Carole Dannepond1,2, Annabel Maruani1–3, Laurent Machet1–3, David Ternant1,4, Gilles Paintaud1,4 and Mahtab Samimi1,2,5

1University Hospital of Tours, University François Rabelais, 2Dermatology Department, Hospital of Tours, 3Inserm, Imagerie et Cerveau UMR U930, 4CNRS, GICC UMR 7292, Laboratory of Pharmacology Toxicology, Hospital of Tours, and 5Laboratory of Molecular Virology and Immunology, ISP 1282 INRA-University François Rabelais, Tours, France

The efficacy of infliximab is influenced by individual variability in its pharmacokinetics and pharmacodynamics. Serum infliximab concentrations could therefore be related to the efficacy and tolerance of infliximab, and assist adjustment of treatment. The aim of this systematic review was to assess the value of measuring serum infliximab concentrations in psoriatic patients. A bibliographic search was performed on MEDLINE, CENTRAL, EMBASE, LILACS for original studies on serum infliximab concentrations in psoriatic patients treated with infliximab. Ten articles were included, representing evaluation of serum infliximab concentrations in 733 patients. Predictive value of higher serum infliximab concentrations on long-term response maintenance was suggested in 3 studies. There was no information regarding the value of such measurements for adjustment of infliximab dosage. Trough serum infliximab concentrations that are at least detectable (> 0.1 mg/l) at steady state (week 22) seem to be associated with maintaining a clinical response in the long term. Key words: infliximab; psoriasis; pharmacokinetics; trough concentration.

Accepted Oct 1, 2014; Epub ahead of print Oct 1, 2014

Acta Derm Venereol

Mahtab Samimi, Department of Dermatology, Laboratory of Molecular Virology and Immunology, ISP 1282, INRA-University François Rabelais, Hospital of Tours, FR-37000 Tours, France. E-mail: samimi.mahtab@yahoo.fr

Infliximab (IFX) is a chimeric monoclonal antibody directed against tumour necrosis factor alpha (TNFα) that is approved for treatment of cutaneous psoriasis, with a recommended dosage schedule of 5 mg/kg/infusion intravenously at weeks 0, 2, 6 and subsequently every 8 weeks. Variable efficacy of IFX in psoriatic patients has been reported (1–3), leading to individual dose adjustments by shortening intervals between infusions and/or dose increase in non-responsive patients (4, 5). These between-patient response differences reflect intra- and inter-individual variability of IFX pharmacokinetics and pharmacodynamics in psoriatic patients, as in other inflammatory diseases. This can be investigated by evaluating the IFX concentration levels in patients’ blood samples just after (peak concentration) and just before (trough concentration) IFX infusions. Serum IFX concentrations in inflammatory rheumatic and bowel diseases have been reported to be related to IFX efficacy (6–14), to be valuable in guiding individual dose adjustment (12, 15–19), to constitute a predictive marker of long-term response to treatment (8, 20–25) and to be a marker of antibodies against infliximab (ATI) (6, 9, 10, 13, 26–29). In such diseases, monitoring of serum IFX concentrations has been recommended in clinical practice in cases of primary inadequate response, secondary loss of response, and in cases of hypersensitivity reactions and autoimmune diseases (8, 16).

There is currently no information on the validity and value of measurement of IFX concentrations in psoriatic patients. We therefore undertook a systematic review of published reports on patients treated with IFX for cutaneous psoriasis and for whom serum IFX concentration had been measured. Our aims were: 1) to report the technical procedures used for such measurement, 2) to describe IFX pharmacokinetics in psoriatic patients, 3) to assess the relationship between serum IFX concentration and IFX efficacy, 4) to assess any association between serum IFX concentration and ATI, 5) to assess any association between serum IFX concentration and the occurrence of adverse side effects, and 6) to investigate whether serum IFX concentrations may be used to guide IFX dose adjustment in order to optimise treatment.

Materials and methods

The PRISMA guidelines were followed for the systematic review.

Search strategy

One author (CD) undertook a systematic search on January 20, 2013 of the electronic databases MEDLINE, CENTRAL, EMBASE, LILACS, with no limitation on date or language, to identify articles about infliximab and psoriasis. No methodological search filters or limits were applied. The keywords “psoriasis” and “infliximab” associated with “AND” were used in a simple MEDLINE search, and with keywords in “title and abstract” in EMBASE, CENTRAL and LILACS.

Inclusion and exclusion criteria

The inclusion criteria were defined as: any original article (study, case series, item of correspondence) reporting measurement of serum IFX concentrations for at least 2 patients treated with IFX for cutaneous psoriasis. The exclusion criteria were defined as: reviews and guidelines, editorials, articles on IFX-induced psoriasis or psoriatic arthritis, and single case reports. Reviews and guidelines mentioning “infliximab concentration”, “infliximab levels”, or “infliximab pharmacokinetics” were excluded from the selection, but their references were analysed by one author (CD) to extend the research.

Study selection strategy

According to the pre-defined criteria, first-line selection based on titles was performed by one author (CD). Second-line selection based on abstracts was performed independently by 2 authors (CD, MS). Discordant selections were discussed. Full texts of the subsequently selected articles were examined independently by 2 authors (CD, MS). Duplicate publications were identified by several criteria (authors, title, intervention characteristics, and number of patients).

Data extraction

The extraction table was developed by 3 authors (CD, MS, AM). The extraction itself was performed independently by 2 authors (CD, MS), and discordance was resolved after discussion. The data collected included the general characteristics of the article (author, title, publication date, study design, key outcomes), patient characteristics (sample size, gender, type of psoriasis), IFX treatment regimen (duration, dosage and adjustments, combination with other systemic drugs), measurement of serum IFX concentrations (technical procedures, time and results of assays, pharmacokinetics), IFX efficiency (clinical scores) and side effects (presence of ATI, occurrence of adverse effects), and authors’ recommendations on the value of measuring IFX serum concentration.

Data analysis

Descriptive continuous variables were reported as medians and ranges, mean and standard deviations, and percentages.

Results

Literature search and characteristics of articles included in the study

The flowchart of the literature search is presented in Fig. S11. After exclusion of inter-database duplicates, 3,733 articles were identified. Selection based on titles included 2,179 articles and selection based on abstracts identified 229 for full text analysis. Overall, 10 articles (3, 26–34) (Table I) met our inclusion criteria and were eligible for data extraction. Eight were original articles (4 randomised clinical trials (3, 26–28), 3 prospective open studies (29–31) and one observational study (32)). Two additional articles (33, 34) were duplicate publications of selected studies, but were retained in the analysis because they provided additional data on assessment of serum IFX concentrations. Population characteristics, infliximab regimen, methods and times of serum IFX concentration assays are summarised in Table I and Table SI1. The studies involved 1,677 patients, most of whom had plaque psoriasis. IFX dosages ranged between 3 and 10 mg/kg, and the drug was administered at weeks 0, 2, 6 and then every 8 weeks. Patients had IFX dosage adjustments in one study (32).

Measurement of IFX concentrations: techniques and pharmacokinetics

Serum IFX concentrations had been measured in 733 patients (43.7%). Measurements were performed by enzyme-linked immunosorbent assay (ELISA) for 334 patients (45.5%) and radioimmunoassay (RIA) for 15 patients (2.1%). The measurement technique was not mentioned for 384 patients (52.4%). Sampling methods, delivery times and storage of samples were available in 2 studies (n = 37 patients) (26, 30) The lowest limit of detection of the ELISA technique was 0.1 mg/l in 4 studies (n = 314 patients) (26–29) and 0.05 mg/l in one study (30) (n = 20 patients). Inter- and intra-assay variability was detailed in one study using RIA (< 20% and < 10%) (32). Serum IFX concentration was measured before infusion (trough serum infliximab, TSI) in 8 studies (n = 733 patients) and one hour after infusion (peak concentration) in 4 studies (n = 305 patients). The pharmacokinetics of TSI are reported in Table II. In the short term (W0, W2, W6 and W14) (5 studies, 520 patients) (3, 26, 28, 29, 31), maximum TSI were obtained at W2, and then gradually decreased until W14. Data after W22 were available in 5 studies (681 patients) (3, 27–29, 31) and showed that TSI reached a steady state at W22, maintained until W70, ranging between 0.1 and 3.7 mg/l. The relationship between IFX dose and serum concentration was assessed by Gottlieb et al. (26) (5 mg/kg vs 10 mg/kg) and Menter et al. (27) (3 mg/kg vs 5 mg/kg). The IFX serum peak at W2 was proportional to the dose (26). TSI at W14 was dose-dependent but not proportional (26). Similarly, TSI at steady state (W22) was 2.6 mg/l in the 5 mg/kg group but undetectable in the 3 mg/kg group (27). The pharmacokinetics of IFX were similar for different clinical subtypes of psoriasis (1 study, 65 patients) (29). In the same study, 14 patients had systemic treatment combined with IFX (methotrexate, oral corticosteroids) but without information on their influence on the IFX pharmacokinetics or on the development of ATI (29).

Relationship between trough serum infliximab levels (TSI) and IFX efficacy

A positive relationship between TSI and clinical efficacy (PASI75 or PASI90) assessed at the same time was reported in 4 studies (89 patients) (28, 30, 32, 34). Long-term responders (over 18 months) had detectable TSI (32). PASI75 increased gradually with TSI (PASI75 response rates at W62 being 60%, 71.4% and 95.7% for TSI lower than 0.1 mg/l, between 0.1 and 1 mg/l and between 1 and 10 mg/l, respectively) (28). TSI over 0.9 mg/l at W48 was associated with increased PASI75 response (30). TSI at W54 was higher in PASI90 responders (median 2.6 mg/l, interquartile range 1.1 to 3.8 mg/l) than in non-responders (median 0.1 mg/l, interquartile < 0.1–1.4 mg/l) (34). In the study by Menter et al. comparing different IFX dosages (3 mg/kg versus 5 mg/kg) (27), the relationship between IFX efficacy and TSI varied when considering the induction or the maintenance phase of IFX treatment. No relationship was evidenced at the induction phase, as both IFX dosages resulted in similar efficacy, whereas median TSI was lower in the 3 mg/kg (6.2 μg/ml) than in the 5 mg/kg (23.5 μg/ml) group. On the other hand, PASI75 responses were better achieved in the 5 mg/kg group (with detectable TSI), compared to the 3 mg/kg group (with undetectable TSI). A positive relationship between TSI assessed at one time and clinical efficacy at subsequent times, reflecting a predictive value, was reported in 3 studies (437 patients) (3, 33, 34). Reich et al. (3) reported that PASI75 responders at W50 had had TSI over 1 mg/l at steady state (W22), compared to levels under 1 mg/l at W22 and undetectable from W30 to W50 for non-responders. Similarly, Torii et al. (34) reported that PASI 90 responders at W46 had had TSI above 2 mg/l at steady state compared to levels under 1 mg/l at W30 and 0.1 mg/l at W46 for non-responders. Another study stated that the proportion of responders was associated with TSI, with no additional information (33).

Relationship between serum IFX concentrations, IFX antibody (ATI) detection and adverse events

Detection of ATI was reported to be associated with «low» (30, 31) or undetectable (28) TSI with no additional data. Among 15 patients who had detectable TSI, none had ATI (32). No study assessed whether serum IFX concentrations were predictive of the development of ATI. No information was available on any relationship between serum IFX concentrations and the occurrence of adverse side effects.

Value of serum IFX concentrations for adjustment of dosage of IFX

No study had assessed the value of measurement of serum IFX concentration for dosage adjustment in psoriatic patients.

According to the authors of the studies included, measurement of serum IFX concentrations may predict effectiveness and maintenance of the clinical response (3, 27, 30).

Discussion

We undertook the first systematic review assessing the validity and value of measurement of serum IFX concentrations in the management of patients treated with IFX for cutaneous psoriasis.

Measurement of serum IFX concentrations: techniques and pharmacokinetics

Serum IFX concentrations were mostly measured before infusion (trough serum infliximab levels, TSI) over the time of treatment with IFX at the usual dosage (5 mg/kg/8 weeks) for plaque psoriasis. The ELISA technique, the technique that was most commonly used, is limited by the threshold of detection and the interference with the detection of ATI (35). RIA, a more sensitive assay (36), was rarely used because it is less widely available. When available, sampling methods, sample management and techniques of measurement were neither homogeneous nor standardised, making it difficult to define reproducible thresholds between different laboratories. However, pharmacokinetics data showed that TSI reached steady state after 4 infusions (W22), the median TSI ranging from 0.8 mg/l to 3.7 mg/l with no long-term drug accumulation (3, 27–29, 31). Inter-individual variability in the elimination half-life and TSI make it difficult to predict individual pharmacokinetics (3, 26). The clinical subtype of psoriasis did not appear to affect the pharmacokinetics (29), but no data were available on the effects of individual factors previously reported to influence infliximab pharmacokinetics, such as gender, weight, albumin serum concentration, degree of systemic inflammation, and combination with other drugs including methotrexate (37).

Relationship between trough serum infliximab levels and IFX efficacy

A positive relationship between TSI and clinical efficacy assessed at the same time was reported in 4 studies (28, 30, 32, 34), in agreement with studies on rheumatoid arthritis (11–14) and inflammatory bowel disease (6–10). This review also points out the interesting positive relationship between higher TSI at steady state (W22) and the long-term maintenance of clinical efficacy in psoriasis (3, 34). The threshold of TSI predictive of response maintenance cannot however be clearly defined, the range in these studies being “detectable” (> 0.1 mg/l) (27), to 1 mg/l (3) or 2 mg/l (34). Such a predictive threshold has also been reported in rheumatoid arthritis and Crohn’s disease, for similar thresholds (20–25). Undetectable TSI might be associated with an increased risk of further loss of response to IFX. However, it is not known whether this reflects inadequate exposure to IFX and thus whether these patients may benefit from dose adjustment of infliximab (3). In rheumatoid arthritis and Crohn’s disease, TSI assessment has been reported to help the clinician with infliximab management in non-responder patients. Indeed, a low TSI would justify dose escalation whereas a high TSI would lead to infliximab withdrawal and change to another drug (12, 15–17, 19). However, we found no studies evaluating such a strategy or the value of TSI for individual IFX dosage adjustment in psoriatic patients.

Relationship between serum IFX concentrations, ATI detection and adverse events

Low TSI in non-responsive patients may also reflect development of ATI. Indeed, ATI increases the clearance of infliximab and decreases its efficacy (35). It has been shown in inflammatory rheumatism that low TSI levels were predictive of ATI development, suggesting that monitoring of TSI might detect underexposed patients at risk of immunisation (38). In our review, some authors indicated that TSI levels at steady state were lower or undetectable in the case of ATI (3, 28, 30) but no further details were available in these reports. It is not known whether low TSI levels could predict ATI development in psoriatic patients, and no study had evaluated whether dosage adjustments based on TSI monitoring would reduce risk of immunisation. Similarly, no information was available on a relationship between TSI and the occurrence of adverse side effects.

Limitations and conclusions

This systematic review is limited by the number of available studies with only 2 papers investigating the evaluation of serum IFX concentrations as a main outcome (30, 32). Serum IFX concentrations were measured using varying technical procedures and the results were often incompletely reported, and/or were for subgroups of patients or limited periods of time. At least detectable TSI levels (> 0.1 mg/l) at steady state (W22) seem to be associated with maintaining a clinical response in the long term. Measurement of serum IFX concentrations could therefore identify patients at risk of loss of clinical response, but further studies are needed to assess whether additional strategies (dose adjustment, combination with methotrexate) would help maintain long term effective response to IFX in these patients. Overall, no study had as its aim the clinical value of long-term TSI monitoring, especially in dose adjustment strategies, and this remains to be evaluated in prospective studies.

ACKNOWLEDGEMENTS

Conflict of interest statement: Gilles Paintaud is involved in clinical studies sponsored by Genzyme, Novartis and Roche Pharma; his research team has received fundings from Abbott Pharma, Chugai, Janssen, LFB (Laboratoire Français des Biotechnologies), Pierre-Fabre Laboratories, Wyeth and Merck Serono.

1http://www.medicaljournals.se/acta/content/?doi=10.2340/00015555-1980

References