FormalPara Certolizumab pegol: clinical considerations in inflammatory autoimmune diseases

Selectively binds and neutralizes TNFα

Reduces CD severity, including after infliximab failure

Improves signs/symptoms and slows radiographic progression of RA (with or without methotrexate after DMARD failure, or in combination with methotrexate in DMARD-naïve patients), PsA (after DMARD failure) and axSpA (after NSAID failure)

Provides continued benefit during longer-term therapy

Generally well tolerated

1 Introduction

Inflammatory autoimmune diseases are often chronic and debilitating [1]. Treatment can vary depending on the type and stage of disease, although common key goals are to reduce inflammation and relieve symptoms [2, 3]. Pharmacological treatment options include anti-inflammatory drugs, such as NSAIDs, and immunosuppressive drugs, such as corticosteroids and certain non-steroidal agents [1, 3]. Disease-modifying anti-rheumatic drugs (DMARDs), are pivotal non-steroidal agents in the management of many autoimmune diseases. Unlike the more conventional synthetic DMARDs (csDMARDs) [e.g. methotrexate], which are thought to act via non-specific mechanisms, biological DMARDs (bDMARDs) [e.g. certolizumab pegol, infliximab, adalimumab, golimumab, etanercept] target and inhibit specific inflammatory mediators, such as TNFα. Certolizumab pegol (Cimzia®) is a TNFα antagonist approved for a variety of inflammatory autoimmune diseases, including Crohn’s disease (CD), rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA). This article overviews key pharmacological, therapeutic efficacy and tolerability data relevant to the use of the drug in these indications.

2 Pharmacological Properties

Certolizumab pegol is a PEGylated, recombinant Fab′ fragment of a humanized anti-TNFα monoclonal antibody that binds selectively and with high affinity to TNFα, neutralizing both soluble and membrane-bound TNFα [4, 5]. Unlike other anti-TNF agents, certolizumab pegol lacks an IgG fragment crystalizable (Fc) region and, consequently, does not mediate complement-dependent or antibody-dependent cell-mediated cytotoxicity (CDC and ADCC) in vitro [6]. Another difference of certolizumab pegol is that it does not induce degranulation of granulocytes or apoptosis of peripheral blood lymphocytes or monocytes in vitro [6], but appears to induce non-apoptotic cell death [7]. Antibodies against certolizumab pegol were detected at least once in 4.4–11.7 % of patients with CD, RA, PsA or axSpA in placebo-controlled trials, and 23 and 13 % of CD and RA patients in open-label studies of up to 7 and 5 years’ duration, respectively [4, 5]. The antibodies may reduce the drug’s efficacy in some patients (Sect. 3), but do not appear to impact its tolerability, and may occur with a lower incidence in patients receiving concomitant immunosuppressants [4, 8].

Certolizumab pegol concentrations in plasma are largely proportional to dose [4, 5]. The drug reaches maximum plasma concentrations 54–171 h after subcutaneous injection, has an absolute bioavailability of ≈80 % [4, 5] and an estimated volume of distribution at steady state of 6–8 L [4]. Its Fab′ fragment undergoes proteolysis to peptides and amino acids and the free PEG moiety is eliminated quickly, possibly via the urine [4, 5]. Certolizumab pegol has a long terminal elimination half-life of ≈14 days [4]. Factors that may impact the drug’s pharmacokinetics include bodyweight (which is inversely related to drug exposure) and anti-certolizumab antibodies (which increase the drug’s clearance 3.6-fold) [4].

3 Therapeutic Efficacy

This section overviews the efficacy of subcutaneous certolizumab pegol in treating various inflammatory autoimmune diseases, with discussion focusing on clinical trials with >500 participants when possible. Where stated, certolizumab pegol induction refers to certolizumab pegol 400 mg administered at weeks 0, 2 and 4. In addition to regular clinical efficacy tools, various standard instruments were used across the studies to assess patient-reported outcomes (PROs) such as health-related quality of life (HR-QOL) [e.g. SF-36, EQ-5D], physical function (HAQ-DI), pain (e.g. VAS, NRS), fatigue (e.g. FAS, NRS) and sleep (MOS-SPI); indication-specific instruments were also used in some studies in patients with CD (WPAI-CD for workplace/home productivity; IBDQ for HR-QOL), RA (WPS-RA for workplace/home productivity), PsA (PsA-QOL and DLQI for HR-QOL) or axSpA (AS-QOL for HR-QOL).

3.1 Crohn’s Disease

Certolizumab pegol is an effective induction and maintenance treatment for adults with moderate to severe CD, including those with secondary failure to infliximab, according to three 26-week phase III studies (PRECISE 1 and 2; WELCOME) and their extensions (PRECISE 3 and 4; WELCOME 2). Generally, a response was defined as a decrease from baseline in CDAI score of ≥100 points and remission as a CDAI score of ≤150, although longer-term studies defined response as a reduction from baseline in HBI score of ≥3 [9] and remission as a HBI score of ≤4 [9, 10].

3.1.1 PRECISE 1 and 2

In PRECISE 1, patients were randomized to receive double-blind induction with certolizumab pegol 400 mg (n = 331) or placebo (n = 329), after which the respective groups received certolizumab pegol 400 mg or placebo every 4 weeks (q4w) to week 24 (i.e. maintenance), with follow-up to week 26 [11]. Induction and maintenance with certolizumab pegol reduced CD severity, being associated with significantly higher response rates than placebo at week 6 (37 vs. 26 %; p = 0.04) and at both weeks 6 and 26 combined (22 vs. 12 %; p = 0.05) in the 298–299 evaluable patients with baseline CRP ≥10 mg/L (coprimary endpoints) [11]. Similar benefit was seen with the drug versus placebo for these measures in the overall patient population (n = 650–652) (35 vs. 27 % at week 6, and 23 vs. 16 % at weeks 6 and 26 combined; each p = 0.02) [11]. Remission rates did not significantly differ between certolizumab pegol and placebo, at week 6 or weeks 6 and 26 combined, in either the CRP ≥10 mg/L subgroup or overall population, but significantly favoured certolizumab pegol at week 4 (19 vs. 11 %) and 26 (29 vs. 18 %) [11].

Unlike PRECISE 1, PRECISE 2 specifically assessed the efficacy of certolizumab pegol maintenance therapy following successful induction [12]. Patients (n = 668) received certolizumab pegol induction, with only those in response at week 6 being randomized to receive double-blind certolizumab pegol 400 mg (n = 216) or placebo (n = 212) q4w over weeks 8–24 (maintenance). Certolizumab pegol was effective in maintaining clinical responses achieved with induction in this study, with the 26-week response rate being significantly (p < 0.001) higher with the drug than placebo among the 6-week responders whose baseline CRP was ≥10 mg/L (n = 213; 62 vs. 34 %) [primary endpoint], as well as in the overall 6-week responder population (63 vs. 36 %) [12]. Testing positive for anti-certolizumab pegol antibodies (17 drug recipients) did not appear to negatively impact these response rates [12]. At week 26, significantly (p ≤ 0.01) more certolizumab pegol than placebo recipients were in remission in both the CRP ≥10 mg/L subgroup (42 vs. 26 %) and the overall population (48 vs. 29 %) [12].

In PRECISE 1 [11] and 2 [12, 13], response and/or remission benefits were seen with certolizumab pegol versus placebo, regardless of whether patients were infliximab naïve or experienced, with the between-treatment difference reaching significance (p < 0.05) in each of these subgroups in PRECISE 2 [12, 13] but in only the infliximab-naïve subgroup in PRECISE 1 [11]. Moreover, certolizumab pegol outcomes in PRECISE 2 appeared better the earlier the drug was initiated after a CD diagnosis [14]. Certolizumab pegol may also be beneficial in fistulizing CD, as significantly more responders with draining fistulas at week 6 in this trial (n = 58) achieved full fistula closure at 26 weeks with certolizumab pegol than with placebo (36 vs. 17 %; p = 0.038), although protocol-defined fistula closure (i.e. ≥50 % closure at two consecutive visits ≥3 weeks apart) did not significantly differ between the two groups [15]. Relative to placebo, certolizumab pegol was associated with clinically and statistically (p < 0.05) significant improvements in various measures of HR-QOL [16], and also significantly (p < 0.05) improved daily activity participation and most measures of work productivity [17].

3.1.2 PRECISE 3 and 4

PRECISE 1 or 2 completers were eligible for PRECISE 3, an open-label extension evaluating up to 7 years’ total treatment with certolizumab pegol 400 mg q4w (without additional induction) [10, 18]. According to the latest PRECISE 3 data (n = 595) [10], more than half of all recipients were in remission over the 7-year period, according to observed case (OC) [55 and 76 % at week 0 and year 7] and last-observation-carried-forward (LOCF) [58, 56 and 55 % at years 1, 3 and 7, respectively] analyses, but not analyses using non-remitter imputation (NRI) [45, 26 and 13 % at years 1, 3 and 7]. In each analysis, remission rates were generally numerically lower in patients receiving certolizumab pegol for the first time in PRECISE 3 (i.e. PRECISE 1 placebo recipients; n = 166) than in patients being re-exposed to the drug (i.e. certolizumab pegol induction then placebo maintenance in PRECISE 2; n = 100) or continuing certolizumab pegol (i.e. certolizumab pegol throughout PRECISE 1 or 2; n = 329) [e.g. 41 vs. 64 and 56 % at 7 years using LOCF] [10].

PRECISE 4 is an open-label extension in which patients who relapsed during PRECISE 1 or 2 received certolizumab pegol induction/re-induction then 400 mg q4w maintenance for up to 360 weeks (i.e. ≈7 years) [9, 19]. In the latest analysis [19], at weeks 52, 156 and 362 (when 47, 23 and 8 % of the 310 patients enrolled remained on therapy), respective overall remission rates were 64, 64 and 85 % using OC cases analysis and 29, 13 and 6 % using NRI (some data estimated from a graph). Thus, some patients who discontinue certolizumab pegol owing to lack/loss of response may benefit from re-induction and maintenance with the drug. However, patients exposed to certolizumab pegol for the first time in this extension had a significantly (p < 0.01) longer mean time to remission loss than those who received re-induction with the drug [19].

3.1.3 WELCOME

In WELCOME, switching to certolizumab pegol provided clinical benefit in CD after loss of response to/intolerance of infliximab [20], supporting the PRECISE 2 subgroup findings (Sect. 3.1.1). WELCOME had an open-label certolizumab pegol induction phase (n = 539), with the patients responding at week 6 then randomized to receive double-blind certolizumab pegol maintenance at 400 mg q2w (n = 161) or q4w (n = 168) through to week 26 [20].

At week 6 (i.e. after induction), a large proportion of patients were in response (62.0 %) [primary endpoint] and 39.3 % were in remission. Among those randomized to maintenance with certolizumab pegol 400 mg q2w or q4w, rates of response (36.6 vs. 39.9 %) and remission (30.4 vs. 29.2 %) at week 26 did not significantly differ between the dosage regimens [20]. Moreover, most patients who relapsed during double-blind maintenance treatment with certolizumab pegol 400 mg q4w (n = 53) or q2w (n = 40) regained their response when treated with open-label certolizumab pegol 400 mg q2w (69.8 and 72.5 %) [20]. Recipients of certolizumab pegol induction and maintenance therapy experienced significant (p < 0.05 vs. baseline) improvements in work productivity and daily activity participation, as well as clinically meaningful improvements in HR-QOL [21]. Longer-term benefit of certolizumab pegol 400 mg q2w or q4w was evident in the open-label extension (WELCOME 2), with 61.8 % of the 166 patients in response with either dosage at the start of the extension remaining in response with continued therapy up to the last visit (week 154 or premature withdrawal) [22].

3.2 Rheumatoid Arthritis

In DMARD-naïve adults with a diagnosis of moderate-to-severe active RA within the last year, using certolizumab pegol in combination with dose-optimized methotrexate was an effective treatment strategy in the 52-week, randomized, double-blind, C-EARLY study [23]. Significantly (p < 0.001) more recipients of certolizumab pegol (induction, then 200 mg q2w) plus methotrexate (n = 655) than of placebo plus methotrexate (n = 213) achieved sustained disease remission (DAS28-ESR <2.6 at both week 40 and 52; primary endpoint) [28.9 vs. 15.0 %] or sustained low disease activity (DAS28-ESR ≤3.2 at both week 40 and 52) [43.8 vs. 28.6 %] [23]. The certolizumab pegol regimen also significantly (p ≤ 0.001) inhibited the progression of radiographic joint damage (assessed by mTSS, erosion score and joint-space narrowing) and significantly (p < 0.05) improved measures of physical functioning, pain and some aspects of HR-QOL, compared with the placebo regimen [23, 24].

Similarly, in adults with moderate to severe RA despite ≥6 months of methotrexate, adding certolizumab pegol to the methotrexate regimen improved the clinical signs and symptoms of RA in the randomized, double-blind, RAPID-1 [25] and -2 [26] trials. Significantly more certolizumab pegol than placebo recipients achieved an ACR20 (primary endpoint), ACR50 or ACR70 response over 24 weeks, regardless of the certolizumab pegol regimen (induction, then 200 mg q2w or 400 mg q2w) [25, 26], and this benefit was maintained up to 52 weeks [25] (Table 1). Certolizumab pegol plus methotrexate also significantly (p ≤ 0.01 vs. placebo) improved disease activity (DAS28-ESR) [25, 26], slowed radiographic measures of joint damage progression, including mTSS (a coprimary endpoint of RAPID-1 at 52 weeks [25]; Table 1) [25, 26], and improved physical function [27, 28], pain [27, 28], fatigue [27, 28], and all/most measures of HR-QOL [27, 28] and workplace/home productivity [29] over 24 and/or 52 weeks. Notably, pooled data from these trials indicate that the productivity improvements with certolizumab pegol plus methotrexate may be associated with clinically meaningful improvements in physical function, pain and fatigue [30], and that the efficacy of the regimen is not influenced by the methotrexate dosage (prespecified analysis) [31].

Table 1 Efficacy of subcutaneous certolizumab pegol in previously-treated adults with moderate to severe rheumatoid arthritis in large double-blind trials
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Longer term, certolizumab pegol plus methotrexate sustained improvements in RA signs and symptoms over up to 4.5 [32] or 5 [33] years of treatment, and continued to inhibit radiographic progression of joint damage over 2 years of therapy (last assessment) [32, 34], in the open-label extensions of RAPID-1 [33, 34] and -2 [32]. In these extensions, patients received certolizumab pegol 400 mg q2w plus methotrexate, with a reduction to 200 mg q2w plus methotrexate after ≥ 6 months in the RAPID-2 extension. According to post hoc analyses of RAPID-1, the likelihood of achieving low disease activity at 1 year is low if disease activity does not improve in the first 12 weeks of receiving certolizumab pegol plus methotrexate, with long-term outcomes appearing more favourable when clinical responses are achieved more rapidly and are of greater magnitude [35, 36].

In the randomized, double-blind, FAST4WARD trial, monotherapy with certolizumab pegol 400 mg q4w improved the clinical signs and symptoms of moderate to severe active RA in adults who had failed ≥1 DMARD [37]. Recipients of the drug had significantly (p < 0.05) greater ACR20 (primary endpoint), ACR50 and ACR70 response rates (Table 1) and improvements in disease activity (measured by DAS28-ESR) compared with placebo recipients after 24 weeks of therapy [37], although patients with anti-certolizumab pegol antibodies had a 1.7-fold lower ACR20 response rate than those who tested negative [4]. Certolizumab pegol also significantly (p < 0.001) improved measures of HR-QOL, physical function, arthritis pain and fatigue relative to placebo over 24 weeks [37]. Continued improvements in disease activity (DAS28-CRP) were seen among the 48 FAST4WARD participants who received certolizumab pegol monotherapy for over ≈5 years in an extension study [38], with these patients also reporting better productivity in the home and participation in activities [39].

3.3 Psoriatic Arthritis

The clinical signs and symptoms of PsA in adults who had failed ≥1 prior DMARD improved with certolizumab pegol (induction, then 200 mg q2w or 400 mg q4w) in the randomized RAPID-PsA study. Over 12 and 24 weeks of double-blind treatment, significantly more recipients of the drug than of placebo achieved an ACR20 (coprimary endpoint at 12 weeks), ACR50 or ACR70 response (Table 2), with the drug providing benefit regardless of concomitant DMARD use or prior TNFα antagonist therapy (post hoc analyses) [40]. Radiographic progression of structural damage slowed with certolizumab pegol over 24 weeks, as measured by changes in mTSS [coprimary endpoint] [41]. The mean change from baseline in mTSS did not significantly differ between certolizumab pegol regimens and placebo when prespecified imputation methodology was used (due to overestimation of progression) [18.3 for the two certolizumab pegol regimens combined vs. 28.9], although more appropriate imputation methods (assessed post hoc) generally demonstrated significantly (p < 0.05) less worsening of mTSS with certolizumab pegol than placebo [41].

Table 2 Efficacy of subcutaneous certolizumab pegol in adults with psoriatic arthritis [40] or axial spondyloarthritis [45] in large double-blind trials
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Certolizumab pegol also significantly improved enthesitis (assessed by LEI), dactylitis (LDI) and nail involvement (mNAPSI) over 24 weeks (all p ≤ 0.003 vs. placebo), as well as measures of psoriatic skin lesion burden (PAS175 and PAS190) [nominal p < 0.005 vs. placebo] [40]. HR-QOL and other PROs, including physical function, pain, fatigue and some measures of workplace/home productivity and activity participation, also improved significantly (p < 0.05) with certolizumab pegol over this period [42, 43].

Longer-term data [from the subsequent dose-blind phase of this trial (weeks 24–48) and the initial 48 weeks of the open-label extension that followed] indicate that responses to certolizumab pegol were maintained over 96 weeks’ therapy, regardless of dosage (200 mg q2w or 400 mg q4w) (Table 2), or prior TNFα antagonist use [44]. Radiographic progression of structural damage did not change to any clinically relevant extent in this time, with mean changes from baseline in mTSS of 0.10 and 0.19 with certolizumab pegol 200 mg q2w or 400 mg q4w (14.0 and 18.1 at baseline) [44]. Improvements in other measures (including enthesitis, dactylitis, nail and skin involvement, HR-QOL, physical function, pain and fatigue) were similarly maintained [44].

3.4 Axial Spondyloarthritis

In the randomized, double-blind, RAPID-axSpA trial conducted in adults with axSpA (including ankylosing spondylitis and non-radiographic axSpA) with prior inadequate response to, or intolerance of, ≥1 NSAID, certolizumab pegol (induction, then 200 mg q2w or 400 mg q4w) improved the clinical signs/symptoms of the disease [45]. Significantly more patients in the certolizumab pegol groups than the placebo group achieved ASAS20 (primary endpoint), ASAS40 or ASAS5/6 responses over 12 weeks’ therapy, with these benefits maintained up to 24 weeks (Table 2) [45, 46]. Disease activity measures (ASDAS and BASDAI) also significantly (p < 0.001) improved with certolizumab pegol versus placebo at these timepoints [45].

Measures of spinal and sacroiliac joint inflammation (ASspiMRI-a Berlin Modification; SPARCC SIJ) in patients who underwent MRI assessment (n = 153) improved significantly (p ≤ 0.001) with certolizumab pegol versus placebo over 12 weeks [47]. Moreover, at 24 weeks, extra-spinal joint inflammation and enthesitis markedly improved with the drug (no statistical analyses conducted) [48], and certolizumab pegol recipients reported significant (p < 0.001 vs. placebo) improvements in spinal mobility (BASMI-linear) [45], spinal function (BASFI) [45] and various other PROs (including pain, fatigue, sleep and HR-QOL) [49], with clinically meaningful PRO improvements and clinical responses being associated with improved work/home productivity [50].

Certolizumab pegol generally provided clinical and PRO benefits regardless of whether patients had ankylosing spondylitis or non-radiographic axSpA [45, 47–49]. Moreover, in a post hoc analysis, the drug was associated with a threefold lower likelihood of comorbid uveitis flares relative to placebo over 24 weeks [3 vs. 10 per 100 patient-years (PY); no statistical analyses performed] [51].

The dose-blind period (weeks 24–48) and subsequent open-label period (weeks 48–204) of RAPID-axSpA demonstrated sustained benefit with longer-term certolizumab pegol use [51–54]. For instance, over 96 weeks of therapy, ASAS response rates (Table 2) and improvements in disease activity, enthesitis, joint inflammation/pain, spinal mobility/function and work/home productivity, were maintained with the drug (regardless of axSpA type) [52, 55, 56], and 58–93 % of recipients were in both clinical and MRI-assessed remission (at the spine and/or sacroiliac joints) [57]. Radiographic progression at the spine was also limited during this period [54]. The efficacy of certolizumab pegol was generally maintained for up to 204 weeks of therapy, with the ASAS20 and ASAS40 response rates being 54 and 44 % at this timepoint (pooled dosages; NRI analysis) [53].

4 Tolerability

Certolizumab pegol regimens are generally well tolerated across all approved indications, with upper respiratory tract infections, rash and urinary tract infections being the most frequent adverse reactions in a pooled analysis of controlled trials (18, 9 and 8 % incidence, respectively) [4]. As its tolerability profile is consistent across the approved arthritic indications [4, 5], discussion in this setting focuses on RA, for which there is a wealth of data.

In a pooled analysis of randomized RA trials, the tolerability profile of certolizumab pegol (n = 2965; total exposure 1302 PY) was generally similar to that of placebo (n = 1137; total exposure 373 PY) in terms of the incidence rate (IR) of adverse events (AEs) [336 vs. 362 per 100 PY] and serious AEs (21 vs. 17 per 100 PY), when used as monotherapy or in combination with other DMARDs [58]. Moreover, there was no increase in the IR of these AEs during longer-term treatment with the drug (n = 4049; total exposure 9277 PY) when uncontrolled/open-label extension data were included [58]. AEs (the most common being ‘infections and infestations’) were usually mild or moderate in severity with certolizumab pegol and occurred mainly in the first 3 months of therapy, with pneumonia being the most common serious AE in both the randomized trials [event rate 0.77 vs. 0.54 per 100 PY with placebo) and the longer-term analysis (0.77 per 100 PY) [58]. The fatal AE IR was threefold greater with certolizumab pegol than placebo (0.84 and 0.27 per 100 PY), and 0.63 per 100 PY with the drug in the longer-term analysis; fatal AEs were mainly cardiovascular events, malignancies or infections [58].

Similarly, in a pooled analysis of randomized CD trials, the AE and serious AE IRs were 514 and 31 per 100 PY with certolizumab pegol (n = 919; total exposure 299 PY) and 561 and 24 per 100 PY with placebo (n = 875; total exposure 262 PY), and did not increase with the drug in the longer term when open-label studies were included (n = 2570; total exposure 4378 PY) [59]. The most common serious AE with certolizumab pegol in this setting was gastrointestinal inflammatory disorders (IR 7.1 vs. 8.1 per 100 PY with placebo; 6.5 per 100 PY across all studies). The death rate due to AEs with certolizumab pegol was consistent with that of CD in general (IR 0.3 vs. 0.4 per 100 PY with placebo; 0.2 per 100 PY across all studies) [59].

4.1 Infections

New infections occurred with an IR of 1.03 per PY with certolizumab pegol versus 0.92 per PY with placebo in RA trials, the most frequent of which were of the upper and lower respiratory tract, urinary tract, or due to herpes virus [5]. The risk of serious infections is increased with certolizumab pegol, particularly when used in combination with other immunosuppressants, with the US prescribing information (PI) carrying a boxed warning to this effect [4]. Indeed, in pooled analyses of randomized trials, the serious infection IR with certolizumab pegol was approximately fourfold higher than with placebo in RA (5.61 vs. 1.35 per 100 PY) [58] and 1.6-fold higher than with placebo in CD (8.5 vs. 5.4 per 100 PY) [59]. However, the IR of serious infections did not increase with prolonged certolizumab pegol exposure across all RA (3.65 per 100 PY) [58] or CD (6.5 per 100 PY) [59] studies. Where specified, the most common serious infection with certolizumab pegol was pneumonia (see earlier discussion) [58]. Factors significantly (p < 0.05) associated with the development of serious infections with certolizumab pegol include being aged ≥65 years or having a disease flare, worsening disability or a treated comorbidity, according to pooled RA trial data (n = 1506) [60].

New/reactivated tuberculosis (TB) is a serious infection that has occurred with certolizumab pegol [4, 58, 59]. For instance, in clinical trials across all indications (n = 5118), TB occurred at an overall rate of ≈0.61 per 100 PY with the drug, with countries with high endemic TB rates experiencing the most cases [4]. Infections due to other pathogenic organisms have also occurred with certolizumab pegol [4], with the most common being bronchopulmonary aspergillosis and oesophageal candidiasis both in randomized RA trials (respective event rates: 0.23 and 0.15 per 100 PY vs. none with placebo) and when open-label RA studies were included (0.03 and 0.08 per 100 PY with certolizumab pegol) [58]. Reactivation of hepatitis B virus infection has also been reported in certolizumab pegol recipients [4, 5]. Consult local PI for warnings and precautions relating to infections (e.g. patient monitoring, drug discontinuation and treatments).

4.2 Other Adverse Events

Malignancies have occurred with TNF antagonists, including certolizumab pegol [4, 5, 58, 59, 61]. For instance, the malignancy rate (exclusive of non-melanoma skin cancers) across controlled and open-label periods of trials in CD and other conditions was 0.5 per 100 PY with certolizumab pegol (n = 4650) and 0.6 per 100 PY with placebo (n = 1319), suggesting no increased malignancy risk with the drug; however, interpretation of these data require consideration of the small size of the placebo group and limited duration of the comparative trials [4]. Certolizumab pegol did not increase the neoplasm risk in patients aged ≤30 years versus patients aged >30 to ≤64 years in pooled analyses of CD trials (n = 902 and 2514) [61]. However, malignancies have been fatal in children, adolescents and young adults who began TNF antagonist therapy when aged ≤18 years, with this information featuring in a boxed warning in the certolizumab pegol US PI [4].

Cases of congestive heart failure have occurred with certolizumab pegol in RA trials [4], and consequently, the drug is contraindicated or requires cautious use in heart failure settings [4, 5]; major adverse cardiovascular events occurred with an event rate of 0.82 per 100 PY with certolizumab pegol in pooled RA trials [58]. Haematological AEs (including clinically significant cytopenia) and symptoms consistent with hypersensitivity reactions (e.g. angioedema, rash, dyspnoea) have been infrequently reported with certolizumab pegol [4, 5]. Autoantibodies may develop with certolizumab pegol therapy [4, 5], although few recipients have developed symptoms of lupus-like syndrome in CD (1 of 1564 patients) or RA (4 of 2367 patients) studies [4]. Neurological disorders also appear to be rare with certolizumab pegol [4, 5]; however, it is not yet known if long-term treatment with the drug affects autoimmune disease development.

5 Dosage and Administration

For all indications (Table 3), the recommended starting regimen in the USA [4] and EU [5] is certolizumab pegol 400 mg (as two 200 mg injections) at 0, 2 and 4 weeks. This is followed by a maintenance dosage of 200 mg q2w for RA and PsA (400 mg q4w can be considered) [4, 5], 200 mg q2w or 400 mg q4w for SpA [4, 5] and 400 mg q4w for CD [4]. The drug may be taken as monotherapy or in combination with non-biological DMARDs, such as methotrexate, depending on the indication and/or region of approval (Table 3) [4, 5]. Certolizumab pegol is not indicated for paediatric use [4, 5] and, being a pregnancy category B drug [4], is not recommended during pregnancy in the EU [5]. Consult local PI for further details, including warnings and other precautions.

Table 3 Certolizumab pegol indications approved in the EU and USA
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6 Place of Certolizumab Pegol in Disease Management

Although the recommended options and sequences of treatment vary among the autoimmune diseases, bDMARDs are common key management tools. For instance, current treatment guidelines recommend bDMARDs (generally TNF inhibitors) for PsA that has responded inadequately to ≥1 csDMARD [62], TNF inhibitors for highly active SpA that persists despite conventional therapies (e.g. NSAIDs, analgesics) [63] and bDMARDs (specifically TNF inhibitors, abatacept, tocilizumab or rituximab) plus methotrexate for RA that has not responded adequately to csDMARDs [64]. Similarly, in moderate to severe CD, it is strongly recommended that TNF inhibitors (alone or with thiopurines) are used to induce remission, and TNF inhibitors and thiopurines are used for remission maintenance [65].

bDMARDs vary in composition and mechanism of action, with some targeting the actions of certain proinflammatory cytokines and others the actions of particular immune cells (Table 4). The first bDMARDs introduced were those targeting TNFα, of which certolizumab pegol is a relatively recent example. Certolizumab pegol is a subcutaneously administered Fab′ fragment of a humanized anti-TNFα antibody conjugated to a PEG moiety (Sect. 2). Unlike other antibody-based DMARDs, it does not contain an Fc region and therefore does not induce ADCC or CDC (Sect. 2), potentially lowering the risk of intracellular infections. Although Fab′ fragments are usually excreted more rapidly than whole antibodies, PEGylation of certolizumab increases the elimination half-life of the drug to that of an intact antibody (i.e. ≈14 days; Sect. 2), enabling q2w or q4w administration, which is less frequent (and potentially more convenient) than that of some other subcutaneous bDMARDs (including once-daily anakinra and once/twice-weekly etanercept). All subcutaneous bDMARDs can be self-injected, which may confer an advantage in terms of adherence, as many patients appear to prefer subcutaneous over intravenous/intramuscular administration and being treated at home rather than in the hospital [66].

Table 4 Biological DMARDs currently available for inflammatory autoimmune diseases
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Certolizumab pegol is indicated for the treatment of a range of inflammatory autoimmune diseases, including CD, RA, PsA and axSpA, based on its benefit in these settings in well-designed clinical trials (Sect. 3), and is generally well tolerated (Sect. 4). However, as bDMARDs act via immune modulation, there are concerns that serious infections and malignancies may develop with these therapies [67]. The risk of serious infections is increased with certolizumab pegol, although does not appear to increase further with prolonged exposure to the drug (Sect. 4.1). Moreover, current data suggest that certolizumab pegol does not increase malignancy risk (Sect. 4.2), although further longer-term trials and clinical experience would be beneficial.

Immunogenicity is also an important aspect of bDMARDs, as antibodies that develop against these agents could potentially impact their efficacy and/or tolerability [68]. PEGylation has the potential to reduce protein immunogenicity, although the possibility of immune responses developing against the PEG moiety itself is recognized [69]. Anti-certolizumab pegol antibodies were detected in some recipients of the drug across approved indications (Sect. 2), and although these antibodies reduced the drug’s efficacy in some patients (Sect. 3), unlike some TNFα inhibitors (e.g. infliximab, adalimumab [68]), they were not associated with any tolerability issues. Using TNF inhibitors like certolizumab pegol in combination with csDMARDs may lessen anti-drug antibody development [70].

In conclusion, subcutaneous certolizumab pegol is an effective and generally well tolerated option for the treatment of CD, RA, PsA or axSpA in adults.

Data selection sources:

Database(s): EMBASE, MEDLINE and PubMed from 1946 to present. Clinical trial registries/databases and websites were also searched for relevant data [searches last updated 16 September 2016]. Records were limited to those in English language.

Search terms: Certolizumab pegol, CDP-870, Cimzia, PHA-738144, Simziya, Crohn, rheumatoid arthritis.