt,A

RMADA

[97]

2467

1555

827

5

Adalim

umab

Keystone[98]

5259

2442

1023

5

Certolizum

abKeystone,RAPID1[99]

5259

1437

821

3

Certolizum

abSm

olen,R

APID2[100]

2457

933

316

1

Etanercept

Moreland[101]

2459

1140

515

1

Golim

umab

Kay

[102]

1660

3737

69

0

Golim

umab

Keystone,GO

FORWARD

[103]

1455

3335

1014

4

Infliximab

Maini,A

TTRACT

[104]

3053

2027

58

0

Infliximab

Abe

[105]

1461

2331

910

0

Abatacept

Kremer,A

IM[106]

5268

4040

1720

7

Abatacept

Kremer

[107]

5263

3642

2021

8

Rituxim

abEdw

ards

[108]

1273

3843

1323

5

Rituxim

abEmery,DANCER[109]

2454

2834

1320

5

Tocilizumab

Smolen,O

PTIO

N[110]

2459

2644

1122

2

Tocilizumab

Maini,C

HARISMA

[111]

1674

4153

2937

16

Tofacitinib

vanderHeijde,ORALSC

AN

[112]

2452

2532

815

1

Baricitininb

Keystone[113]a

1275

4035

1023

2

Ifmorethan

onedosage

oftheactive

drug

was

investigated,d

atafortheapproved

dosage

aregiven

ACR20

improvem

entin

diseaseactivity

of20%

ormoreaccordingto

theAmerican

College

ofRheum

atology,ACR50

improvem

entin

diseaseactivity

of50%or

moreaccordingto

theAmerican

College

ofRheum

atology,

ACR

70im

provem

entin

diseaseactivity

of70%

ormoreaccordingto

theAmerican

College

ofRheum

atology

aNum

bersareestimated

from

Fig.1in

[113]

Rheumatol Ther (2017) 4:247–261 249

(Table 1): First, head-to-head studies in MTX-IRdirectly comparing bDMARDs with differentmodes of action in combination with MTX arescarce. The Ample study investigated the clini-cal efficacy of abatacept versus adalimumab inan MTX-IR RA cohort. Clinical efficacy (ACR 20response rate 64.8% in the abatacept and 63.4%in the adalimumab groups) and inhibition ofradiographic progression were similar withinthese two agents [12]. Tofacitinib was as effec-tive as adalimumab in a randomized study (ACR20 response rates 51.5%, 52.6%, and 47.2%among patients receiving 5 or 10 mg of tofaci-tinib or those receiving adalimumab) [13]. Sec-ond, studies directly comparing TNF inhibitorsare still lacking with the exception of theEXXELARATE trial investigating adalimumaband certolizumab pegol in MTX-IR. Resultsproved that the efficacy of certolizumab pegolwas not significantly different to that of adali-mumab, both in combination with MTX (ACR20 response rates 65% for certolizumab pegoland 67% for adalimumab) [14]. Third, indirectcomparisons strongly point to a similar efficacywithin all bDMARDs when used in combinationwith MTX [15].

In general, bDMARDs are used in combinationwith MTX. However, more than one-third ofpatients are intolerant toMTX [16] andadherenceis often poor, especially when administered orally[17]. Consequently, about 30% of patients inclinical practice are treated with bDMARDs inmonotherapy [18]. Next to MTX, variouscsDMARDs have been analyzed for their efficacyin RA patients. However, the combination ofthese other csDMARDs with bDMARDs has notbeentestedextensively: In theREACT [19] and theoral Sync studies [20], the combination of adali-mumab or tofacitinib, respectively, with differentcsDMARDs including sulfasalazine, leflunomide,antimalarials, azathioprine, and gold demon-strated proven efficacy. Furthermore, the combi-nation of TNF inhibitors with leflunomide was aseffective and equally well tolerated as TNF inhi-bitors plus MTX [21]. Similarly, disease activityand functional disability did not differ signifi-cantly between tocilizumab plus MTX versustocilizumab plus leflunomide [22].

Special focus has to be given to the clinicallyrelevant issue of using bDMARDs or tsDMARDs

in monotherapy: Tocilizumab was the first bio-logical agent to show statistically significantclinical efficacy superior to MTX when used inmonotherapy, although approximately two-thirds of patients in the MTX group reached andmaintained a 20 mg MTX/week dose by week 8[23]. The randomized controlled ADACTA trialevaluated adalimumab versus tocilizumab in RApatients with an insufficient response or intol-erance to MTX—both agents were used inmonotherapy. This superiority study showed asignificantly greater clinical improvement withtocilizumab compared to adalimumab (ACR 20response rates 65.0% vs. 49.4%) [24]. In anopen-label study, tocilizumab was similarlyeffective, when used as monotherapy or incombination with csDMARDs [25]. TheACT-RAY was a double-blind study to compareadding tocilizumab versus switching to tocili-zumab monotherapy in MTX-IR. In this study,no clinically relevant superiority of the additionof tocilizumab to MTX over the switch to toci-lizumab monotherapy was proven, but therewas a modest difference in the percentage ofpatients with DAS28 remission and in theinhibition of radiographic progression favoringthe addition strategy [26, 27]. Adding tocilizu-mab to MTX in patients with active diseasedespite MTX was clinically and radiographicallysuperior compared to switching from MTX totocilizumab in another two randomized trials[28, 29]. Regarding monotherapy withtsDMARDs, ACR 20 response rates were similarfor baricitinib plus placebo compared to barici-tinib plus MTX (nearly 80% in both groups) in arecently published RCT [30], and the effect oftofacitinib was irrespective of the dosage ofbackground MTX [31]. To sum up, the use oftocilizumab or of tsDMARDs is a reasonableevidence-proven strategy in case of monother-apy in RA, especially in patients who do nottolerate or cannot be treated with MTX.

Safety Issues Regarding ApprovedBiological Compounds in RA

Compared to csDMARDs, biological drugs in RAare associated with an increase in the number ofserious infections of six per 1000 patients

250 Rheumatol Ther (2017) 4:247–261

treated each year [32]. Increasing age, comor-bidity, glucocorticoid use, and previous historyof serious infections were significant predictorsof future infections in different databases,including the German RABBIT register. Theoverall relative risk of treatment with TNFinhibitors compared with that of csDMARDswas 1.8 in the RABBIT cohort, meaning that theabsolute risk increase depends on baseline riskin different groups of patients [33]. For dailypractice, an online calculator has been devel-oped [34]. The rates of serious infections inRCTs of newer biologicals appear to be in gen-eral consistent with rates seen in the anti-TNFregisters of between two and six per 100 patientyears of follow-up [35]. The ACR 2015 guidelinefor the treatment of RA has addressed the issueof safety [10]. Supported by low-level evidence,the ACR recommends to use csDMARDs incombination over TNF inhibitors in patientswith previous serious infections and to useabatacept over TNF inhibitors within thesehigh-risk patients, mainly driven by the resultsof the ATTEST trial, demonstrating less seriousinfections with a lower need of hospitalizationsduring therapy with abatacept compared toinfliximab [36, 37]. These recommendations areconditional, meaning that the special recom-mendation is applicable to the majority ofpatients, but some may not want to follow therecommendation.

After approval of TNF inhibitors, reports ofnew onset or deterioration of heart failure werereported for infliximab dosed at 10 mg/kg [38].This could not be reproduced with etanercept[39]. In parallel, a recent review shows that therate of heart failure is not increased in patientsreceiving TNF inhibitors. Furthermore, risk ofsymptomatic congestive heart failure was notincreased in the high risk group of patients withestablished heart failure during therapy withTNF inhibitors [40].

When initiating a biological DMARD, specialfocus relates to the increased risk of oppor-tunistic infections [41] and to check for latenttuberculosis. Risk for reactivation of tuberculo-sis is higher in patients receiving anti-TNFmonoclonal antibodies compared to etanercept.One reason therefore might be the importanceof membrane-bound TNF in protecting against

tuberculosis, which is neutralized by the TNFantibody but not by the TNF receptor fusionmolecule [42, 43]. In contrast, increased risk ofreactivation was not seen during therapy withrituximab in RA. In mice, abatacept did notimpair the ability to control a chronicMycobacterium tuberculosis infection [44].Tuberculosis (TB) was rarely seen during therapywith tofacitinib and it was speculated that someof the observed TB cases were instances of newlyacquired infection during the trial, given thatnearly all the cases occurred in regions of highTB endemicity where exposure would be morelikely [45]. No increased risk for tuberculosisreactivation was seen with tocilizumab in RCTs[46]. In general, prior to treatment with allapproved bDMARDs in MTX-IR, the well-known screening algorithm should be applied[10].

With respect to vaccination, treatment withrituximab and with MTX in monotherapy isassociated with impaired vaccine responses, andtemporary MTX discontinuation improves theimmunogenicity of seasonal influenza vaccina-tion in patients with RA [47, 48]. In contrast,tofacitinib had less impact on vaccinationresponses [49], whereas TNF inhibitors andtocilizumab did not reduce vaccinationresponse [47, 50].

A special safety issue during therapy withtocilizumab is the risk of lower intestinal per-foration (LIP). Recently, real-life data from Eur-ope found a significantly higher rate of LIP intocilizumab-treated patients compared topatients treated with csDMARDs and otherbDMARDs. Importantly, risk for LIP was notattenuated after adjustment for concomitantglucocorticoid use in Cox regression analysis[51]. In our opinion, a medical history positivefor diverticulitis contradicts the use of tocilizu-mab, knowing that most cases with LIP did nothave a history of diverticulitis. Patients shouldbe informed about this risk and the fact thatnegative markers of inflammation cannot beinterpreted during therapy with tocilizumab.

Regarding malignancies, cancer, lymphoma,melanoma, and non-melanoma skin cancer donot occur more frequently in patients on TNFinhibitors compared to patients on conven-tional DMARDs [52, 53]. However, rituximab is

Rheumatol Ther (2017) 4:247–261 251

the first choice in the case of certain comor-bidities, e.g., concomitant multiple sclerosis orpast or present lymphoproliferative disorders.

As 30–40% of RA patients show an inade-quate response to bDMARDs, trials investigatingthe combination of two bDMARDs with differ-ent modes of action have been done. However,the combination of abatacept plus TNF inhibi-tors [54], of an interleukin-1 receptor antagonistplus TNF inhibitors [55], and of rituximab plusTNF inhibitors [56] demonstrated a lack ofadded benefit and at least the first two combi-nations significantly increased the rates ofadverse events including serious infections.

MANAGEMENT IN TNFINSUFFICIENT RESPONDERS(TNF-IR)

There is still ambiguity how to manage RApatients with an inadequate response to the firstTNF inhibitor. Keeping in mind the growingnumber of modes of action and consequentlybDMARDs, this is a central question. Observa-tional data indicate an advantage in changingthe mode of action in TNF-IR [57, 58]. The ACRconsequently recommends the use of anon-TNF biological in case of an insufficientresponse to the first TNF inhibitor [10]. In pri-mary non-responders to the first TNF inhibitor,data from one randomized trial and severalobservational studies point to less clinicalresponse after switching to a second TNF inhi-bitor in primary TNF inhibitor non-responderscompared to secondary non-responders orpatients stopping the first TNF inhibitor becauseof adverse events [59–62]. Within primarynon-responders, disease might be mediated bycytokines other than TNF, and consequentlythese patients could experience greater benefitfrom compounds using modes of action otherthan blocking TNF. In contrast, EULAR recom-mends to employ a second TNF inhibitor or anagent with a different mode of action without ahierarchical ranking, if one TNF inhibitor hasfailed [7]. Randomized controlled head-to-headstudies once more are scarce, with the exceptionof the EXXELARATE study corroborating thisrecommendation: About 60% of patients

switching to a second TNF inhibitor after pri-mary failure to the first TNF inhibitor achieved aDAS28 reduction of at least 1.2 points [14].Recommendation differs in patients failing TNFinhibition in monotherapy: As stated above, theuse of tocilizumab or tsDMARDs is our recom-mended strategy in TNF-IR on monotherapywith bDMARDs.

Patients with secondary inefficacy to TNFinhibitors may have lost response because of thedevelopment of antidrug antibodies; thesepatients would therefore be expected to exhibita clinically relevant response to an antigenicallydistinct treatment. Data from a randomizedplacebo-controlled trial demonstrated efficacyand safety of certolizumab in RA patients withsecondary inadequate response or intoleranceto the previous TNF inhibitors [63]. Impor-tantly, patients developing antibodies to a firstTNF inhibitor are at higher risk for developingantibodies to a subsequently employed TNFinhibitor. Therefore, immunogenicity might bethe cause leading to the lower clinical efficacy ofthe second TNF inhibitor observed in TNF-IR[57, 64]. Within this context, changing themode of action in patients failing treatmentwith TNF inhibitors is worth considering, espe-cially as abatacept [65], golimumab [61], ritux-imab [66–68], tocilizumab [69, 70], tofacitinib[71], and baricitinib [72] demonstrated clinicalefficacy in patients with a previously inadequateresponse to at least one TNF inhibitor (Table 2).However, direct head-to-head comparisonsusing compounds with different modes ofaction in TNF-IR are still lacking. Moreover, westill do not have any data exploring the efficacyand safety of TNF inhibitors used afternon-TNF-inhibiting bDMARDs have failed, of asecond IL-6 receptor inhibitor after tocilizumabhas failed, and of a second JAK inhibitor afterthe first has failed. In summary, selection of thenext bDMARD in TNF-IR is still undetermined,whereas EULAR and ACR both recommendswitching to a non-TNF biological if a secondTNF inhibitor fails.

Despite observational data and indirectcomparisons pointing to a lower risk of infec-tion during treatment with rituximab [73, 74],there was no consensus for making recom-mendations regarding the use of the CD20

252 Rheumatol Ther (2017) 4:247–261

antibody over TNF inhibitors in the setting ofprevious serious infections. A pooled analysis ofsafety data reported a rate of serious infectionswith rituximab that was comparable to thatwith MTX and reactivation of tuberculosis doesnot occur more frequently in RA treated withrituximab [75].

Furthermore, the frequency of serious infec-tions was similar in TNF-IR randomized to abat-acept compared to the placebo group (10.5% and11.3%) [65]. In the few head-to-head trials,incidence of serious infections was not statisti-cally significantly different between two TNFinhibitors (EXXELERATE, 2.2% in certolizumabpegol vs. 2.0% in adalimumab treated patients)[14], and a TNF inhibitor compared to tocilizu-mab and baricitinib [24, 76], whereas abatacepthad a more acceptable safety profile than inflix-imab as already mentioned [36]. In contrast, arecentmeta-analysis suggests an increased risk of

adverse events for certolizumab pegol during thefirst months of treatment [77].

In general, RCTs in TNF-IR ask for a washoutphase of at least 4 weeks after the last injectionor infusion of TNF inhibitors. However, theneed for a washout phase has been rebutted inthe ARRIVE, ACT-SURE, and EXXELARATE trials[14, 69, 78]. In our clinic, we have generallyabandoned the use of a washout period. Wedirectly start the new compound at the datescheduled for the next infusion or injection ofthe formerly used agent in TNF-IR. In ourhands, no increase of adverse events was found(unpublished data).

PRACTICABILITY

In 2017, treating physicians have the possibilityto choose not only among biological

Table 2 Results of randomized controlled trials of biologicals and small molecule JAK inhibitors compared to placebo inTNF insufficient responders

Intervention Trial Follow-up(weeks)

ACR 20 (%) ACR 50 (%) ACR 70 (%)

Intervention Placebo Intervention Placebo Intervention Placebo

Golimumab Smolen, GO

AFTER [61]

24 35 17 16 5 10 3

Abatacept Genovese,

ATTAIN [65]

24 50 20 20 4 10 2

Rituximab Cohen, REFLEX

[66]

24 51 18 27 5 12 1

Rituximab Emery, SERENE

[67]

24 51 23 26 9 9 10

Tocilizumab Emery, RADIATE

[70]a24 50 10 29 4 12 1

Tofacitinib Burmester, ORAL

Step [71]

12 42 24 27 8 14 2

Baricitinib Genovese, RA

BEACON [72]

12 55 27 NA NA NA NA

If more than one dosage of the active drug was investigated, data for the approved dosage are givenACR 20 improvement in disease activity of 20% or more according to the American College of Rheumatology, ACR 50improvement in disease activity of 50% or more according to the American College of Rheumatology, ACR 70improvement in disease activity of 70% or more according to the American College of Rheumatologya Data are given for rituximab 2 9 1000 mg

Rheumatol Ther (2017) 4:247–261 253

compounds with different modes of action butalso with different routes of administration.Abatacept and tocilizumab are approved for usevia subcutaneous injection or intravenousaccess. Head-to-head studies comparing theintravenous and subcutaneous route of admin-istration of these two agents did not show anydifference in clinical efficacy and safety, exceptthat injection site reactions were more commonwith the subcutaneous access [24, 79]. Abata-cept has demonstrated that switching fromweekly subcutaneous to intravenous abataceptand back is effective and safe and may be usedto bridge 4 weeks, e.g., to cover a vacation [80].In real life, about 50% of patients with subcu-taneous injections do not feel confident aboutinjecting themselves [81]. Data investigatingcompliance with the orally administered JAKinhibitors are lacking. In our clinic, we observeda sinusoidal course in disease activity amongpatients treated with tofacitinib in real life,raising the issue of poor compliance. This mightbe the case especially in phases of good controlof inflammation (manuscript underpreparation).

COMPOUNDS NOT YET APPROVEDIN THE TREATMENT OF RA

Sarilumab inhibits IL-6-mediated signalling byspecifically binding to both soluble and mem-brane-bound IL-6 receptors. Administered sub-cutaneously every 2 weeks, sarilumabsignificantly improved disease activity inMTX-IR and TNF-IR [82, 83]. Moreover, sar-ilumab was superior to adalimumab (both inmonotherapy) by improving clinical diseaseactivity in RA patients unable to continue MTX(ACR 20 response rates 71.1% in sar-ilumab-treated patients vs. 58.4% in adali-mumab-treated patients) [84]. Similarly,HAQ-DI score and patient-reported outcomesimproved at a statistically significant greaterextent in the sarilumab group compared to theadalimumab group. The incidence of infectionswas similar between the two groups. Treatmentwith the IL-12/23 antibody ustekinumab andthe IL-23 antibody guselkumab did not signifi-cantly reduce disease activity in rheumatoid

arthritis patients with an inadequate responseto MTX (ACR 20 response 53.6% and 41.3% vs.40.0% in placebo) [85]. The data for the com-pounds secukinumab and brodalumab blockingthe cytokines IL-17 and IL-23 in RA are far dis-appointing [86, 87], whereas ixekizumabimproved RA signs and symptoms in patientsnaive to or with an inadequate response to TNFinhibitors [88]. It is therefore questionable ifIL-17 and IL-23 blocking agents will be com-petitive against the already approved andavailable compounds in RA.

BIOSIMILARS

EULAR mentions that biosimilars approved bythe European Medical Agency (EMA) or the USFood and Drug Administration (FDA) havesimilar efficacy and safety as the respectivebiological originator, and should be preferred ifthey are indeed appreciably cheaper than theoriginator or other biological compounds [7].Biosimilar infliximab is already widely available,whereas biosimilar etanercept and biosimilarrituximab are approved merely by the FDA atthe moment, but the EMA recommendedapproval recently [89]. Furthermore, a substan-tial pipeline of biosimilars is in development,including biosimilar adalimumab, which isrecommended for approval [90].

TAPERING AND WITHDRAWAL

If a patient is in persistent remission after hav-ing tapered steroids, tapering bDMARDs can beconsidered [7]. Reducing from 50 to 25 mgetanercept injected once per week or increasingthe time interval between the etanercept oradalimumab injections was non-inferior tousual continued medication with respect to thepreservation of clinical remission or low diseaseactivity and the rate of clinically relevant flares[91, 92]. In contrast, abrupt cessation ofbDMARD therapy led to flares in many if notmost of the patients, not all of these regainingtheir former state of remission or low diseaseactivity after restart of bDMARDs. In theACT-Ray study, 50% of patients discontinued

254 Rheumatol Ther (2017) 4:247–261

tocilizumab following sustained clinical remis-sion after 1 year. Subsequently, 84% of thesepatients experienced a flare-up with recurrentresponse to the reintroduced drug [93]. In theCERTAIN double-blind randomized trial,patients who achieved remission during treat-ment with certolizumab pegol and csDMARDstopped treatment. Only three of the 17 priorcertolizumab pegol patients maintained remis-sion until week 52 [94]. In line with EULARrecommendations, in cases of persistent remis-sion, tapering the csDMARD could be consid-ered. However, this recommendation is a matterof debate, as many rheumatologists neverwould stop a csDMARD and leave patientswithout any disease-modifying therapy [7].

CONCLUSIONS

In general, important steps for controlling theprogression of the disease have to be taken longbefore choosing a bDMARD: Early identificationof RA represents the crucial step. Therefore wehave to emphasize the importance of awarenessfor RA within the population and general prac-titioners. Perhaps even more challenging is thenext step: Patients suspected of suffering fromRA have to be seen by rheumatologists quickly,and if diagnosed, treatment with preferentiallyMTX should be started immediately. Initiatingtherapy within 3 months of disease onsetplayed the most important role in achievingremission [95]. Even the worst prognostic fac-tors lost significance when patients were treatedaggressively and promptly in the BeST trial [96].Treatment decisions have to be based on mea-sures of disease activity and should be aimed atreaching remission or low disease activity, withrespect to patient factors. Frequent follow-upvisits especially in active disease and the over-arching principle of treat-to-target are particu-larly important for successful therapy of RA.However, predictors for differential response tothe different bDMARDs and tsDMARDs aremissing. We still do not know which patientwill best respond to which drug in which stageof disease and pretreatment. To provide betterjustification for the decision to prefer a specific

bDMARD in different situations, future ran-domized head-to-head studies are urgentlyrequired.

ACKNOWLEDGEMENTS

No funding or sponsorship was received for thisstudy or publication of this article. All namedauthors meet the International Committee ofMedical Journal Editors (ICMJE) criteria forauthorship for this manuscript, take responsi-bility for the integrity of the work as a whole,and have given final approval for the version tobe published.

Disclosures. Philipp Rein: Dr Rein has norelevant financial relationships to disclose.

Ruediger B Mueller: Consultant: AbbVie, UCB,

Roche, BMS, Antares, Pfizer. Research grant:

Roche, BMS, UCB.

Compliance with Ethics Guidelines. Thisarticle is based on previous studies and does notinvolve any new studies on human or animalsubjects performed by the authors.

Open Access. This article is distributedunder the terms of the Creative CommonsAttribution-NonCommercial 4.0 InternationalLicense (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommer-cial use, distribution, and reproduction in anymedium, provided you give appropriate creditto the original author(s) and the source, providea link to the Creative Commons license, andindicate if changes were made.

REFERENCES

1. Gabriel SE. The epidemiology of rheumatoidarthritis. Rheum Dis Clin North Am.2001;27:269–81.

2. Furst DE, Emery P. Rheumatoid arthritis patho-physiology: update on emerging cytokine andcytokine-associated cell targets. Rheumatology(Oxford). 2014;53:1560–9.

Rheumatol Ther (2017) 4:247–261 255

3. Kitas GD, Gabriel SE. Cardiovascular disease inrheumatoid arthritis: state of the art and futureperspectives. Ann Rheum Dis. 2011;70:8–14.

4. Nell VP, Machold KP, Eberl G, Stamm TA, UffmannM, Smolen JS. Benefit of very early referral and veryearly therapy with disease-modifying anti-rheu-matic drugs in patients with early rheumatoidarthritis. Rheumatology (Oxford). 2004;43:906–14.

5. Aletaha D, Neogi T, Silman AJ, et al. 2010 rheuma-toid arthritis classification criteria: an AmericanCollege of Rheumatology/European League AgainstRheumatism collaborative initiative. Ann RheumDis. 2010;69:1580–8.

6. Gremese E, Salaffi F, Bosello SL, et al. Very earlyrheumatoid arthritis as a predictor of remission: amulticentre real life prospective study. Ann RheumDis. 2013;72:858–62.

7. Smolen JS, Landewe R, Bijlsma J, et al. EULAR rec-ommendations for the management of rheumatoidarthritis with synthetic and biological dis-ease-modifying antirheumatic drugs: 2016 update.Ann Rheum Dis. 2017;76:960–77.

8. Braun J, Kastner P, Flaxenberg P, et al. Comparisonof the clinical efficacy and safety of subcutaneousversus oral administration of methotrexate inpatients with active rheumatoid arthritis: results ofa six-month, multicenter, randomized, dou-ble-blind, controlled, phase IV trial. ArthritisRheum. 2008;58:73–81.

9. Muller RB, von Kempis J, Haile SR, Schiff MH.Effectiveness, tolerability, and safety of subcuta-neous methotrexate in early rheumatoid arthritis: aretrospective analysis of real-world data from the St.Gallen cohort. Semin Arthritis Rheum.2015;45:28–34.

10. Singh JA, Saag KG, Bridges SL Jr, et al. 2015 Ameri-can College of Rheumatology guideline for thetreatment of rheumatoid arthritis. ArthritisRheumatol. 2016;68:1–26.

11. Smolen JS, Landewe R, Breedveld FC, et al. EULARrecommendations for the management of rheuma-toid arthritis with synthetic and biological dis-ease-modifying antirheumatic drugs: 2013 update.Ann Rheum Dis. 2014;73:492–509.

12. Weinblatt ME, Schiff M, Valente R, et al. Head-to-head comparison of subcutaneous abataceptversus adalimumab for rheumatoid arthritis: find-ings of a phase IIIb, multinational, prospective,randomized study. Arthritis Rheum.2013;65:28–38.

13. van Vollenhoven RF, Fleischmann R, Cohen S, et al.Tofacitinib or adalimumab versus placebo in

rheumatoid arthritis. N Engl J Med.2012;367:508–19.

14. Smolen JS, Burmester GR, Combe B, et al. Head-to-head comparison of certolizumab pegol versusadalimumab in rheumatoid arthritis: 2-year efficacyand safety results from the randomised EXXELE-RATE study. Lancet. 2016;388:2763–74.

15. Nam JL, Ramiro S, Gaujoux-Viala C, et al. Efficacy ofbiological disease-modifying antirheumatic drugs: asystematic literature review informing the 2013update of the EULAR recommendations for themanagement of rheumatoid arthritis. Ann RheumDis. 2014;73:516–28.

16. Nikiphorou E, Negoescu A, Fitzpatrick JD, et al.Indispensable or intolerable? Methotrexate inpatients with rheumatoid and psoriatic arthritis: aretrospective review of discontinuation rates from alarge UK cohort. Clin Rheumatol. 2014;33:609–14.

17. DiBenedetti DB, Zhou X, Reynolds M, Ogale S, BestJH. Assessing methotrexate adherence in rheuma-toid arthritis: a cross-sectional survey. RheumatolTher. 2015;2:73–84.

18. Soliman MM, Ashcroft DM, Watson KD, Lunt M,Symmons DP, Hyrich KL. Impact of concomitantuse of DMARDs on the persistence with anti-TNFtherapies in patients with rheumatoid arthritis:results from the British Society for RheumatologyBiologics Register. Ann Rheum Dis. 2011;70:583–9.

19. Burmester GR, Mariette X, Montecucco C, et al.Adalimumab alone and in combination with dis-ease-modifying antirheumatic drugs for the treat-ment of rheumatoid arthritis in clinical practice:the Research in Active Rheumatoid Arthritis (ReAct)trial. Ann Rheum Dis. 2007;66:732–9.

20. Strand V, Kremer JM, Gruben D, Krishnaswami S,Zwillich SH, Wallenstein GV. Tofacitinib in com-bination with conventional disease-modifyingantirheumatic drugs in patients with activerheumatoid arthritis: patient-reported outcomesfrom a phase III randomized controlled trial.Arthritis Care Res (Hoboken). 2017;69:592–8.

21. De Stefano R, Frati E, Nargi F, et al. Comparison ofcombination therapies in the treatment ofrheumatoid arthritis: leflunomide-anti-TNF-alphaversus methotrexate-anti-TNF-alpha. Clin Rheuma-tol. 2010;29:517–24.

22. Narvaez J, Diaz-Torne C, Magallares B, et al. Com-parative effectiveness of tocilizumab with eithermethotrexate or leflunomide in the treatment ofrheumatoid arthritis. PLoS One. 2015;10:e0123392.

23. Jones G, Sebba A, Gu J, et al. Comparison of tocili-zumab monotherapy versus methotrexate

256 Rheumatol Ther (2017) 4:247–261

monotherapy in patients with moderate to severerheumatoid arthritis: the AMBITION study. AnnRheum Dis. 2010;69:88–96.

24. Gabay C, Emery P, van Vollenhoven R, et al. Toci-lizumab monotherapy versus adalimumabmonotherapy for treatment of rheumatoid arthritis(ADACTA): a randomised, double-blind, controlledphase 4 trial. Lancet. 2013;381:1541–50.

25. Bykerk VP, Ostor AJ, Alvaro-Gracia J, et al. Com-parison of tocilizumab as monotherapy or withadd-on disease-modifying antirheumatic drugs inpatients with rheumatoid arthritis and inadequateresponses to previous treatments: an open-labelstudy close to clinical practice. Clin Rheumatol.2015;34:563–71.

26. Dougados M, Kissel K, Sheeran T, et al. Addingtocilizumab or switching to tocilizumabmonotherapy in methotrexate inadequate respon-ders: 24-week symptomatic and structural results ofa 2-year randomised controlled strategy trial inrheumatoid arthritis (ACT-RAY). Ann Rheum Dis.2013;72:43–50.

27. Dougados M, Kissel K, Conaghan PG, et al. Clinical,radiographic and immunogenic effects after 1 yearof tocilizumab-based treatment strategies inrheumatoid arthritis: the ACT-RAY study. AnnRheum Dis. 2014;73:803–9.

28. Burmester GR, Rigby WF, van Vollenhoven RF, et al.Tocilizumab combination therapy or monotherapyor methotrexate monotherapy in methotrex-ate-naive patients with early rheumatoid arthritis:2-year clinical and radiographic results from therandomised, placebo-controlled FUNCTION trial.Ann Rheum Dis. 2017;76:1279–84.

29. Kaneko Y, Atsumi T, Tanaka Y, et al. Comparison ofadding tocilizumab to methotrexate with switchingto tocilizumab in patients with rheumatoid arthritiswith inadequate response to methotrexate: 52-weekresults from a prospective, randomised, controlledstudy (SURPRISE study). Ann Rheum Dis.2016;75:1917–23.

30. Fleischmann R, Schiff M, Van der HD, et al. Barici-tinib, methotrexate, or combination in patientswith rheumatoid arthritis and no or limited priordisease-modifying antirheumatic drug treatment.Arthritis Rheumatol. 2017;69:506–17.

31. Fleischmann R, Mease PJ, Schwartzman S, et al.Efficacy of tofacitinib in patients with rheumatoidarthritis stratified by background methotrexate dosegroup. Clin Rheumatol. 2017;36:15–24.

32. Singh JA, Cameron C, Noorbaloochi S, et al. Risk ofserious infection in biological treatment of patients

with rheumatoid arthritis: a systematic review andmeta-analysis. Lancet. 2015;386:258–65.

33. Strangfeld A, Eveslage M, Schneider M, et al. Treat-ment benefit or survival of the fittest: what drivesthe time-dependent decrease in serious infectionrates under TNF inhibition and what does thisimply for the individual patient? Ann Rheum Dis.2011;70:1914–20.

34. RABBIT Risk Score of Infections. http://www.biologika-register.de/en/home/risk-score/. Accessed23 June 2017.

35. Lahiri M, Dixon WG. Risk of infection with biologicantirheumatic therapies in patients with rheuma-toid arthritis. Best Pract Res Clin Rheumatol.2015;29:290–305.

36. Schiff M, Keiserman M, Codding C, et al. Efficacyand safety of abatacept or infliximab vs placebo inATTEST: a phase III, multi-centre, randomised,double-blind, placebo-controlled study in patientswith rheumatoid arthritis and an inadequateresponse to methotrexate. Ann Rheum Dis.2008;67:1096–103.

37. Yun H, Xie F, Delzell E, et al. Risk of hospitalisedinfection in rheumatoid arthritis patients receivingbiologics following a previous infection while ontreatment with anti-TNF therapy. Ann Rheum Dis.2015;74:1065–71.

38. Chung ES, Packer M, Lo KH, Fasanmade AA,Willerson JT. Randomized, double-blind,placebo-controlled, pilot trial of infliximab, a chi-meric monoclonal antibody to tumor necrosis fac-tor-alpha, in patients with moderate-to-severe heartfailure: results of the anti-TNF Therapy AgainstCongestive Heart Failure (ATTACH) trial. Circula-tion. 2003;107:3133–40.

39. Mann DL, McMurray JJ, Packer M, et al. Targetedanticytokine therapy in patients with chronic heartfailure: results of the Randomized EtanerceptWorldwide Evaluation (RENEWAL). Circulation.2004;109:1594–602.

40. Solomon DH, Rassen JA, Kuriya B, et al. Heart fail-ure risk among patients with rheumatoid arthritisstarting a TNF antagonist. Ann Rheum Dis.2013;72:1813–8.

41. Kourbeti IS, Ziakas PD, Mylonakis E. Biologic ther-apies in rheumatoid arthritis and the risk ofopportunistic infections: a meta-analysis. ClinInfect Dis. 2014;58:1649–57.

42. Plessner HL, Lin PL, Kohno T, et al. Neutralizationof tumor necrosis factor (TNF) by antibody but notTNF receptor fusion molecule exacerbates chronic

Rheumatol Ther (2017) 4:247–261 257

murine tuberculosis. J Infect Dis.2007;195:1643–50.

43. Tubach F, Salmon D, Ravaud P, et al. Risk oftuberculosis is higher with anti-tumor necrosis fac-tor monoclonal antibody therapy than with solubletumor necrosis factor receptor therapy: the three-year prospective French Research Axed on Toler-ance of Biotherapies registry. Arthritis Rheum.2009;60:1884–94.

44. Bigbee CL, Gonchoroff DG, Vratsanos G, Nadler SG,Haggerty HG, Flynn JL. Abatacept treatment doesnot exacerbate chronic Mycobacterium tuberculosisinfection in mice. Arthritis Rheum.2007;56:2557–65.

45. Winthrop KL, Park SH, Gul A, et al. Tuberculosisand other opportunistic infections in tofaci-tinib-treated patients with rheumatoid arthritis.Ann Rheum Dis. 2016;75:1133–8.

46. Campbell L, Chen C, Bhagat SS, Parker RA, Ostor AJ.Risk of adverse events including serious infectionsin rheumatoid arthritis patients treated with tocili-zumab: a systematic literature review andmeta-analysis of randomized controlled trials.Rheumatology (Oxford). 2011;50:552–62.

47. Hua C, Barnetche T, Combe B, Morel J. Effect ofmethotrexate, anti-tumor necrosis factor alpha, andrituximab on the immune response to influenzaand pneumococcal vaccines in patients withrheumatoid arthritis: a systematic review andmeta-analysis. Arthritis Care Res (Hoboken).2014;66:1016–26.

48. Park JK, Lee MA, Lee EY, et al. Effect of methotrex-ate discontinuation on efficacy of seasonal influ-enza vaccination in patients with rheumatoidarthritis: a randomised clinical trial. Ann RheumDis. doi:10.1136/annrheumdis-2017-211128.

49. Winthrop KL, Silverfield J, Racewicz A, et al. Theeffect of tofacitinib on pneumococcal and influenzavaccine responses in rheumatoid arthritis. AnnRheum Dis. 2016;75:687–95.

50. Mori S, Ueki Y, Akeda Y, et al. Pneumococcalpolysaccharide vaccination in rheumatoid arthritispatients receiving tocilizumab therapy. Ann RheumDis. 2013;72:1362–6.

51. StrangfeldA,RichterA, SiegmundB, et al.Risk for lowerintestinal perforations in patients with rheumatoidarthritis treated with tocilizumab in comparison totreatment with other biologic or conventional syn-thetic DMARDs. Ann RheumDis. 2017;76:504–10.

52. Mercer LK, Askling J, Raaschou P, et al. Risk ofinvasive melanoma in patients with rheumatoid

arthritis treated with biologics: results from a col-laborative project of 11 European biologic registers.Ann Rheum Dis. 2017;76:386–91.

53. Ramiro S, Gaujoux-Viala C, Nam JL, et al. Safety ofsynthetic and biological DMARDs: a systematic lit-erature review informing the 2013 update of theEULAR recommendations for management ofrheumatoid arthritis. Ann Rheum Dis.2014;73:529–35.

54. Weinblatt M, Combe B, Covucci A, Aranda R,Becker JC, Keystone E. Safety of the selective cos-timulation modulator abatacept in rheumatoidarthritis patients receiving background biologic andnonbiologic disease-modifying antirheumaticdrugs: a 1-year randomized, placebo-controlledstudy. Arthritis Rheum. 2006;54:2807–16.

55. Genovese MC, Cohen S, Moreland L, et al. Combi-nation therapy with etanercept and anakinra in thetreatment of patients with rheumatoid arthritiswho have been treated unsuccessfully withmethotrexate. Arthritis Rheum. 2004;50:1412–9.

56. Greenwald MW, Shergy WJ, Kaine JL, Sweetser MT,Gilder K, Linnik MD. Evaluation of the safety ofrituximab in combination with a tumor necrosisfactor inhibitor and methotrexate in patients withactive rheumatoid arthritis: results from a random-ized controlled trial. Arthritis Rheum.2011;63:622–32.

57. Emery P, Gottenberg JE, Rubbert-Roth A, et al.Rituximab versus an alternative TNF inhibitor inpatients with rheumatoid arthritis who failed torespond to a single previous TNF inhibitor:SWITCH-RA, a global, observational, comparativeeffectiveness study. Ann Rheum Dis.2015;74:979–84.

58. Finckh A, Ciurea A, Brulhart L, et al. B cell depletionmay be more effective than switching to an alter-native anti-tumor necrosis factor agent in rheuma-toid arthritis patients with inadequate response toanti-tumor necrosis factor agents. Arthritis Rheum.2007;56:1417–23.

59. Bombardieri S, Ruiz AA, Fardellone P, et al. Effec-tiveness of adalimumab for rheumatoid arthritis inpatients with a history of TNF-antagonist therapy inclinical practice. Rheumatology (Oxford).2007;46:1191–9.

60. Remy A, Avouac J, Gossec L, Combe B. Clinicalrelevance of switching to a second tumour necrosisfactor-alpha inhibitor after discontinuation of a firsttumour necrosis factor-alpha inhibitor in rheuma-toid arthritis: a systematic literature review andmeta-analysis. Clin Exp Rheumatol.2011;29:96–103.

258 Rheumatol Ther (2017) 4:247–261

61. Smolen JS, Kay J, Doyle MK, et al. Golimumab inpatients with active rheumatoid arthritis aftertreatment with tumour necrosis factor alpha inhi-bitors (GO-AFTER study): a multicentre, ran-domised, double-blind, placebo-controlled, phaseIII trial. Lancet. 2009;374:210–21.

62. Virkki LM, Valleala H, Takakubo Y, et al. Outcomesof switching anti-TNF drugs in rheumatoid arthri-tis—a study based on observational data from theFinnish Register of Biological Treatment (ROB-FIN).Clin Rheumatol. 2011;30:1447–54.

63. Schiff MH, von Kempis J, Goldblum R, Tesser JR,Mueller RB. Rheumatoid arthritis secondarynon-responders to TNF can attain an efficacious andsafe response by switching to certolizumab pegol: aphase IV, randomised, multicentre, double-blind,12-week study, followed by a 12-week open-labelphase. Ann Rheum Dis. 2014;73:2174–7.

64. Jani M, Barton A, Warren RB, Griffiths CE, ChinoyH. The role of DMARDs in reducing the immuno-genicity of TNF inhibitors in chronic inflammatorydiseases. Rheumatology (Oxford). 2014;53:213–22.

65. Genovese MC, Becker JC, Schiff M, et al. Abataceptfor rheumatoid arthritis refractory to tumor necro-sis factor alpha inhibition. N Engl J Med.2005;353:1114–23.

66. Cohen SB, Emery P, Greenwald MW, et al. Ritux-imab for rheumatoid arthritis refractory to anti-tu-mor necrosis factor therapy: results of a multicenter,randomized, double-blind, placebo-controlled,phase III trial evaluating primary efficacy and safetyat twenty-four weeks. Arthritis Rheum.2006;54:2793–806.

67. Emery P, Deodhar A, Rigby WF, et al. Efficacy andsafety of different doses and retreatment of ritux-imab: a randomised, placebo-controlled trial inpatients who are biological naive with activerheumatoid arthritis and an inadequate response tomethotrexate (Study Evaluating Rituximab’s Effi-cacy in MTX iNadequate rEsponders (SERENE)).Ann Rheum Dis. 2010;69:1629–35.

68. Mease PJ, Cohen S, Gaylis NB, et al. Efficacy andsafety of retreatment in patients with rheumatoidarthritis with previous inadequate response totumor necrosis factor inhibitors: results from theSUNRISE trial. J Rheumatol. 2010;37:917–27.

69. Bykerk VP, Ostor AJ, Alvaro-Gracia J, et al. Tocili-zumab in patients with active rheumatoid arthritisand inadequate responses to DMARDs and/or TNFinhibitors: a large, open-label study close to clinicalpractice. Ann Rheum Dis. 2012;71:1950–4.

70. Emery P, Keystone E, Tony HP, et al. IL-6 receptorinhibition with tocilizumab improves treatment

outcomes in patients with rheumatoid arthritisrefractory to anti-tumour necrosis factor biologicals:results from a 24-week multicentre randomisedplacebo-controlled trial. Ann Rheum Dis.2008;67:1516–23.

71. Burmester GR, Blanco R, Charles-Schoeman C, et al.Tofacitinib (CP-690,550) in combination withmethotrexate in patients with active rheumatoidarthritis with an inadequate response to tumournecrosis factor inhibitors: a randomised phase 3trial. Lancet. 2013;381:451–60.

72. Genovese MC, Kremer J, Zamani O, et al. Baricitinibin patients with refractory rheumatoid arthritis.N Engl J Med. 2016;374:1243–52.

73. Salliot C, Dougados M, Gossec L. Risk of seriousinfections during rituximab, abatacept and ana-kinra treatments for rheumatoid arthritis:meta-analyses of randomised placebo-controlledtrials. Ann Rheum Dis. 2009;68:25–32.

74. Xanthouli P, Sailer S, Fiehn C. Rituximab (RTX) asan alternative to TNF-alpha antagonists in patientswith rheumatoid arthritis and high risk of severeinfections: a systematic analysis of the experience inone center. Open Rheumatol J. 2012;6:286–9.

75. van Vollenhoven RF, Emery P, Bingham CO III,et al. Long-term safety of rituximab in rheumatoidarthritis: 9.5-year follow-up of the global clinicaltrial programme with a focus on adverse events ofinterest in RA patients. Ann Rheum Dis.2013;72:1496–502.

76. Taylor PC, Keystone EC, Van der HD, et al. Barici-tinib versus placebo or adalimumab in rheumatoidarthritis. N Engl J Med. 2017;376:652–62.

77. Tarp S, Eric FD, Boers M, et al. Risk of serious adverseeffects of biological and targeted drugs in patientswith rheumatoid arthritis: a systematic reviewmeta-analysis. Rheumatology (Oxford).2017;56:417–25.

78. Schiff M, Pritchard C, Huffstutter JE, et al. The 6-month safety and efficacy of abatacept in patientswith rheumatoid arthritis who underwent a wash-out after anti-tumour necrosis factor therapy orwere directly switched to abatacept: the ARRIVEtrial. Ann Rheum Dis. 2009;68:1708–14.

79. Burmester GR, Rubbert-Roth A, Cantagrel A, et al.Efficacy and safety of subcutaneous tocilizumabversus intravenous tocilizumab in combinationwith traditional DMARDs in patients with RA atweek 97 (SUMMACTA). Ann Rheum Dis.2016;75:68–74.

80. Mueller RB, Gengenbacher M, Richter S, Dudler J,Moller B, von Kempis J. Change from subcutaneous

Rheumatol Ther (2017) 4:247–261 259

to intravenous abatacept and back in patients withrheumatoid arthritis as simulation of a vacation: aprospective phase IV, open-label trial (A-BREAK).Arthritis Res Ther. 2016;18:88.

81. Hiley J, Homer D, Clifford C. Patient self-injectionof methotrexate for inflammatory arthritis: a studyevaluating the introduction of a new type of syringeand exploring patients’ sense of empowerment.Musculoskelet Care. 2008;6:15–30.

82. Fleischmann R, van Adelsberg J, Lin Y, et al. Sar-ilumab and nonbiologic disease-modifying anti-rheumatic drugs in patients with active rheumatoidarthritis and inadequate response or intolerance totumor necrosis factor inhibitors. Arthritis Rheuma-tol. 2017;69:277–90.

83. Genovese MC, Fleischmann R, Kivitz AJ, et al. Sar-ilumab plus methotrexate in patients with activerheumatoid arthritis and inadequate response tomethotrexate: results of a phase III study. ArthritisRheumatol. 2015;67:1424–37.

84. Burmester GR, Lin Y, Patel R, et al. Efficacy andsafety of sarilumab monotherapy versus adali-mumab monotherapy for the treatment of patientswith active rheumatoid arthritis (MONARCH): arandomised, double-blind, parallel-group phase IIItrial. Ann Rheum Dis. 2017;76:840–7.

85. Smolen JS, Agarwal SK, Ilivanova E, et al. A ran-domised phase II study evaluating the efficacy andsafety of subcutaneously administered ustekinumaband guselkumab in patients with active rheumatoidarthritis despite treatment with methotrexate. AnnRheum Dis. 2017;76:831–9.

86. Genovese MC, Durez P, Richards HB, et al. One-yearefficacy and safety results of secukinumab inpatients with rheumatoid arthritis: phase II,dose-finding, double-blind, randomized,placebo-controlled study. J Rheumatol.2014;41:414–21.

87. Martin DA, Churchill M, Flores-Suarez L, et al. Aphase Ib multiple ascending dose study evaluatingsafety, pharmacokinetics, and early clinicalresponse of brodalumab, a human anti-IL-17Rantibody, in methotrexate-resistant rheumatoidarthritis. Arthritis Res Ther. 2013;15:R164.

88. Genovese MC, Greenwald M, Cho CS, et al. A phaseII randomized study of subcutaneous ixekizumab,an anti-interleukin-17 monoclonal antibody, inrheumatoid arthritis patients who were naive tobiologic agents or had an inadequate response totumor necrosis factor inhibitors. Arthritis Rheuma-tol. 2014;66:1693–704.

89. Generics and Biosimilars Initiative Online. Biosim-ilars approved in Europe. 2017. http://www.

gabionline.net/Biosimilars/General/Biosimilars-approved-in-Europe. Accessed 23 June 2017.

90. Barber J. FDA advisory panel backs Amgen’s pro-posed biosimilar of AbbVie’s Humira. 2016. http://www.firstwordpharma.com/node/1399106#axzz4EO2ytw2T. Accessed 23 June 2017.

91. Smolen JS, Nash P, Durez P, et al. Maintenance,reduction, or withdrawal of etanercept after treat-ment with etanercept and methotrexate in patientswith moderate rheumatoid arthritis (PRESERVE): arandomised controlled trial. Lancet.2013;381:918–29.

92. van Herwaarden N, Van der MA, Minten MJ, et al.Disease activity guided dose reduction and with-drawal of adalimumab or etanercept compared withusual care in rheumatoid arthritis: open label, ran-domised controlled, non-inferiority trial. BMJ.2015;350:h1389.

93. Huizinga TW, Conaghan PG, Martin-Mola E, et al.Clinical and radiographic outcomes at 2 years andthe effect of tocilizumab discontinuation followingsustained remission in the second and third year ofthe ACT-RAY study. Ann Rheum Dis.2015;74:35–43.

94. Smolen JS, Emery P, Ferraccioli GF, et al. Cer-tolizumab pegol in rheumatoid arthritis patientswith low to moderate activity: the CERTAIN dou-ble-blind, randomised, placebo-controlled trial.Ann Rheum Dis. 2015;74:843–50.

95. Gremese E, Salaffi F, Bosello SL, et al. Very earlyrheumatoid arthritis as a predictor of remission: amulticentre real life prospective study. Ann RheumDis. 2013;72:858–62.

96. Allaart CF, Goekoop-Ruiterman YP, Vries-BouwstraJK, Breedveld FC, Dijkmans BA. Aiming at low dis-ease activity in rheumatoid arthritis with initialcombination therapy or initial monotherapystrategies: the BeSt study. Clin Exp Rheumatol.2006;24:S-82.

97. Weinblatt ME, Keystone EC, Furst DE, et al. Adali-mumab, a fully human anti-tumor necrosis factoralpha monoclonal antibody, for the treatment ofrheumatoid arthritis in patients taking concomitantmethotrexate: the ARMADA trial. Arthritis Rheum.2003;48:35–45.

98. Keystone EC, Kavanaugh AF, Sharp JT, et al.Radiographic, clinical, and functional outcomes oftreatment with adalimumab (a human anti-tumornecrosis factor monoclonal antibody) in patientswith active rheumatoid arthritis receiving con-comitant methotrexate therapy: a randomized,placebo-controlled, 52-week trial. Arthritis Rheum.2004;50:1400–11.

260 Rheumatol Ther (2017) 4:247–261

99. Keystone E, Heijde D, Mason D Jr, et al. Cer-tolizumab pegol plus methotrexate is significantlymore effective than placebo plus methotrexate inactive rheumatoid arthritis: findings of a 52 week,phase III, multicenter, randomized, double-blind,placebo-controlled, parallel-group study. ArthritisRheum. 2008;58:3319–29.

100. Smolen J, Landewe RB, Mease P, et al. Efficacy andsafety of certolizumab pegol plus methotrexate inactive rheumatoid arthritis: the RAPID 2 study. Arandomised controlled trial. Ann Rheum Dis.2009;68:797–804.

101. Moreland LW, Schiff MH, Baumgartner SW, et al.Etanercept therapy in rheumatoid arthritis. A ran-domized, controlled trial. Ann Intern Med.1999;130:478–86.

102. Kay J, Matteson EL, Dasgupta B, et al. Golimumabin patients with active rheumatoid arthritis despitetreatment with methotrexate: a randomized, dou-ble-blind, placebo-controlled, dose-ranging study.Arthritis Rheum. 2008;58:964–75.

103. Keystone EC, Genovese MC, Klareskog L, et al.Golimumab, a human antibody to tumour necrosisfactor alpha given by monthly subcutaneous injec-tions, in active rheumatoid arthritis despitemethotrexate therapy: the GO-FORWARD study.Ann Rheum Dis. 2009;68:789–96.

104. Maini R, St Clair EW, Breedveld F, et al. Infliximab(chimeric anti-tumour necrosis factor alpha mono-clonal antibody) versus placebo in rheumatoidarthritis patients receiving concomitantmethotrexate: a randomised phase III trial.ATTRACT Study Group. Lancet. 1999;354:1932–9.

105. Abe T, Takeuchi T, Miyasaka N, et al. A multicenter,double-blind, randomized, placebo controlled trialof infliximab combined with low dose methotrexatein Japanese patients with rheumatoid arthritis.J Rheumatol. 2006;33:37–44.

106. Kremer JM, Genant HK, Moreland LW, et al. Effectsof abatacept in patients with methotrexate-resistant

active rheumatoid arthritis: a randomized trial. AnnIntern Med. 2006;144:865–76.

107. Kremer JM, Dougados M, Emery P, et al. Treatmentof rheumatoid arthritis with the selective costimu-lation modulator abatacept: twelve-month resultsof a phase IIb, double-blind, randomized,placebo-controlled trial. Arthritis Rheum.2005;52:2263–71.

108. Edwards JC, Szczepanski L, Szechinski J, et al. Effi-cacy of B-cell-targeted therapy with rituximab inpatients with rheumatoid arthritis. N Engl J Med.2004;350:2572–81.

109. Emery P, Fleischmann R, Filipowicz-Sosnowska A,et al. The efficacy and safety of rituximab in patientswith active rheumatoid arthritis despitemethotrexate treatment: results of a phase IIB ran-domized, double-blind, placebo-controlled,dose-ranging trial. Arthritis Rheum.2006;54:1390–400.

110. Smolen JS, Beaulieu A, Rubbert-Roth A, et al. Effectof interleukin-6 receptor inhibition with tocilizu-mab in patients with rheumatoid arthritis (OPTIONstudy): a double-blind, placebo-controlled, ran-domised trial. Lancet. 2008;371:987–97.

111. Maini RN, Taylor PC, Szechinski J, et al. Dou-ble-blind randomized controlled clinical trial of theinterleukin-6 receptor antagonist, tocilizumab, inEuropean patients with rheumatoid arthritis whohad an incomplete response to methotrexate.Arthritis Rheum. 2006;54:2817–29.

112. van der Heijde, Tanaka Y, Fleischmann R, et al. Tofaci-tinib(CP-690,550) inpatientswithrheumatoidarthritisreceiving methotrexate: twelve-month data from atwenty-four-month phase III randomized radiographicstudy. Arthritis Rheum. 2013;65:559–570.

113. Keystone EC, Taylor PC, Drescher E, et al. Safety andefficacy of baricitinib at 24 weeks in patients withrheumatoid arthritis who have had an inadequateresponse to methotrexate. Ann Rheum Dis.2015;74:333–40.

Rheumatol Ther (2017) 4:247–261 261