Serum infliximab levels and clinical response in hidradenitis suppurativa

Abstract

Background

Infliximab (IFX) is a chimeric immunoglobulin G‐1κ monoclonal antibody that neutralises the biologic activity of tumour necrosis factor‐α, and has shown efficacy (off‐label) for the treatment of severe hidradenitis suppurativa (HS). The relationship between clinical response and IFX pharmacokinetics (PK) in HS is currently unknown.

Objectives

To investigate the relationship between the trough serum concentration of IFX (TSI) and the clinical response to IFX in moderate‐to‐severe HS between 12th and 24th week (W12–W24) after IFX treatment onset.

Methods

We conducted a retrospective, monocentric study in a French dermatology tertiary care centre (Saint‐Louis hospital, Paris) between January 2013 and January 2022. Adult patients treated with IFX for moderate‐to‐severe HS were included if (i) they had at least one IFX serum dosage during follow‐up, and (ii) they had a measurable Hidradenitis Suppurativa Clinical Response (HiSCR) score between the 12th and 24th week (W12–W24). Patients received IFX infusions every 4, 6 or 8 weeks at 5, 7.5 or 10 mg/kg of body weight dosages.

Results

Twenty‐two patients (48.9%; median age: 36 [31–43] years; 7 [31.8%] female) who had at least one IFX serum dosage between W12–W24 were enroled. The median TSI between W12 and W24 was significantly higher in the responding group compared to the nonresponding group of patients: 14.8 (12.1–15.7) versus 1.6 (0.8–3.5) µg/mL, respectively (p = 0.01). Using receiver operating characteristics (ROC) analysis curve, a TSI threshold of 7 µg/mL at W12–W24 showed sensitivity and specificity of 0.75 and 0.94, respectively.

Conclusions

This study supports some degree of correlation between clinical response and TSI in HS, and paves the way for prospective studies investigating correlations between PK, immunogenicity and clinical response in severe HS patients receiving IFX.

INTRODUCTION

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease primarily involving the pilosebaceous unit, which is associated with a major impact on patients' lives and high comorbidity burden in its moderate-to-severe form. Its current treatment algorithm mainly relies on antibiotics, tumour necrosis factor (TNF)-α blockers and surgery. Over the past decade, some biological therapies, either approved (adalimumab [ADA]) or off-label (infliximab [IFX]), have provided real-life benefits for severe HS patients. IFX is a recombinant chimeric immunoglobulin G-1κ monoclonal antibody that neutralises TNF-α biological activity, which is currently approved for the treatment of numerous immune-mediated and inflammatory diseases (IMIDs) including rheumatoid arthritis (RA), ankylosing spondylitis (AS), inflammatory bowel diseases (IBD) such as Crohn's disease (CD), and ulcerative colitis (UC), and psoriasis (Pso). As IFX was the first drug to be reimbursed by French Social Security, it is more frequently prescribed than adalimumab. Monitoring of IFX pharmacokinetics (PK) and detection of antidrug antibodies (ADAs) impacts treatment strategies in patients with other IMIDs than HS. Trough serum IFX (TSI) should be above 3.7 μg/mL for Pso, 3.5 μg/mL for CD, 2.5 μg/mL for UC, 3.2 μg/mL for RA, and 6.7 μg/mL for AS for optimal efficacy. Recent studies suggest that doses above 5 mg/kg every 8 weeks are required for optimal IFX efficacy for the treatment of HS. The objective of this study was to investigate the relationship between TSI and the response to IFX treatment in moderate-to-severe HS.

METHODS

Patients

All adult patients followed up for moderate-to-severe HS (Hurley II or III) in Saint-Louis Hospital Paris (a French Dermatology tertiary care centre), and presenting at least one IFX serum dosage (ISD) in our pharmacy database from 2013 to 2022 (n = 45) were included and retrospectively analysed. Hidradenitis suppurativa Clinical Response (HiSCR) evaluation and blood sampling were carried out on the same day. The following data were collected: sex, age, body mass index (BMI), smoking status, comorbidities, HS family history, HS characteristics (localisations, Hurley stage, HiSCR score [defined as at least a 50% reduction in the total inflammatory nodule count with no increase in abscess count and no increase in draining fistula count relative to baseline], Hidradenitis Suppurativa Physician's Global Assessment (HsPGA), previous treatments and treatment optimisation (increase of posology or adjustment of route of administration), biological data (C-reactive protein [CRP] serum levels, serum leucocytes count, IFX serum levels, ADAs), IFX treatment modalities (dosage and frequency). The initial regimen of IFX was 5 mg/kg W0 W2 W6 for all patients. Fifty-four percent of patients had a regimen at 5 mg/kg every 8 weeks. In addition, there was no evidence for a statistical difference in terms of treatment optimization (increased dosage or increased frequency of infusions).

The PK and ADAs assessments were performed immediately before each IFX infusion.

Biological data

IFX and ADAs quantifications were performed in Saint Louis Hospital Pharmacology Department using a validated ELISA technique (LISA-TRACKER LTI 005 Theradiag; Croissy-Beaubourg).

Statistical analysis

Data are presented as median (interquartile range [IQR]), number [%] and odd-ratios [OR] [95% confidence interval, CI]). We used Fisher's exact test and Mann–Whitney test to compare categorical and unpaired non-normally distributed quantitative data, respectively. Two-tailed p ≤ 0.05 was considered statistically significant. Statistical analysis was computed with GraphPad Prism version8 and R software for receiver operating characteristic (ROC) curve analysis (pROC package). The comparison was performed including patients presenting ISD associated with HiSCR evaluation between W12 and W24 after IFX treatment initiation.

RESULTS

Twenty-two patients were enrolled who had an ISD associated with an HiSCR available evaluation between W12 and W24. Four patients were responders and 18 patients were nonresponders (Figure ).

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Patients' characteristics at baseline were not statistically different between the two groups of patients HiSCR responder and nonresponder (Table ). Nonresponding patients tended (without statistical significance) to show a more severe disease (based on number of involved anatomical areas and on HsPGA), a more inflammatory phenotype (based on median leucocyte count, neutrophil count and median CRP serum level) and more associated inflammatory comorbidities (inflammatory rheumatic disease, psoriasis, IBD) at baseline.

Table 1 Baseline patients characteristics in the HISCR 0 and HiSCR 1 groups of patients with infliximab dosage available between Weeks 12 and 24.

	HiSCR 0 (nonresponders), n = 18	HiSCR 1 (responders), n = 4	Total population, n = 22	p Value
Demographic characteristics
Female, n (%)	6 (33.3)	1 (25.0)	7 (31.8)	0.99
Age at inclusion (years), median (IQR)	39 (30.5–47)	31 (31–31.3)	36 (31–43)	0.20
Clinical features
BMI (kg/m2), median (IQR)	27.7 (24.3–30.8)	26.3 (25.6–27.3)	27.2 (24.9–29.4)	0.66
Obesity, n (%)	5 (27.8)	0 (0)	5 (22.7)	0.54
Active smoking, n (%)	7 (38.9)	0 (0)	7 (31.8)	0.26
Ethylism, n (%)	1 (5.6)	0 (0)	1 (4.5)	0.99
Diabetes, n (%)	2 (11.1)	0 (0)	2 (9.1)	0.99
Arterial hypertension, n (%)	1 (5.6)	0 (0)	1 (4.5)	0.99
Associated inflammatory disease, n (%)	7 (38.9)	1 (25.0)	8 (36.4)	0.99
Axial inflammatory rheumatic disease, n (%)	2 (11.1)	0 (0)	2 (9.1)
Peripheral inflammatory rheumatic disease, n (%)	4 (22.2)	0 (0)	4 (18.2)
Psoriasis, n (%)	3 (16.7)	0 (0)	3 (13.6)
IBD, n (%)	2 (11.1)	1 (25.0)	3 (13.6)
HS characteristics
Disease duration before IFX therapy (years), median (IQR)	9 (6–19)	6 (5–7.8)	7 (5–16)	0.40
HS-related autoinflammatory syndromes, n (%)	1 (5.6)	1 (25.0)	2 (9.1)	0.34
Topography, n (%)
Axillary	16 (88.9)	4 (100)	20 (90.9)	0.99
Genito-perineal	10 (55.6)	0 (0)	10 (45.4)	0.09
Groin	16 (88.9)	3 (75.0)	19 (86.4)	0.47
Mammary/submammary	3 (16.7)	0 (0)	3 (13.6)	0.99
Face	8 (44.4)	0 (0)	8 (36.4)	0.18
Number of involved anatomical areas, n (%)
1–3	6 (33.3)	2 (50.0)	8 (36.4)	0.60
4–5	12 (66.7)	2 (50.0)	14 (63.6)
Hurley grade, n (%)
I–II	2 (11.1)	1 (25.0)	3 (13.6)	0.47
III	16 (88.9)	3 (75.0)	19 (86.4)
HsPGA, n (%)
0–3	4 (22.2)	2 (50.0)	6 (27.3)	0.53
4–5	14 (77.8)	2 (50.0)	16 (72.7)
HS therapeutics history
Number of therapeutic lines, median (IQR)	2 (1–2)	3.5 (2.8–4)	2 (1–3)	0.02
Antibiotics, n (%)	18 (100)	4 (100)	22 (100)
Retinoids	4 (22.2)	3 (75.0)	7 (31.8)
Methotrexate, n (%)	2 (11.1)	0 (0)	2 (9.1)
Corticosteroides, n (%)	2 (11.1)	1 (25.0)	3 (13.6)
Adalimumab, n (%)	1 (5.6)	1 (25.0)	2 (9.1)
Others, n (%)	3 (16.7)	1 (25.0)	4 (18.2)
Surgery	5 (27.8)	3 (75.0)	8 (36.3)
Biological characteristics
Leucocytes (mm3), median (IQR)	10405 (7605–11,775)	8380 (6490–9990)	10,280 (7510–11,700)	0.40
Neutrophil count (mm3), median (IQR)	6990 (4930–9020)	4630 (3615–6800)	6280 (4287–8982)	0.53
CRP plasmatic level (mg/L), median (IQR)	20 (11.6–34.4)	12 (7–21)	19.9 (11.3–32.0)	0.41
ASCA positivity (U/mL), n (%)	2 (40)	1 (25)	3 (13.6)	0.99

Median TSI between W12 and W24 was significantly higher in the HiSCR responder group compared to the HiSCR nonresponder group: 14.8 (12.1–15.7) versus 1.6 (0.8–3.5) µg/mL, respectively (p = 0.01) (Figure ). ADAs to infliximab were detected in three patients (16.7%) in the HiSCR nonresponder group, whereas no ADAs were detected in the HiSCR responder group between W12 and W24. To evaluate TSI as a potential response biomarker, ROC curve was performed. From this analysis, TSI achieved an area under the curve (AUC) value of 0.903 (95% CI: [0.763–1]). TSI value having the best specificity (94%) was 7 µg/mL, with a sensitivity of 75%. A TSI < 7 µg/mL at W12–W24 was significantly associated with an absence of clinical response according to HiSCR scores (p < 0.01). The median follow-up of these 22 patients was 20.5 months (9.2–41.2).

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DISCUSSION

Our study reports a correlation between IFX levels and clinical response to HS between W12 and W24. IFX dosage < 7 µg/mL between W12 and W24 was statistically associated to an absence of clinical response according to HiSCR.

The association between clinical response and TSI has been reported in other IMIDs (RA, UC, Pso, CD, AS), with cutoff concentrations ranking from 2.5 up to 6.7 μg/mL for AS. The analysis in this study suggests that the threshold IFX level that predicts response may be closer to AS and CD than Pso.

In addition, nonresponding patients of our cohort tended to have a more severe disease at baseline based on the number of involved sites, on HsPGA, on associated inflammatory comorbidities. This higher inflammatory burden was reflected by biological biomarkers of inflammation such as leucocytes, neutrophils and CRP. This set of data (more severe disease, low TSI) is suggestive for a relationship between TSI, clinical response and tissular and/or systemic inflammatory burden. This may argue for more intensive treatment (higher dosage and/or more frequent IFX perfusions) in patients with a more inflammatory pattern, according to HsPGA, localisation number, Hurley stage and elevated inflammatory biological parameters (CRP, leucocytes). Inflammatory burden has been reported in HS especially in Hurley III patients with anti-Saccharomyces cerevisiae antibody (ASCA) detection. Similarly, in CD the positivity for ASCA was associated with a more severe clinical course, thus often requiring more aggressive medical treatment.

Our study has some obvious limitations, its retrospective monocentric nature, and the relatively small sample size, which may impact statistical power. In addition, TSI might have been more frequently assessed in nonresponding patients, leading to a smaller HiSCR responder group, and a potential information bias.

A prospective study with IFX pharmacokinetic monitoring would be necessary to determine an IFX threshold of efficacy that could be helpful in the management of patients with HS.

AUTHOR CONTRIBUTIONS

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Florence Assan Erwin Benassaia and Jean-David Bouaziz. The first draft of the manuscript was written by Erwin Benassaia and Florence Assan and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

ACKNOWLEDGEMENTS

This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

CONFLICT OF INTEREST STATEMENT

Jean-David Bouaziz: speaker or advisory board member for Boehringer-Ingelheim, Janssen, Novartis, UCB, Leo Pharma, AbbVie, Eli Lilly, Pfizer, Sanofi. Marie Jachiet: speaker or advisory board member for Leo Pharma, AbbVie, Eli Lilly, Pfizer, Sanofi, Galderma. Lauriane Goldwirt: advisory board: Abbvie, Pfizer, Promise. Martine Bagot: speaker: UCB, Leo Pharma. Hervé Bachelez: advisory board: Biocad, Boehringer-Ingelheim, Bristol Myers Squibb, Dermavant, Janssen, Novartis, UCB. Speaker: Boehringer-Ingelheim, Janssen, Leo Pharma, Novartis, UCB. Consultant: AbbVie, Anaptysbio, Aristea Therapeutics, Avillion, Boehringer-Ingelheim, Bristol Myers Squibb, Eli Lilly, Innovaderm, Janssen, Kyowa Kirin, Leo Pharma Grant support: Boehringer-Ingelheim, Bristol Myers Squibb, Janssen, Leo Pharma, Pfizer.

DATA AVAILABILITY STATEMENT

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

ETHICS STATEMENT

The research was conducted in accordance with the principles embodied in the declaration of Helsinki and in accordance with local statutory requirements.

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