Erythema nodosum

Erythema Nodosum

9 Matti Hannuksela, MD

From

the Uep’crrtmr~t

of Denrtatology, isersity

Finland

0-f Orrlu,

L:HiOulir.

Erythema nodosum (EN) has been known since 1798,’ when it was considered to be a clinical entity. In the latter half of the 19th Leas regarded as the principal cause and century, “rheumatism” tuberculosis as a minor causative factor of EN. During the first four decades of the present century, tuberculosis was reported to be the cause of EN in over 90’b of adult patients, but in the 1940s and 5Os, sarcoidosis. streptococcal. and other infections, and some other causes, were suggested.” During the last 15-20 years. a variety of factors have been found to trigger EN: however, despite thorough investigations, no evident cause for EN can be found in lo-30% of cases (Fig. 1).

Diagnostic Criteria The diagnosis of EN is usually based on the clinical picture only. The nodes are bright red, firm, elevated from the skin surface, and warm in the acute phase. The eruption tends to reach its maximum within l-2 weeks and it subsides in 3-12 weeks, leaving slight scaling and a bluish color for about 2 weeks, but no permanent scarring. The number of nodes varies from one to over ten, and their diameter from 1 to 15 cm or even larger. The front and lateral surfaces of the legs are usually affected. but lesions may also occur on the thighs and arms (Figs. 2 and 3). Erythema nodosum is a symptom seen predominantly in young women. The proportion of women among EN patients is usually 90%. but the difference between both sexes is not seen in children. Fever and malaise. as well as aches and pains in the joints, often precede or accompany the nodules. These symptoms usually disappear before the EN nodules have faded, but some patients may occasionally feel aches and pains for months or years during weather changes. Sarcoid EN occurs predominantly in the first half of the year and streptococcal EN in the cold months, but Yersinia EN shows no definite seasonal onset. The cold season prevalence of EN is apparently due to causative infections occurring in cold months and also to the influence of cold on the cutaneous blood supply, making the legs a locus ni inoris rrsistentiae. Even if the cause of sarcoidosis is unknown, the seasonal onset of sarcoidosis with or without EN

October-December Volume 4 Number 4

1986

09

Erythema Nodosum

tuberculosis

sarcoidosis

1800

1900

1850

FIG. 1. The changing

concept

of the etiology

1950

of erythema

speaks in favor of an infectious origin.3 A more chronic type of erythema nodosum, known as erythema nodosum migrans (ENmi) and as chronic erythema nodosum, is a variant of EN. The nodule(s) are unilateral or asymmetric and usually migrate or burst into smaller nodules, spreading radially.4-6

nodosum

since 1800.

patible with those of typical EN. In ENmi, however, the number of giant cells in the septal infiltrates is often marked.‘j

lmmunohistology Immunoglobulins (IgM or IgG) and C3 can be demonstrated only occasionally in the vessel walls in both typical and migratory EN.s

Histopathology Septal panniculitis is a characteristic feature of EN.7 In the early stage, a sparse neutrophilic infiltrate with occasional eosinophils is located around an increased number of small vessels in edematous septa of the fat tissue. In time, mononuclear cells become more numerous than granulocytes and the infiltrate extends into the lipocytes in the periphery of the fat lobule, where slight necrosis with foam cells also may be seen.6 In older lesions, granulomatous inflammation with histiocytes, dense collections of lymphocytes, and fibrosis of the septa often are present. Although the inflammation in EN is predominantly in the septa of the fat tissue, the lower part of the dermis is also affected. Inflammatory changes in the walls of both arteries and veins of various sizes are occasionally seen, but larger necroses due to this inflammation are never seen.s In ENmi, the histologic changes are com-

Differential Diagnosis Many other nodular lesions on the legs may clinically resemble those of EN. The most important of them, and the principal differential features, are listed in Table 1. In many patients, erythema induratum (Bazin’s disease) may be regarded as a tuberculid responding favorably to antituberculous treatment.10~11 In the majority of patients with erythema induratum, however, there are no signs of active or smoldering tuberculosis. Whitfield’s erythema induratum is considered to be closely related to nodular vasculitis (NV),12 however, one of the two original patients described by Whitfield obviously had Bazin’s disease and the other, EN. Nodular vasculitis was first described as a relatively chronic disease of nontuberculous origin that presents as recurrent nodular lesions on the lower legs.‘*

M. Hannuksela

90

TABLE

Clinics in Dermatology

1. Differential Diagnostic Criteria of Diseases Presenting as Nodules on the Legs

Disease

Clinical Features

Histology

Erythema

nodosum

(EN)

Red, warm nodules, raised from the skin on the frontal aspects of the lower legs. The nodules disappear without visible scarring in 2-12 weeks.

Septal infiltrates of lymphohistiocytic cells, granulocytes, and giant cells. Often slight fat necrosis and lipophages. lmmunoglobulins and complement seen rarely.

and Immunology

Erythema

induratum

(El)

Cold, ulcerating nodules predominantly on the calves. Heals with scarring.

Necrotizing vasculitis, tuberculoid or palisading granulomas. lmmunoglobulins and fibrin in half of the cases.

Nodular vasculitis

(NV)

Small, ulcerating, warm nodules on the calves but also elsewhere on the legs.

Necrotizing vasculitis more prominent and the inflammation more superficial than in El. A variant of El?

Weber-Christian’s

disease

Vtolaceous red, nonulceratlng nodules on the legs. The nodes resolve in 2-3 weeks leaving depressed, pigmented scars, often relapsing.

Lobular panniculitis with fat necrosis, “ghost cells,” and granulocytic infiltrate in the early phase. Later, histiocytic infiltrate with epithelioid and giant cells.

Subacute nodular migratory panniculitis has been proposed to be a disease entity’s 1; and a subclass of NV.** In the original series of Vilanova and Pinol Aguade.‘“?‘” however. the majority of the patients obviously had ENmi, but there were probably also cases of typical EN and of necrobiosis lipoidica. Weber-Christian disease is a real panniculitis with necrosis and heavy inflammation in the fat lobules. In fresh lesions, granulocytes predominate, but in older lesions there is less inflammation and pronounced granuloma formation with foam cells, epithelioid cells, and giant cells. This disease is occasionally associated with pancreatic disease (pancreatitis and pancreatic neoplasm), but the etiology is unknown in most cases.18 Lupus panniculitis, Rothmann-Makai syndrome, cutaneous periarteritis nodosa, and superficial thrombophlebitis may clinically resemble EN but are easily distinguished from it in microscopic examination.

Etiologic Factors As shown

in Figure

1, there

are several

factor triggering EN. These factors differ from one country to another and from year to year. Sarcoidosis, streptococcal infections, yersiniosis, and some other infections are the most common causes of EN (Table 2).2-6,19-53 Roughly, one third of the cases are triggered by sarcoidosis, one third by streptococcal infections, one tenth by yersiniosis, and one fifth to one tenth by other known causes. Despite thorough investigations, no apparent cause can be found in one fifth of the cases.2 In many cases, there are two or more possible factors underlying EN. Sarcoidosis and streptococcal infection,2 and sarcoidosis and yersiniosis38939are examples of multifactorial causes of EN. The etiologic factors of ENmi are the same as those of typical EN apart from yersiniosis, which does not seem to cause this longlasting variant of EN (Table 3).

Clinical Features of Sarcoid Erythema Nodosum The clinical course of EN differs to some extent in the various etiologic groups (Table

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1986

Erythema Nodosum

91

TABLE 2. Etiologic Factors of Erythema Nodosum Etiologic

Factor

Remarks (References)

Sarcoidosis

Erythema nodosum lymphadenopathy

Streptococcal

infection

Rare causes in developed countries. patients with medication (19).

Tuberculosis Lepra infections

Yersiniosis

Bilateral

hilar

The nodes appear within 3 weeks after the infection.

Mycobacteria

Gastrointestinal infestations

(EN) means the onset of sarcoidosis. (BHL) in 99% of the cases.

EN leprosum

is seen usually in

and Both Yersinia enterocolitica

(types III and IX) and Y pseudotuberculosis

infections. Salmonellosis Campylobacter Shigellosis

(2621) colitis

Deep fungous infections Coccidioidomycosis Histoplasmosis Blastomycosis (North American) Deep trichophytosis

(22, 23) (36) Especially in North America. The interval between the symptoms infection and EN is usually l-2 weeks (25-29).

(30)

Other infections

Ornithosis, cat scratch disease, syphilis, inguinale, other chlamydial infections, (2,31-35).

Bowel diseases

Crohn’s disease, ulcerative

Hormonal

causes

gonorrhea, lymphogranuloma infectious mononucleosis

colitis, colon diverticulitis

Pregnancy,

contraceptive

Malignomas

Leukemias,

carcinomas,

Drugs

Iodine, bromine, sulphathiazole, references 2 and 40).

Other causes Periatteritis nodosa Sweet’s syndrome Behcet’s disease

of

(2, 26, 36).

pills. sarcomas,

Hodgkin’s

penicillin,

disease (36, 37).

phenacetin,

pyritinol

(see

Cz41) (42) (36)

4).2743y44 Fever, pain, and aches in joints, and widespread eruption are typical of sarcoidosis. They are also typical of Yersinia EN45; however, in the latter, the appearance of the nodes is usually preceded by gastroenteritis or aches and pain in the upper abdomen and the nodes disappear within 3-4 weeks, while the EN nodes in sarcoidosis seldom evanesce within a month. Erythema nodosum nodes in sarcoidosis are usually large and painful and they are situated especially around the ankles and knees (Figs. 2 and 3).

Joint symptoms include aches and pains in various joints, but real arthritis in sarcoidosis is rare. The pain may be so severe that the patients can hardly walk. Erythema multiforme (EM) is typical of yersiniosis with or without EN44 (Fig. 4). Both EN and EM are seen occasionally in sarcoidosis.2,46 In yersiniosis, it appears with or prior to EN, but in sarcoidosis it usually appears during EN. Both EM and EN are also seen in many infectious diseases (eg, in deep mycoses, in tularemia, and even in paravaccinia virus infection).25p476o

Clinics r

92

M. Hannuksela

Dermatology

FIG. 2 (left). Erythema nodosum lesions on the front surfaces of the legs in a patient with sarcoidosis. FIG. 3 (right).

Erythema

nodo-

sum lesions on the left leg only. The patient had yersiniosis.

FIG. 4. A. (left). Cockade-like erythema multiforme lesions in yersiniosis.

multiforme

lesions In yersiniosis.

B. (right).

Vesicular

erythema

Recurrent Erythema Nodosum

Laboratory Examinations

In about one of seven or eight EN patients, there are one or more recurrences over the years2 In most cases, the cause is different or unknown in two subsequent episodes of EN: however, sarcoidosis and, in particular, streptococcal infections, may elicit EN more than once. Oral contraceptives and pregnancy may also be responsible for recurrent EN.51-53 The interval between EN episodes varies from one patient to another within a wide range, being several years on average.2

High erythrocyte sedimentation rate and slight leucocytosis are the most common abnormalities in routine blood tests, reflecting the grade of inflammation. Abnormally high liver function test results,s4 cryofibrinogen, and alpha-l and alpha-2 globulins in serum electrophoresis also reflect the grade of inflammation but not the cause underlying EN. Beta-hemolytic streptococcus group A can occasionally be found in the throat swabs of

October-December Volume 4 Number 4

1986 Erythema

TABLE 3. Etiologic Factors in 56 Cases of Erythema Nodosum Migrans (ENmi)e Etiologic

Factor*

Sarcoidosis Streptococcal infection Pregnancy Other known causes Cause unknown

No.

%

5 9 10 3 31

9 16 18 5 55

Nodosum

93

eration when patients with EN and BHLare examined. In yersiniosis and tularemia, granulomatous lesions in the lymph nodes may resemble those of sarcoidosis, and yersiniosis manifesting with EN and BHL may be diagnosed incorrectly as sarcoidosis.38 Sarcoidosis patients with EN at the beginning of the disease have a better prognosis than those without acute onset of the disease. Other clinical indicators of good prognosis are: females, young age, BHL without other changes in the lungs, and high tuberculin sensitivity.5*-60 A decreasing level of serum angiotensin-converting enzyme is another sign of rapidly clearing sarcoidosis.61

*In two cases, two possible etiologic factors.

with streptococcal EN. The diagnosis is usually based on patient history, however, suggesting streptococcal sore throat and an elevated (> 250) antistreptolysin titer. Yersinia titers of over 80, with or without a positive culture finding from stools, are suggestive of present or recent Yersinia infection.43 It sould be kept in mind that there is a marked gross agglutination between Yersinia enterocolitica type IX and Brucella abortus.s5@ A chlamydial CF antibody titer of 32 or more is suggestive of recent infection,35 but elevated titers also can be found in patients with active sarcoidosis and sometimes in apparently healthy individuals.57 Salmonellosis, shigellosis, and cambylobatter infections should be verified by stool cultures. patients

Treatment of Erythema Nodosum Erythema nodosum itself rarely needs any other treatment besides bed rest and nonsteroidal, anti-inflammatory drugs.62 In more severe cases, however, potassium iodide (300 mg orally three times daily) has been used with success63T6*;however, in chronic EN, this drug seems to be less effective.65 In prolonged use, adverse reactions such as acne, eczematous eruptions, EN itself, purpura, vasculitis, and iododerma may occur. Systemic corticosteroids are not used because they may lengthen the course of the eruption and worsen the causative disease. The main task for the clinician is to find the cause of EN and to treat it properly.

Roentgenogram Examinations In sarcoid EN, bilateral hilar lymphadenopathy (BHL), with or without sarcoid changes in the lung parenchyma, is seen in about 90% of the cases.2T46 Especially in undeveloped countries, tuberculosis is still an important disease to be taken into consid-

References 1. Willan R. Cited by Vesey CMR, Wilkinson DS. Erythema nodosum: a study of seventy cases. Br J Dermatol. 1959;71:139-155.

TABLE 4. Differences in the Clinical Course of Erythema Nodosum (EN) in Various Etiologic Groups*~+4

(%I

(%)

Duration of EN (Weeks)

40 86 57 21

75 75 49 35

2-20 <4 l-20 l->30

Fever > 38°C Etiologic

Group

Sarcoidosis Yersiniosis Streptococcal infection Cause unknown

Joint Symptoms

Erythema Multiforme < 5% Common Rare

Rare

Preceding Symptoms (%) 60 86 77 28

Clinics in Dermatoloav

M. Hannuksela

94

2. Hannuksela

M. Erythema nodosum \vith sprcial reference to sarcoidosis (Dissertation). Ann Clin Res. 1971;3(suppI 7):1-64.

tissue:

panniculitis.

In:

Fitzpatrick

Dermatology in general medicine. McGraw-Hill, 1979;784-794.

TB, ed. New York:

3. Putkonen T, Hannuksela M, Mustakallio KK. Cold season prevalence of the clinical onset of sarcoidosis. Arch Environ Health. 1966;12: 564-568.

19 Wemambu SNC. Turk JL, Waters MFR, et al. Erythema nodosum Ieprosum: aclinical manifestation of the arthus phenomenon. Lancet. 1969;2:933-935.

4. Bgfverstedt Acta Derm 193.

B. Erythema nodosum migrans. Venereal (Stockh). 1954;34:181-

5. Bafverstedt Acta Derm 384.

B. Erythema nodosum migrans. Venereal (Stockh). 1968;48:381-

20. Morrison WM, Matheson JAB, Hutchison RB, et al. Salmonella gastroenteritis associated with erythema nodosum. Br Med J. 1983;286: 765.

6. Hannuksela Acta Derm 317.

M. Erythema nodosum migrans. Venereol (Stockh). 1973:53:313-

7. Ackerman

AB. Histologic diagnosis of inflam matory skin diseases. Philadelphia: Lea & Febiger, 1978:784-790.

8. Hitaka logical clinical Med J.

Y, Ito Y, Taniguchi Y. A histopathoand clinical study of 102 patients with diagnosis of erythema nodosum. Mie 1979;28:127-133.

9. Niemi KM, Forstrom L, Hannuksela M, et al. Nodules on the lees. Acta Derm Venereol (Stockh). 1977:57:145-154. 10. Fdrstrom L, Hannuksela M. Antituberculous treatment of erythema induratum Bazin. Acta Derm Venereal (Stockh). 1970:50:143-147. S. Erythema induratum 11. la Cour Andersen Bazin treated with isonizid. Acta Derm Venereal (Stockh). 1970;50:65-68. 12. Ryan TJ. Wilkinson DS. Cutaneous vasculitis. “angiitis.” In: Rook A, Wilkinson DS. Ebling FJG, eds. Textbook of dermatology. Oxford: Blackwell Scientific Publications. 1979:99313. Whitfield A. On the nature of the disease known as erythema induratum scrophulosorum. Am J Med Sci. 1901;2:828. 14. Montnomerv H. O’Learv PA. Baker NW. Nodular vascular diseases of the legs: erythema induratum and allied conditions. JAMA. 1945: 128:335-341. 15. Vilanova X, Pinol Aguade J. Hypodermite nodulaire subaigue migratice. Ann Dermatol Syphilol. 1956;83:369-404. 16. Vilanova X, PinoI Aguade J. Subacute nodular migratory panniculitis. Br J Dermatol. 1959;71:45-50. RK. Subacute nodu17. Perry HO, Winkelmann Iar migratory panniculitis. Arch Dermatol. 1964; 89:170-179. 18. de Moragas JM. Disorders of subcutaneous

2’. Grossman ME, Katz B. Salmonellaenteritidis enterocolitis: another cause of diarrhea and erythema nodosum. Cutis. 1984;34:402-403. 22, Ellis ME, Pope J, Mokashi A, et al. Campylobatter colitis associated with erythema nodosum. Br Med J. 1982;285:937. 23, Eastmond CJ. Reid TM. Campylobacter enteritis and erythema nodosum. Br Med J. 1982; 285:1421-1422. 24. Tami LF. Erythema nodosum associated with shigella colitis. Arch Dermatol. 1985;121:590. 25. Medeiros AA, Marty SD, Tosh FE, et al. Erythema nodosum and erythema multiforme as clinical manifestations of histoplasmosis in a community outbreak. N Engl J Med. 1966; 274:415-420. 26. Johnson CC, Hanson NO, Good CA. Erythema nodosum: the possible significance of associated pulmonary hilar adenopathy. Ann Intern Med. 1951;34:983-997. “7. Smith JG Jr. Harris JS, Conant NF, et al. An epidemic of North American blastomycosis. .JAMA. 1955:158:641-646. 28. 0~01s II, Wheat LJ. Erythema nodosum in an epidemic of histoplasmosis in Indianapolis. Arch Dermatol. 1981;117:709-712. Miller DD, Davies SF, Sarosi GA. Erythema nodosum and blastomycosis. Arch Intern Med. 1982;142:1839. A, Llorens-Terol J, Torres JM. 30. Martinez-Roig Erythema nodosum and kerion of the scalp. Am J Dis Child. 1982;136:440-442. ,,, 3 I Sarner M, Wilson RJ. Erythema nodosum and psittacosis: report of five cases. Br Med J. 1965; 2:1469-1470. 32. Daniels WB, Mac Murray FG. Cat scratch disease: report of one hundred sixty cases. JAMA. 1954;154:1247-1251. nodosum luicum. Z 33. Jung EG. Erythema Hautkr. 1963;35:166-170. 34. Hellerstrtim S. A contribution to the knowledge of lymphogranuloma inguinale (Dissertation). Acta Derm Venereal [Suppl] (Stockh). 1929;1:1-224.

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1986

Ewthema Nodosum

35. Kousa M, Saikku P, Kanerva L. Erythema nodosum in chlamydial infections. Acta Derm Venereol (Stockh). 1980;60:319-322.

52.

36. Kaufmann R, Landes E. Zur Wertigkeit nostischer Massnahmen beim Erythema osum. Z Hautkr. 1984;59:79-86.

53.

diagnod-

37. Chalmers RJG, Proctor SJ, Marks JM. Erythema nodosum and Hodgkin’s disease. Br J Dermatol. 1982;106:593-595.

54.

38. Agner E, Larsen JH. Yersinia enterocolitica infection and sarcoidosis. Stand J Respir Dis. 1979;60:230-234.

55.

39. Seebacher C, Hillmann E, Diesterweg I, et al. Yersinia-enterocolitica-Antikbrper bei Sarkoidose. Dermatol Monatsschr. 1979;165:448-450. 40. Eriksen K. Erythema ger. 1979;141:503-505.

nodosum.

Ugeskr

Lae-

41. Churg J, Strauss L. Allergic granulomatosis, aIIergic angiitis and periarteritis nodosa. Am J Pathol. 1951;27:277-301. 42. Spatz SA. Erythema nodosum in Sweet’s syndrome. Cutis. 1985;35:327-330. 43. Ahvonen P. Human yersiniosis in Finland: I. Bacteriology and serology. Ann Clin Res. 1972; 4:30-38. 44. Hannuksela M, Ahvonen P. Skin manifestations in human yersiniosis. Ann Clin Res. 1975;7:368-373. 45. Hannuksela M, Ahvonen P. Erythema nodosum due to yersinia enterocolitica. Stand J Infect Dis. 1969;1:17-19. 46. tifgren S. Erythema nodosum: studies on etiology and pathogenesis of 185 adult cases (Dissertation). Acta Med Stand. 1946;124(suppl 174):1-197. 47. Moreno AJ, Weisman I, Kenney RL, et al. Concurrence of erythema multiforme and erythema nodosum. Cutis. 1983;31:275-278. 48. Hitch JM, Smith DC. Cutaneous manifestations of tularemia. Arch Dermato Syphilol. 1938;38:859-876. A. Skin 49. Syrjtilii H, Karvonen J, Salminen manifestations of tularemia: a study of 88 cases in Northern Finland during 16 Years (1967-1983). Acta Derm Venereoi (Stdckh). 1984;64:513-516. 50. Kuokkanen K, Launis J, Mdrttinen A. Erythema nodosum and erythema multiforme associated with milker’s nodules. Acta Derm Venereol (Stockh). 1976;56:69-72. 51. Holcomb

FD. Erythema

nodosum

Address for correspondence: sity of Oulu, SF-90220 Oulu,

associated

Matti Hannuksela, Finland.

95

with the use of an oral contraceptive. Obstet Gynecol. 1965;25:156-157. Darlington LG. Erythema nodosum and oral contraceptives. Br J Dermatol. 1974;90:209212. Salvatore MA, Lynch PJ. Erythema nodosum, estrogens and pregnancy. Arch Dermatol. 1980;116:557-558. Lehmuskallio E, Hannuksela M, Halme H. The liver in sarcoidosis. Acta Med Stand. 1977;202:289-293. Ahvonen P, Jansson E, Aho K. Marked grossagglutination between brucellae and a subtype of yersinia enterocolitica. Acta Path01 Microbial Immunol Stand. 1969;75:291-295.

56. Ahvonen P, Sievers K. Yersinia enterocolitica infection associated with brucella agglutinins: clinical features of 24 patients. Acta Med Stand. 1969;185:121-125. 57. Refvem 0, Bjernstad RT, Loe K. The ornithosis complement fixation test in sarcoidosis. Ann NY Acad Sci. 1976;278:225-232. 58. Hannuksela M, Salo OP. The significance of the quantitative Mantoux test in sarcoidosis. Stand J Respir Dis. 1969;50:259-264. 59. Hannuksela M, Salo OP, Mustakallio KK. The prognosis of acute untreated sarcoidosis. Ann Clin Res. 1979;2:57-61. 60. Selroos 0, Niemistb M, Riska N. A follow-up study of treated and untreated early pulmonary sarcoidosis. In: Iwai K, Hosoda Y, eds. Proceedings of the VI international conference on sarcoidosis. Tokyo: University Park Press, 1974:525-528. 61. R$mer FK. Correlation between disease activity, one-year prognosis, and angiotensin-converting enzyme in untreated sarcoidosis. Acta Med Stand. 1981;210:111-117. and erythema 62. Morgan GJ Jr. Panniculitis nodosum. In: Kelley WN, Harris ED Jr, Ruddy S, et al. Textbook of rheumatology. Philadelphia: WB Saunders, 1981;1203-1207. of ery63. Schulz EJ, Whiting DA. Treatment thema nodosum and nodular vasculitis with potassium iodide. Br J Dermatol. 1976;94:7578. 64. Horio T, Imamura S, Danno K, et al. Potassium iodide in the treatment of erythema nodosum and nodular vasculitis. Arch Dermatol. 1981;117:29-31. 65. Fine RM, Meltzer HD. Erythema nodosum: a form of allergic cutaneous vasculitis. South Med J. 1968;61:680-686.

MD, Department

of Dermatology,

Univer-