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 articles include Tuberculosis and Pediatric 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. 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.

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. Others have noted that erythema induratum can present as peripheral neuropathy.[12]

Erythema induratum in the setting of renal cell carcinoma has been confirmed with a QuantiFERON test and response to antituberculosis therapy.[13]

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.[14]

Patients can have a history of use of a tumor necrosis-alpha blocker such as etanercept.[15]

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. Disseminated erythema induratum has been reported.[16]

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[17] 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[18] 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.[19]

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.[22, 23, 24]

The CDC[25] 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.[26] 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.[27] Additional reports have stressed the utility of testing for nodular vasculitis, in particular with the QuantiFERON Gold TB test[28] and the interferon-gamma release assay.[29]

Test for hepatitis.[1]

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, as demonstrated in the image below.



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

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, 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,[30] 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:

Stressing the fact that the histology of erythema induratum has a range of presentations and can be a diagnosis of exclusion, Maharaja et al examined 43 cases of erythematous tender nodules, usually occurring on extremities. In 58.5% of cases, a single clinical diagnosis was made, with the remaining cases garnering more than one diagnosis being considered. Fifty-one percent of cases had histological findings concordant with the clinical diagnosis, but 14% had discordant findings and 35% were left undecided.[31]

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.

Hepatitis C–associated erythema induratum has responded to interferon and ribavirin.

Medication Summary

Combination therapy with isoniazid, ethambutol, and rifampicin should be continued for 9 months.[32] 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).[32]

Isoniazid (Nydrazid, Laniazid)

Clinical Context:  Isoniazid is the best combination of effectiveness, low cost, and minor adverse effects. It is a first-line drug unless resistance or another contraindication is known. Therapeutic regimens of less than 6 months demonstrate an 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. Isoniazid is available as a syrup (50 mg/5 mL) and tablet (100 or 300 mg).

Rifampin (Rifadin, Rimactane)

Clinical Context:  Rifampin is for use in combination with at least one other antituberculous drug; it inhibits DNA-dependent bacterial but not mammalian RNA polymerase. Cross-resistance may occur. Treat for 6-9 months or until 6 months have elapsed from conversion to sputum culture negativity. Rifampin is available as a capsule (150 mg or 300 mg) and powder for injection (600 mg).

Ethambutol (Myambutol)

Clinical Context:  Ethambutol diffuses into actively growing mycobacterial cells, such as tubercle bacilli. It impairs cell metabolism by inhibiting the synthesis of 1 or more metabolites, which, in turn, causes cell death. No cross-resistance is demonstrated.

Mycobacterial resistance is frequent with previous therapy. In these patients, use in combination with second-line drugs not previously administered. Administer every 24 hours until permanent bacteriologic conversion and maximal clinical improvement is seen. Absorption is not significantly altered by food. Ethambutol is available as 100- and 400-mg tablets.

Pyrazinamide

Clinical Context:  Pyrazinamide is a pyrazine analog of nicotinamide that may be bacteriostatic or bactericidal against M tuberculosis, depending on the concentration of drug attained at the site of infection; its mechanism of action is unknown. Administer for initial 2 months of a 6-month or longer treatment regimen for patients who are susceptible to the drug. Treat patients who are resistant to the drug with individualized regimens. Pyrazinamide is available as a 500-mg scored tablet.

Class Summary

Antituberculous agents are used for empiric coverage for tubercle bacilli.

Potassium iodide (Thyro-Block, SSKI, Pima)

Clinical Context:  Potassium iodide's mechanism of action is unknown, but it is known to enhance response by potentiating neutrophil activity. It is 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 hours. Most lesions completely subside within 10-14 days.

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. 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.

Author

Noah S Scheinfeld, JD, MD, 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: Serve(d) as a speaker or a member of a speakers bureau for: Abbvie<br/>Received income in an amount equal to or greater than $250 from: Optigenex<br/>Received salary from Optigenex for employment.

Specialty Editors

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.

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

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

Disclosure: Nothing to disclose.

Acknowledgements

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

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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.