Erythema Induratum of Bazin/Nodular Vasculitis

 

Overview

Clinical ·       Erythematous subcutaneous nodules and plaques of lower legs; common on calves, but also on anterolateral legs, feet, and thighs; rarely elsewhere. ·       Commonly associated with venous insufficiency; more frequent in young to middle-aged women. ·       Often, ulceration and scarring, especially on the calves. ·       Chronic, relapsing course. ·       Classically associated with tuberculosis [especially Mycobacterium tuberculosis (MTB)], but similar lesions can be idiopathic or induced by other infectious agents such as fungal, protozoal, and viral or by drugs     Histopathology ·       Mostly lobular or mixed lobular and septal panniculitis with vasculitis in 90%. ·       Extensive necrosis of the adipocytes in the center of the fat lobule. ·       Variable inflammatory infiltrate in the fat lobule: neutrophils in early lesions and epithelioid histiocytes and multinucleated giant cells in fully developed lesions. ·       Vasculitis of the small veins and venules of the fat lobule.   Treatment ·       With positive MTB microbiological, serological or Mantoux tests, or when MTB DNA is demonstrated: a full course of antituberculosis triple-agent therapy. If other infection proven or suspect: treat specific infection. ·       In other cases: potassium iodide, other anti-inflammatory drugs, supporting bandages, support hose, leg elevation, bed rest.

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Introduction

Nodular vasculitis is a form of lobular panniculitis associated with subcutaneous blood vessel vasculitis with subsequent ischemic changes that produce lipocyte injury, necrosis, inflammation, and granulation. 

Synonyms are erythema induratum and Bazin disease, but these terms are now reserved for those cases of nodular vasculitis that are associated with Mycobacterium tuberculosis. They are sequelae of immunologic reactions to hematogenously dispersed antigenic components of Mycobacterium tuberculosis. 

 

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. 

 

Tuberculids can be considered to be cutaneous hypersensitivity reactions to hematogenous dissemination of M. tuberculosis or its antigens from a primary source in an individual with strong antituberculous cell‐mediated immunity. The diagnostic criteria include tuberculoid histology on skin biopsy, a strongly positive Mantoux reaction, and the absence of M. tuberculosis in the smear and negative culture and resolution of the skin lesions with antituberculous therapy.

 

Epidemiology

 

Age

Mean age of the disease is between 30 and 40 years. Additionally, case reports have described erythema induratum in young children. 

 

Erythema induratum of tuberculous etiology occurs more frequently in populations with a high prevalence of tuberculosis.

 

Sex

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

 

 

Pathogenesis

 

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.

 

Although it has been suggested that erythema induratum results from an immune complex-mediated vasculitis, most investigators believe that the process represents a type IV, cell-mediated response to an antigenic stimulus. 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.  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. Infection with M tuberculosis is considered to be an etiologic factor for erythema induratum that is associated with tuberculosis (Bazin disease), and latent or active TB infection is the most common reported identifiable cause of erythema induratum. Disease associations besides TB are rarer.

 

Examples include the following:

 

·        Superficial thrombophlebitis 

 

·        Autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, hypothyroidism, Addison disease, and Takayasu arteritis 

 

·        Inflammatory bowel disease (Crohn disease, ulcerative colitis), including in the setting of vedolizumab therapy for Crohn disease 

 

·        Hematologic disorders such as chronic lymphocytic leukemia and antiphospholipid antibody syndrome 

 

·        Viral infections, including hepatitis C virus, hepatitis C associated with red finger syndrome, and hepatitis B virus 

 

·        Bacterial infections, including Nocardia, Pseudomonas, Fusarium, and Chlamydia pneumoniae  infections

 

·        Mycobacterial infections ( Mycobacterium chelonae, Mycobacterium avis, Mycobacterium monacense) 

 

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

 

A minority of cases of erythema induratum has no identifiable cause and is classified as idiopathic erythema induratum.

 

Histopathology

Histopathological findings correlate with lesion duration, but the common denominator is a mostly lobular or mixed septal and lobular panniculitis

In early lesions, fat lobules contain discrete aggregates of inflammatory cells, with neutrophils predominating. Adipocyte necrosis is present to varying degree, leading to accumulations of foamy histiocytes. In established lesions of EI/NV, collections of epithelioid histiocytes, mutinucleated giant cells, and lymphocytes produce a granulomatous appearance.

Vasculitis is identified in 90% of cases and most frequently involves veins or arteries of connective tissue septa and small venules of the fat lobules. It may be predominantly neutrophilic, lymphocytic, or granulomatous. Intense vascular damage, when present, is accompanied by extensive areas of caseous necrosis, eventuating in tuberculoid granuloma formation. The caseous necrosis may involve the overlying dermis to such an extent that ulceration occurs. Necrosis has been described in both tuberculous and non-tuberculous cases, and the incidence and degree of necrosis are greater in those cases that are positive for M. tuberculosis DNA by PCR methods.

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 (as it is absent in approximately 10% of cases) 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).

 

Clinical features

History

 

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

 

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. 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, has been noted in patients with HIV disease. 

 

 

Cutaneous lesions

 

EI/NV is seen most commonly in young to middle-aged women, presenting as recurrent crops of erythematous to violaceous subcutaneous nodules and deep plaques that most often develop on the lower legs, especially the calves, may be either unilateral or bilateral. Tenderness is usually present, but pain is variable and usually not excruciating. The lesions resolve spontaneously with or without ulceration over several weeks/months. Lesions may ulcerate centrally, and this may be precipitated by cold weather or venous stasis. The ulcers are ragged, irregular and shallow, with a bluish edge. Surface changes include crusting of the ulcers and a surrounding collarette of scale. Lesions are persistent, tend to heal with atrophic, depressed hyper pigmented scarring and are prone to recurrence. Some lesions may heal without ulcer and scarring. The posterior leg calf region is the most frequent location, but lesions may also appear in the anterolateral areas of the legs, the feet, thighs, buttocks, and rarely the arms. An annular arrangement of nodules has been described in M. tuberculosis-related cases. Clinical differences between tuberculous and non-tuberculous cases are minor. EI lesions develop more frequently during winter, and EI is commonly associated with obesity and venous insufficiency.

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. 

 

Disease course and prognosis

Untreated, the disease course is chronic with recurrent crops of new lesions sometimes over many years. Response to antituberculous therapy may take between 1 and 6 months and resolution may be slow, even with adequate therapy, particularly if there are associated erythrocyanotic features.

 

Investigations

The diagnosis is made on characteristic clinical morphology, a positive tuberculin test and circumstantial evidence of tuberculosis elsewhere in the body, supplemented by histopathological findings. Detection of M. tuberculosis DNA by PCR on the skin biopsy specimen may be positive but a negative result does not exclude the diagnosis. 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). Commercially available IGRAs such as the QuantiFERON‐TB Gold test can confirm the presence of latent TB in association with erythema induratum. 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 is positive, leading to the diagnosis of erythema induratum. 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. Although cases of active tuberculosis are rare in erythema induratum, the patient should be fully investigated for subclinical active tuberculosis infection. The diagnosis can be confirmed by a good response to antituberculous therapy. In cases where the diagnosis of tuberculosis seems unlikely, testing for chronic hepatitis C viral infection and other infections including fungi and parasites, should be sought and treated, if present.

 

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

 

 

Treatment

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.

 

In patients with positive MTB cultures, positive skin test or Quantiferon gold test for MTB, treatment with triple agent antituberculosis therapy is indicated. If Quantiferon gold test is negative but clinical suspicion in a high-risk TB area persists, lesional PCR is recommended.

 

Patients with hepatitis B or C should receive appropriate intervention for that disorder. Other infectious etiologies including fungi, parasites, and viruses should be sought and treated, if present. Medications that may have incited EI should be discontinued.

++Anti-inflammatory treatments that have been used in EI/NV not associated with MBT include super saturated potassium iodide (SSKI), non steroidal anti-inflammatory agents (NSAIDS), tetracyclines as well as bed rest, leg elevation, and treatment of venous insufficiency with compression and pentoxifylline. Potassium iodide, while effective, requires caution when used in children or in patients with thyroid disease. 

 

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. Oral potassium iodide is used at a dose of (360-900 mg/day), with pain and swelling decreasing after 2 days and complete resolution after 4 weeks of treatment. 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. 

 

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, mycophenolate mofetil, If immunosuppressive agents are used, continued monitoring for possible infectious etiology is recommended.

 

Therapeutic ladder

First line

Full specific antituberculous therapy should be given according to current recommended guidelines for systemic tuberculosis.

Second line

In some patients simple measures such as bed rest, leg elevation, non‐steroidal anti‐inflammatory drugs and compression bandaging may be helpful.