Erythema Induratum (Nodular Vasculitis) 

Updated: Nov 15, 2019
Author: Esther A Balogh, MD; Chief Editor: William D James, MD 

Overview

Background

Erythema induratum, also known as nodular vasculitis or Bazin disease, is categorized as a tuberculid skin eruption, which is a group of skin conditions associated with an underlying or silent focus of tuberculosis (TB). They are sequelae of immunologic reactions to hematogenously dispersed antigenic components of Mycobacterium tuberculosis.[1] Other members of the tuberculid group include papulonecrotic tuberculid, lichen scrofulosorum, and vascular reactions caused by tuberculosis, namely, nodular tuberculid and nodular granulomatous phlebitis, all of which are distinct from erythema induratum.[2]

In 1861, Ernest Bazin gave the name erythema induratum to a nodular eruption that occurred on the lower legs of young women with tuberculosis. Although nodular vasculitis and erythema induratum (Bazin disease) have historically been considered synonymous, the terms erythema induratum and Bazin disease are currently only used for cases of nodular vasculitis that are associated with M tuberculosis infection.[3] The term nodular vasculitis was coined in 1945 to describe chronic inflammatory nodules of the legs that showed histopathologic changes similar to those of erythema induratum; that is, nodular vasculitis is a form of lobular panniculitis associated with subcutaneous blood vessel vasculitis that leads to ischemic changes.[3]

Although erythema induratum and nodular vasculitis were once considered to be the same disease, 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. Currently, erythema induratum/nodular vasculitis complex is classified into three variants: tuberculosis-associated erythema induratum (Bazin disease), erythema induratum associated with other diseases and drugs, and idiopathic erythema induratum.[4]

Related Medscape Drugs & Diseases articles include Tuberculosis and Pediatric Tuberculosis.

Pathophysiology

The pathogenesis of erythema induratum is not completely understood. The morphologic, molecular, and clinical data suggest that erythema induratum and nodular vasculitis represent a common inflammatory pathway: an immune-mediated hypersensitivity reaction to endogenous or exogenous antigens, one such antigen being M tuberculosis. Histologically, erythema induratum lesions demonstrate a mixed granulomatous inflammatory process triggered by M tuberculosis or other antigens. Because erythema induratum involves vasculitis, it is likely that endothelial antigens are a target of cell-mediated cytotoxic processes occurring in erythema induratum. Patients with erythema induratum have a positive tuberculin skin test result and a marked increase in their peripheral T-lymphocyte response to the purified protein derivative (PPD) of tuberculin, which can cause a delayed-type hypersensitivity reaction. Results of the enzyme-linked immunosorbent assay–based interferon-gamma release assay blood test for tuberculosis are often positive in patients with erythema induratum, again suggesting that erythema induratum is a hypersensitivity reaction to a systemic infection, and that erythema induratum has features of both type III (immune-complex–mediated) and type IV (delayed-type) hypersensitivity reactions.

Etiology

The etiology of erythema induratum remains poorly understood, although there is consensus that the erythema induratum/nodular vasculitis complex is a multifactorial, immune-mediated hypersensitivity reaction. More specifically, erythema induratum is thought to result from an immune-complex–mediated (type III hypersensitivity) vascular injury due to bacterial antigens.[3] Immunoglobulins, complement, and bacterial antigens have all been identified by immunofluorescence, and in some cases mycobacterial DNA sequences have been found by polymerase chain reaction.[3] Infection with M tuberculosis is considered to be an etiologic factor for erythema induratum that is associated with tuberculosis (Bazin disease), and, based on published reports, latent or active TB infection is the most common reported identifiable cause of erythema induratum. In a retrospective study of 65 patients with histologically diagnosed erythema induratum in Spain between 1976 and 1994, 89% had a positive tuberculin skin test.[5] Disease associations besides TB are more rare but have been documented in case reports. Examples include the following:

  • Superficial thrombophlebitis [6]
  • Autoimmune diseases such as systemic lupus erythematosus, [7] , rheumatoid arthritis, [8] hypothyroidism, [6] Addison disease, [9] and Takayasu arteritis [10]
  • Inflammatory bowel disease (Crohn disease, [11] ulcerative colitis [12] ), including in the setting of vedolizumab therapy for Crohn disease [13]
  • Hematologic disorders such as chronic lymphocytic leukemia and antiphospholipid antibody syndrome [14]
  • Viral infections, including hepatitis C virus, [15] hepatitis C associated with red finger syndrome, [16] and hepatitis B virus [6]
  • Bacterial infections, including Nocardia, Pseudomonas, Fusarium, and Chlamydia pneumoniae [17] infections
  • Mycobacterial infections ( Mycobacterium chelonae, Mycobacterium avis, Mycobacterium monacense) [18, 19, 20]

Erythema induratum has also been associated with certain drugs in case reports, such as etanercept and propylthiouracil.[21, 22] In a patient treated for rheumatoid arthritis with certolizumab pegol, erythema induratum occurred together with new-onset TB lymphadenitis.[23] Additionally, recurrence of erythema induratum has also been reported during chemotherapy for breast cancer.[24]

A minority of cases of erythema induratum have no identifiable cause and are classified as idiopathic erythema induratum.

Epidemiology

Frequency

Erythema induratum is an uncommon disease, and it has been reported in the United States, Europe, Asia, Africa, and Australia.[6, 25, 26, 27, 28]

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.[29]

Sex

Eighty percent of patient with erythema induratum are middle-aged women; however, both females and males can be affected.[2] All variants of erythema induratum (TB-associated and non–TB-associated) are vastly more common in females.

Age

Although the age range for individuals affected by erythema induratum is variable, a large series of 86 erythema induratum patients found that the median age was 56 years (range, 23-81 y); another series of TB-associated erythema induratum found the mean age at presentation to be 37 years (range, 13-66 y).[6] Additionally, case reports have described erythema induratum in young children.[30]

Prognosis

The prognosis is good if properly treated. 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.

 

Presentation

History

A typical presentation of erythema induratum (nodular vasculitis) is recurrent crops of tender, violaceous nodules and plaques on the posterior lower limbs. The nodules usually evolve over several weeks and can eventually ulcerate and drain, ultimately healing with depressed scarring and postinflammatory hyperpigmentation. Leg edema also may be present.[31]

A past or present history of infection with M tuberculosis at an extracutaneous site occurs in about 50% of patients; pulmonary tuberculosis (TB) is the most common foci of infection, with tuberculous cervical lymphadenitis being the next most common source. Erythema induratum and renal TB can also be associated.[32] In a patient who presents with TB and nodular vasculitis, it is important to rule out HIV infection, as a variant of erythema induratum, nodular tuberculid, which features granulomatous vasculitis occurring at the dermohypodermal junction, has been noted in five patients with HIV disease.[33, 34]

Although nodular vasculitis is classically associated with M tuberculosis infection, it also can occur due to infection with other agents, as well as from drugs. Non-TB infectious causes of erythema induratum include Nocardia, Pseudomonas, and Fusarium infections. Erythema induratum has also been reported in the setting of etanercept use in a patient with psoriasis.[21] A case of erythema induratum was reported in an infant after BCG vaccination.[35]

Nodular vasculitis also can present in the setting of noninfectious systemic illness. Nodular vasculitis has been reported in Crohn disease patients and the setting of renal cell carcinoma.[11, 36] Painful peripheral neuropathy has also been associated with erythema induratum, with some reports of peripheral neuropathy being a presenting symptom of erythema induratum.[37, 38] Addison disease that occurred during treatment for erythema induratum has been noted, and the authors of this report suggest that TB might have been the cause of the Addison disease.[9]

Physical Examination

Erythema induratum lesions typically occur on the posterior or lateral lower limbs and may be either unilateral or bilateral, although the shins can sometimes be involved. Uncommonly, the trunk, buttocks, thighs, and arms can be involved; disseminated erythema induratum has also been reported.[39] The nodules are concentrated around the lower third of the posterior lower limb, around the ankles. Crops of tender, erythematous-to-violaceous, variably scaly, 1- to 2-cm subcutaneous nodules may be observed, as demonstrated in the image below. The lesions resolve spontaneously with or without ulceration over several weeks/months, and they can heal with atrophic scarring and hyperpigmentation. Tenderness is usually present, but pain is variable and usually not excruciating, if present. The involved lower-limb sites may also show acrocyanosis.[2] Patients with erythema induratum do not usually present with constitutional symptoms, except those related to their underlying disease. Peripheral neuropathy has also been reported in conjunction with erythema induratum.[37, 38]

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

Complications

The clinical course of erythema induratum is chronic, recurrent, and scarring, and, inadequately treated or untreated erythema induratum may result in prolonged disease, persistent and disfiguring ulcerations and scarring, and complications from underlying systemic TB or other infectious disease.[3]

 

DDx

Diagnostic Considerations

Erythema induratum (nodular vasculitis) must be distinguished from the following:

  • Erythema nodosum (EN) [2] : EN has a relatively short duration, develops rapidly, and mainly affects the anterior rather than posterior lower limb. EN lesions consist of tender, painful, scarlet or contusiform nodules that appear spontaneously and do not ulcerate. Histologically, septal panniculitis is seen. EN is generally more painful than erythema induratum.
  • Cutaneous polyarteritis nodosa (PAN): Cutaneous PAN presents as tender, erythematous, purpuric macules, papules, and nodules, often occurring in a livedoid pattern on the lower extremity. Histologically, cutaneous PAN is centered around small subcutaneous arteries rather than broader subcutaneous inflammation on many vessel types as in erythema induratum.
  • Tertiary syphilis: Gummas are usually unilateral and single or may appear as a small, distinct group of lesions.
  • Other infectious panniculitides (panniculitis caused by Mycobacterium massiliense [40] )
  • Inflammatory panniculitides (eg, pancreatic panniculitis, lupus panniculitis, alpha-1 antitrypsin deficiency panniculitis, subcutaneous panniculitic T-cell lymphoma) [2]
  • Traumatic panniculitis (TP): TP occurs as one or a few tender or asymptomatic nodules. TP can occur at any site, the anterior leg (shin) being the most common location. Factitial panniculitis is a subtype of TP. Histologically, there is prominent fat necrosis but no vasculitis.

Differential Diagnoses

  • Cutaneous polyarteritis nodosa (PAN)

  • Erythema Nodosum

  • Inflammatory panniculitis

  • Other infectious panniculitis (eg, M massiliense)

  • Tertiary syphilis

  • Traumatic panniculitis

 

Workup

Approach Considerations

The diagnosis of erythema induratum (nodular vasculitis) is made based on a combination of clinical signs and skin biopsy findings, in conjunction with negative test results for lesional infection.

To evaluate for underlying disease, all patients suspected to have erythema induratum should be tested for underlying disease, especially for tuberculosis (TB), by a tuberculin skin test or interferon-gamma release assay (IGRA), review of systems, and a chest radiograph.[36]

Laboratory Studies

Patients with suspected erythema induratum should be evaluated for underlying disease, especially TB. Laboratory studies include a tuberculin skin test or, preferably, an IGRA.[36]

Other reasonable laboratory testing to investigate for underlying disease in a patient suspected to have erythema induratum includes the following:

  • Complete blood cell count with differential
  • Erythrocyte sedimentation rate
  • Liver function tests
  • Hepatitis C virus serology [15]

Detection of M tuberculosis DNA from formalin-fixed tissue samples from erythema induratum lesions by means of polymerase chain reaction (PCR) testing supports the association of erythema induratum with TB; however, diagnostic sensitivity is variable and is influenced by technical factors.[41, 42, 43] For example, in a retrospective study from the United States, PCR testing of biopsy specimens of erythema induratum for TB was only positive in 5 (25%) of 20 patients, with positive tuberculin skin tests and characteristic lesions that were responsive to anti-TB therapy.[43]

IGRAs are whole blood tests that can aid in diagnosing infection with M tuberculosis.[44] Two IGRAs that the US Food and Drug Administration (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-TB test can confirm the presence of latent TB in association with erythema induratum.[45] The utility of this test is exemplified in a patient with tender ulcerating nodules of the lower extremity, a normal chest radiograph, and a biopsy without acid-fast bacilli, but whose QuantiFERON-TB test was positive, leading to the diagnosis of erythema induratum.[46] IGRAs also have the advantage of avoiding uncomfortable exaggerated hypersensitivities to intradermal purified protein derivative (PPD) testing when screening for M tuberculosis infection in erythema induratum patients.[31]

Imaging Studies

In patients suspected of having erythema induratum, a chest radiograph should be acquired to rule out active or latent pulmonary TB.

Other Tests

PCR provides rapid and sensitive detection of M tuberculosis in formalin-fixed, paraffin-embedded specimens. PCR can be used to differentiate nodular vasculitis from erythema induratum (Bazin disease).

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.

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

A biopsy is required to confirm the diagnosis of erythema induratum. An incisional biopsy or a full-thickness punch biopsy from the lesional skin is preferred to a small or superficial punch biopsy, as small and superficial biopsies are more likely to be nondiagnostic or misinterpreted. Special stains for bacteria, fungi, and mycobacteria are obtained; lesional histochemical stains and lesional cultures are, by definition, negative for pathogens in erythema induratum.

Histologic Findings

The primary pathologic changes in erythema induratum occur in the subcutaneous fat, showing predominantly lobular panniculitis with fat necrosis. There is a mixed inflammatory infiltrate of lymphocytes, plasma cells, histiocytes forming granulomas, neutrophils, and eosinophils. In two thirds of cases, granulomatous, noncaseating inflammation is present. A granulomatous vasculitis of the medium-sized arterioles in the fat can be seen and is the apparent cause of the fat necrosis, although examination of multiple sections may be required to observe this.[2] Stains and cultures for bacteria, mycobacteria, and fungi are negative.

See the images below.

Vasculitis and granulomatous inflammation in the d Vasculitis and granulomatous inflammation in the dermis and subcutaneous fat tissues.
Evidence of panniculitis exhibiting lobular, granu Evidence of panniculitis exhibiting lobular, granulomatous, and lymphohistiocytic inflammation.

The histologic features are not specific and can 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 for erythema induratum and contrasts with erythema nodosum (primarily septal inflammation) and polyarteritis nodosum (medium-vessel vasculitis with minimal lobular inflammation).

In a study of 101 cases of erythema induratum, it was found that erythema induratum has a variety of presentations of vasculitis and that in approximately 10% of cases clinicopathologic patterns of vasculitis could not be demonstrated in erythema induratum specimens.[8]

 

Treatment

Medical Care

Although erythema induratum (nodular vasculitis) is not a life-threatening condition, treatment is usually administered because it can cause significant pain and disfigurement in affected individuals; untreated underlying illnesses such as tuberculosis (TB) can also cause significant morbidity or death if left untreated. TB-associated erythema induratum generally responds well to multidrug anti-TB therapy.[3]

In other cases, nonsteroidal anti-inflammatory drugs (NSAIDs), bed rest, leg elevation, compression stockings, tetracyclines, and potassium iodide have proven effective.[3] Potassium iodide, while effective, requires caution when used in children or in patients with thyroid disease.[4, 31]

If underlying disease cannot be identified and treated, management of erythema induratum can be challenging. In cases of idiopathic erythema induratum or erythema induratum in which the underlying disease cannot be treated or cured, oral potassium iodide is the preferred treatment and may lead to remission.[47] In one study of patients with non–TB-associated erythema induratum, 16 of 17 patients responded to oral potassium iodide (360-900 mg/day), with pain and swelling decreasing after 2 days and complete resolution after 4 weeks of treatment.[48] Treatment with potassium iodide is well tolerated, and recurrences respond well to re-treatment. Long-term treatment with potassium iodide is associated with a risk of hypothyroidism. Other possible adverse effects include gastrointestinal symptoms, salivary gland enlargement, and potassium toxicity.[49] Other therapeutic options for non–TB-associated erythema induratum have been suggested, but evidence for their benefit is limited to case reports. Among these options are systemic glucocorticoids (once infection has been ruled out), dapsone, clofazimine, colchicine, gold salts, mycophenolate mofetil, and topical TB therapy.[3, 28, 50, 51, 52, 53]

 

Medication

Medication Summary

When treating erythema induratum (nodular vasculitis), combination therapy with isoniazid, ethambutol, and rifampicin should be continued for 9 months.[31] Erythema induratum should begin to respond to therapy by 6 weeks.[2] In addition, antipyretics and analgesics usually are required for symptomatic relief. After antituberculotic treatment for tuberculosis (TB), treatment for erythema induratum mirrors that of erythema nodosum (eg, naproxen, potassium iodide).[31]

Antitubercular Agents

Class Summary

Anti-TB agents are used for empiric coverage of M tuberculosis.

Isoniazid (Nydrazid, Laniazid)

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)

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)

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

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.

Antithyroid agents

Class Summary

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

Potassium iodide (Thyro-Block, SSKI, Pima)

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.

NSAIDs

Class Summary

NSAIDs can be used for symptomatic pain relief and in cases of non–TB-associated erythema induratum.

Ibuprofen (Advil, Motrin, PediaCare Children's Pain Reliever/Fever Reducer IB)

Ibuprofen inhibits the synthesis of prostaglandins in body tissues by inhibiting at least two cyclooxygenase (COX) isoenzymes, COX-1 and COX-2. It may inhibit chemotaxis, alter lymphocyte activity, decrease proinflammatory cytokine activity, and inhibit neutrophil aggregation; these effects may contribute to anti-inflammatory activity.

Naproxen (Aleve, Anaprox, Anaprox DS)

Naproxen inhibits the synthesis of prostaglandins in body tissues by inhibiting at least two cyclooxygenase (COX) isoenzymes, COX-1 and COX-2. It may inhibit chemotaxis, alter lymphocyte activity, decrease proinflammatory cytokine activity, and inhibit neutrophil aggregation; these effects may contribute to anti-inflammatory activity.

 

Questions & Answers

Overview

What is erythema induratum (nodular vasculitis)?

What is the pathophysiology of erythema induratum (nodular vasculitis)?

What causes erythema induratum (nodular vasculitis)?

What is the prevalence of erythema induratum (nodular vasculitis) in the US?

What is the global prevalence of erythema induratum (nodular vasculitis)?

What are the sexual predilections of erythema induratum (nodular vasculitis)?

Which age groups have the highest prevalence of erythema induratum (nodular vasculitis)?

What is the prognosis of erythema induratum (nodular vasculitis)?

Presentation

Which clinical history findings are characteristic of erythema induratum (nodular vasculitis)?

Which physical findings are characteristic of erythema induratum (nodular vasculitis)?

What are the possible complications of erythema induratum (nodular vasculitis)?

DDX

Which conditions should be included in the differential diagnoses of erythema induratum (nodular vasculitis)?

What are the differential diagnoses for Erythema Induratum (Nodular Vasculitis)?

Workup

What is the role of lab testing in the workup of erythema induratum (nodular vasculitis)?

What is the role of imaging studies in the workup of erythema induratum (nodular vasculitis)?

What is the role of PMR in the diagnosis of erythema induratum (nodular vasculitis)?

What is the role of a Mantoux test in the diagnosis of erythema induratum (nodular vasculitis)?

What is the role of biopsy in the diagnosis of erythema induratum (nodular vasculitis)?

Which histologic findings are characteristic of erythema induratum (nodular vasculitis)?

Treatment

How is erythema induratum (nodular vasculitis) treated?

Medications

Which medications are used in the treatment of erythema induratum (nodular vasculitis)?

Which medications in the drug class Antithyroid agents are used in the treatment of Erythema Induratum (Nodular Vasculitis)?

Which medications in the drug class Antitubercular Agents are used in the treatment of Erythema Induratum (Nodular Vasculitis)?

Which medications in the drug class are used in the treatment of Erythema Induratum (Nodular Vasculitis)?

Which medications in the drug class NSAIDs are used in the treatment of Erythema Induratum (Nodular Vasculitis)?