Erythema Induratum (Nodular Vasculitis)

Background

Erythema induratum (first named by Ernest Bazin in 1861 and also referred to as nodular vasculitis or Bazin disease), is categorized as a tuberculid skin eruption, a category that includes a group of skin conditions associated with an underlying or silent focus of tuberculosis (TB).^[1] They are sequelae of immunologic reactions to hematogenously dispersed antigenic components of Mycobacterium tuberculosis. Other members of the tuberculid group include papulonecrotic tuberculid, lichen scrofulosorum, and vascular reactions caused by tuberculosis (ie, nodular tuberculid and nodular granulomatous phlebitis), all of which are distinct from erythema induratum.^[2]

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]  Historically, nodular vasculitis and erythema induratum (Bazin disease) have generally been considered synonymous. In current usage, however, the terms erythema induratum and Bazin disease are applied only to cases of nodular vasculitis that are associated with M tuberculosis infection.^[3]  

The historical equation of erythema induratum with nodular vasculitis notwithstanding, nodular vasculitis is now considered a multifactorial syndrome of lobular panniculitis in which TB may or may not be one of a multitude of etiologic components. The erythema induratum–nodular vasculitis complex may be usefully classified into three variant forms as follows^[4] :

• TB-associated erythema induratum (Bazin disease)
• Erythema induratum associated with other diseases and drugs
• Idiopathic erythema induratum

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Pathophysiology

The pathogenesis of erythema induratum has not been fully elucidated. The morphologic, molecular, and clinical data suggest that erythema induratum and nodular vasculitis represent a common inflammatory pathway—namely, 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.

Patients with erythema induratum have a positive tuberculin skin test result and a marked increase in their peripheral T-cell response to the purified protein derivative (PPD) of tuberculin, which can cause a delayed-type hypersensitivity reaction. Results of the enzyme-linked immunosorbent assay (ELISA)-based interferon gamma release assay (IGRA) blood test for TB are often positive in patients with erythema induratum, again suggesting that erythema induratum is a hypersensitivity reaction to a systemic infection and that it has features of both type III (immune-complex–mediated) and type IV (delayed-type) hypersensitivity reactions.

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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 means of immunofluorescence, and in some cases mycobacterial DNA sequences have been found by means of polymerase chain reaction (PCR) assay.^[3]

Infection with M tuberculosis is considered to be an etiologic factor for erythema induratum that is associated with TB (Bazin disease). Published reports, indicate that 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]

Associations with diseases other than TB are rarer but have been documented in case reports. Examples include the following:

• Superficial thrombophlebitis^{[6, 7]}
• Autoimmune diseases (eg, systemic lupus erythematosus [SLE],^[8]  rheumatoid arthritis [RA],^[9] hypothyroidism,^[6] Addison disease,^[10] and Takayasu arteritis^[11] )
• Inflammatory bowel disease (IBD; eg, Crohn disease^[12]  and ulcerative colitis^[13] ), including in the setting of vedolizumab therapy for Crohn disease^[14]
• Hematologic disorders (eg, chronic lymphocytic leukemia and antiphospholipid antibody syndrome^[15] )
• Viral infections (eg, hepatitis C,^[16] hepatitis C associated with red finger syndrome,^[17] and hepatitis B^[6] )
• Bacterial infections (eg, with Nocardia, Pseudomonas, Fusarium, or Chlamydia pneumoniae^[18] )
• Mycobacterial infections (eg, with Mycobacterium chelonei,^[19] Mycobacterium avium,^[20]  or Mycobacterium monacense^[21] )

In case reports, erythema induratum has also been associated with certain drugs (eg, etanercept^[22] and propylthiouracil^[23] ). In a patient treated for RA with certolizumab pegol, erythema induratum occurred together with new-onset TB lymphadenitis.^[24] Additionally, recurrence of erythema induratum has been reported during chemotherapy for breast cancer.^[25]

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

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Epidemiology

Erythema induratum is an uncommon disease overall. Isolated cases of erythema induratum have been reported in the United States, and cases have also been reported in Europe, Asia, Africa, and Australia.^{[6, 26, 27, 28, 29]}  Whereas nodular vasculitis is relatively common, particularly in Europe, erythema induratum is rare in Western countries. Erythema induratum is still prevalent in India, Hong Kong,^[27] and some areas of South Africa. A study from Taiwan found that over the period from 2001 to 2020, most cases of erythema induratum were nodular vasculitis rather than TB-associated.^[30]

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); another series of TB-associated erythema induratum found the mean age at presentation to be 37 years (range, 13-66).^[6]  Additionally, case reports have described erythema induratum in young children.^[31]

Both females and males can be affected; however, 80% of patients with erythema induratum are middle-aged women.^[2] All variants of erythema induratum, whether TB-associated or not, are vastly more common in females.

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Prognosis

The prognosis for patients with erythema induratum is good with proper treatment. 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.

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History

A typical presentation of erythema induratum (also referred to as nodular vasculitis or Bazin disease) consists of 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 may also be present.^[32]

About 50% of patients have a past or current history of M tuberculosis infection at an extracutaneous site. Pulmonary tuberculosis (TB) is the most common focus of infection, with tuberculous cervical lymphadenitis being the next most common source. Erythema induratum and renal TB can also be associated.^[33]

In a patient who presents with TB and nodular vasculitis, it is important to rule out HIV infection, in that a variant of erythema induratum, nodular tuberculid, which features granulomatous vasculitis occurring at the dermohypodermal junction, has been noted in several patients with HIV disease.^{[34, 35]}

Although nodular vasculitis is classically associated with M tuberculosis infection, it can also result from 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 been reported in the setting of etanercept use to treat psoriasis.^[22] It has also been reported after bacille Calmette-Guérin (BCG) vaccination.^{[36, 37]}

Nodular vasculitis can also present in the context of noninfectious systemic illness. It has been reported in Crohn disease patients and in the setting of renal cell carcinoma.^{[12, 38]} Painful peripheral neuropathy has also been associated with erythema induratum, with some reports of peripheral neuropathy being a presenting symptom of erythema induratum.^{[39, 40]} Addison disease that occurred during treatment for erythema induratum has been noted, with the suggestion that TB might have been the cause of the Addison disease.^[10]

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Physical Examination

Erythema induratum lesions typically occur on the posterior or lateral lower limbs and may be either unilateral or bilateral. In some instances, the shins can be involved; uncommonly, the trunk, buttocks, thighs, and arms can be involved. Disseminated erythema induratum has been reported.^[41]

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 (see the image below). The lesions resolve spontaneously with or without ulceration over several weeks to months, and they can heal with atrophic scarring and hyperpigmentation.

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

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, aside from those related to their underlying disease. Peripheral neuropathy has also been reported in conjunction with erythema induratum.^{[39, 40]}

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Complications

The clinical course of erythema induratum is chronic, recurrent, and scarring. 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]

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Approach Considerations

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

All patients suspected of having erythema induratum should be tested for underlying disease, especially for tuberculosis (TB), by means of a tuberculin skin test or interferon gamma release assay (IGRA), a review of systems, and chest radiography.^[38]

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Laboratory Studies

Besides a tuberculin skin test or, preferably, an IGRA,^[38]  other reasonable laboratory testing to investigate for underlying disease in a patient suspected of having erythema induratum includes the following:

• Complete blood count (CBC) with differential
• Erythrocyte sedimentation rate (ESR)
• Liver function tests (LFTs)
• Hepatitis C virus (HCV) serology^[16]

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.^{[43, 44]}  For example, in a retrospective study from the United States, PCR testing of biopsy specimens of erythema induratum for TB was positive in only five (25%) of 20 patients, with positive tuberculin skin tests and characteristic lesions that were responsive to anti-TB therapy.^[45]  PCR can be used to differentiate nodular vasculitis from erythema induratum.

IGRAs are whole-blood tests that can aid in the diagnosis of M tuberculosis infection.^[46]  IGRAs that are approved by the US Food and Drug Administration (FDA) and are commercially available in the United States include 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.^[47] The utility of this test is illustrated by the case of a patient who had tender ulcerating nodules of the lower extremity, a normal chest radiograph, and a biopsy without acid-fast bacilli but whose QuantiFERON-TB test result was positive, leading to the diagnosis of erythema induratum.^[48]

IGRAs also have the advantage of avoiding uncomfortable exaggerated hypersensitivities to intradermal purified protein derivative (PPD) testing in screening for M tuberculosis infection in erythema induratum patients.^[32]

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Imaging Studies

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

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Procedures

Some patients are highly sensitive to tuberculin PPD. Patients should be tested with a 1:10,000 dilution Mantoux test (see the image below).

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Positive Mantoux test reaction in 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, in that 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.

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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, though 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.)

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Vasculitis and granulomatous inflammation in dermis and subcutaneous fat tissues.

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

The histologic features are not specific and can vary according to the age of the lesion undergoing biopsy and the degree of 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 as distinct from erythema nodosum (primarily septal inflammation) and polyarteritis nodosa (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.^[9]

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Medical Care

Although erythema induratum (nodular vasculitis or Bazin disease) is not a life-threatening condition, treatment is usually administered because the condition can cause significant pain and disfigurement in affected individuals. In addition, untreated underlying illnesses (eg, tuberculosis [TB]) can cause significant morbidity or death if left untreated.

TB-associated erythema induratum generally responds well to multidrug anti-TB therapy.^[3]  Combination therapy with isoniazid, ethambutol, and rifampin should be continued for 9 months.^[32]  Erythema induratum should begin to respond to therapy by 6 weeks.^[2]  In addition, antipyretics and analgesics are usually required for symptomatic relief. After antituberculotic treatment, treatment of erythema induratum mirrors that of erythema nodosum (EN).^[32]

In a number of cases, nonsteroidal anti-inflammatory drugs (NSAIDs), bed rest, leg elevation, compression stockings, tetracyclines, and potassium iodide have proved effective.^[3]  When underlying disease cannot be identified and treated, management of erythema induratum can be challenging. Oral potassium iodide is the preferred treatment for such cases, as well as cases of idiopathic erythema induratum, and may lead to remission.^[49] 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.^[50]

Treatment with potassium iodide is well tolerated, and recurrences respond well to repeat 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. Potassium iodide must be used with caution in children and in patients with thyroid disease.^{[4, 32]}

Although other therapeutic options for non-TB-associated erythema induratum have been suggested, evidence for their benefit has generally been limited to case reports. Among these suggested options are systemic glucocorticoids (once infection has been ruled out), dapsone, clofazimine,^[51] colchicine,^{[29, 52]} gold salts,^[53] mycophenolate mofetil,^[54] and topical TB therapy.^{[3, 55]}

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Isoniazid

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Rifampin (Rifadin, Rimactane)

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Ethambutol (Myambutol)

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Pyrazinamide

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Potassium iodide (Iosat, Pima Syrup, SSKI)

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

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Naproxen (Aleve, Anaprox, Anaprox DS)

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