Erythema nodosum leprosum

Thalidomide (USA) a- (N-phthalimido) glutarimide TNF expression inhibitor Erythema nodosum leprosum, cGVHD... 

Clofazimine is a phenazine dye with some my-cobactericidal activity. It is only used in combination with dapsone to reduce the emerging resistance against dapsone. Its efficacy in the management of erythema nodosum leprosum is based on its antiinflammatory activity. 

In 1998, the FDA approved the use of thalidomide for the treatment of lesions associated with erythema nodosum leprosum. Because of thalidomide s potential for causing birth defects, the distribution of thalidomide was permitted only under tightly controlled conditions. Nevertheless, because of its use for patients with leprosy thalidomide has been identified again as a current teratogen, now in South America. 

Thalidomide is approved for use in the United States for the treatment of cutaneous manifestations of erythema nodosum leprosum, a potentially life-threatening systemic vasculitis that occurs in some patients with leprosy. Although not approved for other indications, thalidomide has also been shown to be very effective in the management of Behget s disease, HIV-related mucosal ulceration (aphthosis), and select cases of lupus erythematosus. 

Clofazimine is given to treat sulfone-resistant leprosy or to patients who are intolerant to sulfones. It also exerts an antiinflammatory effect and prevents erythema nodosum leprosum, which can interrupt treatment with dapsone. This is a major advantage of clofazimine over other antileprosy drugs. Ulcerative lesions caused by Mycobacterium ulcerans respond well to clofazimine. It also has some activity against M. tuberculosis and can be used as last resort therapy for the treatment of MDR tuberculosis. 

Recently, thalidomide (50-100 mg capsule form, approved by FDA), an immunomodulatory agent is used in erythema nodosum leprosum (ENL) which is a complication of leprosy occurring in approximately one half of borderline lepromatous and lepromatous leprosy patients. 

Note Thalidomide is labeled for use only in erythema nodosum leprosum in the USA Trastuzumab (Herceptin)... 

Thalidomide Erythema nodosum leprosum See also Chapters 47 and 55. 

Clofazimine [kloe FA zi meen] is a phenazine dye that binds to DNA and inhibits template function. Its redox properties may lead to the generation of cytotoxic oxygen radicals that are also toxic to the bacteria. Clofazimine is bactericidal to M- leprae and has some activity against M- avium intracellulare complex. On oral absorption, it accumulates in tissues, allowing for intermittent therapy, but it does not enter the CNS. Patients may develop a red-brown discoloration of the skin. Eosinophilic enteritis has been reported as an untoward effect. The drug also has some anti-inflammatory activity, thus erythema nodosum leprosum does not develop. 

Thalidomide was initially launched as a sedative/hypnotic drug (Fig. 1.13), but withdrawn because of its extreme teratogenicity. However, under restricted conditions (no administration during pregnancy, or to any woman of childbearing age), it found a new use as an immunomodulator. Thalidomide seems particularly effective in the treatment of erythema nodosum leprosum, a possible complication of the chemotherapy of leprosy [23]. 

Clofazimine has a leprostatic action and an antiinflammatory effect that prevents erythema nodosum leprosum. It causes gastrointestinal symptoms. Reddish discolouration of the skin and other cutaneous lesions also occur, and may persist for months after the drug has been stopped. The t) is 70 days. 

Qofazimine is weakly bactericidal against Mycobacterium leprae. It is active in chronic skin ulcers (BuruU ulcer) and partly against Mycobacterium avium intraceUulare. The usual adult dosage is 50-100 mg/day. At higher doses, its anti-inflammatory effect seems to prevent the development of acute reactions, such as erythema nodosum leprosum. 

Serious cutaneous reactions, such as exfoliative dermatitis, toxic epidermal necrolysis, and erythema multiforme buUo-sum are extremely rare. Erythema nodosum leprosum has been described during dapsone therapy, mostly in the lepro-matous type of leprosy (10). If erythema nodosnm develops before the start of therapy, the drug should be withheld until the reaction has disappeared. Severe erythema nodosum can be controlled by short-term glucocorticoid therapy. Desensitization to dapsone in patients with hypersensitivity reactions has been proposed (29). 

Somorin AO. Erythema nodosum leprosum in Nigeria. Int J Dermatol 1975 14(9) 664-6. 

Duncan ME, Pearson JM. The association of pregnancy and leprosy—III. Erythema nodosum leprosum in pregnancy and lactation. Lepr Rev 1984 55(2) 129-42. 

Sampaio EP, Moreira AL, Sarno EN, Malta AM, Kaplan G. Prolonged treatment with recombinant interferon gamma induces erythema nodosum leprosum in lepromatous leprosy patients. J Exp Med 1992 175(6) 1729-37. 

Thalidomide can cause painful edema of the legs, which is transitory and disappears as treatment continues (68). Peripheral edema was reported in 4.2% of patients with erythema nodosum leprosum, in patients with HIV infection (3.1% of those taking 100 mg/day and 8.3% of those taking 200 mg/day), and in up to 22% of patients with refractory multiple myeloma (21). 

Rash due to thalidomide is commonly described as erythematous, macular, and pruritic it occurs over the back, trunk, and limbs and most commonly occurs 10-14 days after the start of treatment (21). In trials of thalidomide in patients with erythema nodosum leprosum the incidence of rash was 25%, in patients with HIV infection it was 42%, and in patients with myeloma it was up to 26%. 

Clofazimine is used in the treatment of lepromatous leprosy. including dap.sone-resistant forms of the di.sca.se. In sidition to its antibacterial action, the drug appears to possess anti-inflammatory and immune-modulating effects that are of value in controlling neuritic complications and in suppressing erythema nodosum leprosum reactions associated with lepromatous leprosy. It is frequently used in combina-iion with other drugs, such as dapsone or rifampin. 

Thalidomide was formerly used as a sedative/hyp-notic. It was approved in 1998 by the US Food and Drug Administration for use as an immunosuppressant in the treatment of erythema nodosum leprosum. It is also used in the treatment of graft-versus-host disease (Orphan drug status in the United States), macular degeneration, oral ulcers in AIDS patients, and reflex sympathetic dystrophy associated with chronic pain syndromes. 

Case 2. Thalidomide Not approved by the FDA in 1960s 1998—moderate to severe erythema nodosum leprosum (ENL) in leprosy 1957... 

Clofazimine, a substituted aminophenazine dye with lepro-static properties (50 to 100 mg p.o. once daily), is indicated in the treatment of dapsone-resistant leprosy and erythema nodosum leprosum. 

Chloroquine is an antimalarial agent which affects erythema nodosum leprosum. 

Clofazimine (iamprene) hinds preferentially to GC-rich mycobacterial DNA, increases mycobacterial phospholipase Aj activity, and inhibits microbial K transport. It is weakly bactericidal against M. intracellulare. The drug also exerts an anti-inflammatory effect and prevents the development of erythema nodosum leprosum. Clofazimine is recommended as a component of multiple-drug therapy for leprosy. It also is useful for treatment of chronic skin ulcers produced by Mycobacterium ulcerans. 

Thalidomide has been reintroduced to clinical practice as an oral agent for the management of erythema nodosum leprosum (ENL) and in other disease settings, most notably MM. Lenalidomide is a thalidomide derivative with improved potency and safety profile compared to thalidomide. Thalidomide is a nonpolar racemic mixture of cell permeable and rapidly interconverting S(-) and R(+) isomers. The precise mechanisms responsible for thalidomide s clinical activity remain to be elucidated. Multiple distinct, but potentially complementary, mechanisms have been proposed to explain the antitumor activity of thalidomide and its derivatives, including stimulation of T cells and NK cells, inhibition of angiogenesis and tumor cell proliferation, and modulation of hematopoietic stem cell differentiation (Figure 51-6). 

Thalidomide (thalomid) is best known for the severe birth defects it caused when administered to pregnant women. For this reason, it is available only under a restricted distribution program and can be prescribed only by specially licensed physicians who understand that thalidomide should never be taken by women who are pregnant or who could become pregnant while taking the drug. Nevertheless, it is indicated for the treatment of patients with erythema nodosum leprosum (see Chapter 47) and also is used in conditions such as multiple myeloma. Its mechanism of action is unclear. 

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