Erythema Induratum (Nodular Vasculitis)

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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. The Bazin type is related with tuberculous origin, but Whitfield type is not.

One report describes erythema induratum of 3 years’ duration caused by chronic hepatitis C infection in a 49-year-old man. The erythema induratum responded to pegylated interferon and ribavirin therapy for 48 weeks.[1]

Motswaledi and Schulz[2] 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.

Related Medscape Reference articles include Tuberculosis (emergency medicine focus), Tuberculosis (infectious disease focus), Tuberculosis (ophthalmology focus), and Tuberculosis (pediatric focus).

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. Results from the enzyme-linked immunosorbent assay–based IGRA (QuantiFERON-TB Gold In-Tube, Cellestis; Victoria, Australia) blood test for tuberculosis commonly are positive in patients with erythema induratum, again suggesting that that erythema induratum is a hypersensitivity reaction to a systemic infection.

Epidemiology

Frequency

United States

Isolated cases of erythema induratum 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 2002[3] 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.

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. It is important to consider if HIV infection is present when tuberculosis and nodular vasculitis are present.[4]

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.[5]

The simultaneous expression of erythema induratum and episcleritis was reported in a 6-year-old girl.[6]

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.[7]

Erythema induratum of Bazin and renal tuberculosis can be associated.[8] In a patient suffering from pulmonary tuberculosis, co-incident papulonecrotic tuberculid and erythema induratum has been noted.[9] Nodular vasculitis has been noted to occur with Crohn disease.[10]

Silva et al[11] noted distal painful peripheral neuropathy associated with erythema induratum.

Erythema induratum in the setting of renal cell carcinoma has been confirmed with a QuantiFERON test and response to antituberculosis therapy.[12]

Addison disease that occurred during treatment for erythema induratum has been noted, and the authors of this report suggest that tuberculosis might have been the cause of the Addison disease.[13]

Physical

Crops of small, tender, erythematous nodules may be observed, as demonstrated in the image below.


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This patient exhibited tender, erythematous nodules confined to the lower third of the legs.

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 al[14] 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 al[15] 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.

Laboratory 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.[17, 18, 19]

The CDC[20] states that interferon-gamma release assays (IGRAs) are whole-blood tests that can aid in diagnosing infection Mycobacterium tuberculosis. Two IGRAs that the FDA has approved and are commercially available in the United States are the QuantiFERON-TB Gold In-Tube test (QFT-GIT) and the T-SPOT. TB test (T-Spot). The QuantiFERON test can confirm the presence of latent tuberculosis in association with erythema induratum.[21] The utility of this test was stressed in a patient with tender ulcerating nodules of the lower extremity, a normal chest radiograph, and biopsy without acid-fast bacilli, but whose QT was positive, leading to the diagnosis of erythema induratum.[22] Additional reports have stressed the utility of testing for nodular vasculitis, in particular with the QuantiFERON Gold TB test[23] and the interferon-gamma release assay.[24]

Test for hepatitis.[1]

Imaging Studies

Other Tests

Procedures

Histologic Findings

Findings consist of a mixed septal and lobular granulomatous panniculitis with neutrophilic vasculitis, as demonstrated in the photomicrographs below.


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Vasculitis and granulomatous inflammation in the dermis and subcutaneous fat tissues.


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Evidence of panniculitis exhibiting lobular, granulomatous, and lymphohistiocytic inflammation.

Caseationlike necrosis may also be seen in erythema induratum. 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).

Sequra et al,[25] in a study of 101 cases of erythema induratum, found that erythema induratum had a variety of presentations of vasculitis and that in approximately 10% of cases, clinicopathologic patterns of vasculitis in erythema induratum could not be demonstrated. The location of the erythema induratum–vasculitis in this series of patients, in descending order, was as follows:

Medical Care

Medication Summary

Combination therapy with isoniazid, ethambutol, and rifampicin should be continued for 9 months.[26] In addition, antipyretics and analgesics are usually required. In particular After apposite antimicrobial treatment for tuberculosis, treatment for erythema induratum mirrors that for erythema nodosum (eg, naproxen, super-saturated solution of potassium iodide).[26]

Isoniazid (Nydrazid, Laniazid)

Clinical Context:  Best combination of effectiveness, low cost, and minor adverse effects. First-line drug unless resistance or another contraindication is known. Therapeutic regimens of < 6 mo demonstrate unacceptably high relapse rate. Coadministration of pyridoxine is recommended if peripheral neuropathies secondary to isoniazid therapy develop. Prophylactic doses of 6-50 mg of pyridoxine daily are recommended. Available as syr (50 mg/5 mL) and tab (100 or 300 mg).

Rifampin (Rifadin, Rimactane)

Clinical Context:  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).

Ethambutol (Myambutol)

Clinical Context:  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.

Pyrazinamide

Clinical Context:  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.

Class Summary

Used for empiric coverage for tubercle bacilli.

Potassium iodide (Thyro-Block, SSKI, Pima)

Clinical Context:  Mechanism of action unknown, but potassium iodide is known to enhance response by potentiating neutrophil activity.

Not effective for all patients with erythema induratum. Patients who receive medication shortly after the initial onset of induratum respond more satisfactorily than those with chronic induratum.

Class Summary

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

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.

Author

Noah S Scheinfeld, MD, JD, FAAD, Assistant Clinical Professor, Department of Dermatology, Weil Cornell Medical College; Consulting Staff, Department of Dermatology, St Luke's Roosevelt Hospital Center, Beth Israel Medical Center, New York Eye and Ear Infirmary; Assistant Attending Dermatologist, New York Presbyterian Hospital; Assistant Attending Dermatologist, Lenox Hill Hospital, North Shore-LIJ Health System; Private Practice

Disclosure: Optigenex Salary Employment

Specialty Editors

Jean-Hilaire Saurat, MD, Chair, Professor, Department of Dermatology, University of Geneva, Switzerland

Disclosure: Nothing to disclose.

Richard P Vinson, MD, Assistant Clinical Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine; Consulting Staff, Mountain View Dermatology, PA

Disclosure: Nothing to disclose.

Lester F Libow, MD, Dermatopathologist, South Texas Dermatopathology Laboratory

Disclosure: Nothing to disclose.

Joel M Gelfand, MD, MSCE, Medical Director, Clinical Studies Unit, Assistant Professor, Department of Dermatology, Associate Scholar, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania

Disclosure: AMGEN Consulting fee Consulting; AMGEN Grant/research funds Investigator; Genentech Grant/research funds investigator; Centocor Consulting fee Consulting; Abbott Grant/research funds investigator; Abbott Consulting fee Consulting; Novartis investigator; Pfizer Grant/research funds investigator; Celgene Consulting fee DMC Chair; NIAMS and NHLBI Grant/research funds investigator

Chief Editor

William D James, MD, Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous previous authors, Beom Joon Kim, MD, and Kwang-Hyun Cho, MD, to the development and writing of this article.

References

  1. Fernandes SS, Carvalho J, Leite S, et al. Erythema induratum and chronic hepatitis C infection. J Clin Virol. Apr 2009;44(4):333-6. [View Abstract]
  2. Motswaledi HM, Schulz EJ. Superficial thrombophlebitic tuberculide. Int J Dermatol. Nov 2006;45(11):1337-40. [View Abstract]
  3. Ho CK, Ho MH, Chong LY. Cutaneous tuberculosis in Hong Kong: an update. Hong Kong Med J. Aug 2006;12(4):272-7. [View Abstract]
  4. Varshney A, Goyal T. Incidence of various clinico-morphological variants of cutaneous tuberculosis and HIV concurrence: a study from the Indian subcontinent. Ann Saudi Med. Mar-Apr 2011;31(2):134-9. [View Abstract]
  5. 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. [View Abstract]
  6. 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. [View Abstract]
  7. 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. [View Abstract]
  8. 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. Sep-Oct 2004;46(5):295-8. [View Abstract]
  9. Kim GW, Park HJ, Kim HS, Chin HW, Kim SH, Ko HC, et al. Simultaneous Occurrence of Papulonecrotic Tuberculid and Erythema Induratum in a Patient with Pulmonary Tuberculosis. Pediatr Dermatol. Apr 4. 2012;[View Abstract]
  10. Misago N, Narisawa Y. Erythema induratum (nodular vasculitis) associated with Crohns disease: a rare type of metastatic Crohns disease. Am J Dermatopathol. May 2012;34:325-9. [View Abstract]
  11. 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. [View Abstract]
  12. Sharon V, Goodarzi H, Chambers CJ, Fung MA, Armstrong AW. Erythema induratum of Bazin. Dermatol Online J. Apr 15 2010;16(4):1. [View Abstract]
  13. Brandão Neto RA, Carvalho JF. Erythema induratum of Bazin associated with Addison's disease: first description. Sao Paulo Med J. 2012;130:405-8. [View Abstract]
  14. 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. [View Abstract]
  15. Sughimoto K, Nakano K, Gomi A, et al. Aortic valve stenosis associated with Bazin's disease. J Heart Valve Dis. Mar 2007;16(2):212-3. [View Abstract]
  16. 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. [View Abstract]
  17. Jacinto SS, Nograles KB. Erythema induratum of bazin: role of polymerase chain reaction in diagnosis. Int J Dermatol. May 2003;42(5):380-1. [View Abstract]
  18. 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. [View Abstract]
  19. 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. [View Abstract]
  20. Center for Disease Control and Prevention. Fact Sheet: Testing and Diagnosis. Tuberculosis (TB). Available at http://www.cdc.gov/tb/publications/factsheets/testing/igra.htm. Accessed January 30, 2013.
  21. 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. [View Abstract]
  22. Sim JH, Whang KU. Application of the QuantiFERON®-TB Gold test in Erythema Induratum. J Dermatolog Treat. Sep 19 2012;[View Abstract]
  23. Sim JH, Whang KU. Application of the QuantiFERON®-TB Gold test in erythema induratum. J Dermatolog Treat. Jun 2014;25(3):260-3. [View Abstract]
  24. Prajapati V, Steed M, Grewal P, Mahmood MN, Verma G, Brassard A. Erythema induratum: case series illustrating the utility of the interferon-? release assay in determining the association with tuberculosis. J Cutan Med Surg. Oct 2013;17 Suppl 1:S6-S11. [View Abstract]
  25. Segura S, Pujol RM, Trindade F, Requena L. Vasculitis in erythema induratum of Bazin: a histopathologic study of 101 biopsy specimens from 86 patients. J Am Acad Dermatol. Nov 2008;59(5):839-51. [View Abstract]
  26. Gilchrist H, Patterson JW. Erythema nodosum and erythema induratum (nodular vasculitis): diagnosis and management. Dermatol Ther. Jul 2010;23(4):320-7. [View Abstract]
  27. 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. [View Abstract]
  28. 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. [View Abstract]
  29. Bennett NM. Erythema induratum: a case of mistaken identity. Med J Aust. Mar 20 2006;184(6):306; author reply 306-7. [View Abstract]
  30. Chanet V, Amarger S, Pons B, Déchelotte P, Ruivard M, Philippe P. [Nodular thrombophlebitis and granulomatous systemic disease]. Rev Med Interne. Jun 2007;28(6):416-9. [View Abstract]
  31. Cho KH, Lee DY, Kim CW. Erythema induratum of Bazin. Int J Dermatol. Nov 1996;35(11):802-8. [View Abstract]
  32. 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. [View Abstract]
  33. Heymann WR. Panniculitis. J Am Acad Dermatol. Apr 2005;52(4):683-5. [View Abstract]
  34. 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. [View Abstract]
  35. Mascaro JM Jr, Baselga E. Erythema induratum of bazin. Dermatol Clin. Oct 2008;26(4):439-45, v. [View Abstract]
  36. Requena L. Normal subcutaneous fat, necrosis of adipocytes and classification of the panniculitides. Semin Cutan Med Surg. Jun 2007;26(2):66-70. [View Abstract]
  37. Schneider JW, Jordaan HF. The histopathologic spectrum of erythema induratum of Bazin. Am J Dermatopathol. Aug 1997;19(4):323-33. [View Abstract]
  38. White WL. On Japanese baseball and erythema induratum of Bazin. Am J Dermatopathol. Aug 1997;19(4):318-22. [View Abstract]
  39. Wiebels D, Turnbull K, Steinkraus V, Böer A. [Erythema induratum Bazin. "Tuberculid" or tuberculosis?]. Hautarzt. Mar 2007;58(3):237-40. [View Abstract]

This patient exhibited tender, erythematous nodules confined to the lower third of the legs.

A positive Mantoux test reaction in a patient with erythema induratum.

Vasculitis and granulomatous inflammation in the dermis and subcutaneous fat tissues.

Evidence of panniculitis exhibiting lobular, granulomatous, and lymphohistiocytic inflammation.

This patient exhibited tender, erythematous nodules confined to the lower third of the legs.

Vasculitis and granulomatous inflammation in the dermis and subcutaneous fat tissues.

Evidence of panniculitis exhibiting lobular, granulomatous, and lymphohistiocytic inflammation.

A positive Mantoux test reaction in a patient with erythema induratum.