Clinicopathological Characteristics Related to Etiologies of Erythema Nodosum: A 10-Year Retrospective Study

Figures & data

Figure 1 Histopathology of erythema nodosum; (A) Septal panniculitis without vasculitis (Hematoxylin-eosin stain, x40). (B) Higher magnification demonstrating septal fibrosis with lymphohistiocytic infiltration (Hematoxylin-eosin stain, x100).

Table 1 Diagnostic Criteria for Diseases and Conditions Associated with Secondary Erythema Nodosum

Diseases	Criteria for Diagnosis
Mycobacterium tuberculosis (TB) infection	Presence of a positive culture result or a positive nucleic acid amplification test or acid-fast bacilli found in the specimen from the site of infection^Citation27
Latent tuberculosis infection (LTBI)	Positive result of either the TST or IGRA without clinical symptoms of active TB infection^Citation27
Disseminated tuberculosis infection	Presence of evidence of hematogenous spreading of tubercle bacilli^Citation28
Nontuberculous mycobacteria (NTM) infection	Consistent of clinical status, radiologic result, and repeated isolation of NTM by positive culture or nucleic acid amplification test from clinical specimens (sputum, biopsy specimens, or blood)^Citation29,Citation30
Streptococcal infection	Presence of the history of sore throat within the last 3 weeks with a positive throat swab culture or a positive rapid antigen detection test or high level of ASO^Citation6,Citation41
Pseudomonas aeruginosa infection	Considered as the cause of EN if concomitant presence of EN and positive hemoculture result and negative tissue culture result of the pathogen from the EN lesion^Citation5,Citation31
Cytomegalovirus (CMV) infection	CMV as isolated or detected from the clinical specimen^Citation32
Human immunodeficiency virus (HIV) infection	Presence of demonstrable antibodies to HIV and/or HIV or one of its components was detected directly from blood specimen^Citation33
Mumps	Compatible clinical symptoms together with positive serological result^Citation34
Disseminated candidiasis	Presence of evidences demonstrating tissue invasion by Candida spp. from histological or culture results or repeated positive hemoculture results^Citation35
Behçet’s disease (BD)	Present of symptoms as the 1990 ISG criteria for BD^Citation36 or the 2014 ICBD criteria for BD^Citation37
Hematologic malignancies	The diagnoses of myeloid, lymphoid, and myeloproliferative neoplasms were based on WHO classification and cytogenetic abnormalities.^Citation38,Citation39
Sarcoidosis	Compatible clinical features, radiological results and histopathological results of noncaseating granuloma in the absence of other alternative causes of the granuloma^Citation42
Drug-induced EN	Established temporal correlation with the possible causative drugs, which contained the history of medication taken before the patient developed EN and improvement of lesions after ceasing the drug, in the absence of other precipitating causes^Citation40

Abbreviations: ASO, anti-streptolysin-O antibody; BD, Behçet’s disease; CMV, Cytomegalovirus; EN, erythema nodosum; HIV, human immunodeficiency virus; ICBD, International Criteria for Behçet’s disease; IGRA, interferon-gamma release assay; ISG, International Study Group; LTBI, latent Mycobacterium tuberculosis infection; NTM, Nontuberculous mycobacteria; TB, tuberculosis; TST, tuberculin skin test; WHO, World Health Organization.

Figure 2 Recruitment process and the study flow diagram.

Abbreviation: EN, erythema nodosum.

Table 2 Demographic Data, Clinicopathological Results of Erythema Nodosum

Characteristics	(N = 169)
Demographic data
- Mean age at diagnosis (years [± SD])	40.6 ± 17.3
- Sex; N (%)
Male	25 (14.8%)
Female	144 (85.2%)
- Median onset of EN (months [IQR])	1 (0.3–3)
- Median follow-up duration (months [IQR])	2.3 (0.7–7.5)
- Recurrence	55/118 (46.6%)
- Median time of recurrence (months [IQR])	3 (1–5.5)
Symptoms of EN; N (%)
- Asymptomatic	17/165 (10.3%)
- Tenderness	142/165 (86.1%)
- Pruritus	2/165 (1.2%)
- Tenderness and pruritus	4/165 (2.4%)
Morphology; N (%)
- Nodules	128 (75.7%)
- Plaques	52 (30.8%)
- Papules	13 (7.7%)
- Patches	7 (4.1%)
- Macules	4 (2.4%)
- Cellulitis-like lesion	1 (0.6%)
Color; N (%)
- Red	134 (87.6%)
- Brown	33 (21.6%)
- Purple	9 (5.9%)
- Skin-color	5 (3.3%)
- Gray	2 (1.3%)
Location; N (%)
- Lower extremities	159/168 (94.6%)
- Upper extremities	39/168 (23.2%)
- Trunk	11/168 (6.5%)
- Face and neck	6/168 (3.6%)
Pathological result of EN; N (%)
- Acute EN	52 (30.8%)
- Chronic EN	117 (69.2%)

Abbreviations: EN, erythema nodosum; IQR, interquartile range; SD, standard deviation.

Table 3 Etiologies of Erythema Nodosum

Characteristics	(N = 169)
Idiopathic EN	106 (62.7%)
Secondary EN	63 (37.3%)
● Bacterial infections	24 (38.1%)
o Mycobacterium tuberculosis	15 (62.5%)
-TB lymphadenitis	7 (46.7%)
-Pulmonary TB	5 (33.3%)
-Latent TB infection	2 (13.3%)
-Disseminated TB	1 (6.7%)
o Streptococcal infection	4 (16.7%)
o Pseudomonas infection	4 (16.7%)
o Nontuberculous mycobacterium infection	1 (4.1%)
● Viral infections
o CMV	3 (4.8%)
o HIV	1 (33.3%)
o Mumps	1 (33.3%)
● Fungal infection	1 (33.3%)
o Disseminated candidiasis	1 (1.6%)
● Drugs	15 (23.8%)
o Oral contraceptive pills	13 (86.7%)
o Others (G-CSF, Vemurafenib)	2 (13.3%)
● Hematologic malignancies	9 (14.3%)
o AML	4 (44.4%)
o DLBCL	3 (33.3%)
o CLL	1 (11.1%)
o Primary myelofibrosis	1(11.1%)
● Behcet’s disease	5 (7.9%)
● Pregnancy	4 (6.3%)
● Lung cancer	1 (1.6%)
● Sarcoidosis	1 (1.6%)

Abbreviations: AML, acute myeloid leukemia; CLL, chronic lymphocytic leukemia; CMV, cytomegalovirus; DLBCL, diffuse large B-cell lymphoma; EN, erythema nodosum; G-CSF, granulocyte colony-stimulating factor; HIV, human immunodeficiency virus; IQR, interquartile range; SD, standard deviation; TB, tuberculosis.

Table 4 Treatment of Erythema Nodosum

Categories	Idiopathic EN (N = 106)	Secondary EN (N = 63)
Systemic treatment
- Yes	99/106 (93.4%)	Yes 44/63 (69.8%)
- No	7/106 (6.6%)	No 19/63 (30.2%)
Median duration to resolution (weeks [IQR])
- After initiation of treatment	5 (3–10)	4(2–6)
- Spontaneous resolution without treatment	3.5 (1.5–4)	4
Systemic medication
-Colchicine	83/99 (83.8%)	35/44 (79.6%)
-NSAIDs	74/99 (74.8%)	31/44 (70.5%)
o Indomethacin	69/74 (93.2%)	24/31 (77.4%)
o Naproxen	4/74 (5.4%)	6/31 (19.4%)
o Diclofenac	1/74 (1.4%)	0/31 (0%)
o Ibuprofen	0/74 (0%)	1/31 (3.2%)
-SSKI	19/99 (19.2%)	10/44 (22.7%)
-ASA	3/99(3.0%)	0/44 (0%)
-HCQ	1/99 (1.0%)	1/44 (2.3%)

Abbreviations: ASA, acetylsalicylic acid; EN, erythema nodosum; HCQ, hydroxychloroquine; IQR, interquartile range; NSAIDs, non-steroidal anti-inflammatory drugs; SD, standard deviation; SSKI, saturated solution of potassium iodide.

Table 5 Clinicopathological Findings and Investigations in Relations to Secondary Erythema Nodosum

Factors	Logistic Regression Analysis
	OR	95% CI	p-value
Clinical manifestations
- Presence of lesions on upper extremities	2.42	[1.17, 5.01]	0.018*
- Fever	3.33	[1.52, 7.30]	0.003*
- Cough	7.12	[0.78, 65.18]	0.082
- Arthralgia	2.28	[0.89, 5.85]	0.087
- Lymphadenopathy	20.8	[3.12, -]^a	<0.001*
Histopathological findings
- Presence of focal peripheral lobular panniculitis	1.93	[1.01, 3.65]	0.045*
- Presence of focal peripheral lobular panniculitis with eosinophils	0.32	[0.11, 0.90]	0.030*
- Chronic EN	0.83	[0.42, 1.62]	0.578

Notes: *Statistically significant. ^aCannot demonstrate the upper value of 95% confidence interval from the exact logistic regression analysis due to the value of approaching infinity.

Abbreviations: CI, confidence interval; EN, erythema nodosum; OR, odds ratio.

Figure 3 Erythema nodosum at the dorsum of the left hand in a patient diagnosed with acute myeloid leukemia.

Figure 4 Histopathology of primary erythema nodosum; (A) Septal panniculitis with focal peripheral lobular infiltration (Hematoxylin-eosin stain, x40). (B) Higher magnification demonstrating numerous eosinophils in the area of focal peripheral lobular panniculitis (Hematoxylin-eosin stain, x400).

Lewinsohn DM, Leonard MK, LoBue PA, et al. Official American thoracic society/infectious diseases society of America/centers for disease control and prevention clinical practice guidelines: diagnosis of tuberculosis in adults and children. Clin Infect Dis. 2017;64(2):e1–e33. doi:10.1093/cid/ciw694

 PubMed Web of Science ®Google Scholar

Raviglione MC. Tuberculosis. In: Kasper DL, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J, editors. Harrison’s Principles of Internal Medicine. 20th ed. New York, NY: McGraw-Hill Education; 2018:1236–1259.

 Google Scholar

Holland SM. Nontuberculous mycobacterial infections. In: Kasper DL, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J, editors. Harrison’s Principles of Internal Medicine. 20th ed. McGraw-Hill Education; 2018:1266–1270.

 Google Scholar

Griffith DE, Aksamit T, Brown-Elliott BA, et al. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med. 2007;175(4):367–416. doi:10.1164/rccm.200604-571ST

 PubMed Web of Science ®Google Scholar

Mert A, Kumbasar H, Ozaras R, et al. Erythema nodosum: an evaluation of 100 cases. Clin Exp Rheumatol. 2007;25(4):563–570.

 Web of Science ®Google Scholar

Shulman ST, Bisno AL, Clegg HW, et al. Clinical practice guideline for the diagnosis and management of group A streptococcal pharyngitis: 2012 update by the infectious diseases society of America. Clin Infect Dis. 2012;55(10):e86–e102. doi:10.1093/cid/cis629

 PubMed Web of Science ®Google Scholar

Patterson JW, Requena L. Panniculitis. In: Bolognia JL, Schaffer JV, Cerroni L, editors. Dermatology, 4th. Elsevier Health Sciences; 2018:1733–1757.

 Google Scholar

Ramphal R. Infections due to pseudomonas, burkholderia, and stenotrophomonas species. In: Kasper DL, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J, editors. Harrison’s Principles of Internal Medicine. 20th ed. New York, NY: McGraw-Hill Education; 2018:1167–1173.

 Google Scholar

Kotton CN, Hirsch MS. Cytomegalovirus and human herpesvirus types 6, 7, and 8. In: Kasper DL, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J, editors. Harrison’s Principles of Internal Medicine. 20th ed. New York, NY: McGraw-Hill Education; 2018:1361–1366.

 Google Scholar

Fauci AS, Folkers GK, Lane HC. Human immunodeficiency virus disease: AIDS and related disorders. In: Kasper DL, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J, editors. Harrison’s Principles of Internal Medicine. 20th ed. New York, NY: McGraw-Hill Education; 2018:1393–1463.

 Google Scholar

Rubin SA. Mumps. In: Kasper DL, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J, editors. Harrison’s Principles of Internal Medicine. 20th ed. New York, NY: McGraw-Hill Education; 2018:1481–1484.

 Google Scholar

Edwards JEJ. Candidiasis. In: Kasper DL, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J, editors. Harrison’s Principles of Internal Medicine. 20th ed. New York, NY: McGraw-Hill Education; 2018:1529–1532.

 Google Scholar

International Study Group for Behcet’s Disease. Criteria for diagnosis of behcet’s disease. Lancet. 1990;335(8697):1078–1080.

 PubMed Web of Science ®Google Scholar

Davatchi F, Assaad-Khalil S, Calamia KT. International Team for the Revision of the International Criteria for Behcet’s Disease (ITR-ICBD). The International Criteria for Behçet’s Disease (ICBD): a collaborative study of 27 countries on the sensitivity and specificity of the new criteria. J Eur Acad Dermatol Venereol. 2014;28(3):338–347. doi:10.1111/jdv.12107

 PubMed Web of Science ®Google Scholar

Taylor J, Xiao W, Abdel-Wahab O. Diagnosis and classification of hematologic malignancies on the basis of genetics. Blood. 2017;130(4):410–423. doi:10.1182/blood-2017-02-734541

 PubMed Web of Science ®Google Scholar

Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. International Agency for Research on Cancer; 2017.

 Google Scholar

Jain R, Yadav D, Puranik N, Guleria R, Jin JO. Sarcoidosis: causes, diagnosis, clinical features, and treatments. J Clin Med. 2020;9(4):1081. doi:10.3390/jcm9041081

 PubMed Web of Science ®Google Scholar

Papagrigoraki A, Gisondi P, Rosina P, Cannone M, Girolomoni G. Erythema nodosum: etiological factors and relapses in a retrospective cohort study. Eur J Dermatol. 2010;20(6):773–777. doi:10.1684/ejd.2010.1116

 Web of Science ®Google Scholar