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] :
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TB-associated erythema induratum (Bazin disease)
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Erythema induratum associated with other diseases and drugs
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Idiopathic erythema induratum
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.
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:
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Hematologic disorders (eg, chronic lymphocytic leukemia and antiphospholipid antibody syndrome [15] )
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Bacterial infections (eg, with Nocardia, Pseudomonas, Fusarium, or Chlamydia pneumoniae [18] )
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.
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.
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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This patient exhibited tender, erythematous nodules confined to lower third of legs.
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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.
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Positive Mantoux test reaction in patient with erythema induratum.
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