Introduction
TNF-α antagonist
Infliximab
Etanercept
Adalimumab
Golimumab
Certolizumab pegol
Similarity and difference between anti-TNFagents
Switching between various anti-TNF agents
Conclusions
Rheumatoid arthritis (RA) is a chronic inflammatorydisease characterized by progressive joint destruction. As jointsdeteriorate, patients suffer from pain and loss of function, oftenaccompanied by decreasing quality of life and increasing mortality(1). Depending on the severity ofthe disease at onset, the risk of disability may be up to 30%, andmortality can be increased by up to 52%, frequently as a result ofinfection or circulatory disease (2).
RA treatment aims to minimize disease activity,thereby preventing or controlling joint damage and reducing therisk of other serious co-morbidities, such as heart disease orstroke. Early intervention is vital in patients with confirmed RAto preserve joint function (3–5).
Non-steroidal anti-inflammatory drugs (NSAIDs) andglucocorticoids are used to control pain and the inflammatoryprocess (6). Following thediagnosis of RA, patients receive disease-modifying antirheumaticdrugs (DMARDs), which reduce the signs and symptoms of the disease,and potentially inhibit radiographic progression (6). While a number of RA patients respondto DMARDs, a large proportion of RA remains active despite suchtreatments. The approach of targeting cytokines has considerablyimproved the success in the treatment of RA. In the clinicalapplication, five tumor necrosis factor (TNF)-α inhibitors areavailable: infliximab (IFX), etanercept (ETN), adalimumab (ADA)(7–10), golimumab (GOLI) and certolizumabpegol (CZP).
This review focuses on the development of theseagents regarding their effects on symptoms evaluated by theAmerican College of Rheumatology (ACR) response criteria, structure(in the light of the erosion, joint-space narrowing and Sharpscores), and physical function [based on standardizedquestionnaires, such as the Health Assessment Questionnaire(HAQ)].
TNF-α is a significant cytokine that mediatesinflammation in RA. Elevation of TNF-α levels have been observed insynovial fluid and the synovium of patients with RA (11). TNF-α plays an extremely central rolein driving inflammation and bone degradation (12). Due to its influence on various cellsin synovial membrane, such as synoviocytes, macrophages,chondrocytes and osteoclasts, which are able to producemetalloproteinases, collagenase and stromelysin, TNF-α induceslocal inflammation and pannus formation, eventually leading tofurther erosion of cartilage and bone destruction. Introduction ofTNF-α inhibitors has revolutionized RA treatment options resultingin the development of further biologic DMARDs (13). The effects of a TNF-α blockade arepartially dependent on synovial TNF-α expression and infiltrationby TNF-α-producing inflammatory cells (14). The progress in biotechnologycontributes to the development of biological agents, such asanti-TNF-α monoclonal antibodies, as a strategy for the treatmentof chronic inflammatory diseases.
IFX is a recombinant IgG1 monoclonal antibodyspecific for TNF-α that hinders the cytokine from triggering thecellular TNF receptor complex (15). IFX needs to be administered byintravenous infusion and has a terminal half-life of 8–10 days.Thus, it is administered every 4–8 weeks and the dosage varies from3 to 6 (to 10) mg/kg.
The efficacy of IFX with MTX was previouslydemonstrated in several trials (TableI). Patients receiving combination therapy exhibited evidentlyhigher median improvements compared to patients in the MTX plusplacebo (PBO) group (16–18). In addition, the clinical efficacywas similar at varying dosages in the IFX group (16–18).In terms of radiographic images, the combination of IFX plus MTXprevented the radiographic progression and led to lasting clinicalamelioration (16). IFX treatmentinhibited joint damage progression even in patients who did notreceive MTX in the RISING study (18). Compared to the MTX-only-treatedpatients, erosions and joint space narrowing evidently reduced frombaseline in the IFX plus MTX-treated patients, with the exceptionof IFX 3 mg/kg every 8 weeks. There were fewer newly eroded jointsper patient in the IFX plus MTX treatment groups compared to theMTX-only group (17). In theirstudy, St. Clair et al demonstrated that HAQ scores showedimprovement in the IFX group compared to the group receiving MTXalone (16).
The most common adverse events found in clinicaltrials of IFX are infusion reactions and infection. The therapy ofIFX might increase the risk of malignancies and cardiovascularconditions (19). The incidence ofserious infections, acute infusion reactions and death was similarin patients treated with IFX plus MTX and those who received MTXonly (17). Among the seriousinfections, pneumonia and tuberculosis occurred more frequently inthe IFX-treated patients compared to those treated with MTX alone(16,19).
ETN is a genetically engineered protein comprisingtwo molecules of the extracellular domain of TNF receptor II (p75)and the Fc portion of IgG1 (20).Due to its half-life of 3–5.5 days, ETN is administeredsubcutaneously (s.c), either on a weekly basis (50 mg) or twice aweek (25 mg) (21).
The superiority of the combination therapy of ETNplus MTX over ETN or MTX monotherapy in patients with RA has beendemonstrated (Table II) (22–24).The 2-year data from the TEMPO study confirmed that a largerproportion of patients treated with combination therapy exhibitedclinical response compared to those receiving either ETN or MTXmonotherapy (22). Moreover, thecombination-treated patients had predominantly lower erosion changescores (?0.67) compared to patients treated with ETN (0.39) or MTX(3.25) alone (25). Therefore,treatment with a combination of ETN and MTX stopped joint damageand patients exhibited disease remission (25). Sustained efficacy and decreased rateof radiographic progression was observed in patients with earlyaggressive RA who underwent long-term treatment with ETN (26). Patients adopting combination therapyenhanced to a greater extent in function status compared to thosein the monotherapy group (27).Additionally, ETN (50 mg) once weekly was an optimal treatment inmost patients with RA. Increasing the dosage of ETN from 50 mg oncea week to 50 mg twice a week in suboptimal responders did notmarkedly improve response rates (28). With regard to safety and efficacy,no obvious improvement was observed between ETN as monotherapy at50 and 25 mg twice weekly (29).
Injection-site reactions and hypertension were morecommon with ETN compared to MTX or combination therapy (22). These events were mostly mild ormoderate. Nausea and vomiting were more often associated with MTXcompared to ETN or combination therapy. No statisticallysignificant differences were observed in the groups regarding theincidence of serious adverse events (infectious and non-infectious)(22).
Thus, ETN is beneficial for patients with RA.However, the combination of ETN with MTX is superior to amonotherapy with each drug. The combination regimen may reducedisease activity, retard radiographic progression and improvefunction. Furthermore, the treatment with ETN plus MTX iswell-tolerated and does not increase serious adverse events.
ADA is a monoclonal antibody of recombinantimmunoglobulin (IgG1) containing only human sequences of peptides.It is an antagonist of TNF-α, which is able to prevent the bindingof TNF-α to its receptors (6). Ithas a half-life of 10–20 days and may be used as monotherapy or incombination with several other DMARDs, preferably MTX (30–31).The recommended dose of ADA is 25 mg s.c. twice a week.
Treatment with ADA plus MTX was found to bestatistically superior to PBO plus MTX, according to theACR20/50/70 response rates at week 26 (Table III) (32). When receiving ADA plus MTX in earlyRA, patients exhibited rapid clinical and functional improvements(32). ADA regimens decreased therisk of radiographic disease progression (33). In a 5-year, open-label extensionstudy, the addition of ADA led to greater inhibition of structuraldamage compared to patients who continued with MTX monotherapy(Table III) (34). The PREMIER study confirmed thattreatment with ADA plus MTX initiated earlier contributed to higherimprovements in clinical, functional and radiographic responses ascompared to treatment with MTX or ADA alone (35). In addition, ADA plus MTX amelioratedphysical function for patients with RA (33,36).
ADA exhibited a good overall tolerance. Findings ofa previous study demonstrated that the rate of adverse events(serious and nonserious) was similar in the ADA and PBO groups,although the proportion of patients reporting serious infectionswas higher in patients receiving ADA (3.8%) compared to thosereceiving PBO (0.5%) (P<0.02), and was the highest in thepatients administered 40 mg every other week (33). The common adverse events wereinjection site reactions and serious infections, such as militarytuberculosis and cellulitis (35).However, ADA was safe and well-tolerated. Adverse events were notserious and severe side effects were relatively seldom.
GOLI is a human anti-TNF-α monoclonal antibody thatis generated and matured in an in vivo system (37). GOLI has a high affinity andspecificity for human TNF-α and effectively neutralizes TNF-αbioactivity in vitro (38).
The efficacy of GOLI has been demonstrated inseveral groups (Table IV) (37,39–40).The combination of GOLI and MTX was significantly better atimproving the signs and symptoms of RA and physical function(37). No difference has beenobserved in the efficacy between the two GOLI dose groups (50 and100 mg) (37). Comparedindividually with the PBO group, GOLI in combination with MTX inpatients with RA showed greater clinical response, while theresponse rates did not show a clear dose-response pattern in thegroups of GOLI plus MTX (Table IV)(39).
In the multicenter, randomized, PBO-controlledGO-FORWARD study, the mean improvement from baseline in HAQ-DI wassignificantly greater for GOLI 50 mg + MTX and 100 mg + MTX vs. PBO+ MTX (41). However, GOLI + MTXalso elicited a significant better response compared to PBO + MTXin various efficacy parameters, including disease activity score(DAS28) response. Additionally, the combination of GOLI and MTXlimited radiographic progression (42).
The safety of GOLI was demonstrated in varioustrials (39–41). However, adverse events were reportedin the process of treatment. The most frequent adverse events inthe combined GOLI groups were nausea, headache and injection sitereaction (39–41). Most events were mild or moderate(43). In general, GOLI incombination with MTX may alleviate the signs and symptoms of RA andimprove physical function.
CZP is a humanized anti-TNF-α antibody with highaffinity to TNF-α (44). Inmanaging patients with RA, the recommended dose of CZP is 400 mg(given as two s.c. injections of 200 mg) initially and at weeks 2and 4, followed by 200 mg every other week.
An international, multicenter, phase 3, randomized,double-blind, PBO-controlled study had assessed the efficacy of CZPin RA patients for MTX non-responders (45). Compared to PBO treatment, CZP plusMTX effectively reduced the signs and symptoms of RA, and inhibitedprogression of joint damage (TableV) (45–46). No evident differences were observedin clinical efficacy between the two CZP dose groups (45). Additionally, treatment with CZPmonotherapy also provided a rapid, meaningful and durable clinicalresponse and acceptable safety profile (Table V) (47). Increasing the CZP dose from 200 to400 mg did not result in an additional benefit in RA patients(48). A study showed that the meantender joint count (?24.8 vs. ?24.6) or swollen joint count (?18.6vs. ?18.7) was similar between the dose-escalation (200 mgincreased to 400 mg every other week) and stable-dose subgroups(400 mg every other week) (49).The most common adverse reactions were tuberculosis, injection sitepain and injection site reaction (46).
As shown above, CZP monotherapy or the combinationtherapy with MTX as an effective treatment provides a rapid,meaningful and durable clinical response and an acceptable safetyprofile.
It is widely accepted that patients with RA have lowquality of life. Clinical trials have shown that TNF-α blockingagents, such as ETN, IFX and ADA, relieve joint inflammations andslow the radiographic progression of joint damage and improvephysical function in advanced RA (50–52).The availability of newer agents, including CZP and GOLI, hasincreased treatment options for patients with RA. Furthermore,anti-TNF-α agents are more efficacious in promoting the clinicalsigns and symptoms of RA compared to MTX alone. Anti-TNF-α agentsplus MTX show sustained efficacy and remain more effective comparedto anti-TNF-α monotherapy (53).Compared to MTX and PBO, the ACR20, 50 and 70 response rates for1-year treatment with MTX plus any of the TNF inhibitors were 60vs. 25%, 40 vs. 10% and 20 vs. 5%, respectively (54).
However, they have distinct clinical pharmacokineticand -dynamic properties that must be considered when selecting onedrug for therapy (55). Forexample, there are evident differences in the half-lives of thethree agents (IFX, ETN and ADA), with ETN having the shortest(3–5.5 days) and ADA the longest (2 weeks) (21). The three types of biological agentsalso differ from each other in their dosing regimens (55). The larger, yet less frequentlyadministered dose of IFX may result in higher peak serumconcentrations compared to the smaller but more commonlyadministered dose of ETN and ADA, resulting in higher tissueconcentrations (55). Totalefficacies of varying biologics are highly similar, which have beenobserved in most of the studies and adopted by severalinvestigators (55). Nevertheless,a recent study indicated significant differences in the efficacy ofand adherence to therapy with ADA, ETN and IFX (56). IFX had the lowest treatmentresponses, disease remission and drug adherence rates. ADA had thehighest treatment response and remission rate, while ETN had thelongest drug survival rate (56)(Table VI).
In their study, Singh et al (57) demonstrated that patientsadministered ADA plus IFX were at a markedly higher risk comparedto those administered PBO. Indirect companies showed that ADA had ahigher tendency to withdraw compared to ETN (OR 1.89; 95% CI,1.18–3.04) and ETN was less likely than IFX (OR 0.37; 95% CI,0.19–0.70). Additionally, there seemed to be differences in therisk of tuberculosis (TB) among varying biologics, and this mightinfluence the selection of patients likely to receive thebiological agent. TB occurred more frequently in monoclonalantibodies-treated patients (i.e., IFX and ADA) compared to thosetreated with soluble TNF receptor therapy (i.e., ETN) (58–59).The rate of hospitalized infection in patients treated with otheragents was lower compared to that for patients treated with IFX(60). Among these biologicalagents, the incidence of serious infections was higher in the CZPgroup compared to others. ADA, ETN and GOLI were associated with alow incidence of treatment discontinuation due to adverse events,whereas the IFX was not (61).Moreover, the biological agents increased the risk of infections.Consequently, patients with tuberculosis should be excluded andshould receive pneumococcal, influenza and hepatitis B vaccinationsprior to undergoing the therapy with biological agents.
Patients with RA may discontinue their initial drugand switch to a second anti-TNF-α agent due to shortage of drugefficacy. Regarding the effect of the second biological agent, in aretrospective study (62), certainpatients (n=20) switched from ETN to IFX, while others (n=73)received IFX with no prior anti-TNF-α therapy. The C-reactiveprotein, swollen and tender joint counts as well as the morningstiffness ameliorated in the two groups, while no statisticallysignificant difference was observed in the degree of benefitbetween the groups (62). However,IFX may be of additional clinical profit for patients with anincomplete response to ETN. In particular, patients receiving IFXexhibited a better amelioration in the HAQ score compared to thosereceiving ETN (Table VII) (63).
Another study concluded that patients switching toADA exhibited a good clinical response when the therapy of IFX orETN was ineffective (64). Patientswho do not respond to an initial anti-TNF drug may also improvetheir HAQ score, subsequent to switching to a second agent(65). Patients with RA may besuccessfully treated with another TNF-α agent, especially thosewithdrawing due to inefficacy and adverse events (66). The above results demonstrated thatswitching among various biological agents was beneficial.
Biological agents render the treatment of RA a newera, especially for patients with an insufficient response toDMARDs. Biological agents can quickly relieve clinical symptoms anddelay bone destruction. When the TNF-α inhibitors are applied inclinical practice, the combination with DMARDs are conductive toease the symptoms and prevent bone structural damage and elevatephysical function. Moreover, the conversion between various agentsmay have the same function. Certain drugs, such as ETN, incombination with MTX are better compared to monotherapy regardinglong-term efficacy. Most adverse events of agents areinfection-site reactions. Although severe side-effects may betreated appropriately, they still prevent clinical remedy.Physicians should prescribe various treatment regimens according tothe patient’s symptoms as well as constantly explore the immunemechanism of RA, and develop novel biological agents. In thefuture, immunotherapy is likely to bring fundamental changes forpatients with RA.
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