Erythema Induratum (Erythema induratum of Bazin, Nodular Vasculitis)

Are You Confident of the Diagnosis?

What you should be alert for in the history

Erythema induratum (also referred to as erythema induratum of Bazin (EIB) or nodular vasculitis) is a chronic nodular skin disease that is thought to represent a hypersensitivity response to Mycobacterium tuberculosis or its antigens.

Erythema induratum classically presents during early adolescence and peri-menopause as subcutaneous poorly defined erythematous plaques and tender violaceous nodules. The disease preferentially affects the posterior and anterolateral aspects of the lower legs of women; however it can occur in other locations as well as in men and children.

Patients may describe a prolonged history of recurrent episodes over years or decades with new crops of lesions appearing often unpredictably. Typically, lesions are tender but nonpruritic and may be precipitated by cold weather. Patients are otherwise healthy without systemic symptoms and often present with a rash as the only symptom of their disease. Patients may or may not recall a history of tuberculosis infection or exposure.

Characteristic findings on physical examination

On physical examination, affected patients will frequently have heavy or column-like calves, erythrocyanosis, cutus marmmorata and some degree of venous insufficiency. Lesional morphology may range from deep seated areas of subcutaneous induration to well-defined plaques and nodules, characteristically on the posterior or lateral aspects of the lower legs (Figure 1). Less commonly, lesions may appear on the thighs, buttocks, arms and rarely the face and ears.

Figure 1.

The plaques are generally erythematous and indurated, with an overlying scaly surface, and may or may not be tender to deep palpation. Nodules are typically 1-4 cm in size, erythematous to violaceous in color, and have a tendency to ulcerate centrally. Ulcerated nodules exhibit overlying crust with a rolled erythematous, blue-tinged border. Individual lesions typically heal slowly over the course of several months, but may persist for years without appropriate treatment. Nonulcerated lesions heal with only postinflammatory hyperpigmentation, whereas ulcerated lesions may heal with atrophic, hyperpigmented scars.

Expected results of diagnostic studies

No pathognomonic histologic feature of erythema induratum exists, and histologic findings may vary with the age of the lesion (Figure 2). EIB exhibits a predominantly lobular or septolobular pattern of panniculitis indistinguishable from the non-M tuberculosis (MTB) associated cases classified as nodular vasculitis. Early lesions are generally confined to the subcutaneous fat (lobular inflammation) and display a predominantly lymphocytic infiltrate, whereas later lesions may extend into the deep dermis and display noncaseating granulomas typical of TB infection. Caseation necrosis is a late finding evident in approximately one half of cases. As a rule, no foreign body is identified and all histochemical stains and cultures for infection are negative.

Figure 2.

Although the majority of cases present with a lymphocytic vasculitis, it is not a diagnostic requirement; ie, the absence of vasculitis does not exclude the diagnosis of EIB in an otherwise appropriate clinical context. There is still no consensus as to whether venules, larger septal veins, or arterioles are most typically involved.

Work-up

In patients with suspected EIB, start with a complete history and physical examination followed by administration of a purified protein derivative (PPD) tuberculosis skin test and an incisional biopsy involving an adequate amount of subcutaneous fat.

If possible, administer the PPD skin test at a 1 TU per 0.1ml test dose rather than the standard 5 TU per 0.1ml dilution. Individuals with EIB often demonstrate an exaggerated host immunologic response to the purified protein derivative that can result in a bullous type IV hypersensitivity reaction. If negative, this should be followed up in 2-3 weeks with the standard 5TU per 0.1ml test dose or the QuantiFERON-TB test (described below).

Incisional or deep punch biopsies should be taken of an early lesion and submitted for hematoxylin & eosin staining as well as for bacterial, fungal, and acid-fast organisms. The sample may also be sent for PCR analysis for MTB DNA using a formalin fixed paraffin-embedded specimen. PCR studies have documented positive M tuberculosis DNA recovery in a wide range of biopsy samples using primers for the repeat sequence IS6110.

The QuantiFERON-TB [QTB] test is particularly helpful in instances where there is a questionable or definite history of BCG vaccination.

The QTB test is an in vitro interferon-gamma (INF-γ) release assay that uses tuberculous mycobacterial RD1 antigens not shared with the BCG vaccine or other atypical mycobacteria, and is therefore specific for current or past Mum tuberculosis infection. The US Center for Disease Control and Prevention (CDC) recommends the QuantiFERON test can be used safely in all circumstances in which the tuberculosis skin test is currently used.

Laboratory tests

Additional laboratory tests including a complete blood count with differential, chemistry panel, erythrocyte sedimentation rate, and liver function tests are typically normal in erythema induratum.

Imaging

Chest X-ray (CXR), posteroanterior (PA) and lateral, is recommended to rule out underlying active disease and/or past infection.

Other

Early morning sputum, urine and gastric aspirates may be helpful to rule out an underlying active infection, but are generally negative.

In cases with negative TB findings, a work up for hepatitis C and possibly HIV may be recommended.

Diagnosis confirmation

Clinically, EIB can mimic a number of conditions presenting as lower extremity nodules, including:

Arthropod bites and papular uticaria (differentiated by the classically pruritic and non-tender nature of the nodules).

Erythema nodusum (differentiated clinically by the location on the anterior lower extremities, compared to the more characteristic posterior-lateral aspects of the legs of EIB and tendency towards spontaneous healing without ulceration or scarring. Serological studies including antistreptolysin titer O, hepatitis A, and B, Mycoplasma, Bartonella, and Epstein-Barr virus may additionally be positive).

Papulonecrotic tuberculid (differentiated clinically by the tendency toward lesion necrosis and subsequent crusting and histologically by location in the superficial dermis compared to the more characteristic location of EIB in the subcutaneous fat).

Cutaneous polyarteritis nodosa (differentiated clinically by lesions location- typically along medium sized arteries and pressure points; ie,. knees, heels and posterior lower legs and histologically by presence of panarteritis. Patients with cutaneous polyarteritis nodosa may additionally present with generalized symptoms including fever, malaise, joint and muscle aches as well as neurological symptoms including numbness, tingling, sensory disturbances, weakness, and areflexia, whereas patients with EIB are classically asymptomatic).

Pancreatic panniculitis (differentiated clinically by temporal relationship to pancreatic pathology and spontaneous oily brown discharge from lesions due to liquefactive necrosis. Histology will demonstrate a lobular panniculitis with ghost adipoyctes (adipocytes with fine granular basophilic material and no nuclei) and necrosis of adipocytes.

Lupus profundus (also known as lupus panniculitis, differentiated clinically by its more characteristic location on the face and tendency to cause lipodystrophy due to complete destruction of the involved fat cells).

Subcutaneous sarcodiosis (also called Darier-Roussy sarcoidosis- differentiated clinically by the non-tender nature of nodules on the trunk and legs and typical presence of systemic symptoms as well as histopathologic identification of sarcoidal or epithelioid granulomas with mulit-nucleated giant cells).

The diagnosis of erythema induratum is confirmed by the characteristic clinical morphology and histopathologic findings, a positive PPD, QuantiFERON-TB gold test or isolation of MTB DNA from lesional biopsy, and swift resolution with multi-drug antituberculosis therapy.

Who is at Risk for Developing this Disease?

Epidemiology

Although the true prevalence of EIB is unknown, reports from South Africa and Hong Kong indicate that EIB accounts for 12.7% to 86% of all cases of cutaneous tuberculosis and tuberculids. There is a strong female predominance of the disease (11:1), with few reported cases in men and children.

Risk factors

While there are no risk factors other than previous exposure to TB per se, cold weather, venous stasis with poor peripheral blood flow and obesity appear to precipitate the development of lesions.

What is the Cause of the Disease?

Etiology

Pathophysiology

Erythema induratum is classified as a tuberculid or a chronic nodular skin eruption that represents a cutaneous hypersensitivity reaction to disseminated M tuberculosis (MTB) or its antigens. Affected patients are thought to possess a strong anti-MTB cell-mediated immunity. As such, the development and presentation of lesions fluctuate based on the underlying immune status of the host.

Tuberculids are diagnosed by the characteristic absence of M tuberculosis from skin biopsy or culture, a (PPD) skin or QuantiFERON-TB gold test, and prompt resolution of the eruption with anti-tuberculosis therapy. While the use of PCR has strengthened the association between MTB and tuberculids, the reported rates of MTB DNA recover vary widely and the inability to detect MTB DNA from a skin lesion does not exclude the diagnosis.

Entities currently considered tuberculids include erythema induratum of Bazin, lichen scrofulosorum, papulonecrotic tuberculid and most cases of granulomatous phlebitis.

Historical context

Until recently, clinicians long debated the pathogenesis of EIB and the aforementioned association with Mycobacterium tuberculosis. Bazin in 1861 was the first to describe erythema induratum as a benign erythematous scrofulid; however, it was not until after the discovery of the Mycobacterium tuberculid in 1882 that the term scrofulid became commonly associated with TB.

Subsequent authors questioned the causal relationship between EIB and TB, citing the lack of tuberculoid granulomas or acid-fast bacilli in lesional biopsies of EIB; patients and the inability to induce tuberculosis lesions in guinea pigs by inoculation. To address this apparent violation of Koch’s then recently published postulates, Darier in 1896 proposed the term “tuberculid” to describe the cutaneous lesions temporally associated with tuberculosis that failed to demonstrate the tubercle bacillus.

The association between EIB and MTB was later questioned once more by additional reports of patients that presented with a similar clinical picture without positive tuberculin skin tests and no history of TB exposure.

In 1901, Whitfield el al. hypothesized that there may indeed by two types of erythema induratum, TB-related and TB-unrelated. The term “nodular vasculitis” was thus proposed to differentiate the lesions of erythema induratum of non-tuberculosis origin from those of tuberculosis origin (known today as erythema induratum of Bazin).

Currently, erythema induratum and nodular vasculitis are thought to result from a common inflammatory pathway, that is, a hypersensitivity to M tuberculosis (MTB) or non-MTB related antigens. While clinically and histologically similar, unlike nodular vasculitis, patients with erythema induratum typically demonstrate an increased cell mediated response to the Tuberculin Sensitivity or PPD skin test, which may result in a bullous type IV hypersensitivity reaction. The clinical response to anti-tuberculosis therapy can also be used as an indicator to discern the two entities.

Systemic Implications and Complications

Although usually latent, cases of active TB infection associated with erythema induratum have been reported (lungs, pleura, pericardium, peritoneum, lymph nodes, and endometrium).

As such, once a diagnosis of a tuberculid is made, a thorough investigation to evaluate for subclinical or active TB infection should be pursued. Patients with active disease require co-management with appropriate specialists. Additionally, all states require a communicable disease report to be filed with the local county public health department, generally within 24 hours of identification.

Treatment Options

Treatment options for erythema induratum are summarized in Table I.