C-Reactive Protein and Response to Adalimumab in Patients With Hidradenitis Suppurativa: A Post Hoc Analysis of 2 Randomized Clinical Trials

Simon J Gunter; Martina L Porter; Alexa B Kimball

doi:10.1001/jamadermatol.2024.5146

. 2025 Jan 8;161(2):221–223. doi: 10.1001/jamadermatol.2024.5146

C-Reactive Protein and Response to Adalimumab in Patients With Hidradenitis Suppurativa

A Post Hoc Analysis of 2 Randomized Clinical Trials

Simon J Gunter ¹, Martina L Porter ^2,³, Alexa B Kimball ^2,^3,^✉

¹Department of Medicine, Pennsylvania Hospital, Philadelphia

²Clinical Laboratory for Epidemiology and Applied Research in Skin (CLEARS), Department of Dermatology, Beth Israel Deaconess Medical Center, Boston, Massachusetts

³Department of Dermatology, Harvard Medical School, Boston, Massachusetts

Accepted for Publication: October 9, 2024.

Published Online: January 8, 2025. doi:10.1001/jamadermatol.2024.5146

^✉

Corresponding Author: Alexa B. Kimball, MD, MPH, Clinical Laboratory for Epidemiology and Applied Research in Skin (CLEARS), Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA 02215 (clears@bidmc.harvard.edu).

Author Contributions: Dr Gunter had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: All authors.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Gunter.

Critical review of the manuscript for important intellectual content: All authors.

Statistical analysis: Gunter.

Supervision: Porter, Kimball.

Conflict of Interest Disclosures: Dr Gunter reported receiving personal fees from Merck outside the submitted work. Dr Porter reported receiving grants and writing assistance for conference abstracts from AbbVie during the conduct of the study and grants from Janssen, Eli Lilly, Novartis, Pfizer, Incyte, Moonlake, UCB, Aristea, Bristol Myers Squibb, Sonoma Bio, Regeneron, and Acelyrin and personal fees from Janssen, Eli Lilly, Novartis, Pfizer, Incyte, Trifecta Clinical, Moonlake, UCB, Sanofi, and Alumis outside the submitted work. Dr Kimball reported receiving personal fees from AbbVie, Almirall, Alumis, Avalos, Bayer, Boehringer Ingelheim, Eli Lilly, Evoimmune, Innovaderm, Janssen, Novartis, Moonlake, Pfizer, Priovant, Sanofi, Sonoma Bio, Target RWE, UCB, and Union Therapeutics and grants from AbbVie, Admirx, Anapyts Bio, Aristea, Bristol Myers Squibb, Eli Lilly, Incyte, Janssen, Moonlake, Novartis, Pfizer, Prometheus, Sanofi, Sonoma Bio, and UCB outside the submitted work.

Funding/Support: This work was conducted with support from Harvard Catalyst award UM1TR004408 from The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institutes of Health) and financial contributions from Harvard University and its affiliated academic health care centers.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University, and its affiliated academic health care centers or the National Institutes of Health. This publication is based on research using data from AbbVie that has been made available through Vivli, Inc. Vivli has not contributed to, approved, and is not in any way responsible for the contents of this publication.

Data Sharing Statement: See Supplement 3.

Additional Contributions: AbbVie funded the 2 PIONEER trials. AbbVie did not sponsor this study. AbbVie reviewed this article for confidential information before its submission.

^✉

Corresponding author.

PMCID: PMC11840640 PMID: 39775706

Abstract

This post hoc analysis of 2 randomized clinical trials examines whether C-reactive protein estimated response to adalimumab in patients with hidradenitis suppurativa.

Hidradenitis suppurativa (HS) is a chronic inflammatory disorder that causes inflamed nodules, abscesses, sinus tracts, and fistulas. Patients often require treatment with biologics, eg, adalimumab and secukinumab.^1,2 Rates of biologic failure remain substantial. Although dermal tunnels and family history may be associated with timing and duration of response to adalimumab, identifying biomarkers may help clinicians decide on an initial biologic or when to escalate therapy.³ Although nonspecific, serum C-reactive protein (CRP) is an accessible marker of systemic inflammation that correlates with body mass index (BMI) (via the expression of interleukin 6 in adipose tissue) and Hurley stage.⁴ We tested whether CRP was associated with response to adalimumab in patients with HS.

Methods

We conducted a post hoc analysis of 2 phase 3 randomized clinical trials (PIONEER I and II)¹ that studied adalimumab in patients aged 18 to 69 years with moderate to severe HS from November 29, 2011, through January 28, 2014, and December 28, 2011, through April 28, 2014, respectively. The Beth Israel Deaconess Medical Center Committee on Clinical Investigation deemed this study exempt from review and informed consent as it did not constitute human participant research. This study followed the CONSORT reporting guideline.

The trials randomized patients to adalimumab, 40 mg, weekly or placebo for 12 weeks. Clinical improvement was assessed using HS clinical response at week 12. We limited our analysis to patients who completed this period of the trials and had baseline and week 12 laboratory data (eFigure in Supplement 2). Per the trial protocol¹ (Supplement 1), elevated CRP was defined as greater than 0.30 mg/dL.

Hypothesis testing was conducted using χ² tests (sex, self-reported race and ethnicity) and Welch 2-sample t and Wilcoxon rank sum tests. The incidence of HS differs by race and is disproportionate among Black patients. Multivariable logistic regressions were used to study the association between CRP and response to adalimumab. A 2-sided P < .05 was considered significant. Statistical analysis was performed between February 17, 2024, and July 12, 2024, using RStudio, version 1.4.1717 (R Foundation).

Results

Among 588 PIONEER participants who satisfied our inclusion criteria (mean [SD] age, 36.4 [11.2] years; 385 female [65.5%], 203 male [34.5%]), 464 (78.9%) had elevated CRP and 124 (21.1%) had normal CRP (Table 1). The median CRP among patients with an elevated value at baseline was 1.23 mg/dL (IQR, 0.65-2.81 mg/dL). Mean BMI differed between patients with vs without elevated CRP (mean [SD], 34.1 [7.9] vs 28.6 [6.0]; P < .001). Patients with elevated CRP also had more severe cutaneous disease.

Table 1. Patient Demographics and Disease Severity Markers by CRP at Baseline.

Characteristic	No. (%)^a			P value^b
	Total patients (n = 588)	CRP level
	Total patients (n = 588)	>0.3 mg/dL (n = 464)	Normal (n = 124)
CRP, median (IQR), mg/dL	0.85 (0.37-2.25)	1.23 (0.65-2.81)	0.16 (0.10-0.22)	NA
Sex
Female	385 (65.5)	296 (63.8)	89 (71.8)	.12
Male	203 (34.5)	168 (36.2)	35 (28.2)	.12
Race and ethnicity
Asian	14 (2.4)	10 (2.1)	4 (3.2)	.12
Black	79 (13.4)	69 (14.9)	10 (8.0)
White	476 (81.0)	368 (79.3)	108 (87.1)
Other^c	19 (3.2)	17 (3.7)	2 (1.6)
Family history	139 (23.6)	103 (22.2)	36 (29.0)	>.99
BMI, mean (SD)	32.9 (7.8)	34.1 (7.9)	28.6 (6.0)	<.001
Age, mean (SD), y	36.4 (11.2)	36.5 (11.3)	36.1 (10.8)	.68
Hurley stage
II	317 (53.9)	225 (48.5)	92 (74.2)	<.001
III	271 (46.1)	239 (51.5)	32 (25.8)	<.001
IHS4 score, median (IQR)	22 (11-40)	25 (14-45)	12 (7-23)	<.001
No. of abscesses and inflammatory nodules, median (IQR)	10 (6-16)	10 (6-16)	8 (5-11)	<.001
No. of abscesses, median (IQR)	1 (0-3)	1 (0-3)	1 (0-3)	.01
No. of inflammatory nodules, median (IQR)	7 (4-13)	8 (4-14)	6 (4-10)	.01
No. of draining fistulas, median (IQR)	2 (0-5)	3 (1-6)	0 (0-2)	<.001

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Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); CRP, C-reactive protein; IHS4, International Hidradenitis Suppurativa Severity Score System; NA, not applicable.

SI conversion factor: To convert CRP to mg/L, multiply by 10.

^{^a}

Data are reported as No. (%) for categorical variables, median (IQR) for nonnormally distributed variables, and mean (SD) for normally distributed variables.

^{^b}

P values were calculated using χ² for categorical variables, Welch 2-sample t test for normally distributed continuous variables, and Wilcoxon rank sum test for nonnormally distributed continuous variables.

^{^c}

Other races and ethnicities included American Indian or Alaska Native, Native Hawaiian or Pacific Islander, multiracial, and other.

Elevated CRP at baseline was associated with lower odds of clinical response (odds ratio [OR], 0.53; 95% CI, 0.34-0.83) (Table 2). Treatment with adalimumab resulted in higher odds of clinical response in patients with either elevated CRP (OR, 3.18; 95% CI, 2.13-4.81) or normal CRP (OR, 2.25; 95% CI, 1.06-4.88) at baseline. In patients who received adalimumab and had elevated CRP at baseline, each unit increase in CRP was associated with reduced odds of clinical response (OR, 0.99; 95% CI, 0.97-1.00). Assuming linearity, the OR of clinical response for adalimumab recipients with CRP of 2.81 mg/dL (third quartile of elevated CRP) vs 0.30 mg/dL was 0.70 (95% CI, 0.49-0.97).

Table 2. Results of 6 Logistic Regressions of Achieving Hidradenitis Suppurativa Clinical Response in Recipients of Adalimumab and Placebo in PIONEER I and PIONEER II.

Variable	All patients (N = 588)								Elevated CRP at baseline (n = 464)
	Total		Elevated CRP at baseline (n = 464)			Normal CRP at baseline (n = 124)			Total			Adalimumab (n = 227)^a			Placebo (n = 237)^b
	OR (95% CI)	P value	OR (95% CI)	P value	OR (95% CI)		P value	OR (95% CI)		P value	OR (95% CI)		P value	OR (95% CI)		P value
Elevated CRP at baseline	0.53 (0.34-0.83)	.006	NA	NA	NA		NA	NA		NA	NA		NA	NA		NA
CRP laboratory value	NA	NA	NA	NA	NA		NA	0.99 (0.98-1.00)		.03	0.99 (0.97-1.00)		.04	0.99 (0.97-1.00)		.41
Adalimumab	2.94 (2.07-4.21)	<.001	3.18 (2.13-4.81)	<.001	2.25 (1.06-4.88)		.04	3.23 (2.15-4.90)		<.001	NA		NA	NA		NA
Age	1.00 (0.98-1.01)	.74	1.00 (0.98-1.01)	.66	1.00 (0.97-1.04)		.75	1.00 (0.98-1.02)		.77	1.01 (0.99-1.04)		.35	0.98 (0.95-1.00)		.15
BMI	0.98 (0.95-1.00)	.07	0.97 (0.95-1.00)	.053	0.97 (0.91-1.04)		.42	0.97 (0.95-1.00)		.07	0.97 (0.94-1.01)		.15	0.97 (0.94-1.01)		.21
Family history	0.70 (0.52-1.20)	.27	0.81 (0.50-1.32)	.41	0.79 (0.34-1.82)		.58	0.78 (0.48-1.27)		.33	0.65 (0.34-1.26)		.21	0.95 (0.44-1.93)		.88
Hurley stage	0.70 (0.49-1.02)	.06	0.61 (0.41-0.92)	.02	1.46 (0.62-3.56)		.40	0.70 (0.46-1.07)		.10	0.91 (0.52-1.61)		.74	0.48 (0.25-0.93)		.03
Male	0.76 (0.52-1.11)	.16	0.65 (0.41-1.00)	.054	1.42 (0.60-3.43)		.42	0.69 (0.44-1.08)		.11	0.65 (0.36-1.17)		.15	0.72 (0.34-1.45)		.37

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Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); CRP, C-reactive protein; NA, not applicable; OR, odds ratio.

^{^a}

Only includes patients who had an elevated CRP at baseline and were assigned to receive adalimumab.

^{^b}

Only includes patients who had an elevated CRP at baseline and were assigned to receive placebo.

Discussion

In this post hoc analysis, patients with elevated CRP had a higher BMI and more severe HS. Adalimumab appeared equally effective in patients with or without elevated CRP. In patients who received adalimumab and had elevated CRP, each 1-unit increase in CRP was associated with reduced odds of clinical response. Our findings suggest that adalimumab may be less effective in patients with the most severe inflammatory load. When treating nonresponders, clinicians may consider weight-based dosing of adalimumab, checking drug levels, or trialing alternative biologics.⁵ Limitations include that this post hoc analysis was not part of the original study design. Further prospective research is required to establish a more precise cutoff point where patients are unlikely to benefit from adalimumab therapy.

Supplement 1.

Trial Protocol

jamadermatol-e245146-s001.pdf^{(14.8KB, pdf)}

Supplement 2.

eFigure. CONSORT Diagram

jamadermatol-e245146-s002.pdf^{(9.9MB, pdf)}

Supplement 3.

Data Sharing Statement

jamadermatol-e245146-s003.pdf^{(15.3KB, pdf)}

References

1.Kimball AB, Okun MM, Williams DA, et al. Two phase 3 trials of adalimumab for hidradenitis suppurativa. N Engl J Med. 2016;375(5):422-434. doi: 10.1056/NEJMoa1504370 [DOI] [PubMed] [Google Scholar]
2.Kimball AB, Jemec GBE, Alavi A, et al. Secukinumab in moderate-to-severe hidradenitis suppurativa (SUNSHINE and SUNRISE): week 16 and week 52 results of two identical, multicentre, randomised, placebo-controlled, double-blind phase 3 trials. Lancet. 2023;401(10378):747-761. doi: 10.1016/S0140-6736(23)00022-3 [DOI] [PubMed] [Google Scholar]
3.Frew JW, Jiang CS, Singh N, et al. Dermal tunnels influence time to clinical response and family history influences time to loss of clinical response in patients with hidradenitis suppurativa treated with adalimumab. Clin Exp Dermatol. 2021;46(2):306-313. doi: 10.1111/ced.14448 [DOI] [PubMed] [Google Scholar]
4.Jiménez-Gallo D, de la Varga-Martínez R, Ossorio-García L, Albarrán-Planelles C, Rodríguez C, Linares-Barrios M. The clinical significance of increased serum proinflammatory cytokines, C-reactive protein, and erythrocyte sedimentation rate in patients with hidradenitis suppurativa. Mediators Inflamm. 2017;2017:2450401. doi: 10.1155/2017/2450401 [DOI] [PMC free article] [PubMed] [Google Scholar]
5.Williams J, Guzik C, Wadhera A, Naik H. Increased doses of adalimumab are associated with clinical improvement of hidradenitis suppurativa. J Drugs Dermatol. 2023;22(6):615-618. doi: 10.36849/JDD.6868 [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

Trial Protocol

jamadermatol-e245146-s001.pdf^{(14.8KB, pdf)}

Supplement 2.

eFigure. CONSORT Diagram

jamadermatol-e245146-s002.pdf^{(9.9MB, pdf)}

Supplement 3.

Data Sharing Statement

jamadermatol-e245146-s003.pdf^{(15.3KB, pdf)}

[dld240029r1] 1.Kimball AB, Okun MM, Williams DA, et al. Two phase 3 trials of adalimumab for hidradenitis suppurativa. N Engl J Med. 2016;375(5):422-434. doi: 10.1056/NEJMoa1504370 [DOI] [PubMed] [Google Scholar]

[dld240029r2] 2.Kimball AB, Jemec GBE, Alavi A, et al. Secukinumab in moderate-to-severe hidradenitis suppurativa (SUNSHINE and SUNRISE): week 16 and week 52 results of two identical, multicentre, randomised, placebo-controlled, double-blind phase 3 trials. Lancet. 2023;401(10378):747-761. doi: 10.1016/S0140-6736(23)00022-3 [DOI] [PubMed] [Google Scholar]

[dld240029r3] 3.Frew JW, Jiang CS, Singh N, et al. Dermal tunnels influence time to clinical response and family history influences time to loss of clinical response in patients with hidradenitis suppurativa treated with adalimumab. Clin Exp Dermatol. 2021;46(2):306-313. doi: 10.1111/ced.14448 [DOI] [PubMed] [Google Scholar]

[dld240029r4] 4.Jiménez-Gallo D, de la Varga-Martínez R, Ossorio-García L, Albarrán-Planelles C, Rodríguez C, Linares-Barrios M. The clinical significance of increased serum proinflammatory cytokines, C-reactive protein, and erythrocyte sedimentation rate in patients with hidradenitis suppurativa. Mediators Inflamm. 2017;2017:2450401. doi: 10.1155/2017/2450401 [DOI] [PMC free article] [PubMed] [Google Scholar]

[dld240029r5] 5.Williams J, Guzik C, Wadhera A, Naik H. Increased doses of adalimumab are associated with clinical improvement of hidradenitis suppurativa. J Drugs Dermatol. 2023;22(6):615-618. doi: 10.36849/JDD.6868 [DOI] [PubMed] [Google Scholar]

PERMALINK

C-Reactive Protein and Response to Adalimumab in Patients With Hidradenitis Suppurativa

Simon J Gunter, MD, MBA, MPhil

Martina L Porter, MD

Alexa B Kimball, MD, MPH

Abstract

Methods

Results

Table 1. Patient Demographics and Disease Severity Markers by CRP at Baseline.

Table 2. Results of 6 Logistic Regressions of Achieving Hidradenitis Suppurativa Clinical Response in Recipients of Adalimumab and Placebo in PIONEER I and PIONEER II.

Discussion

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

Cite

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PERMALINK

C-Reactive Protein and Response to Adalimumab in Patients With Hidradenitis Suppurativa

Simon J Gunter, MD, MBA, MPhil

Martina L Porter, MD

Alexa B Kimball, MD, MPH

Abstract

Methods

Results

Table 1. Patient Demographics and Disease Severity Markers by CRP at Baseline.

Table 2. Results of 6 Logistic Regressions of Achieving Hidradenitis Suppurativa Clinical Response in Recipients of Adalimumab and Placebo in PIONEER I and PIONEER II.

Discussion

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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