Are You Confident of the Diagnosis?
Erythema nodosum leprosum (ENL) is an immune-mediated complication of leprosy, characterized by the presence of multiple inflammatory cutaneous nodules and systemic symptoms such as fever, malaise, arthritis, iritis, neuritis and lymphadenitis. Histopathologic examination demonstrates an inflammatory infiltrate of neutrophils with vasculitis and/or panniculitis, deposition of immune complexes and complement associated with Mycobacterium leprae antigens. The course is prolonged with recurrent episodes occurring over a period of 12 to 24 months, or longer than 7 years in some cases.
Despite the gradual decrease in the total number of leprosy cases worldwide, reactions remain an important clinical issue. ENL can affect up to 30% to 40% of leprosy patients, causing severe pain and disability. Appropriate management of type 2 reactions can bring substantial benefit to patients and reduce the morbidity associated with leprosy.
What you should be alert for in the history
The initial presentation may be of cutaneous lesions alone or in combination with systemic symptoms. Rarely, each of the isolated systemic manifestations may be the presenting complaint, for instance recurrent episodes of fever with no other apparent cause.
Characteristic features on physical examination
Cutaneous manifestations include the presence of inflammatory nodules that are usually tender, multiple, and bilateral. The lesions differ clinically from erythema nodosum by their extensive number, widespread distribution, and evanescent nature. The lesions may become targetoid, vesicular, boullous, ulcerative, or necrotic in sever reactions. The presence of erythematous painful nodules with a widespread distribution, with or without systemic manifestations in a leprosy patient or in a patient derived from endemic areas, should alert the clinician for the possibility of ENL (Figure 1).
Expected results of diagnostic studies
ENL can usually be diagnosed clinically, but a skin biopsy can be helpful.
Histopathology shows dermal edema, presence of an intense inflammatory infiltrated in the dermis and adjacent subcutaneous adipose tissue, with lobular panniculitis. The infiltrate is composed by lymphocytes, neutrophils and Virchow cell (bacilli rich histiocytes, which ultimatelly are converted to foam cells). Special stains (Fite-Faraco) demonstrate numerous dead and degenerated acid-fast bacilli. Vasculitis is uncommon.
Neutrophilic leukocytosis is often present . An abrupt decrease in hematocrit may occur in severe reactions and can be mistakenly diagnosed as dapsone-induced hemolysis.
Increase in serum markers of inflammation: C-reactive protein (up to 90% of patients), TNF-α, serum amyloid A protein and alpha-1 antitrypsin.
All other conditions known to cause erythema nodosum (EN) must be differentiated from ENL, such as:
-Idiopathic (up to 55 % of cases)
-Infections: streptococcal pharyngitis (28 to 48 percent), mycoplasma, chlamydia, Yersinia spp., histoplasmosis, coccidioidomycosis, Mycobacterium tuberculosis
-Sarcoidosis (11-25%) with bilateral hilar adenopathy
-Drugs (3-10%): antibiotics (e.g., sulfonamides, amoxicillin), oral contraceptives
-Enteropathies (1-4%): regional enteritis, ulcerative colitis
—Lymphoma and other malignancies
—Infections: Bacterial: syphilis, Salmonella spp, Campylobacter spp, rickettsiae, psittacosis, Bartonella spp; Viral: herpes simplex virus, Epstein-Barr virus, hepatitis B and C viruses, human immunodeficiency virus; Parasitic: giardiasis, amoebiasis.
For patients with EN with no known diagnosis of leprosy, the evaluation must include:
-Complete blood count with differential; erythrocyte sedimentation rate and C-reactive protein levels
-Further laboratory evaluation should be requested according to the presenting symptom to identify the etiology:
-Evaluation for streptoccocal infection (ie, throat culture for group A streptococci, rapid antigen test, antistreptolysin-O titer, and polymerase chain reaction assay); Purified protein derivative test, chest radiography; Stool culture and evaluation for ova and parasites in patients with diarrhea or gastrointestinal symptoms.
Who is at Risk for Developing this Disease?
Borderline and lepromatous leprosy patients are susceptible to ENL reactions, which can occur before, during or after treatment with multidrug treatment (MDT). ENL is more prevalent in Southeast Asia and Brazil (25-49% of LL cases), when compared to Africa (5%), probably due to genetic variations. For instance, Brazilian patients who were homozygous C4B-deficient had a higher prevalence of ENL. It was hypothesized that the absence of the C4B allele may impair immune complex clearance and trigger ENL.
-Bacillary index ≥ 4+
-Multi-drug therapy (MDT)
-Infections (screen the patient for subclinical infections, such as dental cavities)
-Vaccinations (All vaccinations may stimulate a systemic immune inflammatory response.)
What is the Cause of the Disease?
ENL is the clinical expression of an immune-complex mediated reaction against M leprae, the causative agent of leprosy (see Leprosy chapter).
ENL is thought to be initiated by the release of mycobacterial antigens, which trigger the formation of immune complexes. Antigen-antibody complexes deposit in tissues and activate the complement cascade. Mononuclear cells release cytokines stimulating the migration of inflammatory cells, in particular of neutrophils. There is also T lymphocyte and macrophage activation, in addition to expression of TNF-α and interleukin (IL)-12 in the skin. The consequence is deposition of fibrin and tissue damage.
Systemic Implications and Complications
Systemic manifestations include fever, malaise, arthralgia, inflammatory arthritis, iritis, orchitis, nephritis and lymphadenitis. Edema of hands and feet with dactylitis may be present (Figure 2). Neuritis may be present, but it is often mild.
Reduced joint mobility. Recurrent episodes may result in scarring of subcutaneous tissues, fixation and reduced joint mobility.
Infertility. Orchitis can be extremely painful and if not immediately treated may lead to testicular atrophy and hypogonadism with consequent gynecomastia, infertility and impotence.
Osteoporosis. Hypogonadism and long-term corticosteroid use may lead to osteoporosis.
Blindness. Chronic iridocyclitis leads to synechiae formation, glaucoma and blindness.
Secondary amyloidosis. Secondary amyloidosis leading to renal impairment may occur when reactions are not well controlled.
Neuritis and permananet nerve damage.
A systematic review of the literature showed that there is no good controlled trial data on the optimum treatment for controlling the acute phase of ENL. The evidence suggests thalidomide and clofazimine may have a beneficial role, but larger controlled trials are necessary.
Mild reactions are defined as the presence of a few erythematous nodules associated with low grade fever and malaise. Mild reactions can be successfully managed with rest, nonsteroidal antiinflammatory drugs (NSAIDS) and/or indomethacin, chloroquine, pentoxifylline, colchicine, clofazimine (300mg/day).
Moderate reactions are characterized by the presence of numerous painful nodules and/or moderate systemic symptoms. Prednisone (20-60mg/day) alone or in combination with NSAIDS can be prescribed. The starting dose of prednisone should be the lowest possible to control ENL and be gradually reduced.
Patients present with disseminated polymorphic cutaneous lesions, such as painful nodules, ulcers, bullae, and targetoid lesions. Severe systemic symptoms may be associated with the cutaneous lesions or the unique presenting sign, and include: intense pain (arthritis, orchitis, and/or neuritis) with or without functional impairment. Aggressive immunosuppressant therapy is indicated with prednisone (1-2mg/kg/day) and thalidomide (200-400mg/day), with or without NSAIDs.
Alternnative medications include methotrexate, mycophenolate mofetil, cyclosporin, and azathioprine. TNF (tumor necrosis factor)-α inhibitors has been successfully used in some cases.
Disseminated strongyloidosis: Patients from endemic areas should be screened for concomitant parasitic infections and properly treated to avoid disseminated strongyloidiasis with high-dose corticosteroid treatment.
Chronic corticosteroid use: Patients requiring prolonged corticosteroid use should be properly monitored to avoid side effects (i.e. ocular complications, osteoporosis, diabetes, systemic hypertension, tuberculosis).
Thalidomide: ENL reactions are very responsive to thalidomide. The initial recommended dose for patients over 50kg are:
-Severe reactions: 400mg/day
In the United States of America, thalidomide can only be prescribed by physicians who are registered with the System for Thalidomide Education and Prescribing Safety (S.T.E.P.S.) Program. The program was created to minimize the chance of fetal exposure to thalidomide, since the main side effect is teratogenicity. The benefits and risks must be outweighed for each particular case and the drug should not be given to women of childbearing age unless they enroll in the S.T.E.P.S. program and use several forms of birth control methods. Other side effects include sedation (bedtime dosing is preferred), drowsiness, peripheral neuropathy, headache, nausea, diarrhea and constipation.
Optimal Therapeutic Approach for this Disease
Figure 3 summarizes management of ENL reactions. All cases should be screened for possible triggering factors. Mild cases can be treated with rest, and symptomatic medications (NSAIDs), with our without second-line agents. Moderate and severe cases require immunosuppressive (prednisone) and/or immunomodulatory (thalidomide) medications.
The treatment of moderate and severe leprosy reactions require prednisone initially in high doses (1-2mg/kg/day) which is slowly tapered down during the course of weeks. The dose can be reduced by 5-10mg every week and readministered if new episodes occur.
Patients should be monitor closely until resolution of the ENL. There is considerable controversy regarding the tapering of the corticosteroids for patients with ENL, particular those susceptible to recurrent episodes. The ILEP Technical Bulletin on the management of ENL recommends treating severe ENL with corticosteroids at a starting dose of 30-60mg and reducing every week by 5-10 mg, with a maintenance dose of 5-10 mg, which may be needed for several weeks to prevent recurrence of ENL. However, severe cases should be managed by experienced staff in order to prevent side effects of chronic corticosteroid use.
Unusual Clinical Scenarios to Consider in Patient Management
Lucio phenomenon: See Leprosy chapter.
Bullous and ulcerative ENL: Rare cases of unusual ENL reactions have been reported and are characterized by superficial bullous ulcerative cutaneous lesions associated with high fever, malaise and edema. Histopathologic analysis demonstrated dermal edema with mononuclear cell infiltrates composed of γδ-positive T lymphocytes and the presence of M. Leprae bacilli within the capillary endothelium. TNF-α and IL-6 were elevated in the serum of the patients at the onset and normalized once the reaction ceased.
What is the Evidence?
Kahawita, IP, Lockwood, DN. “Towards understanding the pathology of erythema nodosum leprosum”. Trans R Soc Trop Med Hyg. vol. 102. 2008. pp. 329-37. (Comprehensive review of ENL pathophysiology.)
Walker, SL, Waters, MF, Lockwood, DN. “The role of thalidomide in the management of erythema nodosum leprosum”. Lepr Rev. vol. 78. 2007. pp. 197-215. (Updated review on ENL and treatment options available.)
Foss, NT, de Oliveira, EB, Silva, CL. “Correlation between TNF production, increase of plasma C-reactive protein level and suppression of T lymphocyte response to concanavalin A during erythema nodosum leprosum”. Int J Lepr Other Mycobact Dis. vol. 61. 1993. pp. 218-26. (Experimental study to evaluate the inflammatory biomarkers in leprosy.)
Esquenazi, D, Moreira, AL, Miranda, A. “Clinical, immunological and histological aspects of an uncommon type II reaction in patients with lepromatous leprosy”. Clin Exp Dermatol. vol. 33. 2008. pp. 294-7. (Case report of three cases with an unusual type II reaction characterized by bullous and ulcerative lesions.)
(ILEP guidelines on the management of ENL)
Van Veen, NH, Lockwood, DN, Van Brakel, WH, Ramirez, J, Richardus, JH. “Interventions for erythema nodosum leprosum. A Cochrane review”. Lepr Rev. vol. 80. 2009. pp. 355-72. (Review article on the current treatment options for ENL.)
(Celgene webpage with detailed information about thalidomide.)
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