Expert Opinion on Biological Therapy

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Adalimumab in the treatment of rheumatoid arthritis Paraskevi V Voulgari MD & Alexandros A Drosos MD FACR To cite this article: Paraskevi V Voulgari MD & Alexandros A Drosos MD FACR (2014) Adalimumab in the treatment of rheumatoid arthritis, Expert Opinion on Biological Therapy, 14:4, 549-561, DOI: 10.1517/14712598.2014.894503 To link to this article: http://dx.doi.org/10.1517/14712598.2014.894503

Published online: 04 Mar 2014.

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Drug Evaluation

Adalimumab in the treatment of rheumatoid arthritis Paraskevi V Voulgari & Alexandros A Drosos† Introduction

2.

Competitive environment

3.

Adalimumab

4.

Comparison with other biologic agents

5.

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1.

Expert opinion

University of Ioannina Medical School, Department of Internal Medicine, Rheumatology Clinic, Ioannina, Greece

Introduction: Rheumatoid arthritis (RA) is a systemic inflammatory disease that causes increased morbidity and mortality. The treatment of the disease has considerably advanced with the addition of biological agents targeting pro-inflammatory cytokines such as tumor necrosis factor (TNF). Adalimumab (ADA) is one of the currently available five TNF inhibitors for clinical use in RA. It is a fully humanized monoclonal antibody which may be prescribed as monotherapy or in combination with methotrexate or other diseasemodifying antirheumatic drugs. Areas covered: This review summarizes the recent available data on efficacy and safety of ADA in patients with early and established RA as well as improvement of quality of life and finally we provide data on biologic drug comparison. Expert opinion: ADA has been evaluated in various randomized placebo-controlled trials in RA, prospective observational studies as well as open-label extensions of the original double-blind trials providing experience and data about the long-term efficacy and safety of the drug. Effectiveness of the drug is sustained, while in most cases RA patients treated with ADA experienced a slower radiographic progression and consequently less disability and improved health-related quality of life outcomes. Clinical trials demonstrated no new safety signals and a safety profile consistent with that of the anti-TNF class. Keywords: adalimumab, anti-TNF-a, drug comparison, efficacy, rheumatoid arthritis, safety Expert Opin. Biol. Ther. (2014) 14(4):549-561

1.

Introduction

Rheumatoid arthritis (RA) is a chronic immune-mediated inflammatory disease that affects 0.5 -- 1.0% of the general population and has worldwide distribution. It is characterized by chronic synovitis which leads to cartilage damage, progressive joint destruction, functional status decline, disability, comorbidity, and premature mortality [1-3]. RA is a heterogeneous disease, in terms of clinical expression (number of involved joints, presence of extraarticular manifestations, etc.), severity, long-term course, and response to therapy. Genetic and environmental factors are clearly implicated in its etiology and pathogenesis. Proinflammatory cytokines such as tumor necrosis factor a (TNF-a), interleukin (IL)-1, and IL-6 play a pivotal role in the pathogenesis of RA. The self-perpetuating mechanisms of disease usually relapse when therapy is discontinued even if a full remission has been achieved. Thus, it is difficult to establish optimal treatment strategies for RA patients since different therapeutic ‘opportunities’ may exist for early versus established disease patients. However, the treatment of RA has significantly advanced over the past decades. Methotrexate (MTX) is the gold standard traditional synthetic disease-modifying antirheumatic drug (DMARD) for RA treatment. However, sulfasalazine, hydroxychloroquine, ciclosporin A and more recently leflunomide are also used in RA patients [4-7]. Their 10.1517/14712598.2014.894503 © 2014 Informa UK, Ltd. ISSN 1471-2598, e-ISSN 1744-7682 All rights reserved: reproduction in whole or in part not permitted

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P. V. Voulgari & A. A. Drosos

Box 1. Drug summary. Drug name Phase Indication Pharmacology description Route of administration Chemical structure Pivotal trial(s)

Adalimumab Launched Rheumatoid arthritis TNF-a antagonist Injectable Biological protein, monoclonal antibody [8,9,106,108]

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adverse effects are mostly different comparing to biologic DMARDs and their costs are substantially lower. Synthetic DMARDs are used early on the disease course followed by combination with other DMARD or a biologic agent in case of poor response. The first biologic agents studied and subsequently approved were inhibitors of TNF [8,9] followed by abatacept, an inhibitor of T-cell costimulation [10], rituximab, an agent leading to B-cell depletion [11] and tocilizumab, an IL-6 receptor blocker [12]. Although there is little direct comparison data between the five currently approved TNF inhibitors (adalimumab [ADA], certolizumab pegol, etanercept [ETA], golimumab, and infliximab [IFX]) or other biological agents, reviews and meta-analyses of clinical trial data suggest these compounds have similar efficacy [12-16]. The current biologic agents have different molecular structures (chimeric, humanized or human monoclonal antibodies, or recombinant receptor constructs) and route of administration (intravenous or subcutaneous [SC]). In this review the efficacy, safety and long-term use of ADA is presented (Box 1). 2.

Competitive environment

TNF-a inhibitors currently approved for the treatment of RA are ADA (Humira), IFX (Remicade), ETA (Enbrel), certolizumab pegol (Cimzia), and golimumab (Simponi). The five TNF-a inhibitors block the biologic effects of TNF-a although there are some differences in their structure, pharmacokinetics, and mechanisms of action [17]. The safety profile of the TNF-a inhibitors can be considered as a class effect. IFX is a chimeric human/murine IgG1 (human immunoglobulin) monoclonal antibody, ADA and golimumab are human monoclonal antibodies, certolizumab pegol is composed of the fragment antigen-binding domain of a humanized anti-TNF monoclonal antibody combined with polyethylene glycol to increase its half-life in the body, and finally, ETA is a fusion protein consisting of the TNF-a receptor p75 jointed to the Fc domain of IgG1 [18-20]. Data concerning efficacy and safety of TNF-a inhibitors can be provided by various registries. In these registries patients are treated according to usual clinical practice and 550

direct comparisons can be made with the limitation that the patients are not randomized among treatment options and exposure to various therapeutic agents may be in different order. 3.

Adalimumab

Chemistry ADA is a recombinant, fully human IgG monoclonal antibody against TNF-a. It is composed of heavy and light chain variable regions and IgG1:k constant regions. It is produced using phage display technology in a Chinese hamster ovary cell line. It binds two soluble TNF-a molecules having even the potential to form multimeric complexes, thus preventing soluble TNF-a from binding to the natural TNF-a receptors (p55/CD120a and p75/CD120b). Alternatively, ADA binds two membrane TNF-a molecules with the potential of cross-linking and reverse intracellular signaling. ADA may thus mediate its actions through various mechanisms: direct neutralization of soluble TNF-a and membrane TNF-a, apoptosis and cytokine suppression through reverse membrane TNF-a-mediated signaling, antibody-dependent, cell-mediated cytotoxicity, and complement-dependent cytotoxicity directed against cells expressing membrane TNF-a. ADA does not bind to or neutralize, lymphotoxin (TNF-b) [21-24]. 3.1

Pharmacodynamic and pharmacokinetic properties

3.2

In vitro studies required an ADA concentration of 0.16 nmol/l to inhibit binding of TNF-a to its receptor on human U937 cells by 50% IC50. In murine L929 cells, ADA inhibited human TNF-a-induced cytotoxicity with an IC50 of 0.13 nmol/l [21]. A maximum serum ADA concentration (Cmax) of 4.7 µg/ml was reached 131 h (time for reaching a maximum serum ADA concentration [Tmax]) after a single SC 40 mg dose in healthy individuals [25]. At steady state, the mean trough serum ADA concentration was 5.83 and 3.80 µg/ml, when 40 mg of the drug was administered subcutaneously every other week with and without MTX in RA patients [26]. Mean Cmax values were 9.97 and 7.7 µg/ml with and without MTX, respectively, and the corresponding mean Tmax values were 83.2 and 89.6 h. Average steady-state serum concentrations of the drug were 7.63 and 5.45 µg/ml, with and without MTX, respectively [27]. It appears that MTX enhances the effect of ADA. Steady-state clearance was 20 and 29 ml/h in patients receiving SC ADA 40 mg every other week with and without MTX, respectively [21]. The apparent clearance of intravenous ADA was reduced by 22% after a single dose with concomitant administration of MTX. Population pharmacokinetic analysis suggests that the apparent clearance of ADA increases in the presence of anti-ADA antibodies and decreases in patients aged ‡ 40 years. The mean terminal half-life of ADA was 10 -- 13.6 days in patients receiving a single

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Adalimumab

intravenous dose of 0.5 -- 10 mg/kg, and 14.7 -- 19.3 days in patients receiving a single intravenous dose of 0.25 -- 5 mg/kg and MTX [21,28]. Approved use ADA was approved by the USA FDA in 2002 and received approval from the European Medicines Agency (EMA) in September 2003 for the treatment of RA. ADA was subsequently approved by the FDA for the following indications: psoriatic arthritis (in 2005), ankylosing spondylitis (in 2006), Crohn’s disease (in 2007), and for juvenile-idiopathic arthritis as well as chronic plaque psoriasis (both in 2008). ADA is also approved for the treatment of these diseases by the EMA [29]. ADA in combination with MTX is indicated for the treatment of moderate to severe active RA [30] in adult patients when the response to DMARDs including MTX has been inadequate. It is also indicated for the treatment of severe, active, and progressive RA in adults not previously treated with MTX. It can be given as monotherapy in case of intolerance to MTX or when continued treatment with MTX is inappropriate. The recommended dose of adult patients with RA is 40 mg ADA administered every other week as a single dose via SC injection. Some patients receiving ADA monotherapy may achieve additional benefit from weekly administration; however, there are no data of long-term use of ADA weekly in RA patients. It can be combined with MTX or other DMARDs and glucocorticoids [31]. All patients should be evaluated for active or latent tuberculosis (TB) before starting ADA therapy.

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3.3

Clinical efficacy The Safety Trial of Adalimumab in RA (STAR) [31] the DE011 trial [32], the anti-TNF-a Research Study Programme of the Monoclonal Antibody Adalimumab in RA (ARMADA) [33], and the DE019 [34] were the first randomized double-blind placebo-controlled trials that examined the efficacy, safety, and tolerability of ADA in RA patients. These studies included adult RA patients with, on average, long-standing, moderately to severely active disease inadequately treated with previous DMARD therapy except for STAR which enrolled DMARD-naı¨ve patients. The above trials had ‡ 24 weeks of double-blind treatment phase, except the DE019 (52-week X-ray analysis). The American College of Rheumatology (ACR) 20% response to ADA was superior to placebo in all trials. The outcomes for the secondary endpoints ACR50 and 70% were consistent with the primary analysis. The onset of response was quick: ACR20% response rates at week 1 (ARMADA) or week 2 (STAR, DE011, and DE019) were significantly greater than placebo for all ADA doses tested. ‘Responsiveness’ could be determined after 12 weeks of treatment as the number of responders increases very little after this point. Non-response was noted in 3.4

‡ 30% of patients. The first clinical trials showed clinical efficacy with a 40 -- 60% reduction of swollen and tender joint counts compared with baseline. In addition, mean C-reactive protein (CRP) was significantly reduced versus placebo and Health Assessment Questionnaire (HAQ) response improved. In the PREMIER study, the efficacy and safety of ADA plus MTX versus MTX monotherapy or ADA monotherapy in patients with early, aggressive RA, MTX naı¨ve were studied [35]. This was a 2-year, multicenter, double-blind, active comparator-controlled study of 799 RA patients with disease duration < 3 years. Combination therapy was superior to both MTX and ADA monotherapy in all outcomes measured. At year 1, more patients receiving combination therapy exhibited an ACR50 response (62%) compared to MTX or ADA monotherapy (46 and 41%, respectively; p < 0.001). Similar superiority of combination therapy was seen in ACR20, 70, and 90 response rates at 1 and 2 years. In the Adalimumab Research in Active RA (ReAct) trial 6610 patients were enrolled at 450 sites in 11 European countries and Australia [36]. ReAct was a 12-week open-label study of patients with active established RA and previous failure of synthetic DMARDs or even TNF-a inhibitors with an optional extension phase. The ReAct data confirmed the results observed in earlier pivotal trials of ADA [31-35]. Thus, ADA was proven effective and safe for both the treatment of 819 patients with prior discontinuation of IFX and/or ETA (due to inadequate response 171 patients, loss of response 260 patients, or intolerance 169 patients, median duration of 10 months of anti-TNF therapy), and TNF inhibitor naı¨ve patients. Patients who had been for £ 1 year of ReAct were allowed to participate to ReAlise, a study evaluating the long-term efficacy and safety of ADA. Among 658 patients who have completed 3 years in ReAlise, ACR20/50/70 response rates were 85, 65, and 40%, which are at least comparable to the respective baseline (at ReAlise initiation) values of 80, 59, and 35% [37]. A 4-year extension of the ARMADA study [38] evaluated 271 original patients (262 received at least one dose of ADA). At the time of analysis, 162 out of 262 (62%) patients had remained in the study and received treatment for a mean of 3.4 years. In 147 patients who completed the 4-year treatment, efficacy achieved at 6 months was maintained. At 4 years 78, 57 and 31% had achieved ACR20, 50, and 70 response criteria, respectively. Clinical remission was noticed in 43% (disease activity score for 28 joint indices [DAS-28] < 2.6) and 22% had no function abnormalities (HAQ = 0). Results were similar for 196 patients who received treatment for 2 -- 4 years. Efficacy was maintained in many patients when dosages of steroids (63% of patients), MTX (42%), or both (12%) were decreased [38]. In the study from Stockholm TNF-a follow-up registry (STURE), 36 patients who received ADA after secondary loss of efficacy to IFX (27 patients) or ETA (9 patients)

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were compared with 26 TNF inhibitor naı¨ve patients who were treated with ADA and it was found that switching to ADA can restore a good clinical response [39]. These results were in agreement with another open-label, 12-month study where clinical improvement was similar in switchers and TNF inhibitors naı¨ve RA patients [40]. Optimal Protocol for Treatment Initiation with MTX and Adalimumab (OPTIMA) study is a Phase IV, multinational, randomized, double-blind, controlled trial from December 2006 to July 2010. The study included 1032 active RA patients who were randomly assigned 1:1 to ADA plus MTX or placebo plus MTX for 26 weeks (first period) [41]. Treatment modifications were to be made in a subsequent study period based on achievement of low disease activity (LDA) of DAS-28(CRP) < 3.2 at weeks 22 and 26. Post hoc analyses compared patients achieving stable remission using DAS-28 and 2010 ACR/European League Against Rheumatism (EULAR) criteria with those achieving LDA but not remission [42]. Among patients completing 6 months, 44% of ADA + MTX versus 24% placebo + MTX patients achieved stable LDA at weeks 22 and 26 (p < 0.001). Combination therapy was statistically superior to MTX in obtaining higher ACR20/50/70 responses, more clinical remission, greater mean reduction in DAS-28(CRP), no radiographic progression, and normal function status at week 26 (p < 0.001 for all). The only factor predicting stable LDA was disease activity at week 12. Another study, a year 5 analysis of an open-label extension (OLE) assessed radiographic progression, clinical efficacy, and safety of ADA with concomitant MTX for active RA patients. It is the extension of DE019 trial and of 457 patients who had enrolled in the OLE, 304 remained in the study at year 5 [43]. A 52-week delay in adding ADA to MTX led to worse radiographic, functional, and clinical outcomes at year 5 for most patients who initially received placebo instead of ADA [43]. ADA plus MTX significantly improved physical functioning and health-related quality of life in patients with early RA over 2 years of treatment [44]. In addition, ADA-treated RA patients showed clinically important and statistically significant improvement in health-related quality of life already in the first three months [45]. Table 1 summarizes the main studies of ADA in RA patients. Ongoing clinical trials CONCERTO trial showed that patients treated with ADA in combination with MTX 2.5, 5, 10, or 20 mg per week experience similar improvements in patient-reported outcomes by week 8 and that are maintained through 26 weeks. The differences associated with MTX dose are not statistically significant and, in general, not clinically meaningful [46]. In addition, clinical responses and ADA serum concentrations generally appeared similar between 10 and 20 mg MTX arm [47]. Furthermore, MTX dose has minimal effects on MTX-related toxicity in patients with early RA treated in combination with ADA [48]. However, the MUSICA study 3.5

552

showed that in RA patients with incomplete response to MTX, slightly higher mean ADA serum levels were achieved when combined with high than low MTX dose [49]. Compared to 20 mg MTX, lowering MTX weekly dose to 7.5 mg in combination with ADA resulted in small differences in clinical and ultrasonographic outcomes [50]. Radiographic progression Long-term inhibition of radiographic progression was initially assessed in a 2-year follow-up of a Phase I study in which 47 patients with established RA were given ADA monotherapy [27]. In PREMIER study [35] increases in the modified total sharp score (mTSS) were significantly less in the ADA plus MTX group compared to the ADA monotherapy and MTX monotherapy groups both at years 1 and 2. After 3 years of open-label treatment, patients initially randomized to ADA plus MTX had less radiographic progression from baseline than patients initially randomized to ADA or MTX monotherapy (mTSS change from baseline: 2.8, 7.4, 9.2 for the three groups, respectively). After 5 years no radiographic progression was observed in half of patients initially randomized to the combination therapy, compared to one-third of patients in the initial monotherapy groups. Furthermore, between years 2 and 5 less radiographic progression was observed in patients initially randomized to either ADA group than to MTX monotherapy group [51]. A 5-year follow-up of patients with established RA who had participated in the DE019 study yielded similar results. At year 5 the original ADA 40 mg every other week plus MTX group experienced the best radiographic outcomes concerning mean changes in mTSS, joint erosion, and joint space narrowing scores compared the other two groups (ADA 20 mg weekly plus MTX and placebo + MTX) [52]. In the OPTIMA study [41] patients treated with ADA plus MTX had significantly less radiographic progression compared with those receiving placebo plus MTX (p < 0.001). After 26 weeks, 87% of patients receiving combination therapy had no evidence of radiographic progression, compared with 72% of patients in the placebo plus MTX group (p < 0.001) [41]. Analyzed data from patients enrolled in the PREMIER trial and the DE032 study showed that the combination treatment of ADA plus MTX inhibited both joint erosion and joint space narrowing progression independently of disease activity [51,53]. The double blind randomized controlled trial HIT HARD evaluated patients with active early RA (disease duration £ 12 months) and compared ADA plus MTX with MTX plus placebo for 24 weeks and then MTX monotherapy up to week 48. A greater reduction in radiographic progression after initial combination therapy with ADA and MTX was seen at week 48, even after discontinuation of ADA treatment at week 24 [54]. In the Strategies in Early Arthritis Management (STREAM) randomized trial, however, patients with early 3.6

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Adalimumab

Table 1. Summary of the main studies of adalimumab in rheumatoid arthritis patients. Studies

Number of patients (initially enrolled)

STAR [31] DEO11 [32] ARMADA [33] DEO19 [34] PREMIER [35] ReAct/ReAlise [36] ARMADA 4-year extension [38] OPTIMA [41]

636 544 271 619 799 6610 271 1032

Drug

ADA ADA ADA ADA ADA ADA ADA ADA

+ DMARDs + + + + + +

MTX MTX MTX DMARDs MTX MTX

Comparator

Placebo + DMARDs Placebo MTX MTX ADA or MTX

Placebo + MTX

Duration of treatment (months) 6 6 6 12 24 3 48 6

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ADA: Adalimumab; DMARDs: Disease-modifying antirheumatic drugs; MTX: Methotrexate.

arthritis (symptom duration £ 2 years), both aggressive tightcontrol therapy including ADA and conventional therapy resulted in remission rates around 50%, low radiographic damage and excellent functional status after 2 years. In this study the sample size of the groups was small lacking statistical power [55]. The 10-year open extension of DE019 showed that patients with long-standing RA, treated with ADA plus MTX experienced effective disease control and inhibition of radiographic progression [56]. ADA efficacy has also been demonstrated in RA patients using musculoskeletal ultrasound [57] and magnetic resonance imaging techniques [58]. Safety The safety profile of ADA appears comparable to that of other TNF antagonists. Infections (especially TB and opportunistic infection) and malignancies (mainly lymphomas) are the adverse effect of special interest. Other adverse effects such as demyelinating disease, congestive heart failure, and lupuslike syndrome although significant whenever they occur have a very low incidence rate and appear to be similar among TNF inhibitors [59-63]. Although no new safety signals have emerged there are published cases of autoimmune diseases induced by anti-TNF agents [64]. Randomized clinical trials, large observational studies registries, and meta-analyses have been used to compare safety. Risk of serious infections (SI) was assessed in three metaanalyses. Bongartz et al. found an odds ratio (OR) of 2.01 (95% confidence interval [CI] 1.31 -- 3.00) for IFX and ADA versus controls, whereas in two other meta-analyses an increased risk was not found for TNF-a blockers as a class and for the individual drugs compared with each other [65-68]. For ADA, safety data across 36 clinical placebo-controlled and non-controlled trials and their long-term extensions (nearly 12 years) showed a rate of SI in RA patients of 4.6 events/100 patients year [59]. In retrospective cohort studies the adjusted hazard ratio (aHR) for SI in RA patients was lower compared to IFX and ETA [69,70]. 3.7

In a report from the British Society for Rheumatology Biologics Register, SI were significantly more likely with TNF-a blockers than non-biologic DMARDs (aHR 1.2, 95% CI 1.1 -- 1.5) with the risk of SI being highest in the first 6 months of treatment. However, there was no significant difference in the occurrence of SI among the three TNF-a inhibitors ADA, ETA, and IFX [71]. TNF-a blockers conferred a significantly increased risk of shingles compared with DMARDs (aHR 1.8, 95% CI 1.2 -- 2.8). In the LORHEN registry use of ADA, ETA, or IFX did not influence the ratio of SI or the site of infection [72]. Wallis et al. first identified the risk of granulomatous infection analyzing FDA post-marketing surveillance data with IFX having more reports compared with ETA (p < 0.0001) [68,73-75]. In two observational studies, a higher incidence of TB was found for ADA and IFX than ETA, though the number of cases was very small compared with the number of patients treated [76]. In the French RATIO registry, the ORs for ADA and IFX were 17.1 and 13.3, respectively, compared with ETA. The methodology of the RATIO registry that employed a case-controlled analysis using crude estimate of exposure has been criticized to have limited accuracy of the reported data [68]. On the other hand, none of the 69 cases that have received correct prophylactic treatment with isoniazid presented with TB. A decrease of 83% in the rate of TB in RA patients after official recommendations were released and observed by practitioners was noticed in Spain [77]. In addition, the rates of new cases did not differ among ADA, IFX, and ETA [78]. The rate of TB remained stable 0.3 cases/100 patient year over 12 years of observation [59]. Advanced age and comorbidities have been reported in some analyses as risk factors for immunomodulatory therapy toxicity [79,80]. Before initiating treatment with ADA individual patient evaluation of the benefit/risk ratio should be carefully considered [41]. A meta-analysis of 21 studies showed that the overall standardized incidence ratio (SIR) for malignancy for RA was 1.05 (95% CI 1.01 -- 1.09) with a twofold increase in

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Table 2. Comparison of adalimumab with other TNF inhibitors.

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Study

Source

Hetland et al. [94]

Danish registry DANBIO

Greenberg et al. [95]

US CORONA registry

Bazzani et al. Marchesoni et al. [96,97]

Italian LOHREN registry

Flouri et al. [98]

Greek registry

Kievit et al. [99]

Dutch DREAM registry

Heiberg et al. [101]

Norwegian NOR- diseasemodifying antirheumatic drug registry Meta-analysis of four randomized trials Meta-analysis of three randomized controlled trials

Hochberg et al. [102] Lee et al. [103]

Outcome At 6 months ADA versus IFX more likely achieved ACR50/70, EULAR responses DAS and CDAI remission OR 1.78 -- 2.76 ADA versus ETA OR 1.15 -- 1.58 (significant for good EULAR response and CDAI remission) Similar OR for achieving modified ACR50/70 response DAS-28 and CDAI remission among ADA, ETA, INF EULAR good response was lower for IFX than for ADA or ETA at 6, 24, 36 months. ETA had better drug survival at 36 months Response rates were compared among anti-TNF agents. Overall 5-year drug survival was < 50%, with IFX demonstrating increased safety-related discontinuations ADA was better concerning DAS-28 than IFX (p < 0.001) and ETA (p = 0.031). EULAR response and survival rate at 12 months were similar for ADA and ETA; better than IFX (p < 0.05) No difference in the survival rate among ADA, IFX, and ETA No difference in ACR20 and 50 responses ADA was more efficacious compared to ETA but comparable to IFX

ADA: Adalimumab; ETA: Etanercept; IFX: Infliximab;

lymphoma risk and also an elevated SIR for lung cancer 1.63 (95% CI 1.43 -- 1.87) [81]. The risk for lymphoma seems to be increased in RA at least two to threefold especially for non Hodgkin lymphoma [68,81,82]. Patients with active disease have the greater risk [83]. No increased risk for malignancies overall with anti-TNF-a use compared with the general population has been found in large observational cohorts [59,84-87] and metaanalyses [66,67] although an elevated risk specific for nonmelanoma skin cancer (NMSC) has been reported (SIR 1.39) [59]. In the French RATIO registry an increased risk for lymphoma was reported for ADA and IFX compared with ETA but this was not reproduced in other registries [84,85,88]. In RA controlled and non-controlled clinical trials the SIR for malignancies (excluding NMSC) was 0.93 (95% CI 0.83 -- 1.06) for NMSC 1.39 (1.19 -- 1.60) and for melanoma 1.5 (0.84 -- 2.47). For lymphoma the SIR among RA patients was 2.74 (1.83 -- 3.93) indicating an increased incidence of lymphoma in ADA-treated patients compared with the US-based age- and sex-matched population [59]. However, this lymphoma risk compares well with the risk for lymphoma that RA itself confers to patients, especially those with active disease, who besides, are more likely to be treated with biologics [89]. On the other hand, in the same study [59] ADA was not associated with an increased risk for lymphoma in the rest of its approved indications (ankylosing spondylitis, psoriasis and psoriatic arthritis, juvenile idiopathic arthritis and Crohn’s disease). It is thus strongly debatable whether the excess lymphomas observed in RA patients 554

treated with ADA is just a matter of treatment or of the underlying condition as well [89]. Analysis of adverse events (serious infections, tuberculosis NMSC, malignancy, and lymphoma) through 12 years of ADA exposure in clinical trials of 23,458 patients, demonstrated a long-term safety profile consistent with known information about the anti-TNF class [59]. Studies in RA patients receiving ADA with or without concomitant DMARDs showed that anti-ADA antibodies develop more often in the absence of concomitant DMARDs, and are associated with lower serum ADA concentrations and with poorer clinical response [90-92]. MTX reduces immunogenicity in ADA-treated RA patients in a dose-dependent manner [93]. 4.

Comparison with other biologic agents

Comparison of ADA with other TNF inhibitors In registries where patients are treated according to usual clinical practice, direct comparisons can be made with the limitation that the patients are not randomized among treatment options (Table 2). In the Danish registry (DANBIO), 2326 RA patients were treated with ADA (n = 675, 29%), ETA (n = 517, 22%), and IFX (n = 1134, 49%). ACR50/70, good, and good/moderate EULAR responses, DAS remission and Clinical Disease Activity Index (CDAI) remission were evaluated. At 6 months ADA was significantly more likely than IFX to produce any of the above outcomes with the corresponding OR ranging from 4.1

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Adalimumab

Table 3. Comparison of adalimumab with other biologic agents.

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Study

Drug comparison

Duration

Primary end point

Weinblatt et al. [106] AMPLE study

Subcutaneous (SC) abatacept 125 mg per weight versus SC adalimumab biweekly in rheumatoid arthritis (RA) patients with inadequate response to methotrexate (MTX)

2 years

Non-inferiority according ACR20 at 1 year

Gabay et al. [108] ADACTA study

Tocilizumab versus ADA monotherapy in RA patients intolerant to MTX or unable to continue MTX

24 weeks

Superiority study. Change in DAS-28 from baseline to week 24

1.78 to 2.76. For ADA versus ETA, the ORs ranging from 1.15 to 1.58 and were significant only for good EULAR response and CDAI remission. At 48 months, withdrawal rates were highest for IFX and lowest for ADA [94]. In the US CORONA registry, the ORs for achieving modified ACR50/70 response (without requirement of acute phase reactants to maximize available patient data) CDAI and DAS-28 remission were similar for ADA, ETA, and IFX [95]. In the Italian LOHREN registry at 6 months the EULAR good response was lower for IFX (23.7%) than for ADA (36.6%) or ETA (32.2%, p < 0.05). Similar outcomes were observed after 24 and 36 months [96]. After 36 months drug survival was significantly higher for ETA 62.5% than IFX 49.1% or ADA 53.6% [97]. Similar outcomes have been also reported for the cohort of Greek patients [98]. In the Dutch DREAM registry, ADA was significantly better as regards DAS-28 course over 12 months than IFX (p < 0.001) and ETA (p = 0.031). The EULAR response and survival rate at 12 months were similar for ADA and ETA but both were significantly better than IFX (p < 0.05) [99]. ETA had better survival rates in the Italian GISEA registry compared with ADA and IFX [100]. However, in the Norwegian NOR-DMARD registry for anti-TNF-a naı¨ve patients there was no difference in the survival rate among the three drugs [101]. A meta-analysis of four randomized trials of the three anti-TNF drugs and their adjusted indirect comparison showed no difference in ACR20 and 50 responses [102]. An indirect comparison among the three anti-TNF agents was presented in a meta-analysis of three randomized controlled studies (duration up to 54 weeks) in established RA. The results implied that ADA was more efficacious compared to ETA, but comparable to IFX in terms of ACR20/50/70 responses. Conversely, ETA was associated with fewer withdrawals due to adverse events compared to ADA [103]. In a retrospective study of RA patients IFX continuation rates over 2 years were significantly lower than ETA and

Findings At 1 year 64.8% in abatacept and 63.4% in adalimumab (ADA) showed ACR20 response. Comparable efficacy between two drugs in response rates, inhibition of radiographic progression, similar safety profile (more local injection site reactions in ADA) Mean change in DAS-28 was significantly greater in tocilizumab (-3.3) versus ADA (-1.8)

ADA [104] although similar discontinuation rates across the three drugs were reported in another retrospective study [105]. Comparison of ADA with other biologic agents A head-to-head 2-year comparison of SC abatacept 125 mg weekly versus 40 mg SC ADA biweekly for RA patients with inadequate response to MTX was undertaken (AMPLE study). The primary end point was treatment noninferiority, assessed according ACR20 at 1 year. Of the 646 patients who were randomized and treated 86.2% receiving SC abatacept and 82% receiving SC ADA completed 12 months of treatment. At 1 year, 64.8% of patients in the SC abatacept and 63.4% in the ADA demonstrated an ACR20 response. SC abatacept and SC ADA have comparable efficacy in patients with RA as shown by similar kinetics of response and comparable inhibition of radiographic progression over 1 year of treatment. The safety was generally similar, other than the occurrence of significantly more local injection site reactions in patients treated with ADA (Table 3) [106]. Year 2 data from this study showed that the improvements in patient-related outcomes, including productivity and independence were maintained up to year 2 with similar onset and durability of response [107]. The ADACTA study is a randomized double-blind, controlled Phase IV superiority study which evaluated tocilizumab monotherapy versus ADA monotherapy in 326 RA patients who were intolerant to MTX or were inappropriate to continued MTX treatments. At week 24 mean change from baseline in DAS-28 was significantly greater in the tocilizumab group (-3.3) than in the ADA group (-1.8) patients (difference -1.5, 95% CI -1.8 to -1.1, p < 0.0001). Of 162 patients, 16 (10%) in the ADA versus 19 (12%) in the tocilizumab group had serious adverse events. More patients in the tocilizumab group than the ADA group had increased low-density lipoprotein cholesterol, and alanine aminotransferase concentrations as well as reduced platelet and neutrophil counts. Thus, tocilizumab monotherapy was superior to ADA monotherapy for reduction of signs 4.2

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and symptoms of RA [108]. In this study, however, the SC dose of 40 mg ADA weekly was not assessed (Table 3).

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5.

Expert opinion

ADA is an effective treatment choice for RA in combination with MTX or other DMARDs or in monotherapy reducing disease activity and inhibiting radiographic progression. It is well tolerated with a safety profile established by following a large number of patients with no new safety signals. Effectiveness, safety, experience, and easy administration make it a valuable tool in the armamentarium for RA treatment. In addition, patients with RA receiving ADA experienced considerably longer periods of work and continuous employment and greater rates of clinical responses than patients treated synthetic with DMARDs [109]. Furthermore, ADA plus MTX reduced job loss and improved productivity in early RA when compared with MTX alone, which supports the early use of anti-TNF therapy and suggests its cost efficacy [110]. Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

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Affiliation Paraskevi V Voulgari1 MD & Alexandros A Drosos†2 MD FACR † Author for correspondence 1 Associate Professor of Rheumatology, University of Ioannina Medical School, Department of Internal Medicine, Rheumatology Clinic, 45110 Ioannina, Greece 2 Professor, University of Ioannina Medical School, Department of Internal Medicine, Rheumatology Clinic, 45110 Ioannina, Greece Tel: +30 26510 07503; Fax: +30 26510 07054; E-mail: [email protected]

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Adalimumab in the treatment of rheumatoid arthritis.

Introduction: Rheumatoid arthritis (RA) is a systemic inflammatory disease that causes increased morbidity and mortality. The treatment of the disease...
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