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.
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.
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.
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.
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.
Chest X-ray (CXR), posteroanterior (PA) and lateral, is recommended to rule out underlying active disease and/or past infection.
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.
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?
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.
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?
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.
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 for erythema induratum are summarized in Table I.
|Medical Treatment||Surgical Procedures||Physical Modalities|
|Anti-tuberculosis treatment (rifampin, isoniazid, and pyrazinamide)||Not indicated||Rest|
|Non-steroidal anti-inflammatory agents||Compression stockings|
|Potassium iodide||Supportive bandages|
|Oral gold salts|
Optimal Therapeutic Approach for this Disease
-multidrug antituberculosis therapy (att) with rifampin, isoniazid, pyrazinamide and ethambutol is the cornerstone of treatment for erythema induratum. monotherapy should not be used due to the high risk of resistance. longer duration (6+ month), multidrug regimens have also demonstrated improved disease clearance and decreased relapse; however, the risks of anti-tuberculosis therapy are not trivial. as such, it is recommended that att be reserved for cases in which the patient demonstrates a strongly positive reaction to the mantoux skin test (ppd skin test), a positive quantiferon-tb test, or recover of m tuberculosis dna by pcr.
-Ensure you have ruled out a hidden focus of active TB. Active TB infections should be treated more aggressively than latent infections.
Treatment regimens for adults and children with active TB vary depending on region and authority; the CDC and the World Health Organization (WHO). Currently, the CDC recommends a 6-month, four-drug course with 2 months or RIPE (rifampin, isoniazid, pyrazinamide, ethambutol), followed by 4 months of isoniazid. Similar regimens have been shown effective in erythema induratum even in the absence of proven TB.
Basic CDC recommendations for the common four drug therapy are listed below. Please see the American Thoracic Society, Center for Disease Control and Infectious Diseases Society of America’s 2003 Guidelines for the Treatment of Tuberculosis for a more complete treatment algorithm and dosing schedule
Adults: 5 mg/kg/day (max: 300 mg orally daily)
Children: 10-15 mg/kg/day (max: 300 mg orally daily)
Adults: 10mg/kg/day (max: 600mg orally/intravenously daily) *** Dose may need to be adjusted when there is concomitant use of protease inhibitors or nonnucleoside reverse transcriptase inhibitors.
Children: 10-20mg/kg/day (max: 600mg orally/intravenously daily)
Adults: Suggested dosing using whole tablets (Adults weighing 45-90 kg)
-Weight 40-55 kg: 1000mg orally daily (18.2–25.0mg/kg/day)
-Weight 56-75 kg: 1500mg orally daily (20.0–26.8mg/kg/day)
-Weight 76-90kg: 2000mg orally daily (maximum dose regardless of weight) (22.2–26.3mg/kg/day)
Children: 15–30mg/kg/day (max: 2.0 g orally daily)
Adults: Suggested dosing using whole tablets (Adults weighing 45-90 kg)
– Weight 40-55 kg: 800mg orally daily (14.5–20.0mg/kg/day)
-Weight 56-75 kg: 1,200mg orally daily (16.0–21.4 mg/kg/day)
-Weight 76-90 kg: 1,600mg orally daily (maximum dose regardless of weight) (17.8–21.1 mg/kg/day)
< Age 13: Use with caution
>Age 13: 15–20mg/kg daily (max: 1.0g orally daily)
Compression stockings or supportive bandages can result in improvement of lesions and may warrant a trial in patients with mild disease prior to advancing to systemic treatment. In patients with moderate to severe symptoms, encourage the use of combination medical and physical modalities for potential synergistic effects.
Nonsteroidal antiinflammatory agents (NSAIDS) may alleviate discomfort associated with nodular or ulcerated lesions and should also be considered.
Although less well studied, potassium iodide, dapsone, gold salts, and doxycycline have also been used with success in the treatment of erythema induratum.
At this time there is no role for surgical approaches in the treatment of erythema induratum.
The diagnosis of erythema induratum is clinicopathologic with no pathognomonic histologic features. The disease can masquerade as numerous chronic nodular conditions and the diagnosis can easily be missed. As such, patients may have suffered a protracted course for many years prior to diagnosis.
Explain to the patient the importance of compliance with anti-tuberculosis treatment before beginning therapy. Prolonged, multidrug treatment is necessary to prevent relapse and avoid drug resistance, and progress may be slow. Patients will likely need to be co-managed with an infectious disease physician to monitor the response to therapy.
Encourage patients to persist with treatment. If an active focus of TB is uncovered, appropriate imaging studies should be performed at regular intervals to monitor regression of disease. Patients with active disease require more aggressive follow up and may warrant treatment with directly observed therapy (DOT) if there is any concern for noncompliance.
For patients with latent disease and multiple co-morbidities, the risks of systemic antituberculosis therapy should be carefully weighed against the benefits. Regular follow up at 4-6 week intervals is recommended during the active treatment period to ensure clearance of the lesions.
Inadequately treated disease may result in relapse of lesions or persistent ulcerations and/or complications secondary to systemic tuberculosis. The prognosis of erythema induratum is excellent with appropriate treatment.
Unusual Clinical Scenarios to Consider in Patient Management
While relatively rare, atypical presentations of EIB may occur. Men and even young children may present with the disease, and lesions may appear in unusual locations including the feet, buttocks, thighs, arms and rarely the face and ears. Patients may seemingly have no risk factors for prior TB exposure, and be otherwise completely healthy.
In these situations, a high index of clinical suspicion is required. A good rule of thumb is, if a patient presents with chronic, relapsing, ulcerating nodules demonstrating mostly lobular panniculitis, an assessment for latent and active TB is warranted.
What is the Evidence?
Bazin, E. “Lecons theoriques et cliniques sur la scrofule”. 1861. pp. 146(The original description of erythema induratum as a benign scrofulid.)
White, WL. “On Japanese baseball and erythema induratum of Bazin”. Am JDermatopathol. vol. 19. 1997 Aug. pp. 318-22. (An excellent review of the nosological history and management of erythema induratum.)
Mascaró, JM, Lowe, DG, Munro, DD. “Erythema induratum (Bazin's disease)”. J Am Acad Dermatol. vol. 21. 1989 Oct. pp. 740-5. (A clinical and histopathologic review of 26 patients with erythema induratum, providing circumstantial evidence to support the hypothesis that erythema induratum is a true tuberculid with additional evidence demonstrating the effectiveness of prolonged anti-tuberculosis therapy.)
Requena, L, Sánchez Yus, E. “Panniculitis. Part II. Mostly lobular panniculitis”. J Am Acad Dermatol. vol. 45. 2001 Sep. pp. 325-61. (An in-depth discussion of the histologic distinction of diseases manifesting lobular panniculitis.)
Angus, J, Roberts, C, Kulkarni, K, Leach, I, Murphy, R. “Usefulness of the QuantiFERON test in the confirmation of latent tuberculosis in association with erythema induratum”. Br J Dermatol. vol. 157. 2007 Dec. pp. 1293-4. (A case report demonstrating the utility of the QuantiFERON test in the confirmation of suspected latent tuberculosis in the management of erythema induratum.)
Montgomery, H, O’Leary, PA, Barker, NW. “Nodular vascular diseases of the legs; erythema induratum and allied conditions”. JAMA. vol. 128. 1945 June. pp. 335-41. (An excellent discussion differentiating nodular vasculitis, erythema induratum and allied conditions.)
Ho, MH, Ho, CK, Chong, LY. “Atypical mycobacterial cutaneous infections in Hong Kong:10-year retrospective study”. Hong Kong Med J. vol. 12. 2006. Feb. pp. 21-6. (A prevalence study of erythema induratum in Hong Kong.)
Feiwel, M, Munro, DD. “Diagnosis and treatment of erythema induratum (Bazin)”. Br Med J. vol. 1. 1965 Apr 24. pp. 1109-11. (A case series of 12 patients with erythema induratum of Bazin with accompanying clinical results of multi-drug anti-tuberculosis therapy.)
“Treatment of Tuberculosis. American Thoracic Society, CDC, and Infectious Diseases Society of America”. (The CDC, American Thoracic Society and Infectious Diseases Society of America's expert recommendations for the treatment of tuberculosis.)
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