Moderate-to-severe atopic dermatitis patients show&nbsp;increases in serum C-reactive protein levels, correlating with skin disease activity

Anjali S. Vekaria; Patrick M. Brunner; Ahmad I. Aleisa; Lauren Bonomo; Mark G. Lebwohl; Ariel Israel; Emma Guttman-Yassky

doi:10.12688/f1000research.12422.2

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Research Article

Revised

Moderate-to-severe atopic dermatitis patients show increases in serum C-reactive protein levels, correlating with skin disease activity

[version 2; peer review: 3 approved]

Previously titled: Atopic dermatitis patients show increases in serum C-reactive protein levels, correlating with skin disease activity

Anjali S. Vekaria¹^*, Patrick M. Brunner²^*, Ahmad I. Aleisa¹, [...] Lauren Bonomo¹, Mark G. Lebwohl¹, Ariel Israel³, Emma Guttman-Yassky ^1,2

Anjali S. Vekaria¹^*, Patrick M. Brunner²^*, [...] Ahmad I. Aleisa¹, Lauren Bonomo¹, Mark G. Lebwohl¹, Ariel Israel³, Emma Guttman-Yassky ^1,2

^* Equal contributors

PUBLISHED 27 Oct 2017

Author details Author details

¹ Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
² The Laboratory for Investigative Dermatology, The Rockefeller University, New York, NY, 10065, USA
³ Department of Family Medicine, Clalit Health Services, Jerusalem, 954323, Israel

Anjali S. Vekaria
Roles: Data Curation, Investigation, Project Administration, Resources, Validation, Writing – Original Draft Preparation

Patrick M. Brunner
Roles: Formal Analysis, Investigation, Methodology, Writing – Original Draft Preparation

Ahmad I. Aleisa
Roles: Data Curation

Lauren Bonomo
Roles: Data Curation, Writing – Review & Editing

Mark G. Lebwohl
Roles: Writing – Review & Editing

Ariel Israel
Roles: Data Curation, Formal Analysis

Emma Guttman-Yassky
Roles: Conceptualization, Funding Acquisition, Investigation, Methodology, Resources, Supervision, Writing – Review & Editing

OPEN PEER REVIEW

REVIEWER STATUS

Abstract

Background: Atopic dermatitis (AD), the most common chronic inflammatory skin disease, is evolving as a systemic disease, and associated systemic inflammation is possibly linked to increases in cardiovascular disease.
Methods: We assessed levels of the inflammatory marker CRP in 59 patients with moderate-to-severe AD compared to matched healthy controls, and to determine correlation with skin disease severity. Clinical severity was measured using SCORing of Atopic Dermatitis (SCORAD) and body surface area (BSA). Control subjects (n=118), matched by age, gender, smoking status and ethnicity, were obtained from the National Health and Nutrition Survey (NHANES).
Results: AD patients had significantly increased serum CRP levels compared to controls (0.7±1.0 vs. 0.4±0.7mg/dl; p=0.001), and 52.5% of them showed CRP levels >0.3mg/dl, predicting high cardiovascular risk. CRP levels were significantly correlated with both SCORAD (r=0.427, p=0.0008) and BSA (r=0.407, p=0.0015). IgE levels in AD were highly elevated (median 2903U/ml, IQR [234,10655]), but only weakly correlated with SCORAD (r=0.282, p=0.0427) and BSA (r=0.382, p=0.0052), but not with CRP levels. AD patients also showed increased LDH levels, but without significant correlations with disease severity (SCORAD, BSA) or CRP.
Conclusions: Our study strongly supports CRP as a marker for disease severity in moderate-to-severe AD patients, further demonstrating its chronic systemic nature.

Keywords

Atopic dermatitis, C-reactive protein, systemic inflammation, disease biomarker

Corresponding author: Emma Guttman-Yassky

Competing interests: PMB has received personal fees from LEO Pharma and Sanofi. EGY is a board member for Sanofi Aventis, Regeneron, Stiefel/GlaxoSmithKline, MedImmune, Celgene, Anacor, AnaptysBio, Celsus, Dermira, Galderma, Glenmark, Novartis, Pfizer, Vitae, Leo Pharma, Abbvie and Asana Biosciences; has received consultancy fees from Regeneron, Sanofi, MedImmune, Celgene, Stiefel/GlaxoSmithKline, Celsus, BMS, Amgen, Drais, AbbVie, Anacor, AnaptysBio, Dermira, Galderma, Glenmark, LEO Pharma, Novartis, Pfizer, Vitae, Mitsubishi Tanabe, Eli Lilly, Abbvie, and Asana Biosciences; and has received research support from Janssen, Regeneron, Celgene, BMS, Novartis, Merck, LEO Pharma, Dermira, Glenmark, Innovaderm, and UCB. The rest of the authors declare that they have no relevant conflicts to disclose.

Grant information: PMB was supported in part by grant # UL1 TR0001866 from the National Center for Advancing Translational Sciences and National Institutes of Health, Clinical and Translational Science Award program.
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright: © 2017 Vekaria AS et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Data associated with the article are available under the terms of the Creative Commons Zero "No rights reserved" data waiver (CC0 1.0 Public domain dedication).

How to cite: Vekaria AS, Brunner PM, Aleisa AI et al. Moderate-to-severe atopic dermatitis patients show increases in serum C-reactive protein levels, correlating with skin disease activity [version 2; peer review: 3 approved]. F1000Research 2017, 6:1712 (https://doi.org/10.12688/f1000research.12422.2) First published: 20 Sep 2017, 6:1712 (https://doi.org/10.12688/f1000research.12422.1) Latest published: 27 Oct 2017, 6:1712 (https://doi.org/10.12688/f1000research.12422.2)

Revised Amendments from Version 1

We have changed our article as per the reviewer's request. We have modified the title to more accurately reflect the disease severity of patients studied. We have also updated the Abstract to reflect the percentage of patients in the range of cardiovascular high-risk CRP levels. Also, the axis labeling was updated in the correlation graphs of Figures 1 and 3, for a more clear display of CRP levels.

See the authors' detailed response to the review by Alexander A. Navarini

Introduction

Atopic dermatitis (AD), the most common chronic inflammatory skin disease, frequently starts during infancy, and in adults it has usually been present for several decades¹. Similar to moderate-to-severe psoriasis, there is now evolving evidence that AD also has a systemic component beyond the classic atopic/allergic comorbidities, with increases in cardiovascular risk factors such as obesity^2–4, and associations with cardiovascular diseases in population-based studies^2,5. A comparison of AD and psoriasis patients with healthy individuals, using cardiac computed tomography angiography, showed higher rates of coronary artery disease in both psoriasis and AD, compared to controls⁶. Systemic immune activation in adult moderate-to-severe AD patients is reflected by highly activated circulatory T-cells as measured using T-cell activation markers (ICOS and HLA-DR), at even higher frequencies than in psoriasis⁷. Also, several inflammatory blood biomarkers (e.g. Thymus and Activation Regulated Chemokine /TARC or CCL17) were consistently shown to correlate with AD clinical severity⁸. The important contribution of chronic inflammation to the development of atherosclerosis and cardiovascular disease events is now well established⁹. Therefore, C-reactive protein/CRP, an acute phase reactant reflecting systemic inflammation, has been suggested as potential biomarker for cardiovascular disease⁹. In patients with a history of myocardial infarction, the anti-inflammatory monoclonal antibody canakinumab (IL-1β blocker) led to a significant decrease in cardiovascular events¹⁰. Patients also showed reductions in serum CRP levels, without changes in their lipid profile¹⁰, demonstrating that anti-inflammatory treatment can indeed have an impact on cardiovascular disease. In psoriasis, it has been demonstrated that CRP is significantly elevated and associated with disease severity¹¹. One recent study suggests that CRP levels are also increased in adult chronic AD patients vs. matched controls¹², but it remains to be determined whether CRP could serve as a marker for disease severity. In contrast to adults, studies in children and adolescents with active AD did not show increases in overall CRP levels compared to controls¹³, and elevated CRP levels early in life were claimed to have a protective role against the development of AD¹⁴ and allergic sensitization¹⁵, suggesting that chronic low-grade inflammation in infants might provide some protection from allergen sensitization. In order to better clarify the potential role of CRP as disease biomarker, we sought to investigate CRP serum levels in moderate-to-severe adult AD patients in relation to skin disease severity.

Methods

Study population

We retrospectively assessed CRP levels in serum from 59 adult AD patients (>18yo), with active AD and a Body Surface Area/BSA>10% (mean 59.6±27.9%, range 11–99%), that had presented to the outpatient clinic of the Department of Dermatology at Mount Sinai Hospital, New York, NY. All patients reported chronic AD since early infancy, and were off systemic anti-inflammatory AD treatment. Clinical severity was measured using SCORing of Atopic Dermatitis (SCORAD), and the vast majority of patients were in the moderate-to-severe category¹⁶ (mean SCORAD 62.2±20.86, range 15–97.5). Other demographic data was also collected, including age (mean 39.5±15.2, range 18–67 years), gender (49.2/51.8% F:M), BMI (mean 27.5±5.6kg/m², range 18.99–41.62), blood pressure (mean 123.5/77.1mmHg, range systolic 80–154, diastolic 58–109), smoking status (11.9% smokers), total serum IgE (median 2903U/ml, IQR [234,10655]), ethnicity, comorbid conditions, concomitant medications and lipid profiles (Dataset 1¹⁷). We also evaluated serum lactate dehydrogenase/LDH (mean 293.8U/L±115.3, range 117–597U/L), previously reported as a possible serum biomarker of AD severity¹⁸. None of the patients showed clinical signs of active skin infection.

Matching

Matched control subjects were obtained with a ratio of 2-to-1 (n=118) from the National Health and Nutrition Survey/NHANES (https://www.cdc.gov/nchs/nhanes). They were matched to AD patients for age, gender, smoking status and ethnicity, using the R procedure MatchIt, method ‘nearest’, with a ratio of 2 control subjects for each case subject. We used individuals from the SPRINT survey nationwide between the years 2005 and 2010, for which CRP laboratory data were available. There were no changes (from the previous 2 years of NHANES) to equipment, laboratory methods or lab site.

CRP serum level measurement

Serum CRP levels in AD patients were assessed using an immunoturbidimetric test (Abbott Laboratories, Lake Bluff, Illinois). For NHANES, CRP levels were assessed using a Siemens/Behring Nephelometer (Siemens HealthcareDiagnostics, Deerfield, IL), as described at https://wwwn.cdc.gov/Nchs/Nhanes/2009-2010/CRP_F.htm. Both assays had a lower limit of detection of 0.02mg/dl. While different assays were used to measure CRP levels in patients and controls, both methods have the same lower level of detection (0.02mg/dL) and were shown to be comparable¹⁹.

Statistical analysis

For comparisons between AD and the control group, we used the two sample t-test for age; Fisher exact test for gender, ethnicity and smoking status; and the two sample Wilcoxon test for biomarkers. When variables were missing for some of the individuals, comparison was performed only for the individuals for which the variable was available.

Pearson correlation coefficients were used to calculate the association between the logarithm of the biomarkers (CRP, LDH, total serum IgE) and disease activity measures SCORAD and BSA. We used a univariate linear regression formula to draw the regression line for these correlations. Each correlation was performed only for the individuals for which relevant biomarker data was available. All analyses were performed using R statistical software (Version 3.3).

Results

There were no significant differences between demographic data of AD patients and controls (age, gender, ethnicity), blood lipids (triglycerides, LDL, HDL), body mass index (BMI), or smoking status (Table 1).

Table 1. Baseline characteristics and blood biomarker levels.

	Control	Atopic Dermatitis	p-value
	n= 118	n= 59
Age in years, mean (SD)	40.3 (14.2)	39.5 (15.2)	0.707
Female gender	58 (49.2%)	29 (49.2%)	1.000
Race and Ethnicity (%)			0.883
Hispanic	8 (6.8%)	6 (10.2%)	0.555
Non-Hispanic White	71 (60.2%)	35 (59.3%)	1.000
Non-Hispanic Black	21 (17.8%)	9 (15.3%)	0.832
Other	18 (15.3%)	9 (15.3%)	1.000
Smoking (%)			1.000
Missing	4 (3.4%)	2 (3.4%)	1.000
NO	100 (84.7%)	50 (84.7%)	1.000
YES	14 (11.9%)	7 (11.9%)	1.000
CRP mg/dL (SD)	0.4 (0.7)	0.7 (1.0)	**0.001
LDH U/L (SD)	132.7 (30.3)	293.8 (115.3)	***< 0.00001
Triglycerides mg/dL (SD)	136.1 (158.3)	130.0 (69.8)	0.482
LDL mg/dL (SD)	116.1 (31.3)	111.5 (38.2)	0.357
HDL mg/dL (SD)	54.1 (14.4)	60.6 (27.8)	0.376
Body Mass Index kg/m² (SD)	28.1 (6.8)	27.5 (5.6)	0.781

Comparisons of AD patients with matched healthy controls. Two samples t-test (age), Fisher exact test (gender, ethnicity, smoking), Wilcoxon test (CRP, LDH, triglycerides, LDL, HDL, BMI).

AD patients had significantly increased serum CRP levels (0.7±1.0mg/dl) when compared to controls (0.4±0.7mg/dl; p=0.001; Table 1 and Figure 1a). CRP levels in AD ranged from undetectable in one patient (<0.02mg/dl) to a maximum value of 6.2mg/dl in a patient with very severe AD and a SCORAD of 95 (Dataset 1¹⁷). 23 out of 59 patients (39%) showed CRP levels outside the reference range of 0-0.5mg/dl. Furthermore, CRP levels were significantly correlated with both SCORAD (Figure 1b) and BSA (Figure 1c). As 14 patients reported a history of asthma, a disease that has been shown to be associated with increased CRP blood levels²⁰, we performed a sensitivity analysis to assess the non-asthma AD patients (Supplementary Table 1). However, differences between CRP levels in AD patients and controls remained highly significant after exclusion of all the patients with a history of asthma (Figure 2, Supplementary Table 1).

Figure 1. C-reactive protein levels are increased in AD patients.

Comparison of CRP levels (mg/dL) in AD patients and healthy control subjects; Wilcoxon-test: p=0.001 (a); Pearson correlation and linear regression of CRP levels with SCORAD (b) and body surface area/BSA (c).

Figure 2. C-reactive protein levels are increased in AD patients without asthma.

CRP levels (mg/dL) in AD patients excluding those with a history of asthma, compared to matched healthy control subjects; Wilcoxon-test: p<0.001.

Consistent with previous publications¹⁸, the AD patients also showed increased LDH levels, but without significant correlations with disease severity measures (SCORAD, BSA) or CRP (Figure 3a–c). While IgE levels in AD were highly elevated (median 2903U/ml, IQR [234,10655]) and correlated with SCORAD and BSA, they were not correlated with CRP (Figure 3d–f).

Figure 3. Blood biomarker and skin correlations.

LDH and total serum IgE levels correlated with SCORAD, body surface area/BSA and CRP levels (a–f); Pearson correlation and linear regression.

Age	Gender	Ethnicity	Smoking status	CRP	LDH	Triglycerides	LDL	HDL	BMI	Systolic blood pressure	Diastolic blood pressure	SCORAD	Comorbid Conditions	Concomitant Medication at time of presentation	IgE (U/mL)	group
19	F	Hispanic	NO	0	NA	74	141	53	20.94	110	70	51	asthma, allergic rhinitis	zafirlukast, cetrizine	14910	AD
50	F	Non-Hispanic White	NO	6.23	338	114	96	51	36.45	133	70	95	arterial hypertension, depression	paroxetine, amlodipine, atenolol, doxepin	17900	AD
30	M	Non-Hispanic Black	NO	3.54	NA	90	111	38	31.9	137	80	66.5	none	montelukast, hydroxyzine	21240	AD
27	F	Non-Hispanic Black	YES	2.67	264	56	116	58	NA	NA	NA	80	none	none	NA	AD
46	M	Other	NO	1.39	469	149	105	30	31.14	116	67	79.5	arterial hypertension	doxepin	6640	AD
38	F	Non-Hispanic White	NO	1.33	381	79	73	51	26.7	128	86	70	allergic rhinitis	hydroxyzine	83	AD
54	F	Non-Hispanic White	NO	1.31	386	154	100	69	34.12	137	96	63.3	none	none	323	AD
34	M	Hispanic	YES	0.99	211	334	123	29	37.31	130	88	75	none	none	7580	AD
51	M	Non-Hispanic White	NO	0.95	301	80	106	56	22.53	129	69	46.6	none	none	1435	AD
49	F	Non-Hispanic White	Missing	0.89	207	177	93	50	20.47	128	82	60	anxiety, depression	hydroxyzine, sertraline	4315	AD
29	M	Non-Hispanic White	NO	0.58	537	184	121	45	27.93	122	67	51.7	asthma, allergic rhinitis	none	23630	AD
24	F	Non-Hispanic White	Missing	0.54	160	NA	NA	NA	NA	NA	NA	50	none	none	48	AD
24	M	Non-Hispanic Black	NO	0.49	NA	131	162	42	36.64	133	88	97.5	keratoconus	none	25070	AD
33	F	Non-Hispanic White	NO	0.47	313	95	99	41	34.48	118	75	70	none	none	1360	AD
27	M	Non-Hispanic White	NO	0.45	272	69	96	58	21.25	113	77	63.8	none	none	360	AD
51	M	Non-Hispanic Black	NO	0.45	290	129	259	53	29.29	154	109	67.7	arterial hypertension, hyperlipidemia	atenolol, losartan, rosuvastatin	191	AD
37	F	Non-Hispanic White	NO	0.4	597	139	120	45	28.24	124	70	45	none	doxepin	972	AD
60	M	Non-Hispanic White	NO	0.33	257	54	61	72	30.83	138	88	30.8	arterial hypertension, hyperlipidemia, depression, Hashimoto's thyroiditis	levothyroxine, losartan, rosuvastatin, bupropion, ASS	234	AD
57	F	Non-Hispanic White	NO	0.32	210	204	156	50	23.88	132	82	53.7	allergic rhinitis	budesonide nasal spray, gabapentin	7390	AD
23	F	Non-Hispanic White	NO	0.29	185	237	64	68	24.46	125	89	41.8	none	none	217	AD
66	F	Non-Hispanic White	NO	0.25	200	92	127	105	19.98	137	89	32	arterial hypertension	labetalol, chlorthalidone	11	AD
33	M	Non-Hispanic Black	NO	0.22	213	50	59	43	34.12	110	58	30.7	asthma	none	454	AD
55	M	Non-Hispanic White	NO	0.22	NA	269	128	63	29.57	138	88	61.4	arterial hypertension	metoprolol	2991	AD
25	F	Non-Hispanic White	NO	0.13	227	305	125	60	23.59	124	84	66.8	asthma, allergic rhinitis	none	293	AD
50	F	Other	NO	0.13	473	73	143	101	21.29	124	73	80.4	none	none	4603	AD
32	F	Other	NO	0.12	504	176	133	97	25.56	110	72	30	allergic rhinitis, asthma	cetirizine, albuterol inhaler	6530	AD
46	M	Hispanic	NO	0.2	206	149	165	49	30.43	138	96	85.7	ulcerative colitis, acromegaly	none	5	AD
20	M	Other	NO	0.1	301	73	87	52	19.65	108	70	88.2	none	doxepin	23420	AD
26	F	Non-Hispanic White	NO	0.1	NA	105	103	61	25.2	117	66	38.4	asthma, allergic rhinitis	none	3070	AD
25	M	Non-Hispanic White	NO	0.14	212	133	94	35	34.6	124	75	57.4	depression, asthma	duloxetine	1727	AD
23	F	Other	NO	0.04	254	153	112	51	18.99	118	80	86.5	allergic rhinitis	hydroxyzine	35040	AD
25	M	Other	NO	0.11	274	29	76	54	24.16	115	73	60	none	levocetirizine	34600	AD
49	F	Hispanic	NO	0.4	272	112	106	60	20.65	104	60	25	none	none	7050	AD
19	F	Non-Hispanic White	NO	0.03	NA	NA	NA	NA	19.6	80	60	62.3	asthma	fluticasone/salmeterol inhaler, montelukast, diphenhydramine, albuterol inhaler	10420	AD
27	F	Other	NO	0.03	117	80	117	60	19.31	110	72	21.4	allergic rhinitis	cetirizine	17610	AD
28	F	Non-Hispanic White	NO	0.03	165	NA	NA	NA	21.22	120	83	40	asthma, allergic rhinitis	mometasone/formoterol inhaler, albuterol inhaler	3136	AD
18	F	Non-Hispanic White	NO	1.07	189	89	87	53	23.6	113	69	85	asthma	none	3794	AD
22	M	Non-Hispanic White	NO	1.11	NA	84	57	62	26.71	NA	NA	80	asthma	doxepin	22480	AD
45	M	Other	NO	0.2	482	175	182	56	25.95	109	64	57.2	urticaria, seasonal allergies	diphenhydramine	2782	AD
66	M	Non-Hispanic Black	YES	0.13	NA	111	103	57	26.04	136	69	69	arterial hypertension	amlodipine, losartan, ASS, cetirizine	NA	AD
66	F	Non-Hispanic White	NO	0.46	NA	36	83	88	23.54	127	71	45.2	asthma	estradiol, progesterone, fluticasone/salmeterol inhaler, albuterol inhaler	14	AD
22	M	Hispanic	NO	0.15	NA	103	61	44	32.46	100	68	51.5	none	none	228	AD
51	M	Non-Hispanic Black	NO	0.56	426	114	65	29	33.7	125	64	78.7	arterial hypertension, hyperlipidemia, diabetes mellitus, allergic rhinitis, CAD	ASS, clopidogrel, furosemide, metoprolol, simvastatin, enalapril, insulin detemir, nifedipine	NA	AD
26	F	Non-Hispanic Black	NO	0.07	288	73	117	65	33.2	116	77	47.7	asthma, allergic rhinitis	levocetirizine, hydroxyzine, albuterol inhaler	2815	AD
57	M	Non-Hispanic White	NO	1.24	256	279	118	38	34.43	128	82	96.6	arterial hypertension, allergic rhinitis	quinapril	42490	AD
18	M	Hispanic	NO	3.06	180	93	64	33	22.27	136	80	50	none	none	NA	AD
39	M	Other	NO	0.12	228	92	166	68	22.85	118	78	70	alopecia universalis	none	NA	AD
24	M	Non-Hispanic White	NO	0.12	384	44	59	62	21.25	119	67	85	eosinophilic esophagitis, asthma, urticaria	hydroxyzine, doxepin	47340	AD
36	M	Non-Hispanic White	NO	0.24	249	205	45	181	35.06	125	77	45	none	none	48	AD
49	F	Non-Hispanic White	YES	0.29	489	66	69	167	26.16	115	70	65	mixed connective tissue disease	hydrochloroquine	112	AD
48	F	Non-Hispanic White	NO	1.07	198	236	126	60	NA	NA	NA	90	hypothyroidism	levothyroxine	335	AD
50	F	Non-Hispanic White	YES	0.12	285	160	158	78	30.79	120	73	35	none	doxepin	156	AD
66	M	Non-Hispanic White	NO	0.07	241	55	114	59	28.55	143	88	15	hypothyroidism	levothyroxine	232	AD
67	M	Non-Hispanic Black	NO	0.53	465	141	104	33	29.84	140	89	69.5	arterial hypertension	losartan	7830	AD
57	M	Non-Hispanic White	NO	0.99	NA	106	120	49	24.03	137	81	65.7	none	none	249	AD
46	M	Non-Hispanic White	NO	1.15	192	139	156	58	29.48	119	86	90	none	none	NA	AD
48	M	Non-Hispanic White	YES	1.11	NA	101	131	95	32.65	127	88	90	none	none	11360	AD
31	F	Non-Hispanic White	YES	1.44	176	237	137	52	41.62	118	75	90	allergic rhinitis, anxiety	sertraline, bupropion	72	AD
65	F	Non-Hispanic White	NO	0.71	285	193	147	57	26.57	138	83	75	diabetes mellitus	metformin	NA	AD
23	F	Non-Hispanic White	NO	0.47	102	254	147	73	29.83	130	84	NA	NA	NA	NA	control
32	F	Other	NO	0.43	128	69	131	65	29.95	114	56	NA	NA	NA	NA	control
22	M	Hispanic	NO	0.14	93	110	112	52	21.39	128	88	NA	NA	NA	NA	control
39	M	Other	NO	0.08	112	93	84	68	25.33	106	78	NA	NA	NA	NA	control
30	F	Other	NO	0.35	122	225	106	81	32.98	120	70	NA	NA	NA	NA	control
24	M	Non-Hispanic White	NO	0.04	96	61	92	47	22.86	112	60	NA	NA	NA	NA	control
24	M	Non-Hispanic Black	NO	0.51	130	NA	NA	36	29.8	NA	NA	NA	NA	NA	NA	control
25	M	Non-Hispanic White	NO	0.03	106	47	53	65	22.33	114	54	NA	NA	NA	NA	control
65	F	Non-Hispanic White	NO	0.16	151	233	83	55	36.63	106	68	NA	NA	NA	NA	control
25	M	Non-Hispanic White	NO	0.11	NA	NA	NA	60	17.64	116	86	NA	NA	NA	NA	control
49	F	Non-Hispanic White	Missing	2.47	148	NA	NA	51	30.76	104	62	NA	NA	NA	NA	control
25	F	Non-Hispanic White	NO	1.93	95	109	86	49	33.48	128	64	NA	NA	NA	NA	control
29	M	Non-Hispanic White	NO	1.28	156	NA	NA	35	28.04	130	76	NA	NA	NA	NA	control
50	F	Non-Hispanic White	NO	0.05	118	NA	NA	74	24.17	130	76	NA	NA	NA	NA	control
57	M	Non-Hispanic White	NO	0.05	132	109	175	61	23.86	116	68	NA	NA	NA	NA	control
24	F	Non-Hispanic White	Missing	4.77	128	NA	NA	43	20.91	110	68	NA	NA	NA	NA	control
30	F	Other	NO	1.17	102	110	126	65	37.99	110	70	NA	NA	NA	NA	control
26	F	Non-Hispanic Black	NO	0.5	168	NA	NA	40	34.24	118	76	NA	NA	NA	NA	control
66	M	Non-Hispanic Black	YES	0.29	113	NA	NA	35	27.03	180	90	NA	NA	NA	NA	control
25	M	Other	NO	0.01	115	NA	NA	64	22.52	106	70	NA	NA	NA	NA	control
26	F	Non-Hispanic White	NO	0.62	111	NA	NA	75	26.75	114	66	NA	NA	NA	NA	control
49	F	Hispanic	NO	0.37	104	NA	NA	39	36.21	122	70	NA	NA	NA	NA	control
25	F	Non-Hispanic White	NO	0.39	131	149	121	69	28	108	66	NA	NA	NA	NA	control
57	M	Non-Hispanic White	NO	0.1	143	68	115	67	27.01	120	80	NA	NA	NA	NA	control
46	M	Non-Hispanic White	NO	0.21	197	113	51	36	35.58	154	100	NA	NA	NA	NA	control
27	F	Non-Hispanic Black	YES	1.14	138	NA	NA	54	56.76	NA	NA	NA	NA	NA	NA	control
23	M	Non-Hispanic Black	NO	0.61	114	45	82	47	26.84	136	72	NA	NA	NA	NA	control
22	M	Non-Hispanic Black	NO	0.04	82	147	72	79	29.26	NA	NA	NA	NA	NA	NA	control
50	F	Non-Hispanic White	YES	0.19	NA	NA	NA	74	20.49	148	84	NA	NA	NA	NA	control
44	F	Other	NO	0.03	132	NA	NA	79	24.93	106	76	NA	NA	NA	NA	control
22	M	Non-Hispanic Black	NO	0.43	110	126	89	42	39.17	106	72	NA	NA	NA	NA	control
24	F	Non-Hispanic White	Missing	1.33	123	231	135	75	37.98	112	56	NA	NA	NA	NA	control
51	M	Non-Hispanic White	NO	0.06	131	NA	NA	38	25.79	108	80	NA	NA	NA	NA	control
60	M	Non-Hispanic White	NO	0.18	112	65	146	58	NA	132	74	NA	NA	NA	NA	control
23	F	Non-Hispanic White	NO	0.17	181	125	85	41	23.35	106	84	NA	NA	NA	NA	control
66	M	Non-Hispanic Black	YES	0.56	147	NA	NA	52	19.93	104	26	NA	NA	NA	NA	control
51	M	Non-Hispanic White	NO	0.17	139	NA	NA	54	37.6	120	82	NA	NA	NA	NA	control
66	M	Non-Hispanic White	NO	0.14	156	126	98	53	26.4	138	52	NA	NA	NA	NA	control
28	F	Non-Hispanic White	NO	0.02	89	89	86	46	23.46	96	62	NA	NA	NA	NA	control
36	M	Non-Hispanic White	NO	0.03	141	1297	NA	28	26.45	108	66	NA	NA	NA	NA	control
24	M	Non-Hispanic White	NO	0.05	133	NA	NA	53	20.25	122	76	NA	NA	NA	NA	control
33	M	Non-Hispanic Black	NO	0.11	209	93	99	45	25.83	126	74	NA	NA	NA	NA	control
57	F	Non-Hispanic White	NO	0.05	112	153	125	60	24.18	112	64	NA	NA	NA	NA	control
51	M	Non-Hispanic Black	NO	0.13	146	131	138	48	32	118	86	NA	NA	NA	NA	control
37	F	Non-Hispanic White	NO	0.1	140	NA	NA	77	22.44	108	74	NA	NA	NA	NA	control
28	M	Other	NO	0.01	126	NA	NA	83	18.73	114	64	NA	NA	NA	NA	control
48	M	Non-Hispanic White	YES	0.1	132	NA	NA	43	26.72	NA	NA	NA	NA	NA	NA	control
42	F	Other	NO	0.13	157	NA	NA	64	21.2	NA	NA	NA	NA	NA	NA	control
60	M	Non-Hispanic White	NO	0.21	134	NA	NA	45	29.94	116	72	NA	NA	NA	NA	control
49	F	Non-Hispanic White	YES	0.08	121	NA	NA	40	22.44	94	74	NA	NA	NA	NA	control
66	M	Non-Hispanic White	NO	0.35	124	130	81	55	36.39	102	52	NA	NA	NA	NA	control
38	F	Non-Hispanic White	NO	0.48	131	NA	NA	51	36.72	130	88	NA	NA	NA	NA	control
39	M	Other	NO	0.03	129	48	93	61	25.22	NA	NA	NA	NA	NA	NA	control
48	F	Non-Hispanic White	NO	0.77	109	190	130	53	37.84	108	66	NA	NA	NA	NA	control
51	M	Non-Hispanic Black	NO	4.16	293	NA	NA	32	26.27	106	64	NA	NA	NA	NA	control
49	F	Hispanic	NO	0.69	157	NA	NA	41	31.8	132	82	NA	NA	NA	NA	control
55	M	Non-Hispanic White	NO	0.09	135	144	99	31	23.54	114	74	NA	NA	NA	NA	control
22	M	Hispanic	NO	0.13	157	62	83	44	23.01	114	44	NA	NA	NA	NA	control
49	F	Non-Hispanic White	Missing	0.74	115	133	151	46	33.24	110	66	NA	NA	NA	NA	control
23	M	Other	NO	0.23	84	83	129	52	20.49	112	70	NA	NA	NA	NA	control
27	M	Non-Hispanic White	NO	0.18	119	135	177	37	27.48	134	80	NA	NA	NA	NA	control
34	M	Hispanic	YES	0.08	137	NA	NA	55	23.49	122	70	NA	NA	NA	NA	control
50	F	Other	NO	0.17	149	NA	NA	53	24.85	120	74	NA	NA	NA	NA	control
65	F	Non-Hispanic White	NO	0.33	155	64	131	94	27.25	134	76	NA	NA	NA	NA	control
24	M	Non-Hispanic Black	NO	0.04	132	81	134	52	23.51	116	58	NA	NA	NA	NA	control
39	F	Non-Hispanic White	NO	0.17	107	NA	NA	62	21.88	112	84	NA	NA	NA	NA	control
57	F	Non-Hispanic White	NO	0.13	152	96	106	74	24.04	118	62	NA	NA	NA	NA	control
31	F	Non-Hispanic White	YES	1.09	131	207	159	33	34.99	112	66	NA	NA	NA	NA	control
26	F	Non-Hispanic Black	NO	1.14	133	34	110	50	39.32	106	78	NA	NA	NA	NA	control
24	M	Non-Hispanic White	NO	0.58	135	NA	NA	28	34.23	116	54	NA	NA	NA	NA	control
37	F	Non-Hispanic White	NO	0.92	166	NA	NA	36	37.88	126	72	NA	NA	NA	NA	control
57	M	Non-Hispanic White	NO	0.32	134	280	128	41	31.88	134	68	NA	NA	NA	NA	control
49	F	Non-Hispanic White	YES	0.1	126	67	133	74	23.63	100	68	NA	NA	NA	NA	control
27	F	Other	NO	0.12	130	75	145	45	25.31	98	66	NA	NA	NA	NA	control
54	F	Non-Hispanic White	NO	0.25	132	NA	NA	78	25.9	140	82	NA	NA	NA	NA	control
33	F	Non-Hispanic White	NO	1.88	141	95	95	37	34.77	NA	NA	NA	NA	NA	NA	control
31	F	Non-Hispanic White	YES	0.03	109	NA	NA	54	24.09	134	96	NA	NA	NA	NA	control
48	F	Non-Hispanic White	NO	0.14	96	67	90	63	20.72	114	64	NA	NA	NA	NA	control
51	M	Non-Hispanic Black	NO	0.37	139	NA	NA	41	26.27	98	78	NA	NA	NA	NA	control
26	F	Non-Hispanic White	NO	1.36	149	NA	NA	41	47.11	128	90	NA	NA	NA	NA	control
39	F	Non-Hispanic White	NO	0.01	131	86	109	54	24.41	124	74	NA	NA	NA	NA	control
50	F	Non-Hispanic White	YES	0.06	107	250	189	47	26.44	122	52	NA	NA	NA	NA	control
46	M	Non-Hispanic White	NO	0.01	128	NA	NA	60	19.78	NA	NA	NA	NA	NA	NA	control
30	M	Non-Hispanic Black	NO	0.04	147	NA	NA	69	24	126	78	NA	NA	NA	NA	control
26	F	Other	NO	0.04	109	136	130	64	22.79	102	58	NA	NA	NA	NA	control
28	F	Non-Hispanic White	NO	0.08	132	33	51	72	21.44	116	48	NA	NA	NA	NA	control
29	M	Non-Hispanic White	NO	0.06	115	NA	NA	57	21.42	102	74	NA	NA	NA	NA	control
66	F	Non-Hispanic White	NO	0.19	92	83	138	54	NA	NA	NA	NA	NA	NA	NA	control
33	M	Non-Hispanic Black	NO	0.04	107	NA	NA	60	28.08	116	62	NA	NA	NA	NA	control
57	M	Non-Hispanic White	NO	0.22	151	113	98	45	33.55	142	74	NA	NA	NA	NA	control
55	M	Non-Hispanic White	NO	0.28	144	100	150	50	27.9	146	86	NA	NA	NA	NA	control
54	F	Non-Hispanic White	NO	0.93	187	164	119	44	27.87	116	68	NA	NA	NA	NA	control
44	F	Other	NO	0.04	254	121	134	72	27.66	126	90	NA	NA	NA	NA	control
34	M	Hispanic	YES	0.42	154	91	142	78	36.06	110	78	NA	NA	NA	NA	control
67	M	Non-Hispanic Black	NO	0.06	123	85	170	61	27.92	NA	NA	NA	NA	NA	NA	control
32	F	Other	NO	0.4	100	NA	NA	38	24.04	NA	NA	NA	NA	NA	NA	control
66	F	Non-Hispanic White	NO	0.66	139	NA	NA	33	38.6	NA	NA	NA	NA	NA	NA	control
27	F	Non-Hispanic Black	YES	0.1	123	NA	NA	52	28.14	114	68	NA	NA	NA	NA	control
36	M	Non-Hispanic White	NO	0.57	132	NA	NA	39	24.79	126	92	NA	NA	NA	NA	control
33	F	Non-Hispanic White	NO	0.6	132	NA	NA	68	46.68	NA	NA	NA	NA	NA	NA	control
39	F	Non-Hispanic White	NO	0.07	126	112	127	53	28.02	NA	NA	NA	NA	NA	NA	control
41	M	Other	NO	0.01	104	87	125	43	23.39	120	70	NA	NA	NA	NA	control
38	F	Non-Hispanic White	NO	0.02	114	54	107	61	17.23	96	70	NA	NA	NA	NA	control
27	M	Non-Hispanic White	NO	1.13	168	246	96	26	29.14	152	114	NA	NA	NA	NA	control
67	M	Non-Hispanic Black	NO	0.03	205	NA	NA	74	27.87	148	72	NA	NA	NA	NA	control
46	M	Hispanic	NO	0.03	144	NA	NA	76	30.18	112	70	NA	NA	NA	NA	control
66	F	Non-Hispanic White	NO	0.23	154	NA	NA	65	33.33	146	70	NA	NA	NA	NA	control
39	F	Non-Hispanic White	NO	0.39	135	NA	NA	38	44.98	112	82	NA	NA	NA	NA	control
51	M	Non-Hispanic Black	NO	0.05	NA	NA	NA	NA	24.37	122	76	NA	NA	NA	NA	control
46	M	Hispanic	NO	0.06	125	NA	NA	38	23.13	118	74	NA	NA	NA	NA	control
66	F	Non-Hispanic White	NO	0.07	140	73	184	62	27.28	102	52	NA	NA	NA	NA	control
22	M	Non-Hispanic White	NO	0.04	122	NA	NA	71	22.74	104	62	NA	NA	NA	NA	control
20	M	Other	NO	0.01	96	137	88	56	18.4	100	72	NA	NA	NA	NA	control
22	M	Non-Hispanic White	NO	0.38	123	NA	NA	49	22.18	110	74	NA	NA	NA	NA	control
30	M	Non-Hispanic Black	NO	0.08	160	126	112	55	36.62	124	82	NA	NA	NA	NA	control
46	M	Other	NO	0.08	115	92	139	38	23.19	108	82	NA	NA	NA	NA	control
48	M	Non-Hispanic White	YES	0.01	101	NA	NA	51	20.37	126	60	NA	NA	NA	NA	control

Dataset 1.Individual demographics, biomarkers and comorbid conditions of the AD study patients.

Discussion

This study is the first to demonstrate a correlation of AD disease severity with CRP levels in moderate-to-severe adult AD patients with decades of chronic disease activity, independent of co-existence of asthma. This finding is in line with the evolving concept that chronic AD has a considerable systemic inflammatory component¹² that is directly linked with the overall inflammatory burden in the skin. This increase in systemic inflammation might not only be a biomarker for skin disease severity, but one might speculate that it could also contribute to AD comorbid conditions, such as the evolvement of cardiovascular disease². This concept is strongly supported by the fact that canakinumab led to a significant reduction in serum CRP levels and cardiovascular events in a recent clinical trial¹⁰. Interestingly, a case series using the IL-6R blocker tocilizumab was efficacious in AD, and decreased CRP levels, but was not followed further due to bacterial superinfection²¹. According to the joint guidelines of the Centers for Disease Control and Prevention and the American Heart Association on CRP levels and cardiovascular risk¹¹, 20 of our AD patients (33.9%) showed CRP levels in the range of ≥0.1mg/dl and ≤0.3mg/dl, predicting intermediate risk, and 31 patients (52.5%) showed CRP levels >0.3mg/dl, which is within the high risk range. While CRP is predominantly produced by hepatocytes, it has also been detected in tape stripping experiments from AD skin, and its expression responded to emollients²².

Future large and prospective studies in chronic severe AD patients should determine whether the up-regulated CRP levels observed in our AD cohort are indeed linked to increased cardiovascular risk, beyond its role as a marker of systemic inflammation. Nevertheless, there is some circumstantial evidence that even these small increases might be clinically relevant, as CRP above 0.42mg/dL showed differences in statin treatment outcomes for cardiovascular events in a clinical trial²³, and CRP levels in the canakinumab trial were in the same order of magnitude¹⁰.

Future clinical trials investigating new therapeutic agents might follow changes in CRP levels during treatment as a potential serum biomarker of disease severity and systemic inflammation, and these may clarify whether correcting CRP can serve as a surrogate for decreasing cardiovascular risk in AD patients. However, increases in CRP levels can be a result of various conditions such as infections and malignancies, which needs to be taken into account.

Our study harbors a few limitations. Besides being a retrospective study, healthy controls were not available at our site and were based on published historic controls matched for age, gender, and ethnicity. Also, it focused on a moderate-to-severe AD patient population (all but two patients had moderate-to-severe AD, i.e. a SCORAD >25¹⁶) in a large tertiary academic center in New York, while controls were obtained across the United States, which might introduce some bias. To ensure that our results are applicable to the general AD population across ethnicities, larger international studies across different ethnic backgrounds that will also evaluate for existence of “silent” cardiovascular disease in chronic AD patients are needed. However, our data supports the role that persistent skin disease has in the systemic burden of inflammation in AD patients, mandating further investigation.

Ethical statement

This study has been approved by the IRB of the Icahn School of Medicine at Mount Sinai, New York, NY (approval number, 16-00717), according to the Declaration of Helsinki.

Data availability

Dataset 1: Individual demographics, biomarkers and comorbid conditions of the AD study patients. doi, 10.5256/f1000research.12422.d177784¹⁷

Competing interests

PMB has received personal fees from LEO Pharma and Sanofi. EGY is a board member for Sanofi Aventis, Regeneron, Stiefel/GlaxoSmithKline, MedImmune, Celgene, Anacor, AnaptysBio, Celsus, Dermira, Galderma, Glenmark, Novartis, Pfizer, Vitae, Leo Pharma, Abbvie and Asana Biosciences; has received consultancy fees from Regeneron, Sanofi, MedImmune, Celgene, Stiefel/GlaxoSmithKline, Celsus, BMS, Amgen, Drais, AbbVie, Anacor, AnaptysBio, Dermira, Galderma, Glenmark, LEO Pharma, Novartis, Pfizer, Vitae, Mitsubishi Tanabe, Eli Lilly, Abbvie, and Asana Biosciences; and has received research support from Janssen, Regeneron, Celgene, BMS, Novartis, Merck, LEO Pharma, Dermira, Glenmark, Innovaderm, and UCB. The rest of the authors declare that they have no relevant conflicts to disclose.

Grant information

PMB was supported in part by grant # UL1 TR0001866 from the National Center for Advancing Translational Sciences and National Institutes of Health, Clinical and Translational Science Award program.

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Supplementary material

Supplementary Table 1. Baseline characteristics and blood biomarker levels of AD subset without asthma. AD patients excluding those with a history of asthma, compared with matched healthy controls. Two samples t-test (age), Fisher exact test (gender, ethnicity, smoking), Wilcoxon test (CRP, LDH, triglycerides, LDL, HDL, BMI).

Click here to access the data.

Faculty Opinions recommended

References

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2. Brunner PM, Silverberg JI, Guttman-Yassky E, et al.: Increasing Comorbidities Suggest that Atopic Dermatitis Is a Systemic Disorder. J Invest Dermatol. 2017; 137(1): 18–25. PubMed Abstract | Publisher Full Text
3. Silverberg JI, Greenland P: Eczema and cardiovascular risk factors in 2 US adult population studies. J Allergy Clin Immunol. 2015; 135(3): 721–8.e6. PubMed Abstract | Publisher Full Text
4. Zhang A, Silverberg JI: Association of atopic dermatitis with being overweight and obese: a systematic review and metaanalysis. J Am Acad Dermatol. 2015; 72(4): 606–16.e4. PubMed Abstract | Publisher Full Text
5. Silverberg JI: Association between adult atopic dermatitis, cardiovascular disease, and increased heart attacks in three population-based studies. Allergy. 2015; 70(10): 1300–8. PubMed Abstract | Publisher Full Text
6. Hjuler KF, Böttcher M, Vestergaard C, et al.: Increased Prevalence of Coronary Artery Disease in Severe Psoriasis and Severe Atopic Dermatitis. Am J Med. 2015; 128(12): 1325–34.e2. PubMed Abstract | Publisher Full Text
7. Czarnowicki T, Malajian D, Shemer A, et al.: Skin-homing and systemic T-cell subsets show higher activation in atopic dermatitis versus psoriasis. J Allergy Clin Immunol. 2015; 136(1): 208–11. PubMed Abstract | Publisher Full Text
8. Thijs J, Krastev T, Weidinger S, et al.: Biomarkers for atopic dermatitis: a systematic review and meta-analysis. Curr Opin Allergy Clin Immunol. 2015; 15(5): 453–60. PubMed Abstract | Publisher Full Text
9. Yousuf O, Mohanty BD, Martin SS, et al.: High-sensitivity C-reactive protein and cardiovascular disease: a resolute belief or an elusive link? J Am Coll Cardiol. 2013; 62(5): 397–408. PubMed Abstract | Publisher Full Text
10. Ridker PM, Everett BM, Thuren T, et al.: Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med. 2017; (in press). PubMed Abstract | Publisher Full Text
11. Strober B, Teller C, Yamauchi P, et al.: Effects of etanercept on C-reactive protein levels in psoriasis and psoriatic arthritis. Br J Dermatol. 2008; 159(2): 322–30. PubMed Abstract | Publisher Full Text
12. Wang J, Suárez-Fariñas M, Estrada Y, et al.: Identification of unique proteomic signatures in allergic and non-allergic skin disease. Clin Exp Allergy. 2017. PubMed Abstract | Publisher Full Text
13. Silverberg JI: Association between childhood atopic dermatitis, malnutrition, and low bone mineral density: a US population-based study. Pediatr Allergy Immunol. 2015; 26(1): 54–61. PubMed Abstract | Publisher Full Text
14. Marschan E, Kuitunen M, Kukkonen K, et al.: Probiotics in infancy induce protective immune profiles that are characteristic for chronic low-grade inflammation. Clin Exp Allergy. 2008; 38(4): 611–8. PubMed Abstract | Publisher Full Text
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16. Pucci N, Lombardi E, Novembre E, et al.: Urinary eosinophil protein X and serum eosinophil cationic protein in infants and young children with atopic dermatitis: correlation with disease activity. J Allergy Clin Immunol. 2000; 105(2 Pt 1): 353–7. PubMed Abstract | Publisher Full Text
17. Vekaria AS, Brunner PM, Aleisa AI, et al.: Dataset 1 in: Atopic dermatitis patients show increases in serum C-reactive protein levels, correlating with skin disease activity. F1000Research. 2017. Data Source
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Version 2

VERSION 2 PUBLISHED 20 Sep 2017

Author details Author details

Anjali S. Vekaria
Roles: Data Curation, Investigation, Project Administration, Resources, Validation, Writing – Original Draft Preparation

Patrick M. Brunner
Roles: Formal Analysis, Investigation, Methodology, Writing – Original Draft Preparation

Ahmad I. Aleisa
Roles: Data Curation

Lauren Bonomo
Roles: Data Curation, Writing – Review & Editing

Mark G. Lebwohl
Roles: Writing – Review & Editing

Ariel Israel
Roles: Data Curation, Formal Analysis

Emma Guttman-Yassky
Roles: Conceptualization, Funding Acquisition, Investigation, Methodology, Resources, Supervision, Writing – Review & Editing

Competing interests

Grant information

PMB was supported in part by grant # UL1 TR0001866 from the National Center for Advancing Translational Sciences and National Institutes of Health, Clinical and Translational Science Award program.
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Article Versions (2)

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Published: 27 Oct 2017, 6:1712

https://doi.org/10.12688/f1000research.12422.2

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Published: 20 Sep 2017, 6:1712

https://doi.org/10.12688/f1000research.12422.1

© 2017 Vekaria AS et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Data associated with the article are available under the terms of the Creative Commons Zero "No rights reserved" data waiver (CC0 1.0 Public domain dedication).

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Vekaria AS, Brunner PM, Aleisa AI et al. Moderate-to-severe atopic dermatitis patients show increases in serum C-reactive protein levels, correlating with skin disease activity [version 2; peer review: 3 approved] F1000Research 2017, 6:1712 (https://doi.org/10.12688/f1000research.12422.2)

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ApprovedThe paper is scientifically sound in its current form and only minor, if any, improvements are suggested

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Version 2

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PUBLISHED 27 Oct 2017

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Reviewer Report 21 Nov 2017

Alan Menter, Division of Dermatology, Baylor University Medical Center, Dallas, TX, USA

Isabel Haugh, Baylor Dermatology Residency Program, Baylor University Medical Center, Dallas, Texas, USA

Approved

https://doi.org/10.5256/f1000research.14051.r27679

This is a quality and important review by Vekaria et al from the Dermatology program of Mount Sinai in New York with Emma Guttman-Yassky- a leading clinician and researcher in the field of Atopic Dermatitis worldwide as corresponding author.

The nature of Atopic Dermatitis as a systemic inflammatory disease with comorbidities has been significantly accelerated over the past five years, especially with the initiation of the International Eczema Council (IEC) by Dr.s Guttman-Yassky and Paller. Of interest are the 3 meetings the IEC has had with the International Psoriasis Council (IPC) comparing the imuunopathogenesis and comorbidities of Atopic Dermatitis and Psoriasis.

Of interest, in this C-reactive protein review of 59 patients in Atopic Dermatitis Reference #11 (B. Strober et al¹) mentions the increased levels of CRP in psoriasis. It is important to recognize now that psoriasis has been demonstrated to be a systemic immune-mediated disease that CRP levels in psoriasis patients with moderate to severe disease are significantly lower than in psoriasis patients who develop Psoriatic Arthritis and also are lower than other immune-mediated systemic disease, e.g. Crohn's or Rheumatoid Arthritis.

We do believe it should be emphasized in the title and abstract that this CRP review was carved out in adults only. In addition, it should be clarified in the method section that data was obtained retrospectively.

We all recognize that CRP is an acute phase reactant that can increase with infections/autoimmune/cancer as well as cardiovascular disease. Thus, reference should be made in this article to comorbidities in this group of 59 Atopic Dermatitis patients which could have possibly played a role in the increases of CRP.

Is the work clearly and accurately presented and does it cite the current literature?

Yes
Is the study design appropriate and is the work technically sound?

Yes
Are sufficient details of methods and analysis provided to allow replication by others?

Yes
If applicable, is the statistical analysis and its interpretation appropriate?

Yes
Are all the source data underlying the results available to ensure full reproducibility?

Partly
Are the conclusions drawn adequately supported by the results?

Yes

References

1. Strober B, Teller C, Yamauchi P, Miller JL, et al.: Effects of etanercept on C-reactive protein levels in psoriasis and psoriatic arthritis.Br J Dermatol. 2008; 159 (2): 322-30 PubMed Abstract | Publisher Full Text

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Psoriasis

We confirm that we have read this submission and believe that we have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

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Reviewer Report 20 Nov 2017

Alexander A. Navarini, Department of Dermatology, University Hospital of Zurich, Zurich, CH-8091, Switzerland

Approved

https://doi.org/10.5256/f1000research.14051.r27404

Thank you, my concerns ... Continue reading

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Reviewer Report 06 Nov 2017

John C. Su, Department of Dermatology, Eastern Health Clinical School, Monash University, Melbourne, Vic, Australia

Approved

https://doi.org/10.5256/f1000research.14051.r27475

1. This is an interesting and considered study, a single-centre series of 59 adult patients matched 1:2 with controls from the nationwide NHANES survey. CRP, LDH and sIgE were correlated with AD severity, assessed by SCORAD and BSA.

Was there a reason for choosing SCORAD over objective SCORAD or EASI, which rely only on objective measures? Of interest, was CRP in adult AD vs non-AD using the NHANES data itself done (cf Silverberg Pediatr Allergy Immunol 2015)?

2. CRP, a marker of cardiovascular risk, was found to be elevated in AD, and correlated with AD severity. sIgE correlated with AD severity, but not with CRP. LDH did not show significant correlation with AD severity or CRP.

In addition to the Silverberg pediatric paper, Park et al¹ presented a pediatric inpatient study of 67 children examining the relationship between eczema severity (mild-moderate vs severe) and a number of laboratory markers. They did not find correlation with CRP, LDH or skin cultures. That paper was pediatric, written in Korean and also has limitations, but may be worth referencing for comparison.

3. Some potential confounders were considered. Sensitivity analysis was performed for non-asthma AD patients; this subgroup still showed correlation between CRP and AD severity. The patients did not have clinical infection. Were any swabs done? Some patients in the dataset had other co-morbidities that could have contributed to the CRP. The nature of the control group may not allow ready comparison of these, but a comment about possible or unlikely confounding from co-morbidities as the case may be worth considering.

Is the work clearly and accurately presented and does it cite the current literature?

Yes
Is the study design appropriate and is the work technically sound?

Yes
Are sufficient details of methods and analysis provided to allow replication by others?

Yes
If applicable, is the statistical analysis and its interpretation appropriate?

Yes
Are all the source data underlying the results available to ensure full reproducibility?

Yes
Are the conclusions drawn adequately supported by the results?

Yes

References

1. Park G, Park J, Hwang Y, Sung M, et al.: The correlation between the severity of atopic dermatitis classified by SCORing atopic dermatitis index and the laboratory tests. Allergy Asthma & Respiratory Disease. 2013; 1 (1). Publisher Full Text

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Pediatric dermatology and inflammatory skin disease

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

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Reviewer Report 11 Oct 2017

Alexander A. Navarini, Department of Dermatology, University Hospital of Zurich, Zurich, CH-8091, Switzerland

Approved with Reservations

https://doi.org/10.5256/f1000research.13452.r26213

Vekaria, Brunner et al. present a nice and clear clinical Investigation into AD severity and CRP levels.
The title should be adapted to "Moderate-to-severe AD patients ..." as you have really investigated just this population.

In the correlations, the patients with high CRP Levels are omitted for some (graphical?) reason. Please state why and whether the Pearson r is calculated with or without them. I don't think this changes the conclusion of the paper but IMHO should be shown. If you have access to the raw SCORAD data, you might be able to check whether subcomponents of the SCORAD have a closer connection to the Serum CRP than others:
- eczema involvement of some body regions
- crusting, oozing
- excoriations (scratch marks)

I think it may be worth adding to the abstract that >50% of the moderate-to-severe AD patients were in the range of cardiovascular high-risk CRP levels. Also, you should probably discuss all ways to lower the high CRP. The best of them may be anti-IL6R, which also works in atopic dermatitis according to a case series.

Is the work clearly and accurately presented and does it cite the current literature?

Yes
Is the study design appropriate and is the work technically sound?

Yes
Are sufficient details of methods and analysis provided to allow replication by others?

Yes
If applicable, is the statistical analysis and its interpretation appropriate?

Partly
Are all the source data underlying the results available to ensure full reproducibility?

No
Are the conclusions drawn adequately supported by the results?

Yes

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Inflammatory skin disease

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

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Author Response 27 Oct 2017

Emma Guttman-Yassky, The Laboratory for Investigative Dermatology, The Rockefeller University, New York, 10065, USA

27 Oct 2017

Author Response

We thank the reviewer for his positive and encouraging comments. We have changed the title accordingly.

All patients have been included in the graphs. We have now corrected the ... Continue reading We thank the reviewer for his positive and encouraging comments. We have changed the title accordingly.

All patients have been included in the graphs. We have now corrected the axis labeling for a more clear display of CRP levels in the correlation graphs Figures 1b and 1c, and Figures 3c and 3d.

Due to the retrospective nature of the study, we do not have access to the sub-components of SCORAD. Therefore, we cannot calculate these correlations.

We have now modified the abstract and the discussion section accordingly.

We thank the reviewer for his positive and encouraging comments. We have changed the title accordingly.

All patients have been included in the graphs. We have now corrected the axis labeling for a more clear display of CRP levels in the correlation graphs Figures 1b and 1c, and Figures 3c and 3d.

Due to the retrospective nature of the study, we do not have access to the sub-components of SCORAD. Therefore, we cannot calculate these correlations.

We have now modified the abstract and the discussion section accordingly.
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Author Response 27 Oct 2017

Emma Guttman-Yassky, The Laboratory for Investigative Dermatology, The Rockefeller University, New York, 10065, USA

27 Oct 2017

Author Response

We thank the reviewer for his positive and encouraging comments. We have changed the title accordingly.

All patients have been included in the graphs. We have now corrected the ... Continue reading We thank the reviewer for his positive and encouraging comments. We have changed the title accordingly.

All patients have been included in the graphs. We have now corrected the axis labeling for a more clear display of CRP levels in the correlation graphs Figures 1b and 1c, and Figures 3c and 3d.

Due to the retrospective nature of the study, we do not have access to the sub-components of SCORAD. Therefore, we cannot calculate these correlations.

We have now modified the abstract and the discussion section accordingly.

We thank the reviewer for his positive and encouraging comments. We have changed the title accordingly.

All patients have been included in the graphs. We have now corrected the axis labeling for a more clear display of CRP levels in the correlation graphs Figures 1b and 1c, and Figures 3c and 3d.

Due to the retrospective nature of the study, we do not have access to the sub-components of SCORAD. Therefore, we cannot calculate these correlations.

We have now modified the abstract and the discussion section accordingly.
Competing Interests: No competing interests were disclosed. Close
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Alexander A. Navarini, University Hospital of Zurich, Zurich, Switzerland
John C. Su, Monash University, Melbourne, Australia
Alan Menter, Baylor University Medical Center, Dallas, USA

Isabel Haugh, Baylor University Medical Center, Dallas, USA

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13 Views

21 Nov 2017 | for Version 2

Alan Menter, Division of Dermatology, Baylor University Medical Center, Dallas, TX, USA

Isabel Haugh, Baylor Dermatology Residency Program, Baylor University Medical Center, Dallas, Texas, USA

13 Views Cite this report Responses(0)

Approved

Is the work clearly and accurately presented and does it cite the current literature?

Yes
Is the study design appropriate and is the work technically sound?

Yes
Are sufficient details of methods and analysis provided to allow replication by others?

Yes
If applicable, is the statistical analysis and its interpretation appropriate?

Yes
Are all the source data underlying the results available to ensure full reproducibility?

Partly
Are the conclusions drawn adequately supported by the results?

Yes

References

Competing Interests

No competing interests were disclosed.

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Psoriasis

We confirm that we have read this submission and believe that we have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

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13 Views

20 Nov 2017 | for Version 2

Alexander A. Navarini, Department of Dermatology, University Hospital of Zurich, Zurich, CH-8091, Switzerland

13 Views Cite this report Responses(0)

Approved

Thank you, my concerns have now been fully addressed.

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Inflammatory skin disease

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

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Reviewer Report

16 Views

06 Nov 2017 | for Version 2

John C. Su, Department of Dermatology, Eastern Health Clinical School, Monash University, Melbourne, Vic, Australia

16 Views Cite this report Responses(0)

Approved

Is the work clearly and accurately presented and does it cite the current literature?

Yes
Is the study design appropriate and is the work technically sound?

Yes
Are sufficient details of methods and analysis provided to allow replication by others?

Yes
If applicable, is the statistical analysis and its interpretation appropriate?

Yes
Are all the source data underlying the results available to ensure full reproducibility?

Yes
Are the conclusions drawn adequately supported by the results?

Yes

References

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Pediatric dermatology and inflammatory skin disease

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

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Reviewer Report

26 Views

11 Oct 2017 | for Version 1

Alexander A. Navarini, Department of Dermatology, University Hospital of Zurich, Zurich, CH-8091, Switzerland

26 Views Cite this report Responses(1)

Approved With Reservations

Is the work clearly and accurately presented and does it cite the current literature?

Yes
Is the study design appropriate and is the work technically sound?

Yes
Are sufficient details of methods and analysis provided to allow replication by others?

Yes
If applicable, is the statistical analysis and its interpretation appropriate?

Partly
Are all the source data underlying the results available to ensure full reproducibility?

No
Are the conclusions drawn adequately supported by the results?

Yes

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Inflammatory skin disease

Respond to this report

Responses (1)

Author Response

27 Oct 2017

Emma Guttman-Yassky, The Laboratory for Investigative Dermatology, The Rockefeller University, New York, 10065, USA

We thank the reviewer for his positive and encouraging comments. We have changed the title accordingly.

All patients have been included in the graphs. We have now corrected the axis labeling for a more clear display of CRP levels in the correlation graphs Figures 1b and 1c, and Figures 3c and 3d.

Due to the retrospective nature of the study, we do not have access to the sub-components of SCORAD. Therefore, we cannot calculate these correlations.

We have now modified the abstract and the discussion section accordingly.

View more View less

Competing Interests

No competing interests were disclosed.

Alongside their report, reviewers assign a status to the article:

Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested

Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.

Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions

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Moderate-to-severe atopic dermatitis patients show increases in serum C-reactive protein levels, correlating with skin disease activity

Abstract

Keywords

Revised Amendments from Version 1

Introduction

Methods

Study population

Matching

CRP serum level measurement

Statistical analysis

Results

Table 1. Baseline characteristics and blood biomarker levels.

Figure 1. C-reactive protein levels are increased in AD patients.

Figure 2. C-reactive protein levels are increased in AD patients without asthma.

Figure 3. Blood biomarker and skin correlations.

Discussion

Ethical statement

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Competing interests

Grant information

Supplementary material

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