Review

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Current immunotherapy in rheumatoid arthritis

Rheumatoid arthritis is a common autoimmune disease primarily manifesting as chronic synovitis,

subsequently leading to a change in joint integrity. Progressive disability and systemic complications are
strongly associated with a decreased quality of life. To maintain function and health in patients with
rheumatoid arthritis, early, aggressive and guided immunosuppressive therapy is required to induce clinical
remission. Antirheumatic drugs are capable of controlling synovial inflammation and are therefore named
‘disease-modifying antirheumatic drugs’ (DMARDs). This article aims to bridge the beginning of DMARD
therapy with agents such as methotrexate, leflunomide, sulfasalazine, injectable gold and
(hydroxy)chloroquine with biological therapies, and with the new era of kinase inhibitors. Mechanisms
of action, as well as advantages and disadvantages of DMARDs, are discussed with respect to the current
literature and current recommendations.

KEYWORDS: antirheumatic agent n biological agent n combination therapy Florian MP Meier1‡,

n immunotherapy n methotrexate n protein kinase inhibitor n recommendations
Marc Frerix1‡,
n rheumatoid arthritis n tofacitinib n treatment
Walter Hermann*1
& Ulf Müller-Ladner1
Rheumatoid arthritis (RA) is a common autoim- the treatment of RA. Glucocorticoids will not 1
Department of Internal Medicine
mune disease that primarily manifests as chronic be discussed in this respect. & Rheumatology,
Justus‑Liebig‑University Giessen,
inflammatory arthropathy [1]. Persistent synovi- Kerckhoff-Klinik, Bad Nauheim,
tis leads to cartilage destruction, bone erosions cDMARDs for the treatment of RA Germany
and periarticular decalcification, subsequently Inflammation is a dynamic process that is main- *Author for correspondence:
w.hermann@kerckhoff-klinik.de
resulting in impaired joint function. Beside the tained by intra-, extra- and inter-cellular path- ‡
Authors contributed equally
development of long-term disability and systemic ways. cDMARDs are considered to act by cross-
complications, pain is the predominant sequelae ing the cell membrane barrier; however, although
for a patient with RA and, therefore, quality of the primary interaction might be intracellular,
life is limited. Thus, RA is not only a burden extracellular effects are also directly linked.
for the affected individual, but also bears high
socioeconomic costs [2]. „„ Methotrexate
Pain relief is a major goal in the treatment of Methotrexate (MTX) belongs to the group of
RA, but is only partly achieved by NSAIDs or opi- folate inhibitors and was synthesized for the first
oids. Moreover, those drugs do not have any influ- time in 1947 [3]. Originally, and still used as an
ence on the autoimmune character of the disease. antitumor agent, the first reported application in
Glucocorticoids (locally and systemically) and RA was in 1962 [4]. Thereafter, MTX developed
immunosuppressive agents, however, are capable to be the most important and most frequently
of achieving clinical remission, at least in part, and prescribed substance for the treatment of RA,
normally only in combination. Frequently, glu- despite several new therapeutic options [5].
cocorticoids are used to reduce pain and inflam- The rather short half-life of MTX of approxi-
mation in the short-term, but over an extended mately 5–8 h is compensated by intracellular
period of time, higher doses can induce severe side polyglutamation, which leads to accumulation of
effects. Hence, agents that possess the ability to MTX, thus extending the half-life. Cellular uptake
constantly reduce inflammation and, therefore, is maintained by a ubiquitous membrane trans-
maintain joint integrity, with side effects that are port system, the reduced folate carrier. Further-
manageable, are preferred for the treatment of RA. more, specific folate receptors, which are expressed
This article aims to give an overview of the on cells that are important in the pathophysiology
current immunotherapy in RA and is divided of RA, such as synovial macrophages and lympho-
into three parts: conventional disease-modifying cytes, contribute to the transport of MTX [6,7].
antirheumatic drugs (cDMARDs), biological The effect of MTX is explained by competitive
DMARDs (bDMARDs) and new agents for inhibition of folate-dependent enzymes such as part of

10.2217/IMT.13.94 © 2013 Future Medicine Ltd Immunotherapy (2013) 5(9), 955–974 ISSN 1750-743X 955
Review Meier, Frerix, Hermann & Müller-Ladner

dihydrofolate reductase, thymidilate synthase, radiographic progression was clearly demon-

5-aminoimidazole-4-carboxamide ribonucleo- strated [19]. MTX has proven its efficacy as mono-
tide-transformylase [8]. Genetic mutations in these therapy and in combination, and the long-term
enzymes can result in different efficacies of MTX. safety profile is clinically acceptable [20]. There-
MTX prevents de novo purine and pyrimidine fore, the recommendations from the European
synthesis, which are essential for DNA and RNA League Against Rheumatism (EULAR) state that
synthesis. Subsequently, proliferation of lympho- MTX monotherapy should be the initial choice
cytes, which sustains the inflammatory process, and instituted at the earliest time point if no
is impaired [8]. Furthermore, anti-inflammatory contraindications are present [20]. It is of interest
properties are exerted by increased extracellular whether new observations that found induction
levels of 5-aminoimidazole-4-carboxamide ribo- therapy with a combination of DMARDs better
nucleotide, thus leading to an inhibition of ade- than MTX monotherapy will make their way into
nosine- and AMP-deaminase. Hereby, adenosine the next update of recommendations [21].
and AMP accumulates in the extracellular space
and by binding to the adenosine-A 2a receptor, an „„ Leflunomide
increase of the anti-inflammatory cytokine IL‑10 Leflunomide is an isoxazole derivate that inhibits
and inhibition of the proinflammatory transcrip- the mitochondrial enzyme dehydroorotate dehy-
tion factor NF‑kB are observed [9]. More informa- drogenase, a key enzyme in the pathway for the
tion on pharmacological actions of MTX can be de novo synthesis of pyrimidine ribonucleotides
found in Table 1 and the review by Wessels et al. [8]. such as rUMP [22]. Activated lymphocytes require
To treat RA, a typical dosage of 15–25 mg of high levels of rUMP (and other pyrimidine ribo-
MTX once a week is recommended, administered nucleotides) to progress through the cell cycle;
either orally or subcutaneously, and is usually fol- thus, leflunomide leads to reduced T-cell prolif-
lowed by 5 mg of folic or folinic acid the day eration rates and less autoantibody production by
after to reduce side effects [10]. One meta-ana­ B cells (Table 1).
lysis reports efficacy of MTX to placebo [5], and Two meta-analyses provided strong evidence for
cites five randomized controlled trials including the efficacy of leflunomide to act as a cDMARD
300 patients in which MTX was administered in RA [23–25]; one included three randomized con-
between 12–26 weeks with 7.5–25 mg per week trolled trials and the second included three addi-
[11–15]. Higher doses of MTX (20–30 mg) are tional trials, among them two long-term follow-up
more effective than lower ones (7.5–15 mg), studies of 24 months [19,26–31]. Leflunomide was
as is subcutaneous compared with oral appli- neither superior nor inferior to MTX or sulfasala-
cation [16–18]. The efficacy of MTX to reduce zine in several studies [19,26,27], and it is capable

Table 1. Mode of action of approved intracellular-acting therapies in rheumatoid arthritis.

Drug Target Function of target and effect
Methotrexate Folate-dependent enzymes DHFR, TS and ATIC ↓: impaired pyrimidine and purine synthesis leads
(DHFR, TS, ATIC) to inhibition of lymphocyte proliferation
AICAR ↑­: high adenosine levels show anti-inflammatory effects
Leflunomide DHODH DHODH ↓: impaired pyrimidine synthesis leads to inhibition of
lymphocyte proliferation
Sulfasalazine Folate-dependent enzymes Unclear mechanism of action; inhibition of folate-dependent enzymes
was observed (see methotrexate); further described effects are:
blockade of IκB and induction of apoptosis of neutrophils and
macrophages
Gold salts Interaction with sulfur-containing Inhibition of signal transduction and antigen presentation
amino acids in plasma or
intracellular proteins
(Hydroxy)chloroquine Lysosomes, lysosomal enzymes, Lysomotropic properties hinder antigen presentation
TLR‑9 Impaired activation of the innate immune system
Tofacitinib JAK1 and JAK3 (>JAK2 and TYK) Leukocyte maturation and activation ↓
Cytokine production ↓
Immunoglobulin production ↓
↓: Decrease; ↑: Increase; AICAR: 5-aminoimidazole-4-carboxamide ribonucleotide; ATIC: 5-aminoimidazole-4-carboxamide ribonucleotide transformylase;
DHFR: Dihydrofolate reductase; DHODH: Dehydroorotate dehydrogenase; TLR: Toll-like receptor; TS: Thymidilate synthase.

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 Current immunotherapy in rheumatoid arthritis Review
of slowing radiographic progression [29]. If con- cells, lymphocytes and chondrocytes [46–49]. Like
traindications to MTX are present, leflunomide other immunosuppressive agents, gold suppresses
as sulfasalazine or injectable gold salts should be the activity of NF‑kB, so the extracellular cyto-
considered as first-line therapy [20]. Although there kine milieu shifts from a pro- to an anti-inflam-
is currently no evidence that these agents are infe- matory signature, and increased IL‑4 levels turn
rior to MTX, the quality of efficacy and safety the balance to Th2 populations (Table 1) [46,47].
data puts MTX in first place. In terms of efficacy and inhibition of radio-
graphic progression, injectable gold is compa-
„„ Sulfasalazine rable with other cDMARDs [43–45,50,51], but
Sulfasalazine consists of sulfapyridine and 5-ami- toxicity is a major concern. In a 10-year follow-
nosalicylic acid, is split by the action of bacterial up study, the drug survival rate was 58% after
azoreductases in the large intestine, and is either 1 year, and decreased to 26% after 5 years and
absorbed intact or as sulfapyridine [32]. Whereas only 8% after 10 years [51]. The most impor-
5-aminosalicylic acid is believed to influence ara- tant side effects that led to discontinuation were
chidonic acid metabolism and thereby inflam- skin and mucosal irritations [51].
mation in inflammatory bowel diseases, intact
sulfasalazine or sulfapyridine have been found „„ Antimalarial agents
in synovial fluid in concentrations slightly lower Strong evidence supports the efficacy and safety
than that of plasma, and both appear to be of antimalarial agents, such as hydroxychloro-
active in RA [33]. The exact mechanism is still quine and chloroquine, which are used mostly
unclear, but like MTX, sulfasalazine inhibits in rheumatology disorders [52]. Although used
folate-dependent enzymes leading to an impaired for over decades, the exact mechanism of
function of lymphocytes [34,35]. Moreover, it was action in terms of immunosuppression has
shown that sulfasalazine is able to block the deg- not been definitively resolved. They mainly
radation of the inhibitor of kB and, therefore, act as weak lipophilic bases, entering lyso-
TNF‑a-mediated translocation of NF‑kB was somes and influencing cell function by raising
prevented in vitro in a colon cell line [36]. Induc- pH levels [53]. This effect is mainly attributed
tion of apoptosis of neutrophils and macrophages to APCs, thus antigen presentation to CD4+
may further contribute to the beneficial effect of T cells is hindered. Furthermore, an impact
sulfasalazine in RA (Table 1) [37,38]. on intracellular Toll-like receptors, especially
Two meta-analyses including 15 controlled on Toll-like receptor‑9, has been described
and randomized controlled studies provide good (Table 1) [54]. Their positive effect on outcome
evidence for the efficacy, safety and tolerability of parameters such as tender and swollen joints,
sulfasalazine [39,40]. Starting with 500 mg daily, pain and the erythrocyte sedimentation rate
the dose is increased by 500 mg each week up has been well documented [52]. However, the
to 2 g (or more if required). In comparison with effect of antimalarial agents on radiographic
antimalarial agents (chloroquine or hydroxychlo- progression seems to be less substantial when
roquine), sulfasalazine was not superior in terms compared with other cDMARDs such as sul-
of clinical- and patient-reported outcomes, but fasalazine [41,55]. This is one reason why anti-
was also able to reduce radiographic progression malarial drugs are generally only considered
[41]. This explains why monotherapy with sul- for very mild disease or in combination therapy
fasalazine or antimalarial agents is only recom- [20]. A randomized comparison between the
mended for mild forms of the disease [20]; com- two antimalarial agents in terms of efficacy
bination therapy is preferred. Sulfasalazine may and safety is unfortunately still not available.
also be the medication of choice in women who Retrospectively analyzed data shows, however,
desire to have children [42]. that hydroxychloroquine has slightly higher
drop-out rates than chloroquine due to inef-
„„ Injectable gold ficiency [56]. Attention has to be paid to retinal
Parenteral gold salts (aurothiomalate) are a matter toxicity as a specific side effect of this class of
of intensive debate. However, they are deemed drugs [57].
important in the recommendations [20] due to a
high level of evidence [43–45]. No central mecha- „„ Combination therapy of cDMARDs
nism of action is known as yet, although they in RA
demonstrate broad immunosuppression. Several As outlined above, despite several available
major cell types in the pathophysiology of RA are cDMARDs and new biological agents, MTX is
influenced by gold such as macrophages, dendritic still the ‘anchor drug’ in the treatment of RA, and

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Review Meier, Frerix, Hermann & Müller-Ladner

the adequate first choice in most DMARD-naive of leflunomide and cyclosporine are more effi-
patients [10,58]. cient than each drug alone [79], but may be used,
For patients who fail to respond to MTX, there after failure of other combination regimens and
are generally two options: first, to add a biologic when bDMARDs are contraindicated as a reserve
agent (which will be discussed below), or second, therapy because of the toxicity of cyclosporine.
to start a combination therapy with cDMARDs There are several other potential combination
[59]. There is no universal rule to the decision pro- therapies, mostly including MTX,;for example,
cess and rheumatologists have to decide between MTX and sulfasalazine [80–82], MTX and anti-
these options individually in agreement with the malarial agents [83,84], MTX and azathioprine
patient. [85,86], and MTX in combination with antibiot-
One option is the triple therapy of MTX, sul- ics such as doxycycline [87] or bucillamine [88].
fasalazine and hydroxychloroquine, a very popu- In addition, other combination therapies have
lar therapeutic regimen since the landmark study been studied, such as, sulfasalazine in combina-
of O’Dell and colleagues in 1996, the so-called tion with leflunomide [89], cyclosporine [90] or
‘O’Dell scheme’ [60]. However, the intake of a lot hydroxychloroquine [91]. These are less often used
of different drugs is somehow uncomfortable for and of little benefit. Within this review, not all
patients, but it is an effective and safe treatment options can be discussed in detail, so for the inter-
strategy [61]. In patients with early RA and high ested reader we recommend the meta‑ana­lysis of
disease activity, a first-line triple therapy may be Katchamart et al. [62].
preferred, as it was shown to be safe and superior Although this review does not focus on gluco-
to MTX [21,62,63] or sulfasalazine monotherapy corticoids, their use is of crucial benefit, especially
[64]. Some studies suggest an efficacy comparable in the initial phase of early RA, as was clearly
with the combination of MTX and a bDMARD demonstrated by the BeST trial [92]. Irrespec-
[65], whereas others found combination therapy tive of several available glucocorticoids without
to be better [66]. Most recently, another impor- relevant differences in pharmacokinetics, a new
tant study was published showing that triple prednisone with a modified-release mechanism
therapy is noninferior to the combination of was shown to decrease the duration of morning
MTX with etanercept in patients failing initial stiffness in RA patients compared with standard
MTX monotherapy [67]. The implementation of prednisone [93].
these results in daily practice is controversially The American College of Rheumatology
discussed at the moment. Another rarely used (ACR) and EULAR have published recommen-
triple therapy, which was investigated by a step- dations for the use of cDMARDs in the treat-
up approach, is the use of MTX, sulfasalazine ment of RA and can be accessed by the ACR and
and cyclosporine [68,69]. EULAR homepage [20,94,201,202].
Besides triple therapy, the concomitant treat-
ment of MTX and leflunomide is a useful com- bDMARDs for the treatment of RA
bination therapy because of the different mecha- Over the last 15 years, along with the advance-
nisms of action [69,70]. However, clinicians should ment in knowledge of the pathogenesis of RA,
be aware of gastrointestinal side effects and a several new bDMARDs have been developed and
potential higher risk of hepatotoxicity [62]. Nev- ushered a new era for the treatment of RA. After
ertheless, this combination is frequently used and treatment failure with cDMARDs, rheumatolo-
severe complications are rare [71,72]. gists have the possibility to choose the best therapy
With a broad armamentarium of several new for their patients out of a diverse armamentarium
cDMARDs and biologics, the use of intra- of biologics, but this can also complicate the issue
muscular gold was a long-forgotten treatment of the best therapeutic decision for the individual
option since the results of the studies in the early patient. At present, five different TNF inhibitors,
1990s [73,74], mainly because of adverse reactions one inhibitor of IL‑1 and of IL‑6, as well as one
[51]. However, in patients with a suboptimal B- and one T-lymphocyte-targeting bDMARD
response to MTX, the addition of intramuscu- are available. The main characteristics are briefly
lar gold can be worthwhile to consider, when described in Tables 2 & 3 and Figure 1. The following
other cDMARDs failed, taking the convincing section provides a short overview of and discusses
results of the randomized double-blind, double- the main differences between the bDMARDs [94].
observer, placebo-controlled METGO study into Recently, a new era in RA treatment has begun
account [45]. as small molecules that target intracellular kinases
The combination of MTX and cyclosporine have become available as therapeutic options. This
(the so-called ‘Tugwell scheme’ [75–78]), and also will be discussed in the next section.

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 Current immunotherapy in rheumatoid arthritis Review
„„ TNF inhibitors Table 2. List of cytokines or cluster of differentiation antigens of
TNF inhibitors have been the initiators of the approved immune-targeted therapies in rheumatoid arthritis.
biologic era, thus we have gained the largest
Cytokine Produced/expressed by Agent
experience out of controlled trials, patient
registries, clinical studies and daily prac- IL‑1 Monocytes/macrophages, B cells, Anakinra
tice of TNF inhibitors among the different synovial fibroblasts, chondrocytes and
epithelial cells
bDMARDs. The most significant side effects
of TNF inhibitors are local injection reactions IL‑6R, Activated B cells and plasma cells Tocilizumab
and an increased risk of all types of infections, membrane- (strong) and most leukocytes (weak);
bound (CD126, soluble form arises from proteolytic
including tuberculosis. Thus, prior to the ini-
IL‑6Ra) or soluble cleavage
tiation of a treatment with TNF inhibitors, a
screening for latent tuberculosis infection is rec- TNF‑a Monocytes/macrophages, T cells, B cells, Adalimumab,
ommended for every patient, regardless of the NK cells, PMNs, mast cells, synovial certolizumab pegol,
fibroblasts and osteoblasts etanercept,
presence of risk factors of tuberculosis [20,94]. golimumab and
In patients with latent tuberculosis infection, a infliximab
prophylactic antibiotic medication prior to ini-
CD20 B cells Rituximab
tiation of anti-TNF therapy should be started,
or a different bDMARD option may be pre- CD28 T-cell subsets and activated B cells Not targeted
ferred in these patients. Screening for latent CD80 B-cell subsets Abatacept
tuberculosis is generally recommended for all CD86 Monocytes, activated B cells and Abatacept
bDMARDs, as for HBV. Additionally, TNF dendritic cells
inhibitors should be used carefully in patients PMN: Polymorphonuclear leukocyte; R: Receptor.
with heart failure [95,96]. Data taken from [1,194,195].

‘Established’ first generation of is a chimeric murine–human IgG1 monoclonal

anti-TNFs: etanercept, infliximab antibody against TNF‑a, which binds to both
& adalimumab circulating and transmembrane TNF‑a. The
Etanercept chimeric molecule structure may induce human
Etanercept was the first TNF inhibitor approved antichimeric antibodies. This immunogenicity
by the US FDA in 1998 for use in RA [203]. In can reduce functional drug levels and, therefore,
comparison with other TNF inhibitors, etan- the clinical response to this treatment [105]. Con-
ercept is not an antibody, but a recombinant sequently, combination therapy of infliximab and
human soluble fusion protein, functioning as a MTX is strongly recommended, as MTX may not
decoy receptor and, therefore, inhibits the bind- prevent the formation, but reduce levels of, anti-
ing of TNF‑a to its regular receptor. Among infliximab antibodies; consequently, MTX might
the TNF inhibitors, etanercept has the shortest prolong the survival of infliximab treatment [106].
half-life (~3–6 days) and is usually administered The mobility of patients with RA is an important
subcutaneously once a week in a dose of 50 mg factor, which should be considered as infliximab
(25 mg twice a week is the alternative). Etaner- is usually administered intravenously in intervals
cept shows a lower incidence rate of tuberculosis of 4–8 weeks following an induction phase, with
compared with other TNF inhibitors [97]. Hence, loading doses at week 0, 2 and 6.
when TNF inhibitory therapy is suggested for a
patient at risk for tuberculosis, etanercept may Adalimumab
be preferably selected. Generally, among the A few years after approval of etanercept and inf-
TNF inhibitors, etanercept might be the safest liximab for therapy of RA, adalimumab was the
choice [98–100]. In contrast to other TNF inhibi- second TNF inhibitor administered by subcuta-
tors (especially infliximab and adalimumab), neous injection, and the first fully human mono-
antidrug antibodies seem to play a minor role clonal antibody binding to TNF. The advantage
in terms of clinical efficacy of etanercept [101], of adalimumab is a less frequent injection interval
which might also explain the high long-term of every other week. Although not being chime-
drug survival of etanercept among the TNF ric but a fully human antibody, the potential of
inhibitors [102–104]. developing antibodies to adalimumab has been
similarly observed. Antiadalimumab antibodies
Infliximab may lead to lower serum concentrations of adali-
Inf liximab was the second biologic agent mumab and account for an attenuated therapy
approved by the FDA for treatment of RA, and response [107,108]. However, overall treatment

future science group www.futuremedicine.com 959

Review Meier, Frerix, Hermann & Müller-Ladner

Table 3. Short overview of the currently available biological disease-modifying antirheumatic drugs for the
treatment of rheumatoid arthritis.
Name Target Structure Mechanism Administration Dose Half-life Approval
(US FDA)
Infliximab TNF Chimeric Ab binding iv. infusion Loading dose of 9 days 1999
murine–human to TNF 3–5 mg/kg at week 0, 2 First-line treatment,
IgG1 and 6; maintain dose only in combination
monoclonal every 4–8 weeks; with MTX
Ab adjustment of
7–10 mg/kg
Etanercept TNF Recombinant Decoy sc. injection 50 mg once a week (or 3–6 days 1998
human soluble receptor 25 mg twice a week) First-line treatment,
fusion protein binding to monotherapy or
soluble TNF concomitantly with
MTX
Adalimumab TNF Fully human Ab binding sc. injection 40 mg every other ~2 weeks 2002
monoclonal to TNF week (10–20 days) First-line treatment,
Ab monotherapy or
concomitantly with
MTX
Golimumab TNF Human Ab binding sc. injection 50 mg once a month ~2 weeks 2009
monoclonal to TNF First-line treatment,
Ab only in combination
with MTX
Certolizumab TNF Fc-free Fab´ sc. injection Loading dose of 400 mg 14 days 2009
pegol humanized fragment at week 0, 2 and 4; First-line treatment,
pegylated binding to maintain dose of monotherapy or
anti-TNF Fab’ TNF 200 mg every other concomitantly with
fragment week (or 400 mg once a MTX
month)
Anakinra IL‑1 Recombinant Binding to sc. injection 100 mg once a day 4–6 h 2001
human IL‑1 IL‑1 type-1 First-line treatment,
receptor receptor monotherapy or
antagonist concomitantly with
MTX
Tocilizumab IL‑6 Recombinant Binding to a iv. infusion 4–8 mg/kg every 11–13 days 2010
humanized soluble 4 weeks First-line treatment,
anti-human membrane- monotherapy or
IL‑6 receptor bound IL‑6 concomitantly with
monoclonal receptor MTX
Ab
Abatacept T lymphocyte CTLA-4 IgG1 T-cell iv. infusion or sc. iv. protocol: loading 13 days 2005
fusion protein costimulation injection dose of 500–1000 mg (range: First-line treatment,
blocker (weight-based) at week 8–25 days) monotherapy or
0, 2 and 4; maintain concomitantly
interval every 4 weeks with MTX
sc. protocol: loading
dose of a single infusion,
followed by sc. injection
(125 mg) within 1 day
and weekly thereafter
Rituximab B lymphocyte Chimeric Binding to iv. infusion Usually biannual cycles 18 days 2006
murine–human and of two separate (range: Second-line
monoclonal depletion of infusions of 1000 mg; 5–76 days) treatment after TNF
IgG1k Ab CD20- intervals may be failure, only in
positive shortened to 4 months combination
B cells with MTX
Ab: Antibody; iv.: Intravenous; MTX: Methotrexate; sc.: Subcutaneous.

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 Current immunotherapy in rheumatoid arthritis Review
CD80/86
Adalimumab
Abatacept
Certolizumab
Etanercept DC
Golimumab CD80/86
Infliximab Rituximab

CD20
B cell
CD28

TNF-α
T cell IL-1
Soluble IL-6R
Anakinra

Tocilizumab
Proteolytic Mφ
cleavage Membrane-bound IL-6R

FLS
Immunotherapy © Future Science Group (2013)

Figure 1. Mechanisms of action of approved biological therapies in rheumatoid arthritis.

Simplified description of cytokines and receptors that are targeted by available biological disease-
modifying antirheumatic drugs. No respect was paid to compartments such as bone marrow, blood
or synovial tissue.
DC: Dendritic cell; FLS: Fibroblast-like synoviocyte; Mf: Macrophage; R: Receptor.

response and disease remission rates seemed to also beneficial in patients who previously failed a
be higher for therapy with adalimumab than TNF inhibitor therapy [112].
infliximab, but comparable with etanercept [109],
whereas other studies revealed no significant dif- Certolizumab pegol
ferences between all three compounds [110,111], The new story behind certolizumab pegol was
including one noninferiority study of etanercept that this compound is an Fc-free humanized
versus adalimumab [110]. pegylated anti-TNF Fab’ fragment, with a dif-
ferent mechanism of action compared with other
‘Next generation’ of anti-TNFs: TNF inhibitors [113]. The different structure
golimumab & certolizumab pegol might be an explanation for the possibly higher
After a gap of 7–11 years and the development of efficiency of certolizumab pegol in comparison
the initial three TNF inhibitors, one might won- with other TNF inhibitors in recent indirect
der whether there was a need for different TNF comparison studies [99,114]. However, certoli-
inhibitors? In the meantime, new biological agents zumab pegol is being discussed to be associated
targeting IL‑1 and IL-6, and B and T cells have with a higher risk of withdrawal due to adverse
been added as therapeutic options for RA (dis- events and serious infections compared with
cussed below). However, effort was undertaken to most of the biologics, although these data are
improve pharmacological properties of anti-TNF rather due to the trial design than the clinical
therapy, resulting in two recently available TNF reality [99,115]. A unique feature of certolizumab
inhibitors, golimumab and certolizumab pegol. pegol compared with other subcutaneously
administered TNF inhibitors is the regimen of
Golimumab a loading dose of 400 mg in week 0, 2 and 4,
In 2009, golimumab was approved by the FDA as a maintaining a dose of 200 mg biweekly there-
monthly subcutaneous injection for the treatment after (in some cases 400 mg every 4 weeks may
of moderate-to-severely active RA. Golimumab is be considered).
a human monoclonal antibody with a half-life of Currently, there are only limited data on the
approximately 2 weeks, which binds to soluble and immunogenicity of both certolizumab pegol and
transmembrane forms of TNF‑a to inhibit its bio- golimumab, so no further conclusions whether
logic activity. Golimumab is approved in combina- drug-induced antibodies may affect their efficacy
tion with MTX only, and efficacy and safety was and safety can be drawn at the moment.

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Review Meier, Frerix, Hermann & Müller-Ladner

„„Other inflammatory cytokine B- & T-lymphocyte targeting agents

„„
inhibitors Rituximab
Anakinra (IL‑1 inhibitor) Rituximab is a chimeric anti-CD20 mono-
Owing to high circulating plasma levels of clonal antibody that depletes CD20-positive
IL‑1b and their correlation with clinical dis- B cells. Initially, it had been approved for the
ease activity in patients with RA, IL‑1b was treatment of B-cell lymphomas in 1997, until
thought to play a central role in the pathogene- approval by the FDA was given in 2006 for the
sis of RA [116]. Anakinra, a recombinant human use in adult patients with moderate-to-severe
IL‑1 receptor antagonist, is the only therapy R A, who have not responded adequately to
for RA that targets IL‑1. Anakinra, which was TNF antagonists. Usually, rituximab is used
approved by the FDA in 2001, was the first in combination with MTX, but leflunomide
non-anti-TNF biologic at that time. In recent may also be an effective and safe alternative,
years, it has been shown that anakinra is less concomitant treatment [127,128]. Rituximab is
effective than TNF inhibitors [98,114,117]. Hence, the only biologic therapy that is solely approved
because of several other more favorable biologic for second-line therapy after anti-TNF failure,
treatment options and the incommodious daily contrary to all other bDMARDs, which have,
administration by subcutaneous injection, this meanwhile, been approved for first-line therapy
compound plays only a minor role in routine besides TNF inhibitors. However, it was shown
clinical care of patients with R A. There are that rituximab performed better than a second
several other diseases, however, where anakinra TNF inhibitor in patients with inadequate
plays a more important role; for example, in disease control under previous TNF inhibitor
acute gout [118] and chondrocalcinosis [119], adult therapy, especially in a cohort of patients with
Still syndrome [120], the IL‑1-dependent autoin- antibodies against citrullinated proteins [129]. In
flammatory cryopyrin-associated periodic syn- spite of the general long-term safety of rituximab
dromes [121] or the neonatal-onset multisystem [130], an increased risk of progressive multifocal
inflammatory disease [122]. leukoencephalopathy for one case per 25,000
RA patients treated with rituximab has been
Tocilizumab (IL‑6 receptor inhibitor) described [131,132].
In January 2010, the FDA approved tocili-
zumab for the treatment of RA. Tocilizumab Abatacept
is a humanized recombinant IgG1 monoclonal Abatacept is approved as mono- or combina-
antibody binding to both soluble and mem- tion-therapy with other non-bDMARDs for
brane-bound IL‑6 receptors. It is administered the treatment of moderate-to-severely active
as intravenous infusion every 4 weeks; an addi- R A. In contrast with other biologics, it is a
tional approval of a subcutaneous injection is recombinant human soluble fusion protein of
sought for the future. In patients with refrac- the extracellular domain of human CTLA‑4
tory arthritis under TNF inhibitor therapy, and an Fc domain of human IgG1. Abata-
tocilizumab is a reasonable treatment option cept selectively modulates the costimulation
[123], and it is also licensed for first-line treat- of T lymphocytes by inhibiting their activa-
ment in RA after inadequate response to one tion through binding to CD80/CD86 and
or more cDMARDs. Recently, the results of thereby preventing the interaction with CD28
the ADACTA trial suggested that tocilizumab expressed on T cells. Additionally, it is the only
monotherapy is superior to adalimumab mono- biologic agent in RA at the moment that can
therapy [124], and also more cost-effective in be administered either by subcutaneous injec-
a trial from the USA [125]. Some safety dif- tion (once a week) or intravenous infusion
ferences have to be noted in comparison with (every 4 weeks). The results of the AMPLE
other biologic agents; for example, rare events study [133], a head-to-head study of subcuta-
of gastrointestinal perforations have been neous abatacept versus adalimumab, revealed
reported. It is very important for the treating comparable efficacy and generally comparable
physician and the patient to be aware of the safety of these drugs. Also in direct comparison
inhibited production of acute phase proteins to infliximab, abatacept showed a comparable
linked to IL‑6 by tocilizumab, especially CRP. efficacy and a good safety profile [134]. Hence,
Even in cases of serious infections, CRP levels next to TNF inhibitors, abatacept may also be a
can be normal [126], thus clinical examination reasonable option for the first-line treatment of
may be more useful than trust in laboratory RA patients with active disease and inadequate
markers. response to MTX [135].

962 Immunotherapy (2013) 5(9) future science group

 Current immunotherapy in rheumatoid arthritis Review
„„ Current recommendations for the introduction of biological agents for the treat-
use & a short comparison of bDMARDs ment of RA. The development of monoclonal
in RA antibodies, fusion proteins of soluble recep-
The ACR and the EULAR have published rec- tors, and cytokine inhibitors is still a promis-
ommendations for the use of cDMARDs and ing principle in this respect. New targets, for
bDMARDs in the treatment of RA [20,94]. The example, B-cell activating factor of the TNF
combination therapy of a biologic agent with family [157], or optimization of this principle,
MTX (or another non-bDMARD such as leflu- for example, construction of nanobodies [158],
nomide [127,136,137]) is generally more effective demonstrate that progress in this area is still
than monotherapy, as has been shown for TNF being achieved.
inhibitors [138,139], rituximab [140] and tocilizumab However, a new chapter in the therapy of
[141]. In most cases, combination therapy consists RA has started with the FDA approval of the
of a bDMARD (a TNF inhibitor is usually used first kinase inhibitor, tofacitinib, in November
as first choice) next to a cDMARD for the treat- 2012 [204]. Therefore, the following summary
ment of RA patients with inadequate response will focus on this new therapeutic opportunity
to cDMARD monotherapy, despite the fact that [159,160]. In comparison with biologics, kinase
nearly all other biologics (except of rituximab) inhibitors are small, low molecular drugs that
have been licensed for first-line treatment in are administered orally. Protein kinases, which
recent years. There is weak evidence that tocili- can be blocked by unselective, as well as selec-
zumab might have higher response rates than TNF tive inhibitors, are essential for the intracel-
inhibitors or abatacept [142], and TNF inhibitors lular signal transduction process. A stimulus,
might be superior to abatacept in first-line therapy for example, the binding of a cytokine to its
after inadequate response to MTX [143]. In some related receptor, can induce a broad variety of
patients with early RA and high disease activ- chemical reactions in the cells, among them
ity, an induction therapy with a TNF inhibitor phosphorylation of specific proteins, regula-
may be beneficial [92,138,144–146]. For second-line tion of ion channel permeability, formation or
treatment of RA patients with inadequate disease degradation of protein complexes or modifica-
control under TNF inhibitor therapy, a significant tion of enzymatic activity [161]. At the end of
improvement has been shown for abatacept, ritux- this process a change in gene transcription is
imab and tocilizumab [123,147,148], whereas anakinra the key event. Several classes of kinases have
was not effective in patients with RA who did not been related to immune responses in RA such
respond to anti-TNF therapy in the first place [149]. as MAPK, JAK, Syk or Btk. Furthermore, tran-
However, switching to a different TNF inhibitor scription factors (e.g., NF‑kB or AP‑1) [161,162],
can also be effective [150]. Out of these options for which directly interfere with gene transcrip-
second-line treatment after inadequate response to tion, are considered future intracellular targets
TNF inhibitors, no bDMARD seems to be gener- in RA. A brief outline will be given at the end
ally favorable compared with another [143,151]. Gen- of this section.
erally, combination therapy of bDMARDs should
be avoided due to potential serious and severe com- „„ p38 MAPK inhibitors
plications. From the results of systematic reviews, Among the first kinases to be examined in RA
meta-analyses, mixed treatment comparisons and was p38 MAPK, a serine–threonine kinase,
studies using a Bayesian approach for indirect which allows the transduction of extracellular
comparison, results show evidence for a higher stress to the cell nucleus [163]. Four isoforms
efficacy and cost–effectiveness of etanercept and of the p38 MAPK have been described, but
certolizumab [114,152–155]. the a-isoform was postulated to be the most
However, indirect comparison studies have important in the regulation of inflammation
limitations, are not without problems and head- by an increase of proinflammatory cytokines
to-head studies are still lacking [156], whereas the (IL‑1, IL-6 and TNF-α), nitric oxide, pros-
first new drug class of oral JAK inhibitors super- taglandins/prostacyclins, COX-2 and matrix-
venes RA treatment and several other potential metalloproteinases [162,163]. Thus, it was no
drugs are in development. surprise that by inhibition of this kinase, the
onset of collagen-induced arthritis in rats was
New & upcoming agents for the prevented [164]. However, three different p38
treatment of RA MAPK inhibitors (pamapimod, VX‑702 and
As outlined in the previous part of this review SCIO‑469) have been tested in clinical trials
article, the past decade was dominated by the so far, but the results were mainly negative

future science group www.futuremedicine.com 963

Review Meier, Frerix, Hermann & Müller-Ladner

[165–168].While clinically no superiority of Pharmacokinetics showed that the peak con-

the drugs to placebo was observed, a decrease centration of tofacitinib in blood is reached by
of acute-phase reactants, such as CRP, was 1 h, with a half-life of 3 h, and 40% of the com-
detected during the first weeks of the study. But pound is protein-bound. Tofacitinib is cleared
these effects did not convert into an apparent by multiple elimination pathways such as
improvement of the patients and lasted a short CYP3A4 (≈53%), CYP2C19 (≈17%), and renal
time only. Two major conclusions have been excretion (≈30% [205]). The proposed indica-
drawn from the p38 MAPK problem: first, a tion is moderate-to-severely active RA, with an
high degree of selectivity of kinase inhibitors inadequate response to one or more DMARDs.
was questioned [169] and, second, targeting Monotherapy, as well as coadministration with
kinases that function upstream in the signaling MTX or other non-bDMARDs may be con-
cascade might be more promising [170]. In terms sidered. The FDA approved the dose of 5‑mg
of p38 MAPK, this means that on one hand, tablets twice daily.
the specificity for p38 does not take the obser- The Phase II program of tofacitinib included
vation into account that p38g is also expressed five placebo-controlled randomized clinical
in inflammatory tissues, and on the other, that studies with 1617 patients over a period of 6
blocking kinases higher in the signaling path- up to 24 weeks and a dose range between 1 to
way such as MKK-3 or MKK-6 might be more 30 mg twice daily [176–180]. From the Phase IIb
promising [171]. It will be of interest to observe dose-ranging study by Kremer et al., it was
if further efforts in this direction will be made concluded that a dose of greater than 3 mg
in the future. twice daily is effective and safe over a period of
24 weeks [176].
„„ Tofacitinib & other JAK inhibitors In a Phase III trial, the five placebo-controlled
Conversely, not all evidence for kinase inhibi- randomized studies included 3315 patients and,
tion is as disappointing as so far mentioned. to date, three have been already published
Encouraging results from Phase II clinical trials [181–183]. Details regarding study design, popu-
from compounds that target JAK or Syk signal- lation, background treatment and primary end
ing were observed soon afterwards [162]. In par- point can be found in Table 4 . By creating dif-
ticular, inhibition of pathways in which JAKs ferent settings in Phase III, several important
are involved became a success story as already questions are challenged in parallel:
mentioned. ƒƒ
Should mono- or combination-therapy with
JAKs comprise a group of four kinases: MTX or a different cDMARD be preferred?
JAK1, JAK2, JAK3 and TYK, which belong to
the superfamily of tyrosine kinases. Upon stim- ƒƒ
Is tofacitinib effective in terms of inhibiting
ulation of a tyrosine kinase-associated receptor, radiographic progression?
the signal from the cell surface is transmitted ƒƒ
Compared with TNF antagonists, what is the
into the nucleus by phosphorylation and acti- benefit of tofacitinib?
vation of STAT proteins. Multiple cytokines
ƒƒ
Do patients profit from tofacitinib after TNF
known to be relevant in RA pathophysiology,
such as IL‑2, IL-4, IL-6, IL-7, IL-9, IL-15 failure?
and IL-21 are regulated in a JAK-dependent Hereby, the role and place of tofacitinib
manner. will be clarified soon after launch, and is fur-
Tofacitinib, the first approved kinase inhibi- ther reflected by the rather broad approval of
tor for use in patients with RA, shows a com- the FDA for this compound. Furthermore,
bined inhibition of JAK1 and JAK3 (to a lesser over 4000 patients entered long-term safety
extent JAK2 and TYK) (Ta ble 1). Preclinical and efficacy extension studies [184], in which,
observations revealed that monocytes and during this controlled setting, 20.8% of the
synoviocytes treated with tofacitinib respond patients discontinued due to adverse events
with less IL‑6 production to TNF stimulus (10.7%; most commonly infections – naso-
compared with control, and that human T pharyngitis, upper respiratory and urinary
cells obtained from the blood and synovium tract infections, infestations, gastrointestinal
produce less interferon and IL‑17, mainly due disorders and musculoskeletal disorders), lack
to reduced expression of STAT1 and STAT3 of efficacy (2.0%) and others (8.1%). Until
[172–174]. In two animal models, JAK3 inhibi- now, several safety issues have to be considered
tion was found to be effective in terms of bone and observed during therapy with tofacitinib
resorption [175]. that are, first, (severe) infections, including

964 Immunotherapy (2013) 5(9) future science group

 Table 4. Overview of Phase III studies of tofacitinib in active rheumatoid arthritis.
Name Publication Population Study design Background Treatment Primary end point Distinguishing Ref.
(NCT medication duration feature
number) (months)
‘Scan’ van der MTX IR Tofacitinib 5/10 mg b.i.d. p.o. vs PBO for MTX 24 ACR20 at 6 months; mTSS at x-ray [198]

future science group

NCT00847613 Heijde et al. (n = 797) 3–6 months, then tofacitinib 5/10 mg 6 months; HAQ-DI score at
b.i.d. p.o. 3 months; DAS28-4 (ESR) <2.6 at
6 months
‘Sync’ Smolen et al. DMARD IR Tofacitinib 5/10 mg b.i.d. p.o. vs PBO for DMARDs 12 ACR20 at 6 months; HAQ-DI score at Background [199]
NCT00856544 (n = 792) 3–6 months, then tofacitinib 5/10 mg 3 months; DAS28-4 (ESR) <2.6 at DMARDs
b.i.d. p.o. 6 months
‘Standard’ van MTX IR Tofacitinib 5/10 mg b.i.d. p.o. with PBO was MTX 12 ACR20 at 6 months; HAQ-DI score at Active control [182]
NCT00853385 Vollenhoven (n = 717) matched to adalimumab 40 mg sc. e.o.w. 3 months; DAS28-4 (ESR) <2.6 at (adalimumab)
et al. with PBO and PBO alone for 3–6 months, 6 months
then tofacitinib 5/10 mg b.i.d. p.o. with
PBO was matched to adalimumab 40 mg
sc. e.o.w with PBO
‘Step’ Burmester TNF IR Tofacitinib 5/10 mg b.i.d. p.o. vs PBO for MTX 6 ACR20 at 6 months; HAQ-DI score at TNF failures [183]
NCT00960440 et al. (n = 399) 3 months, then tofacitinib 5/10 mg 3 months; DAS28-4 (ESR) <2.6 at
b.i.d. p.o. 6 months
‘Solo’ Fleischmann DMARD IR Tofacitinib 5/10 mg b.i.d. p.o. vs PBO for None 6 ACR20 at 6 months; HAQ-DI score at Monotherapy [181]
NCT00814307 et al. (n = 610) 3 months, then tofacitinib 5/10 mg 3 months; DAS28-4 (ESR) <2.6 at

www.futuremedicine.com
b.i.d. p.o. or early determination 6 months
ACR: American College of Rheumatology; ACR20: Response rate of the ACR indicating an improvement of at least 20%; b.i.d.: Twice daily; DAS28-4: Disease Activity Score Using 28-Joint Count; DMARD: Disease-
modifying antirheumatic drug; e.o.w.: Every other week; ESR: Erythrocyte sedimentation rate (four variables); HAQ-DI: Health Assessment Questionnaire – Disability Index; IR: Inadequate response; mTSS: Modified Total
Sharp Score; MTX: Methotrexate; NCT: National Clinical Trial; p.o.: Per os; PBO: Placebo; sc.: Subcutaneously.
Current immunotherapy in rheumatoid arthritis
Review

965
Review Meier, Frerix, Hermann & Müller-Ladner

tuberculosis; second, decreased hemoglobin target. Furthermore, Syk associates with non-
levels; third, increased levels of low-density immunoglobulin receptors of osteoclasts.
lipoprotein cholesterol; fourth, discrete rise Against this background, Syk is theoretically
in serum creatinine levels; fifth, elevated liver connected to inflammation and bone resorp-
enzymes; and sixth, neutropenia. Data to tion. Three Phase II studies have currently
estimate true incidence rates of malignancies been published, demonstrating superiority of
and cardiovascular events are limited at the fostamatinib over placebo [192–194]. The results
moment, but current analyses described similar describe benefit for RA patients with an inad-
rates for patients on tofacitinib compared with equate response to MTX, but not for failure of
DMARDs [185,186]. By continuing the exten- TNF inhibition. Of note, an increase in blood
sion studies, a more detailed safety profile of pressure of approximately 5 mmHg 1 month
this new agent will be available and is of great after initiation of treatment has been noted
importance as approval for further conditions, and is currently being further evaluated in a
such as ulcerative colitis, psoriasis and organ separate clinical trial [206]. Although efficacy
transplantation, is anticipated [187]. of fostamatinib has been reported, important
As JAK inhibition proved to be an effective side effects, such as neutropenia, elevated liver
new treatment option for RA, several different enzymes, diarrhea, infections and increase of
JAK inhibitors are currently being tested and are blood pressure, need to be studied in detail,
in various stages of development. Especially in and results of the Phase III program are eagerly
terms of efficacy and safety, it will be interest- awaited.
ing to follow which of the JAK inhibitors make
their way to clinical use. Baricitinib (formerly „„ NF‑κB inhibitor
LY3009104/INCB028050), a JAK1/2 inhibi- In Japan and China exclusively, iguratimod, an
tor, has been evaluated in a 24‑week blinded inhibitor of NF‑kB and COX-2, has been devel-
Phase IIb study in patients with moderate-to- oped [195]. In combination with MTX, ACR20
severe RA with an inadequate response to MTX response rates of 69.5 versus 30.7% in the placebo
[188]. Baricitinib was administered in combina- group have been achieved.
tion with cDMARDs and the ACR20 (response As demonstrated in this section, novel thera-
rate of the ACR indicating an improvement of peutic achievements in the treatment of RA are
at least 20%) response of the 4- and 8‑mg doses nevertheless possible. And as Miossec has stated
were significantly higher compared with placebo previously: “After MTX and biotherapies, oral
(75 and 78 vs 41%, respectively). VX‑509 is a treatment with signaling inhibitors could represent
selective JAK‑3 inhibitor, which has been evalu- the next milestone in RA treatment” [160].
ated as monotherapy in a dose-finding Phase II
clinical trial in patients with active RA who pre- Conclusion & future perspective
viously failed cDMARD therapy [162]. Further- Several issues will be of great importance in
more, JAK inhibitors that are currently tested the next years to optimize the treatment of
in RA are: ruxolitinib (formerly INCB018424), RA. Remission was always the major goal of
a JAK1/2 inhibitor and primarily tested in immunotherapy, but for a long, time, it was
myelofibrosis [189]; GLPG0634, a selective JAK1 simply not achievable. Nowadays, a broad
inhibitor, evaluated in a proof-of-concept trial armamentarium of DMARDs is available and
including 24 RA patients on background MTX remission can be achieved in more and more
therapy [190]; and ASP015K, a JAK1/3 inhibi- patients due to improvements over the past
tor, is going to be further evaluated in Phase II years. Personalizing treatment is one of the
trials [191]. challenges we are facing in order to improve
outcomes and minimize side effects. Taking
„„ Syk inhibitor the autoantibody status into account is just
Besides targeting JAK, inhibition of Syk by one step in this direction, however, several
fostamatinib (formerly R406; R788 is the pro- more are going to follow. Biomarkers and pre-
drug), another tyrosine kinase, proved clini- determination of pharmacokinetics are very
cal efficacy and a tolerable safety profile and promising in this respect. Another great chal-
therefore proceeded to an extended Phase III lenge will be the handling of the downside
program [192–194]. Expressed by hematopoietic of biological therapies: the cost–effectiveness.
cells and being a major downstream regulator To evaluate and decide which patient should
of signaling through Fcg and immunoglobu- receive or would benefit from a biological
lin receptors, Syk appeared to be a promising therapy and thus, has a rationale, so to say,

966 Immunotherapy (2013) 5(9) future science group

 Current immunotherapy in rheumatoid arthritis Review
will be not only a difficult socioeconomic, what evolves from that knowledge can only be
but also a provocative ethical and scientific seen by long-term experience. However, stud-
question. The impact of biosimilars and their ies that deal with the question of tapering or
implementation might therefore be a mercy, stopping therapy are strongly needed in the
but also a challenge, if prices are not about future. Moreover, we are going to take part
to drop significantly. The first available bio- in an exciting future, where immunotherapy
similar for R A therapy will be rituximab constantly changes its face as new targets,
and the availability of biosimilars may lead intracellular and extracellular, are approached.
to decreased therapy costs, thus combination The new era of kinase inhibition was just the
therapy of biosimilars will then be discussed first change of paradigms, but more are yet to
in a different light. Despite a considerable fear come. On this background, the installation
of severe side effects, combined therapy of dif- of broad and sufficient documentation based
ferent biologic agents such as TNF inhibition, on therapy and population will be crucial to
IL‑6 receptor blockade, B-cell depletion and observe and define the best therapy regimens
inhibition of T-cell activation in lower doses in times that regularly offer new agents.
might be a feasible treatment option in the
future to block various proinflammatory path- Financial & competing interests disclosure
ways in parallel; particularly in patients who FMP Meier received a grant from Pfizer for an
have failed to achieve remission. In addition, investigator-initiated research project and speaker fees
by future diagnostic advances (synovial biop- from Pfizer, AbbVie and Chugai. M Frerix received
sies, miniarthroscopy and biomarkers), evalu- speaker fees from Pfizer and AbbVie. W Hermann received
ation of activated pathways in the individual speaker fees from Pfizer, AbbVie, UCB and Chugai. U
patient might be available, thus providing a Müller-Ladner received speaker fees from AbbVie, Pfizer,
rationale for an individualized combination BMS, UCB, Chugai, Roche and MSD. The authors have
of treatments. Thereby, costs of antirheumatic no other relevant affiliations or financial involvement
therapy for the society will increase. In the with any organization or entity with a financial interest
light of recent results by O’Dell and colleagues in or financial conflict with the subject matter or materi-
[67] a revival of the triple therapy of cDMARDs als discussed in the manuscript apart from those
seems conceivable. To what extent the immune disclosed.
system and its memory is modulated by the No writing assistance was utilized in the production of
current state-of-the-art immunotherapy and this manuscript.

Executive summary
Conventional disease-modifying antirheumatic drugs for the treatment of rheumatoid arthritis
ƒƒ Methotrexate (MTX) is the first-line therapy of rheumatoid arthritis (RA) and should be initiated soon after diagnosis. It is generally
accompanied by low-dose glucocorticoid therapy and folate supplementation.
ƒƒ Leflunomide, sulfasalazine and injectable gold salts are also effective in moderate-to-severe RA, whereas (hydroxy)chloroquine as
monotherapy is generally considered for mild disease forms only.
ƒƒ Triple therapy of MTX with sulfasalazine and hydroxychloroquine shows comparable efficacy to a combination of a biological agent
with MTX and is affordable.
ƒƒ Side effects are generally observed and should be monitored closely.
ƒƒ If treatment response cannot be achieved within the first 3–4 months, therapy should be questioned and changed or addition of drugs
is recommended.
Biological disease-modifying antirheumatic drugs for the treatment of RA
ƒƒ Several concepts of biological therapy have been approved for the treatment of RA: fused receptor molecules, chimeric, humanized or
human monoclonal antibodies, pegylated antibody fragments or receptor antagonists.
ƒƒ Amongst the different targets are TNF‑a, IL‑1, IL‑6 receptor, CD20 and CD80/86.
ƒƒ In most of the cases a biological therapy is combined with and commenced after a conventional drug such as MTX has failed, but most
work also as monotherapy; here, differences between the agents exist.
ƒƒ New targets such as B-cell-activating factor of the TNF family or optimization of pharmacokinetics are currently tested.
ƒƒ Biosimilars for the treatment of RA will be available soon.
New & upcoming agents for the treatment of RA
ƒƒ Tofacitinib is the first approved kinase inhibitor in RA targeting mainly JAK1 and JAK3.
ƒƒ Several different kinase inhibitors are currently in clinical Phase II and III trials showing promising results, among the most advanced is
the concept of Syk inhibition.

future science group www.futuremedicine.com 967

Review Meier, Frerix, Hermann & Müller-Ladner

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