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DOI: 10.1111/jdv.12549

REVIEW ARTICLE

Clinical relevance of immunogenicity of biologics in psoriasis: Implications for treatment strategies J.-M. Carrascosa,1,* M.B.A. van Doorn,2 M. Lahfa,3 F.O. Nestle,4 D. Jullien,5,6 J.C. Prinz7 1

Department of Dermatology, Hospital Universitari Germans Trias i Pujol, Barcelona,Spain Department of Dermatology, Erasmus MC University Medical Centre, Rotterdam, The Netherlands 3 ^pital Larrey, Toulouse, France Department of Dermatology, Ho 4 St. John’s Institute of Dermatology, King’s College London School of Medicine, London, UK 5 Faculty of medicine, University of Lyon, Lyon, France 6 ^pital Edouard Herriot, Lyon, France Department of Dermatology, Ho 7 Clinic for Dermatology and Allergology, Ludwig-Maximilians-University, Munich, Germany *Correspondence: J.-M. Carrascosa. E-mail: [email protected] 2

Abstract Biological drugs such as the tumour necrosis factor inhibitors have revolutionized the treatment of psoriasis, but some have the potential to induce an unwanted immune response. This immunogenicity may be associated with low trough drug levels, reduced clinical efficacy, reduced drug survival and an increased risk for adverse events. This article presents a literature review of the evidence on immunogenicity of biologics used in the treatment of psoriasis and considers the implications for therapeutic decision-making in the management of patients with moderate-to-severe psoriasis. Received: 27 November 2013; Accepted: 10 April 2014

Conflicts of Interest JM Carrascosa has been both a member of an advisory board and speaker for AbbVie, Janssen, MSD, Novartis and Pfizer, and acted as an investigator for AbbVie, Amgen, Eli Lilly, Janssen, MSD, Novartis and Pfizer. M van Doorn has acted as a consultant for Abbott, Janssen, LEO Pharma and Pfizer, and has been an investigator for Eli Lilly, Idera Pharmaceuticals and Novartis. D Jullien has been both a member of an advisory board and consultant for Abbott, Eli Lilly, Janssen, MSD, Novartis and Pfizer, and has also been a speaker for Abbott, Janssen, MSD and Pfizer. F Nestle has acted as a consultant for Abbott, AbbVie, Celgene, Janssen, Novartis and Pfizer. J Prinz has been a speaker for Biogen-Idec, MSD, Novartis, Pfizer, Serono and Wyeth, on an advisory board for Novartis, Pfizer and Serono and acted as an investigator for Centocor and Serono.

Funding sources This manuscript was developed by an unrestricted grant from Pfizer Inc. Medical writing support was provided by Synergy Medical.

Introduction to immunogenicity and its relevance for psoriasis clinical management Biological drugs have revolutionized the treatment of chronic inflammatory diseases over the past decade.1 Biologics – therapeutic products made by biotechnology processes – have become the gold standard for the treatment of moderate-to-severe psoriasis in terms of efficacy, safety and quality of life for patients who have failed or have contraindications for traditional systemic treatments.2 However, biologics have the potential to induce an unwanted immune response in the patient (i.e. immunogenicity).3 Humoural immune responses represent the formation of antibodies against a specific antigen.3 Immunogenicity is influenced by various factors, including the molecular structure

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of the drug, treatment regimen and patient characteristics.4 Loss of clinical response to some tumour necrosis factor inhibitors (TNFi) has been shown to be associated with low drug trough levels (the drug concentration measured just before the next dose) and presence of antibodies directed against the drugs.5,6 Infusion reactions, serum sickness and anaphylactic reactions also occasionally occur, particularly with infliximab.7 A systematic review of the evidence on immunogenicity of biologics used to treat psoriasis was conducted by searching PubMed using the terms ‘psoriasis’ plus ‘immunogenicity’ plus the drug name, then again replacing ‘immunogenicity’ with ‘antibodies’. No exclusions were placed on date of publication. Abstracts of articles were scanned for any mention of

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immunogenicity data from psoriasis patients, and appropriate articles collated. Reference lists of other papers examining immunogenicity in psoriasis were also scanned for potentially relevant articles. This article presents the results of this systematic review and considers implications for therapeutic decisionmaking in the management of patients with moderate-to-severe psoriasis.

Antidrug antibodies (ADAs) Potential mechanisms of immunogenicity of biologics proposed in psoriasis

A key determinant of the potential immunogenicity of a drug is its molecular structure. The first therapeutic antibodies were of mouse origin and were highly immunogenic as they represent xenogeneic proteins. Replacement of murine constant regions with human ones resulted in chimeric antibodies such as infliximab, which are less immunogenic but can still induce the formation of human antichimeric antibodies. Humanization of the variable regions further reduced the immunogenic potential, but even fully human antibodies (such as adalimumab and ustekinumab) may lead to the production of human anti-human (drug) antibodies.3 Antibody formation against human therapeutic antibodies is usually directed against the idiotype (the portion of the variable region of the antibody molecule that confers antigenic specificity) rather than the allotype (inherited variant portion of the Fc fragment), as antibodies directed against TNF, IL17F, p40 or p19 subunits do not occur naturally. Antiidiotypic antibodies directed against the TNF-binding portion of TNFi may compete with TNF binding and lead to neutralization of the drug effects.8 A recent study demonstrated that the immune response against adalimumab is limited to the idiotype, with all (polyclonal) ADAs resulting in functional neutralization of the drug.9 Unlike the monoclonal antibody (mAb)-based TNFi, etanercept is a fusion protein made up of the extracellular domain of the p75 TNF receptor (CD120b) and the hinge and Fc domains of human IgG1, therefore binding the targeted cytokine through a structure that belongs to self.10 The potential immunogenicity of fusion proteins such as etanercept depends on their similarity to native proteins; the fusion part of these molecules may contain human neo-epitopes recognized as foreign by the immune system.3,8 ADAs against etanercept appear to be non-neutralizing, as they do not affect the TNF-binding site of the molecule. However, both neutralizing and non-neutralizing ADAs generate an immune complex that may favour increased clearance, with a potential impact on efficacy and safety.3 Clinical significance of antidrug antibodies

Neutralizing ADAs to mAb biologics may reduce therapeutic activity in two ways: by blocking the binding site and by increasing drug clearance due to the formation of immune complexes

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with a relatively short half-life.3 Neutralizing ADAs have been shown to develop in patients treated with the TNF inhibitors infliximab and adalimumab. In rheumatoid arthritis (RA) and spondyloarthritis, development of ADAs in 19–26% of patients treated with infliximab has been shown to be associated with low trough drug levels during the initiation period, poor clinical response, increased infusion reactions and a greater likelihood of drug discontinuation.11,12 Similarly, development of ADAs against adalimumab in 28% of RA patients was associated with lower drug concentrations and a lower likelihood of minimal disease activity or clinical remission.6 While the incidence of ADAs against the anti-IL12/23p40 mAb ustekinumab appears low (5%),13 psoriasis patients with antibodies tended to have lower serum drug concentrations and lower efficacy.14 ADAs have been detected in as many as 18% of etanercept-treated psoriasis patients, but these have been shown to be non-neutralizing and to have no effect on clinical efficacy.15 Neutralizing ADAs to infliximab may increase the incidence of infusion reactions through the formation of large immune complexes.16 Injection-site reactions can also occur with etanercept, but these are believed to be due to T-lymphocyte-mediated delayed-type hypersensitivity reactions.17 Other reactions may include immediate-type reactions (IgE mediated) that can be diagnosed using skin prick testing and may respond to subcutaneous desensitization.18 Rarely, Arthus-like reactions may occur.19 What influences the development of ADAs?

Intramuscular and subcutaneous routes have been shown to be more immunogenic than intravenous administration.20 Dosage and total amount of drug may both affect immunogenicity, and length of treatment is also important.4 Products given continuously are usually less immunogenic than those given intermittently.20 Patient-related factors may include genetics, age, disease-related factors including other treatments and previous exposure to similar proteins.20 Concomitant methotrexate appears to be efficient in reducing immunogenicity in a dosedependent manner in RA patients treated with adalimumab.21 How are ADAs measured?

Many studies have used standard ELISAs to measure ADA levels.22 However, while sensitive, these are not very specific and are prone to false-positive results and non-specific binding.1 More recently, two alternative types of assay have been widely used. The two-site (bridging) ELISA is highly specific and sensitive, but it is very susceptible to interference by drug present in the patient’s serum that results in immune complex formation.3 The radioimmunoassay antigen binding test has a low background and can detect clinically relevant antibodies, but the use of radioactivity is a disadvantage.3 Whereas the bridging ELISA can only detect ADAs in the absence of detectable amounts of circulating drug, the radioimmunoassay is less susceptible to drug interference.23

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Other approaches include a reporter-gene assay24 and a pH-shift-anti-idiotype antigen binding test.25 The latter involves dissociation of immune complexes and blocking of their refformation, enabling detection of ADAs even in the presence of a large excess of circulating drug.25

ADAs against biological treatments used in psoriasis Strong evidence for immunogenicity of biological drugs exists in various diseases, including RA, spondyloarthritis and Crohn’s disease, and data in psoriasis are now emerging. The results of a literature review, undertaken to collate the available data for biologics used in psoriasis now as well as potential new agents, are summarized below and in Table 1. Infliximab

Gottlieb et al.26 found anti-infliximab antibodies up to week 26 in 27.6% of psoriasis patients who received 3 mg/kg infliximab at weeks 0, 2 and 6, and in 19.5% of those on 5 mg/kg. The rate of infusion reactions was similar in patients with and without ADAs up to week 26, but was higher in antibody-positive patients who were retreated at week 26 (23% vs. 8% in antibody-negative patients). Menter et al. also found higher ADA levels in patients treated with 3 mg/kg (46.2–51.5%) than with 5 mg/kg infliximab (35.8– 41.5%).27 Antibody-positive patients were less likely to maintain response to treatment and had a greater risk of infusion reactions.27 Reich et al. found ADAs in 27% of infliximabtreated patients; maintenance of response to treatment from weeks 10 to 50 was lower in patients with antibodies (39% vs. 81%).28 Adisen et al. found anti-infliximab antibodies in 5/15 patients.29 In this pilot study, a similar number of infliximab infusions failed to satisfactorily reduce the mean PASI scores of ADA-positive (P = 0.1) compared with ADAnegative patients (P = 0.01).29 Addition of methotrexate

(5–15 mg/week) led to clinical improvement and disappearance of ADAs after 8 weeks.29 Adalimumab

Menter et al. found antiadalimumab antibodies in 8.8% of patients, and some evidence for loss of response in antibodypositive patients.30 Papp et al. found ADAs in 6% of patients; ADAs were associated with an increased risk of failure to re-achieve efficacy following treatment discontinuation and relapse.31 Lecluse et al. found a higher rate of ADA development with adalimumab (45%), although this study included only 29 patients.32 Differences in response rates among patients with low, high and undetectable ADAs at the drug trough level were significant at weeks 12 (P = 0.04) and 24 (P < 0.001).32 The median adalimumab trough concentrations varied significantly among the three groups (1.30, 0.0 and 9.6 mg/L; P < 0.001) and were also correlated with response.32 In this study, none of the patients with high levels of ADAs achieved a significant response. After 1 year, 46% of 59 patients had developed antibodies: 10 before week 12, 14 between weeks 12 and 24 and 3 between weeks 24 and 52.33 Takahashi et al. found trough levels were positively associated with clinical response and were significantly lower in patients with ADAs.34 None of these studies found any association between antiadalimumab antibodies and adverse events. Etanercept

Levels of antietanercept antibodies vary between studies. Three studies found antietanercept antibodies in 1.1–1.6% of patients,35–37 but no association with response to etanercept treatment was seen. Another study of extended exposure to etanercept 50 mg twice weekly found a higher rate of ADAs (18.3%), but again the antibodies were all non-neutralizing and had no apparent effect on the efficacy or safety profile.15 The higher rate of ADA formation seen in this study might be

Table 1 Summary of available data on ADAs in psoriasis* Biological drug

Molecule

No of studies

No of patients

ADA (%)

Association of ADA with: Clinical response

30–34

Adverse events

Adalimumab

Humanized MAb

4

1194

6–46

Yes

No

Brodalumab42

Humanized MAb

1

160

5.0–9.8

–

–

Certolizumab pegol41

PEGylated Fab fragment of humanized MAb

1

188

4–25

No

–

Etanercept15,35–37

Fusion protein

4

2138

1.1–18.3

No

No

Golimumab45

Humanized MAb

1

405

5.4

–

–

Infliximab26–29,34

Chimeric MAb

5

675

19.5–51.5

Yes

Yes

Secukinumab43,44

Fully human MAb

2

413

0

–

–

Ustekinumab38–40

Fully human MAb

3

2328

3.8–5.1

Yes

No

*Integrated analysis of 14 clinical trials. ADA, antidrug antibody; MAb, monoclonal antibody.

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explained by the high dose (50 mg twice weekly) of etanercept used.15 Ustekinumab

Zhu et al.14 summarized the immunogenicity results from three Phase 3 trials with ustekinumab in moderate-to-severe psoriasis.38–40 The overall incidence of antiustekinumab antibodies was 5%, and titres remained stable over time.14 Most antibodies (76%) were neutralizing, and patients with ADAs tended to have lower serum drug concentrations and a lower response to ustekinumab. ADAs were not associated with injection-site reactions or hypersensitivity.14 New biological drugs

Several new biological drugs are in development for psoriasis, and some early studies have reported on immunogenicity. Reich et al. found anticertolizumab-pegol antibodies at week 12 in 5% and 4% of psoriasis patients treated with 200 mg and 400 mg twice weekly; at week 24, the rates were 18% and 25%.41 Cumulatively, development of antibrodalumab antibodies was reported in 7.9%, 7.7%, 5.0% and 9.8% of patients treated with 70 mg, 140 mg, 210 mg and 280 mg of brodalumab, respectively, in samples obtained at baseline and weeks 4, 16 and 22; however, no neutralizing antibodies were detected by bioassay.42 Two studies found no ADA development in patients treated with secukinumab.43,44 In the GO-REVEAL trial,45 5.4% of golimumab-treated patients developed antibodies. ADAs were less common in patients treated with baseline methotrexate, and in patients who increased the dose from 50 mg to 100 mg compared with those on a stable dose.45 No studies have yet reported immunogenicity results for ixekizumab.

Implications of immunogenicity for therapeutic decision-making in the management of patients with moderate-to-severe psoriasis Treatment efficacy and drug survival

Clinical guidelines such as the German S3 guideline or the recently updated Spanish guidelines on the treatment of psoriasis recognize that immunogenicity can affect the efficacy of biological drugs and increase the risk of infusion reactions with infliximab.46,47 An absence of ADAs was seen among psoriasis patients well controlled on long-term treatment with TNF inhibitors.48 Infliximab-treated psoriasis patients with fewer ADAs are more likely to sustain their response to treatment.27,28 Immunogenicity in intermittent therapy and tailored dose adjustment

Drug-free remission is a desirable goal that could theoretically reduce adverse events, improve quality of life and reduce overall

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costs.49 Whilst this goal may not be achievable in all psoriasis patients,46 long-term episodes of remission are possible in some; although these may be followed by relapse, some patients may have long disease-free intervals.50 In individual patients, demonstration of remission may be achieved by stopping treatment or prolonging the dosing interval; as such, flexibility of dosing is preferable. Patients with ADAs may need higher doses or decreased dosing intervals to overcome loss of efficacy associated with immunogenicity. Longer drug survival with less immunogenic drugs would be expected. Indeed, a systematic review of 19 trials of biological drugs in psoriasis found drug survival to be longer for etanercept than infliximab.51 The OSCAR study also found etanercept had a survival rate of 51.4 months compared with 34.7 months for adalimumab and 36.8 months for infliximab.52 In contrast, data from the Danish DERMBIO registry show better drug survival for infliximab than for adalimumab or etanercept in psoriasis.53 However, this may be partly explained by the fact that the dose of infliximab was often adjusted upwards (sometimes above the recommended 5 mg/kg every 8 weeks) to maintain response (dose escalation) in around one to every three patients.54 In consensus guidelines, dose adjustment has been proposed as a standardized option for infliximab in psoriasis.55 Development of ADAs may reduce (but do not abrogate) the likelihood of recovering a good clinical response in patients who resume treatment after discontinuation. Presence of ADAs against adalimumab was associated with an increased risk of failure to reachieve efficacy following treatment discontinuation and relapse.31 However, other factors may be involved when etanercept treatment is discontinued in psoriasis patients who show a complete response, or in response to life events, as 69–85% are able to regain a response to retreatment.56,57 Thus, an increased clearance related to non-neutralizing ADA as well as additional pharmacokinetic factors can be speculated.58 Addressing immunogenicity in clinical practice: the role of methotrexate in psoriasis

Concomitant methotrexate treatment may reduce the immunogenicity of mAbs such as adalimumab and infliximab in RA and other conditions,1 and a dose–response effect has been demonstrated.21 However, data on the use of concomitant methotrexate in psoriasis patients are very limited. In one adalimumab study, only 5/59 patients used concomitant methotrexate, and only one of them developed low-level ADA.32,33 Adding methotrexate to infliximab led to negative ADA status and achieved a sustained clinical efficacy in previously ADA-positive patients.29 However, the tolerability of methotrexate would need to be taken into account before it is prescribed to reduce immunogenicity (rather than to treat the psoriasis), and this warrants further investigation. In this sense, the prevalence of three of the four identified risk factors for MTX-related fibrosis, that is,

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In patients with an optimal response, continue treatment ADA+ Start treatment

In patients with a loss of response after a good response or suboptimal response, consider monitoring serum drug trough levels

Suboptimal drug levels

Switch to a different TNF inhibitor

Measure ADA levels ADA– Increase drug dose or dosing frequency where indicated*

Optimal drug levels

Switch to a biologic with a different mechanism of action

*ADA-negative patients who continue to show suboptimal drug levels and response, even after increased dosing, may need to switch to a different drug. Figure 1 Proposed treatment decision tree when monitoring drug levels in patients on biologics starting with TNFinhibitors.

obesity, diabetes mellitus and alcohol intake is higher in psoriasis compared with other inflammatory chronic diseases like RA.59 The lack of clinically relevant immunogenicity to etanercept monotherapy may be advantageous; this should be weighed against the optimal clinical response that can be achieved using the recommended dosing regimen of 25 mg twice weekly or 50 mg once weekly in comparison with other TNFi. Value of drug level and ADA testing

Comparison of rates of ADA development in different studies is hampered by a lack of standardization of assay methods.22 None of the available assays can detect all different forms of ADAs. Assays differ in specificity and sensitivity, and the presence of drug can interfere with the results.3 Therefore, performing immunogenicity measurements at the drug trough level is important. Routine drug level monitoring and ADA measurement may be useful in guiding biological treatment in non-responders. Vincent et al. proposed a model for the clinical application of such measurements, whereby the dosage or dosing frequency of a TNFi is increased only in the presence of suboptimal drug levels and the absence of ADAs.1 Patients with ADAs should be switched to another TNFi, whereas non-responders with optimal drug levels and no ADAs should be switched to a biological with a different mechanism of action. Garces et al. have recently shown how in a cohort of 105 patients with established RA receiving biologics, those who had therapeutic decisions concordant with a proposed algorithm introducing immunogenicity assessment had a higher probability of achieving response and lower disease activity.60 Drug level and ADA testing may help to optimize management of psoriasis with biological therapies.1 Such techniques could be used in the daily management of biological therapy in

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the near future when measurement of drug level and immunogenicity testing become more widely available.58 A pragmatic algorithm regarding the indications and practical consequences of ADA and drug trough level measuring is proposed in Fig. 1.

Summary Immunogenicity may affect the pharmacokinetics of mAbs used to treat psoriasis and may result in reduced clinical efficacy and drug survival, and dose escalation. In some cases, immunogenicity is associated with a higher risk of adverse events, especially infusion reactions. Infliximab, adalimumab and ustekinumab are associated with development of neutralizing ADAs; in contrast, antibodies to etanercept are non-neutralizing and appear unrelated to clinical response. Drug trough levels supported by ADA testing may help optimize psoriasis management with biological therapy. Flexible biological dosing in response to clinical response and life events is desirable in a long-term condition like psoriasis. Immunogenicity should be taken into account alongside factors such as the clinical efficacy of the drug, the impact on comorbidities and the safety profile.

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