AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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Background

In 1861, Bazin gave the name erythema induratum to a nodular eruption that occurred on the lower legs of young women with tuberculosis. In 1945, Montgomery et al, while fully acknowledging the existence of tuberculosis-associated erythema induratum, coined the term nodular vasculitis to describe chronic inflammatory nodules of the legs that showed histopathologic changes similar to those of erythema induratum, that is, vasculitis of the larger vessels and panniculitis.

Erythema induratum and nodular vasculitis had been considered the same disease entity for a long time. However, nodular vasculitis is now considered a multifactorial syndrome of lobular panniculitis in which tuberculosis may or may not be one of a multitude of etiologic components. Therefore, erythema induratum/nodular vasculitis complex is classified into 2 variants. Erythema induratum of Bazin type and nodular vasculitis or erythema induratum of Whitfield type. Bazin type is related with tuberculous origin, but Whitfield type is not.

Motswaledi and Schulz¹ noted that erythema induratum of Bazin, lichen scrofulosorum, and papulonecrotic tuberculide are the 3 recognized tuberculides, which are sequelae of immunologic reactions to hematogenously dispersed antigenic components of Mycobacterium tuberculosis. A fourth tuberculide, called nodular granulomatous phlebitis, is distinct from erythema induratum.

See Tuberculosis (emergency medicine focus), Tuberculosis (infectious disease focus), Tuberculosis (ophthalmology focus), and Tuberculosis (pediatric focus) for more information on this condition. Also see Medscape's CME course ICAAC 2007: Coinfections and Comorbidities in HIV -- Viral and Bacterial Infections, Malignancy, and Tuberculosis.

Pathophysiology

The morphologic, molecular, and clinical data suggest that erythema induratum and nodular vasculitis represent a common inflammatory pathway, that is, a hypersensitivity reaction to endogenous or exogenous antigens. One such antigen is the tubercle bacillus. Patients with erythema induratum have a positive tuberculin skin test result and a marked increase in their peripheral T lymphocyte response to purified protein derivative (PPD) of tuberculin, which can cause a delayed-type hypersensitivity reaction.

Frequency

United States

Isolated cases have been reported in the United States.

International

While nodular vasculitis is quite common, particularly in Europe, erythema induratum is rare in Western countries. Erythema induratum is still prevalent in India, Hong Kong, and some areas of South Africa. Erythema induratum was the most common (86%) form of cutaneous tuberculosis (tuberculid) in Hong Kong found between 1993 and 2002² and was mostly found in women and mostly on the legs. In this period (1993-2002), 127 patients with erythema induratum out of a total of 147 patients with either cutaneous tuberculosis or tuberculids were reported.

Mortality/Morbidity

To date, no fatal cases of erythema induratum have been reported. However, the chronic, recurrent, painful nodules and resultant scarring can be a source of significant morbidity.

Sex

Erythema induratum shows female predominance, and lower extremities are the most common sites in both male and female patients; however, it also may occur in other areas.

Age

Erythema induratum most commonly affects women aged 20-30 years. The condition is more common in young women than in other people, but it may occur later in life.

CLINICAL

Section 3 of 11  

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• Multimedia
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History

• A past or present history of tuberculosis at an extracutaneous site occurs in about 50% of patients.
• • Pulmonary tuberculosis is most common.
  • Tuberculous cervical lymphadenitis is the next most common finding.
• Tender, erythematous nodules are present on the lower legs.
• • The nodules have a chronic, recurrent course.
  • The lesions heal with ulcerations or depressed scars.
• Leg edema may be present.
• An infant erythema induratum was reported to occur after BCG vaccination.³
• The simultaneous expression of erythema induratum and episcleritis was reported in a 6-year-old girl.⁴
• A variation of erythema induratum, termed nodular tuberculid, with the distinguishing feature of a granulomatous vasculitis occurring at the dermohypodermal junction, has been noted in 5 patients with HIV disease.⁵
• Erythema induratum of Bazin and renal tuberculosis can be associated.⁶
• Silva et al⁷ noted distal painful peripheral neuropathy associated with erythema induratum.

Physical

• Crops of small, tender, erythematous nodules may be observed (see Media File 1).
• • Commons sites are the calves, although the shins are also sometimes involved. Uncommonly, the trunk, buttocks, thighs, and arms can be involved.
  • The nodules are concentrated on the lower third of the legs, especially around the ankles.
  • Lesions may ulcerate with bluish borders, which may be precipitated by cold weather. These irregular and shallow ulceration can result in permanent scarring and hyperpigmentation of the lesions.
  • In 2007, Ramdial et al⁸ reported on 5 patients with tuberculous epididymo-orchitis. A histopathological evaluation confirmed papulonecrotic tuberculids in 4 patients and erythema induratum in 2 patients. Most patients responded to appropriate antibiotics. The researchers concluded that tuberculids incite a sentinel cutaneous manifestation of visceral tuberculosis and help identify occult or asymptomatic tuberculous epididymo-orchitis, as the underlying cause of tuberculids.
  • Sughimoto et al⁹ described a patient with aortic valvular lesions of tuberculosis that manifest at the same time as erythema induratum, with granulomatous changes being demonstrated by the aortic valve pathology.

Causes

Erythema induratum/nodular vasculitis complex is a multifactorial disorder. M tuberculosis and delayed-type hypersensitivity are considered etiologic factors for erythema induratum of Bazin type. Recently, hepatitis C virus has been suggested, but a direct relationship remains unclear.

• M tuberculosis is the cause of erythema induratum.
• The cause is unknown in cases of nodular vasculitis with a negative tuberculin skin test reaction.
• Atypical erythema induratum Bazin with tuberculous osteomyelitis has been reported, suggesting that boney changes can be detected clinically.¹⁰

DIFFERENTIALS

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Other Problems to be Considered

Chilblain
Subcutaneous panniculitic T-cell lymphoma
Erythema nodosum leprosum
Factitial panniculitis
Infectious panniculitis due to agents other than M tuberculosis
Alpha-1 antitrypsin deficiency panniculitis
Pancreatic panniculitis
Lupus panniculitis

WORKUP

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Lab Studies

• A complete blood cell count may be performed.
• The erythrocyte sedimentation rate may be increased.
• The diagnosis of erythema can be made with the help of polymerase chain reaction testing.^{11, 12, 13}
• The QuantiFERON test is a simple blood test that can confirm the presence of latent tuberculosis in association with erythema induratum.¹⁴

Imaging Studies

• Chest radiography may be performed. Search for evidence of active or previous infection.

Other Tests

• Polymerase chain reaction provides rapid and sensitive detection of M tuberculosis in formalin-fixed, paraffin-embedded specimens. Polymerase chain reaction can be applied to differentiating nodular vasculitis from erythema induratum of Bazin because the demonstration of mycobacteria emerges as the only reliable criterion in erythema induratum of Bazin type.

Procedures

• Some patients are highly sensitive to tuberculin PPD. Patients should be tested with a 1:10,000 dilution Mantoux test (see Media File 4).
• An excisional biopsy containing adequate subcutaneous fat is recommended. Special stains for bacterial, fungal, and acid-fast organisms, as well as tissue for culture of these organisms, are generally obtained.

Histologic Findings

Findings consist of a mixed septal and lobular granulomatous panniculitis with neutrophilic vasculitis (see Media Files 2-3). Caseationlike necrosis may also be seen. The histologic features are not specific; they vary depending on the age of the lesion undergoing biopsy and the overlap with other forms of panniculitis. Vasculitis is not always identified and is not a requisite for the diagnosis. The presence of both septal granulomatous inflammation and lobular granulomatous inflammation is, nonetheless, characteristic of erythema induratum and contrasts with erythema nodosum (primarily septal) and polyarteritis nodosa (medium vessel vasculitis with minimal lobular inflammation).

TREATMENT

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Medical Care

• Erythema induratum of Bazin is treated with antituberculous therapy. Antituberculosis monotherapy has been abandoned because of high resistance; a multidrug combination regimen is more widely accepted.
• Bed rest with systemic steroids may be indicated.
• Potassium iodide is sometimes applied, with high efficacy; however, this therapy requires caution when used in children or in patients with thyroid disease.

MEDICATION

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Combination therapy with isoniazid, ethambutol, and rifampicin should be continued for 9 months. In addition, antipyretics and analgesics are usually required.

Drug Category: Antituberculous agents

Used for empiric coverage for tubercle bacilli.

Drug Name	Rifampin (Rifadin, Rimactane)
Description	For use in combination with at least one other antituberculous drug; inhibits DNA-dependent bacterial but not mammalian RNA polymerase. Cross-resistance may occur. Treat for 6-9 mo or until 6 mo have elapsed from conversion to sputum culture negativity. Available as cap (150 mg or 300 mg) and powder for injection (600 mg).
Adult Dose	10 mg/kg/d PO or 450-600 mg PO qd; not to exceed 600 mg qd
Pediatric Dose	15-25 mg/kg PO qd
Contraindications	Documented hypersensitivity
Interactions	Induces microsomal enzymes, which may decrease effects of acetaminophen, oral anticoagulants, barbiturates, benzodiazepines, beta-blockers, chloramphenicol, oral contraceptives, corticosteroids, mexiletine, cyclosporine, digitoxin, disopyramide, estrogens, hydantoins, methadone, clofibrate, quinidine, dapsone, tazobactam, sulfonylureas, theophyllines, tocainide, and digoxin; blood pressure may increase with coadministration of enalapril; coadministration with isoniazid may result in higher rate of hepatotoxicity than with either agent alone (discontinue 1 or both agents if alterations in LFTs occur)
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Obtain CBC counts and baseline clinical chemistries prior to and throughout therapy; in liver disease, weigh benefits against risk of further liver damage; interruption of therapy and high-dose intermittent therapy are associated with thrombocytopenia that is reversible if therapy is discontinued as soon as purpura occurs; if treatment is continued or resumed after appearance of purpura, cerebral hemorrhage or death may occur Body fluids (tears, saliva, urine) and feces may turn a red-orange color; warn patients of this side effect

Drug Name	Ethambutol (Myambutol)
Description	Diffuses into actively growing mycobacterial cells, such as tubercle bacilli. Impairs cell metabolism by inhibiting synthesis of 1 or more metabolites, which, in turn, causes cell death. No cross-resistance demonstrated. Mycobacterial resistance is frequent with previous therapy. Use in these patients in combination with second-line drugs not previously administered. Administer q24h until permanent bacteriologic conversion and maximal clinical improvement is seen. Absorption is not significantly altered by food. Available as 100- and 400-mg tab.
Adult Dose	15-25 mg/kg PO qd
Pediatric Dose	10-15 mg/kg PO qd
Contraindications	Documented hypersensitivity; optic neuritis (unless clinically indicated); children <12 y, owing to oculopathy
Interactions	Aluminum salts may delay and reduce absorption (give several hours before or after ethambutol dose)
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Reduce dose in impaired renal function; may have reversible visual adverse effects if promptly discontinued

Drug Name	Pyrazinamide
Description	Pyrazine analog of nicotinamide that may be bacteriostatic or bactericidal against M tuberculosis, depending on concentration of drug attained at site of infection; mechanism of action is unknown. Administer for initial 2 mo of a 6-mo or longer treatment regimen for patients who are susceptible to drug. Treat patients who are resistant to drug with individualized regimens. Available as 500-mg scored tab.
Adult Dose	15-30 mg/kg PO qd; not to exceed 2 g/d
Pediatric Dose	20 mg/kg PO qd; not to exceed 2 g/d
Contraindications	Documented hypersensitivity; severe hepatic damage and acute gout;
Interactions	None reported
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Use only in combination with other effective antituberculous agents; inhibits renal excretion of urates; may result in hyperuricemia (usually asymptomatic); perform baseline serum uric acid determinations; discontinue drug if signs of hyperuricemia with acute gouty arthritis; perform baseline LFTs (closely monitor in liver disease); discontinue if signs of hepatocellular damage appear; caution in history of diabetes mellitus; CDC has recommended not to combine pyrazinamide and rifampin due to several reports of severe liver injury and death of patients

Drug Category: Antithyroid agents

These agents relieve lesional tenderness, arthralgia, and fever. Relief may occur in 24 h. Most lesions completely subside within 10-14 d.

FOLLOW-UP

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Complications

• Inadequately treated or untreated erythema induratum may result in prolonged disease, persistent ulcerations, and complications due to coexistent systemic tuberculosis.

Prognosis

• The prognosis is good if treated properly.

MISCELLANEOUS

Section 9 of 11  

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Medical/Legal Pitfalls

• A thorough understanding of the various adverse effects of antituberculous medications, including hepatotoxicity, is required.

MULTIMEDIA

Section 10 of 11  

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Media file 1:  This patient exhibited tender, erythematous nodules confined to the lower third of the legs.
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Media file 2:  Vasculitis and granulomatous inflammation in the dermis and subcutaneous fat tissues.
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Media file 3:  Evidence of panniculitis exhibiting lobular, granulomatous, and lymphohistiocytic inflammation.
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Media file 4:  A positive Mantoux test reaction in a patient with erythema induratum.
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REFERENCES

Section 11 of 11

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1. Motswaledi HM, Schulz EJ. Superficial thrombophlebitic tuberculide. Int J Dermatol. Nov 2006;45(11):1337-40. [Medline].
2. Ho CK, Ho MH, Chong LY. Cutaneous tuberculosis in Hong Kong: an update. Hong Kong Med J. Aug 2006;12(4):272-7. [Medline].
3. Inoue T, Fukumoto T, Ansai S, Kimura T. Erythema induratum of Bazin in an infant after Bacille Calmette-Guerin vaccination. J Dermatol. Apr 2006;33(4):268-72. [Medline].
4. Leahy TR, Downey P, Ramsay B, Philip RK. Erythema induratum of Bazin and episcleritis in a 6 year old girl. Arch Dis Child. Nov 2005;90(11):1132. [Medline].
5. Friedman PC, Husain S, Grossman ME. Nodular tuberculid in a patient with HIV. J Am Acad Dermatol. Aug 2005;53(2 Suppl 1):S154-6. [Medline].
6. Daher Ede F, Silva Junior GB, Pinheiro HC, Oliveira TR, Vilar Mdo L, Alcantara KJ. Erythema induratum of Bazin and renal tuberculosis: report of an association. Rev Inst Med Trop Sao Paulo. Sept-Oct 2004;46(5):295-8. [Medline].
7. Silva MT, Antunes SL, Rolla VC, Galhardo MC, Sant'ana FM, do Valle AF. Distal painful peripheral neuropathy associated with erythema induratum of Bazin. Eur J Neurol. Dec 2006;13(12):e5-6. [Medline].
8. Ramdial PK, Calonje E, Sydney C, Subrayen S, Meyiwa PS, Aboobaker J. Tuberculids as sentinel lesions of tuberculous epididymo-orchitis. J Cutan Pathol. Nov 2007;34(11):830-6. [Medline].
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10. Degonda Halter M, Nebiker P, Hug B, Oberholzer M, Fluckiger U, Bassetti S. [Atypical erythema induratum Bazin with tuberculous osteomyelitis]. Internist (Berl). Aug 2006;47(8):853-6. [Medline].
11. Jacinto SS, Nograles KB. Erythema induratum of bazin: role of polymerase chain reaction in diagnosis. Int J Dermatol. May 2003;42(5):380-1. [Medline].
12. Chen YH, Yan JJ, Chao SC, Lee JY. Erythema induratum: a clinicopathologic and polymerase chain reaction study. J Formos Med Assoc. Apr 2001;100(4):244-9. [Medline].
13. Schneider JW, Jordaan HF, Geiger DH, Victor T, Van Helden PD, Rossouw DJ. Erythema induratum of Bazin. A clinicopathological study of 20 cases and detection of Mycobacterium tuberculosis DNA in skin lesions by polymerase chain reaction. Am J Dermatopathol. Aug 1995;17(4):350-6. [Medline].
14. Angus J, Roberts C, Kulkarni K, Leach I, Murphy R. Usefulness of the QuantiFERON test in the confirmation of latent tuberculosis in association with erythema induratum. Br J Dermatol. Dec 2007;157(6):1293-4. [Medline].
15. Alothman A, Al Qahtani M, Al-Khenaizan S. Erythema induratum: what is the role of Mycobacterium tuberculosis?. Ann Saudi Med. Jul-Aug 2007;27(4):298-300. [Medline].
16. Baselga E, Margall N, Barnadas MA, Coll P, de Moragas JM. Detection of Mycobacterium tuberculosis DNA in lobular granulomatous panniculitis (erythema induratum-nodular vasculitis). Arch Dermatol. Apr 1997;133(4):457-62. [Medline].
17. Bennett NM. Erythema induratum: a case of mistaken identity. Med J Aust. Mar 20 2006;184(6):306; author reply 306-7. [Medline].
18. Chanet V, Amarger S, Pons B, Dechelotte P, Ruivard M, Philippe P. [Nodular thrombophlebitis and granulomatous systemic disease.]. Rev Med Interne. Jun 2007;28(6):416-419. [Medline].
19. Cho KH, Lee DY, Kim CW. Erythema induratum of Bazin. Int J Dermatol. Nov 1996;35(11):802-8. [Medline].
20. Hay RJ. Cutaneous infection with Mycobacterium tuberculosis: how has this altered with the changing epidemiology of tuberculosis?. Curr Opin Infect Dis. Apr 2005;18(2):93-5. [Medline].
21. Heymann WR. Panniculitis. J Am Acad Dermatol. Apr 2005;52(4):683-5. [Medline].
22. Koga T, Kubota Y, Kiryu H, Nakayama J, Matsuzoe D, Shirakusa T. Erythema induratum in a patient with active tuberculosis of the axillary lymph node: IFN-gamma release of specific T cells. Eur J Dermatol. Jan-Feb 2001;11(1):48-9. [Medline].
23. Requena L. Normal subcutaneous fat, necrosis of adipocytes and classification of the panniculitides. Semin Cutan Med Surg. Jun 2007;26(2):66-70. [Medline].
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Article Last Updated: Mar 17, 2008