immunogenicity of anti-tnfα therapy in psoriasis: a clinical issue?

1. Introduction

2. Immunologic responses

elicited by anti-TNFa agents

3. Immunogenicity of anti-TNFaagents may reduce the efficacy

of treatment

4. Lack of efficacy of anti-TNFaagents in dermatologic

diseases: is immunogenicity a

problem?

5. Conclusion

6. Expert opinion

Review

Immunogenicity of anti-TNFatherapy in psoriasis: a clinicalissue?Clara De Simone†, Paolo Amerio, Giuseppe Amoruso, Federico Bardazzi,Anna Campanati, Andrea Conti, Paolo Gisondi, Giulio Gualdi,Claudio Guarneri, Luca Leoni, Francesco Loconsole, Annamaria Mazzotta,Maria Letizia Musumeci, Stefano Piaserico, Concetta Potenza &Francesca Prestinari†Catholic University of the Sacred Heart, Department of Dermatology, Rome, Italy

Introduction: Immunogenicity of antitumor necrosis factor-alpha (TNFa)agents has been proven to play a significant role in the variability of clinical

responses among patients with chronic inflammatory diseases. However, its

clinical impact on the outcome of patients with psoriasis and psoriatic arthritis

receiving anti-TNFa treatment is not yet fully clear. Despite the high rates of

efficacy of anti-TNFa agents in psoriasis, a substantial proportion of patients

remain who experience a primary or secondary failure or significant side

effects, which are potentially ascribable to immunogenicity.

Areas covered: Topics include immunologic response elicited by anti-TNFaagents, the impact of immunogenicity on treatment response to anti-TNFa and

the role played by immunogenicity in the lack of efficacy of anti-TNFa agents

(infliximab, adalimumab and etanercept) in psoriasis.

Expert opinion: Based on data available in the literature and the clinical expe-

rience of the authors, this article suggests the optimal approach to drug mon-

itoring and antidrug antibody assay and the most effective use of biologic

immunotherapies in this setting. Immunogenicity should be taken into

account in the adoption of therapeutic choices in psoriatic patients, such as

anti-TNFa agent intensification, or switching to another anti-TNFa agent or

a drug with a different mechanism of action.

Keywords: anti-TNFa agent, immunogenicity, psoriasis

Expert Opin. Biol. Ther. [Early Online]

1. Introduction

The prognosis of several autoimmune diseases, including psoriasis and psoriaticarthritis (PsA), has improved considerably in the past decade with the introductionof antitumor necrosis factor-alpha (TNFa) agents (i.e., infliximab, adalimumab,etanercept and golimumab), which are thought to be more efficacious and tolerablethan conventional therapies such as cyclosporine and methotrexate (MTX), owingto their activity on the specific therapeutic target [1]. However, infusion reactionsand lack or loss of response are significant clinical issues still associated with currentbiologic therapies, and immunogenicity of anti-TNFa recombinant proteinspotentially plays a role in these issues [2].

Immunogenicity appears to be related to the specific molecular structure of theanti-TNFa agent, with the constitution of each acting as a different immunologicstimulus. The clinical consequences of antidrug antibody (ADA) development arealso heterogeneous, including severe allergic and anaphylactic reactions and a reduc-tion or loss of therapeutic efficacy. The incidence and clinical relevance of these con-sequences have been extensively investigated in patients with rheumatoid arthritis

10.1517/14712598.2013.848194 © 2013 Informa UK, Ltd. ISSN 1471-2598, e-ISSN 1744-7682 1All rights reserved: reproduction in whole or in part not permitted

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http://informahealthcare.com/journal/EBT

(RA) and Crohn’s disease (CD) [3]. On the whole,immunogenicity-associated issues may have a significantimpact on the efficacy and safety of treatment, the complianceto therapy and the individualization of patient management.Fewer data are available for patients with psoriatic diseases

than for those with rheumatologic and intestinal diseases;however, data from clinical studies seem to indicate that theimmunogenicity of anti-TNFa drugs may be a relevant prob-lem in the management of psoriatic diseases. Based on dataavailable in the literature and the clinical experience of theauthors, this article attempts to evaluate the impact of immu-nogenicity with anti-TNFa therapy on patients with psoriasisand PsA, and to define the optimal approach to monitoringdrug and ADA levels and the most effective use of biologicimmunotherapies in this setting.

2. Immunologic responses elicited byanti-TNFa agents

All biotechnology-derived therapeutic proteins, whetherentirely of human origin, chimeric or ‘humanized’ can elicitimmune responses, because they contain unique sequences

that generate antibodies against themselves [4]. These immuneresponses are complex and can contribute to the appearanceof adverse events, as well as to treatment failure. However,the different molecular structures of the various anti-TNFaagents translate to different immunogenicity profiles, with dis-tinctive clinical implications. Chimeric drugs such as infliximab(chimeric mouse/human anti-TNFa monoclonal antibody)may induce the production of antibodies against the murinecomponent of Fab fragments [5], whereas fully humananti-TNFa monoclonal antibodies (e.g., adalimumab andgolimumab) elicit anti-idiotypic antibodies [6]. In the case ofetanercept (a TNF-receptor-IgG fusion protein), only the junc-tion region between the TNF receptor and the Fc fragment ofhuman IgG1 incorporates immunogenic epitopes [3,7].

The lack or loss of clinical response in patients with ADAsmay be explained by immune--complex formation betweenanti-TNFa agents and ADAs, leading to their increased clear-ance, or to the impossibility of drug fixation to TNFa, andthereby to inhibition of its biologic activity. The latter is par-ticularly true for ADAs directed against anti-TNFa agents(infliximab, adalimumab, golimumab), which are inducedby the hypervariable region of the Fab fragment, essentialfor the link to TNFa [8-11]. Conversely, antietanercept anti-bodies are not usually neutralizing, as they target the centralpart of the molecule and do not block the site of interactionwith TNFa (Figure 1) [12,13].

In addition to treatment failure, the presence of ADAs maybe associated with adverse events, such as acute or delayedinfusion reactions, including headache, pruritus, hypotension,nausea, fever, skin rash and arthralgias. Such reactions aremore frequent in patients treated with infliximab (15 -- 20%of patients) and the risk is doubled in those with anti-infliximab antibodies [8,9]. By contrast, the development ofADAs directed against adalimumab and etanercept does notappear to be associated with an increased risk of adverseeffects [10-13].

3. Immunogenicity of anti-TNFa agents mayreduce the efficacy of treatment

Several pieces of evidence reveal a significant impact of immu-nogenicity on treatment response to anti-TNFa drugs,although it must be stressed that the quantification of ADAsis challenging and may be undertaken by different assays,and quantitative data are difficult to compare across clinicalstudies [9,14]. The wide variations in ADA prevalence depend-ing on the type of assay used, together with the false-negativeresults and nonspecific binding that may occur with some ofthese, make it difficult to precisely assess the clinical impactof immunogenicity.

This phenomenon has been studied mainly in patients withRA and CD treated with infliximab. In these patients, theprevalence of anti-infliximab antibodies varies from 6 to60% [3] and appears to be inversely associated with seruminfliximab level and clinical response. In the same subgroup

Article highlights.

. Prognosis of psoriasis and PsA improved considerablywith the introduction of anti-TNFa agents. However,immunogenicity of anti-TNFa recombinant proteins canplay a role in infusion reactions and lack or loss ofresponse of these therapies.

. The reported extent of ADA development in psoriaticpatients treated with infliximab ranges from 15 to 50%,with an inverse correlation with serum drug levels andclinical response. Fewer data are available foradalimumab (ADA prevalence ranging from 6 to 45%),whereas etanercept appears to be less immunogenicthan anti-TNFa antibodies and ADAs to etanercept arenot associated with clinical response or adverse events.

. A better knowledge of the implications of biologicimmunogenicity in psoriasis and PsA would allow amore rational approach to the management of patientswith primary or secondary failure, with the adoption oftherapeutic choices such as anti-TNFa agentintensification, switching to another anti-TNFa agent orto a drug with a different mechanism of action. As lowserum levels of drug have been associated with a morelikely appearance of ADAs, the issue of immunogenicityshould also be considered in patients with a goodclinical response, in which reducing drug dosage orfrequency of infusions, although apparently a rationalapproach with significant short-term economic benefits,may favor the development of immunogenicity.

. The appraisal of immunogenicity of anti-TNFa agentscan translate into a better understanding of patients’clinical heterogeneity and in a practical tool for theoptimization and personalization of therapeuticapproach in psoriasis and PsA.

This box summarizes key points contained in the article.

C. De Simone et al.

2 Expert Opin. Biol. Ther. (2013) 13(12)

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of patients, clinical studies show a prevalence of antiadalimu-mab antibodies between 1 and 87%, also mainly negativelycorrelated to serum drug level and therapeutic response [3].By contrast, the use of etanercept was associated with the devel-opment of antietanercept antibodies in 0 -- 5% of patients withRA, without apparent effect on serum etanercept concentrationor effectiveness [3].

In a recent systematic review and meta-analysis of865 patients with immune-mediated inflammatory diseases,ADAs against infliximab or adalimumab reduced drugresponse rate by 68%, whereas antietanercept antibodieswere not detected [15]. The authors concluded that drugimmunogenicity should be considered in clinical practice,because detectable ADAs may decrease anti-TNFa responseby as much as 80%. This is in contrast to the descriptionsin most randomized clinical trials, which do not considerimmunogenicity to be a major problem.

Several factors may influence the clinical impact of drugimmunogenicity, and their identification may be useful for theoptimization and personalization of biologic therapies. Con-comitant immunosuppressive therapy can significantly reduceimmunogenicity, by reducing the frequency of ADA detectionor delaying its appearance [2,16,17]. In the earlier mentionedmeta-analysis of 865 patients, concomitant MTX reducedADA frequency by 41% [15]. Concomitant MTX has beenshown to reduce immunogenicity in a dose-dependent mannerand coadministration of azathioprine has been demonstrated tobe inversely correlated to the rate of ADA formation [18,19].

Lower doses of anti-TNFa agents would result in moreADAs, as would an intermittent regimen compared with con-tinuous treatment [16,20]. There is no evidence that ADAs cancross-react between the various anti-TNFa agents; therefore,the presence of an ADA does not contraindicate switchingto another drug of the same class [21,22].

Although these data suggest that ADAs play at least a partialrole in the loss of treatment effect or failure of the disease torespond to treatment, the presence of antibodies does not nec-essarily cause loss of drug efficacy. In many cases, the develop-ment of an antibody response does not impair disease control,

and its clinical relevance is not clearly established in thesepatients. Alongside the characteristics of neutralizing or notneutralizing antibodies, the underlying disease may also influ-ence the clinical impact of immunologic responses. For exam-ple, immunogenicity may be greater in patients with CD,where there is a prominent component of bacterial triggers [5].In ankylosing spondylitis incidence of ADAs seems to be highercompared with RA, and MTX fails to influence infliximabpharmacokinetics [16,23]. The dose and administration scheduleof biologics used in various autoimmune diseases alsopotentially accounts for heterogeneity in ADA formation.

4. Lack of efficacy of anti-TNFa agents indermatologic diseases: is immunogenicity aproblem?

Psoriasis is a common, chronic, immune-mediated disease thatusually requires long-term treatment. Patients with severe andmoderate forms of the disease, and those with PsA, may benefitfrom biologic therapies, including anti-TNFa agents [24].Despite their high rates of efficacy, in a substantial proportionof patients, anti-TNFa drugs fail to demonstrate efficacy (pri-mary failure) or induce significant side effects. In placebo-controlled clinical trials, 40 -- 60% of patients with active PsAtreated with adalimumab or infliximab did not show an Amer-ican College of Rheumatology 20 (ACR20) response [25,26]. Inpatients with PsA receiving etanercept, 30 -- 40% did notachieve an ACR20 response [27,28]. The rate of patients withplaque psoriasis not achieving at least a Psoriasis Area andSeverity Index (PASI) 75 improvement with anti-TNFatherapy has been reported to vary between 20 and 50% [29].

In some patients, the anti-TNFa agents have shown a ten-dency to lose efficacy with long-term use (secondary failure).Only ~ 75 -- 85% of patients with psoriasis who achieve aPASI 75 response with anti-TNFa agents in the first periodof treatment maintain that response in the long term [30-32].

As in other chronic inflammatory diseases, the immunoge-nicity of anti-TNFa agents may be responsible for a decreased

MurineFv

HumanFv

HumanFv

HumanTNFR2

Infliximab Golimumab Adalimumab Etanercept

HumanFcγ1

HumanFcγ1

HumanFcγ1

HumanFcγ1

Figure 1. Immunogenicity profiles of anti-TNFa agents in relation to their molecular structure.TNF: Tumor necrosis factor.

Immunogenicity of anti-TNFa therapy in psoriasis: a clinical issue?

Expert Opin. Biol. Ther. (2013) 13(12) 3

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or absent response to these drugs, at least in a proportion ofpatients with psoriasis. However, it is difficult to quantify theextent of ADA formation in psoriatic patients and their impacton the therapeutic efficacy of different anti-TNFa drugs.

4.1 InfliximabIn a large series of 249 patients with severe plaque psoriasis,ADAs were detected by enzyme-linked immunosorbent assay(ELISA) in 27.6% of patients receiving 3 mg/kg of infliximaband in 19.5% of those receiving the higher dose (5 mg/kg).The presence of antibodies to infliximab was associated withinfusion reactions only in patients retreated after a 20-weekinterval (23% of infusion reactions in ADA-positive patientsvs 8% in ADA-negative ones) [33]. A similar incidence ofADAs (27%) was observed by Reich et al. in patients with mod-erate-to-severe plaque psoriasis receiving infliximab 5 mg/kg [31].In a trial of 835 patients with moderate-to-severe psoriasis,

randomized to induction therapy with infliximab 3 or 5 mg/kg(or placebo) then to scheduled or intermittent maintenanceregimens at their induction dose, higher rates of ADAs wererecorded. Antibodies to infliximab were detected in35.8 and 41.5% of patients in the 5 mg/kg every 8 weeksand as-needed groups, respectively, and in 51.5 and 46.2%of patients in the 3 mg/kg every 8 weeks and as-neededgroups, respectively. Antibody-positive patients were lesslikely to maintain response at week 50 than antibody-negativepatients, although positive-antibody status did not precludeclinical responsiveness. Moreover, ADA-positive patients hada greater risk of experiencing an infusion reaction thanADA-negative patients [34].In patients with active PsA treated with infliximab 5 mg/kg

(IMPACT 2 trial), ADA development was observed in15.4%. Antibodies to infliximab were more frequent inpatients not receiving MTX at baseline (26.1 vs 3.6%in patients receiving MTX) and showed an inverse correlationwith clinical response: the median percentage ACR improve-ment at week 54 for patients who were ADA-positive was lowerthan for those who were ADA-negative (21.7 vs 33.3%, respec-tively). Among antibody-positive patients, an ~ 3.5-foldincrease in the incidence of mild-to-moderate infusion reac-tions occurred compared with antibody-negative patients [35].

4.2 AdalimumabData are more limited for the anti-TNFa agent adalimumab.An ADA incidence as high as 45% was reported in a smallseries of adalimumab-treated patients with psoriasis, with asignificant inverse correlation with serum drug level and clin-ical response. All patients with high titers of antibodies to ada-limumab at weeks 12 or 24 were nonresponders, andsignificant differences in response rates were recorded amongpatients with low, high and no titers of ADAs [36]. However,antiadalimumab antibodies were detected in only 6 and 9%of patients with psoriasis receiving 40 or 80 mg of adalimu-mab in two large trials enrolling 285 and 1212 patients,respectively; both trials suggested a negative impact of ADAs

on clinical outcomes [11,37]. The use of a different method ofADA detection might partially explain these differences.

In a small study of 22 patients with PsA specifically assessingthe incidence of antiadalimumab antibodies and the relation-ship with serum drug concentration and clinical response,ADAs were detected in 18% of patients. Those with antiadali-mumab antibodies had lower median adalimumab concentra-tions than those without (1.7 vs 9.8 mg/l at 12 months), andserum levels of adalimumab were undetectable in patientswith high concentrations of antibodies. In addition, patientswith antibodies appeared to lose their initial good response [38].

No evidence of an association between antiadalimumabantibodies and adverse events was reported in these trials.

4.3 EtanerceptAs earlier mentioned, etanercept is thought to be less immu-nogenic than anti-TNFa antibodies. In patients with psoria-sis, the frequency of detection of antietanercept antibodieshas ranged from 1.5 to 2.8% [39-41], although an open-labelextension of one large Phase III trial in 591 patients reporteda rate of 18.3% ADA-positive patients [42]. In one study ofpatients with PsA treated with 25 mg etanercept twice weekly,no evidence of ADA development was found among the 205patients enrolled [28].

Where detectable, in each case antietanercept antibodieswere nonneutralizing. To date, no association has beenreported between ADAs to etanercept and serum drug levels,clinical response or adverse events.

4.4 Other agentsAmong other anti-TNFa agents, the fully human anti-TNFaantibody golimumab is indicated, alone or in association withMTX, for the treatment of patients with PsA not respondingto other disease-modifying antirheumatic drug. In this categoryof patients, subcutaneous golimumab has been shown to signif-icantly improve arthritic manifestations of PsA and associatedskin disease, and reduce radiographic progression [43,44]. Theconstant regions of golimumab are identical to the correspond-ing human constant regions of infliximab, but the variableregions of golimumab, at variance from infliximab, have fullyhuman sequences. The reported frequency of antigolimumabADAs ranges from 0 to 7%, without apparent association withclinical response and adverse events [3]. In PsA patients receivinggolimumab therapy, ADAs have been detected in 4 -- 5% ofcases, without correlation with clinical response [43-45].

The incidence and clinical characteristics of ADAs inpatients with psoriasis and PsA are summarized in Table 1.

5. Conclusion

Immunogenicity of recombinant proteins has been shown to sig-nificantly impact on the clinical outcome of patients withchronic inflammatory diseases receiving anti-TNFa therapy.The evidence available in the literature confirms immunogenicityto anti-TNFa agents may be present in a variable but significant

C. De Simone et al.


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Table

1.Incidence

andclinicalch

aracteristicsofADAsin

patients

withpso

riasisandPsA

.

Anti-TNFa

agent

Disease

Patients

(n)

Dose

ADAs(assay)

Association

withdrug

level(assay)

Associationwithclinical

outcome

Association

withAEs

Ref.

Inflixim

ab

Psoriasis

249

3mg/kg

5mg/kg

27%

(ELISA)

20%

(ELISA)

NR

NR

Incidence

ofinfusionreactions

afterinterval:23%

inADA+pts

vs8%

inADA--

[33]

Inflixim

ab

Psoriasis

378

5mg/kg

27%

(NR)

NR

LoRatwk50:61%

ADA+pts

vs19%

ADA--pts

NR

[31]

Inflixim

ab

Psoriasis

835

5mg/kgevery

8weeks

36%

(NR)

NR

ADA+pts

less

likely

tomaintain

response

atwk50than

ADA--pts

Greaterincidence

ofinfusion

reactionin

ADA+pts

thanin

ADA--pts

[34]

5mg/kgondemand

41%

(NR)

3mg/kgevery

8weeks

51%

(NR)

3mg/kgondemand

46%

(NR)

Inflixim

ab

PsA

200

5mg/kg

15%

(NR)

NR

MedianACRim

provementat

wk54:22%

forADA+pts

vs33%

forADA--pts

3.5-fold

increase

inincidence

of

infusionreactionsin

ADA+pts

comparedwithADA--pts

[35]

Adalim

umab

Psoriasis

29

40mg

45%

(RIA)

Negatively

associated

(p<0.001)

(ELISA)

Clinicalresponse

negatively

associatedwithADAtiters

(p<0.001)

NR

[36]

Adalim

umab

Psoriasis

1212

40mg

9%

(NR)

NR

LoR:43%

inADA+pts

vs28%

inADA--pts

No

[37]

Adalim

umab

Psoriasis

285

40or80mg

6%

(ELISA)

NR

Negatively

associatedwith

response

rate

NR

[11]

Adalim

umab

PsA

22

40mg

18%

(RIA)

Negatively

associated

(p=0.031)

(ELISA)

LoRmore

frequentin

ADA+pts

thanin

ADA--pts

NR

[38]

Etanercept

Psoriasis

652

25--100mg/w

eek

1.6%

(ELISA)

NR

No

No

[41]

Etanercept

Psoriasis

583

50--100mg/w

eek

2.8%

(ELISA)

NR

No

No

[40]

Etanercept

Psoriasis

618

100mg/w

eek

1.5%

(ELISA)

NR

No

No

[39]

Etanercept

Psoriasis

591

100mg/w

eek

18.3%

(ELISA)

NR

No

No

[42]

Etanercept

PsA

205

50mg/w

eek

0%

(NR)

NA

NA

NA

[28]

Golim

umab

PsA

405

50or100mg

4.6%

(ELISA)

NR

No

No

[43]

Golim

umab

PsA

405

50or100mg

5.4%

(NR)

NR

NR

NR

[45]

ACR:AmericanCollegeofRheumatology;

ADA:Antidrugantibody;

AE:Adverseevent;ELISA:Enzyme-linkedim

munosorbentassay;

LoR:Loss

ofresponse;NA:Notapplicable;NR:Notreported;PsA

:Psoriaticarthritis;

RIA:Radioim

munoassay.



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percentage of patients with psoriasis or PsA and be variably asso-ciated with therapeutic response and adverse events.The implications for the clinical practice of biologic immu-

nogenicity in dermatologic patients are still poorly character-ized, although a better knowledge of this issue would allow amore rational approach to the management of patients with pri-mary or secondary treatment failure. Because low serum levels ofdrug have been associated with a greater likelihood for develop-ment of ADAs, the issue of immunogenicity should also be con-sidered in patients with a good clinical response. In thesepatients, reducing drug dosage or frequency of infusions mayappear to be a rational approach, with significant economic ben-efits; however, this should be weighed against the risk ofpromoting ADA development and then secondary failure.A reliable definition of the predictive power of therapeutic

drug level and ADA detection in the adoption of therapeuticchoices such as anti-TNFa agent intensification, or switchingto another anti-TNFa agent or a drug with a different mech-anism of action, could drastically change the management ofpatients in the future. Given the economic costs of these drugsand the costs associated with therapeutic failure (in terms oflack of improvement or worsening of damage), the potentialusefulness of therapeutic drug monitoring and ADA assess-ment could be quantified and justified from an economicpoint of view. As illustrated further, the evaluation of theseparameters could efficaciously support therapeutic choices inclinical practice. In patients with inadequate disease control,this might drive the strategy to improve therapeutic response.In responding patients, the demonstration that higher drugdoses may actually decrease immunogenicity might result inan improved cost/effectiveness ratio in the long term, despitethe high costs of anti-TNFa drugs.On the whole, the appraisal of immunogenicity of anti-

TNFa agents may eventually lead to a better understandingof patients’ clinical heterogeneity and to a practical tool forthe optimization and personalization of therapeutic approachin treating psoriasis and PsA.

6. Expert opinion

Available data clearly point to a significant incidence of ADAsin patients with psoriasis or PsA treated with anti-TNFaagents. Approximately 15 -- 50% of patients treated with inflix-imab and 10 -- 40% of those receiving adalimumab are at riskof developing ADAs [3]. However, the real impact of immuno-genicity on clinical outcome is more difficult to ascertain, as isthe proportion of primary or secondary failures that might beascribed to ADA development. A clinically significant reduc-tion in therapeutic efficacy may be seen in patients developinganti-infliximab or antiadalimumab antibodies, but how thistranslates to rate of response is not yet established. Moreover,in many nonresponders no evidence of immunogenicity isseen, and some patients show a good treatment responsedespite the presence of ADAs [36,46,47]. A significant proportionof these uncertainties may be related to the limits that most

commonly used assays for drug monitoring and ADA detectionpresent when used in a clinical setting.

At present, the decision to modify the dose or frequency ofadministration as well as to switch to another drug is based onclinical response and safety profile. A rational approach tothese therapeutic changes, considering potential clinicalimplications of drug immunogenicity, might benefit fromdrug monitoring and ADA detection, although treatmentdecisions cannot rely solely on laboratory parameters, mainlydue to the lack of standardization of these methods.

6.1 The need for serum drug monitoringThe efficacy of anti-TNFa agents is dose-dependent. Higherserum trough levels of infliximab, adalimumab or etanercepthave been shown to correlate with increased clinical responserates in RA [47-49]. In patients with psoriasis, plasma troughlevels of adalimumab and infliximab were reported to bepositively associated with clinical response [36,50].

Even for equal drug dosages, interindividual variability inthe pharmacokinetics of anti-TNFa agents is relevant andmay be ascribed to patient characteristics, genetic back-ground, underlying disease and concomitant drugs [48]. Inaddition, ADA presence may reduce the half-life and serumlevel of infliximab and adalimumab by increasing their clear-ance. Therefore, in patients with absent or suboptimal diseaseresponse to anti-TNFa therapy, determining serum drug con-centration may be clinically useful in informing therapeuticstrategy. If steady-state trough serum levels are low or unde-tectable, increasing drug dosage or frequency of injectionsmay be a rational approach; conversely, if serum levels arewithin the target range, switching to another anti-TNFaagent or class of drugs may be recommended, as dose increaseis unlikely to add to disease control. Anti-TNFa intensifica-tion in patients with low drug level and evidence of immuno-genicity is more controversial: some authors reported aless-frequent clinical improvement in response to doseescalation or shortened infusion intervals in patients withanti-infliximab antibodies [51,52]. However, higher exposureto infliximab may reduce ADA levels in a significant propor-tion of patients [52]. The influence of serum drug concentra-tion on therapeutic efficacy thus may justify drug-levelmonitoring, even in terms of cost-effectiveness.

6.2 The need for ADA assayThe presence and titers of ADAs might also influence thera-peutic decisions in patients with inadequate disease controlor adverse events. If ADA development is detected in a patientwith primary or secondary failure, and the drug serum level iswithin the target range, switching to another TNFa antago-nist should be considered. ADAs do not show cross-reactivity,and experience in RA has demonstrated that patients with aprevious clinical failure associated with ADA presence usuallyshow a good response after switching to another TNFa antag-onist [22,53]. However, in patients who experience a failure notascribable to immunization, switching to another anti-TNFa

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agent is often ineffective, probably because different or multi-ple pathogenetic mechanisms are involved, and a drug withanother mechanism of action should be considered. There-fore, ADA detection can be helpful in deciding which patientswould benefit from switching, and may be part of a personal-ized treatment regimen.

Addition of an immunosuppressant drug, such as MTX,might be another choice in patients with evidence of immuni-zation, because its association with anti-TNFa agents reducesADA formation [16,18,54].

In patients with clinical adverse drug reactions to inflixi-mab, ADAs can be evaluated to assess if the adverse event isrelated to immunization [55]. If ADAs are detected, readminis-tration of the same drug may be dangerous. However, even inthe absence of detectable ADAs, the decision to continue withthe same antagonist must be taken with caution, and the pos-sibility of a false-negative induced by interference by thecirculating anti-TNFa agent ruled out [14].

6.3 When and how to switch?Based on the above considerations, switching to another anti-TNFa agent may be considered for patients with absent or

inadequate response or with clinical-relevant adverse events.Patients who stopped their first anti-TNFa treatment becauseof toxicity are more likely to respond after switching toanother anti-TNFa than those who experienced a failure [56]

and in this setting, no rational for the use of a specificanti-TNFa agent in terms of clinical outcome is available.

Patients with inadequate disease control, and without evi-dence of low serum drug levels that can suggest a doseincrease, may benefit from switching to a second anti-TNFaagent if ADAs are present, as ADA-negative patients aremore likely to respond to drugs with a different mechanismof action. However, it has been reported that patients whodeveloped immunogenicity against a first anti-TNFa agentwere more likely to produce ADAs against a second. In astudy in patients with RA, switchers with anti-infliximab anti-bodies were reported to form antibodies against adalimumabmore often than anti-TNFa-naıve patients [53]. However,switching to etanercept from infliximab or adalimumab hasbeen shown to induce a better clinical outcome in patientswith ADAs compared with those without evidence of immu-nogenicity. These data need to be confirmed in the psoriasissetting, and suggest a potential influence of immunogenicity

Anti-TNFα therapy

Infusion reaction

ADA assay

-+

Resume thedrug?

Switch to anotheranti-TNFα

Disease control

NoYes

Drug level assayContinue treatment

LowHigh

ADA assayADA assay

-+

IntensificationIntensification orswitch to another

anti-TNFα

-+

Switch to a differentclass of drug

Switch toanother

anti-TNFα

Figure 2. Proposed algorithm for clinical management of anti-TNFa agent immunogenicity. Therapeutic decisions may be

based on laboratory tests as long as these have been standardized and their clinical relevance assessed. When negative results

are obtained in ADA-binding assays, a retesting with a cell-based functional assay may be advisable before changing therapy.ADA: Anti-drug antibody; TNF: Tumor necrosis factor.



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status not only in the decision to switch to another agent butalso in the choice of which anti-TNFa drug to use.

6.4 Unmet needsMost reported evidence on the clinical consequences ofimmunogenicity in patients receiving anti-TNFa therapyhas been obtained in rheumatologic and intestinal diseases.How applicable these data are to patients with psoriasis andPsA and the impact of immunogenicity on therapeuticchoices in these setting still need to be established throughwell-designed clinical studies. In relation to these issues, dif-ferences among the various chronic inflammatory diseasesalso need to be defined, as well as among the various anti-TNFa agents, including the imminently available biosimilars.In addition, international consensus is needed on the ther-

apeutic range of serum drug concentrations, and detectionand characterization of ADAs. At present, a number of meth-ods are generally used to detect the presence of ADAs(standard ELISA, two-site or bridging ELISA and radioim-munoassay antigen-binding test), and the prevalence ofADAs may vary widely depending on which assay is used.All these tests are error-prone when used in a clinical setting,as for example many of them are ‘drug-sensitive’ and cannotdetect ADA in the presence of the drug in the sample, which

may results in false-negative data. Moreover, the frequentlyused two-site ELISA fails to detect IgG4 antibodies, commonin long-term treated patients. Mostly importantly, all bindingassays do not assess functionality of measured drug and ADA,a factor that may affect the in vivo relevance of data generatedwith these tests [57]. Standardization of these methods and thedevelopment of assays able to measure the functionality ofboth drugs and ADAs are warranted to assure the clinicalutility of therapeutic drug monitoring.

Even considering these limitations, an algorithm for theclinical management of anti-TNFa agent immunogenicityand for the application of drug level and ADA measurementmay be proposed (Figure 2), whose clinical applicability neces-sarily rely on the availability of reliable assays for drug andADA determination.

Declaration of interest

This work, including travel and meeting expenses, was funded byan unrestricted grant by Pfizer. The sponsor had no role inreviewing the literature, defining recommendations, drafting orreviewing the article, or in the decision to submit the manuscriptfor publication. All views expressed are solely those of the authors.The authors have no other competing interests to declare.

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AffiliationClara De Simone†1, Paolo Amerio2,

Giuseppe Amoruso3, Federico Bardazzi4,

Anna Campanati5, Andrea Conti6,

Paolo Gisondi7, Giulio Gualdi8,

Claudio Guarneri9, Luca Leoni10,

Francesco Loconsole11, Annamaria Mazzotta12,

Maria Letizia Musumeci13, Stefano Piaserico14,

Concetta Potenza15 & Francesca Prestinari16

†Author for correspondence1Catholic University of the Sacred Heart,

Department of Dermatology, L.go A.Gemelli 8;

00168 Rome, Italy

Tel: +390630154227;

Fax: +39063016293;

E-mail: [email protected]

2University G. D’Annunzio,

Dermatologic Clinic,

Department of Oncology and Neuroscience,

Chieti, Italy3University of Catanzaro (Italy) C/O Fondazione

per la Ricerca e la Cura dei Tumori ‘Tommaso

Campanella’ COE, Dermatology Unit, Viale

Europa, 88100 Germaneto di Catanzaro (CZ),

Italy4University of Bologna, S.Orsola-Malpighi

Hospital, Department of Specialistic,

Diagnostic and Experimental Medicine,

Dermatology Unit, Via Albertoni 15,

40138 Bologna, Italy5Marche Polytechinic University, Department of

Medicine and Applied Biotechnology, Section of

dermatology, Via Brecce Bianche, 1,

60131 Ancona, Italy6University of Modena and Reggio Emilia,

Department of Dermatology, Via Del Pozzo 71 -

41100, Modena, Italy7University of Verona, Department of Medicine,

Section of Dermatology and Venereology,

Verona, Italy8University of Brescia, Department of

Dermatology, Piazzale Spedali Civili 1,

25123 Brescia, Italy9University of Messina (Italy) c/o A.O.U,

Department of Clinical and Experimental

Medicine, Section of Dermatology, ‘G. Martino’,

Consolare Valeria, 1, 98125 Messina, Italy10IDI-IRCCS, Via Monti Creta, 104,

00167 Rome, Italy11University of Bari, Dermatology Clinic, Piazza

Giulio Cesare 11, 70124 Bari, Italy12University of Rome ‘Tor Vergata’,

Department of Dermatology,

Viale Oxford 81, 00133 Rome, Italy13AOU Policlinico-Vittorio Emanuele,

Department of Dermatology, PO G. Rodolico,

Via S. Sofia 78 -- 95123 Catania, Italy14University of Padova, Department of Medicine,

Dermatology Unit, via Cesare Battisti 206,

35128 Padova, Italy15Sapienza University, Polo Pontino, A. Fiorni

Terracina Hospital, UOC of Dermatology

‘Daniele Innocenzi’, Rome, Italy16S.Anna Hospital, Department of Dermatology,

Como, Italy

C. De Simone et al.


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