Leprosy: Treatment and prevention

INTRODUCTION — 

Leprosy (also known Hansen's disease) is an infection of the skin and peripheral nerves caused by Mycobacterium leprae and Mycobacterium lepromatosis.

M. leprae and M. lepromatosis comprise Mycobacterium leprae complex [1]. The deoxyribonucleic acid (DNA) sequences of M. leprae and M. lepromatosis differ enough to distinguish them as separate species, but they share many similarities (both are obligate intracellular parasites with a tropism for nerves) and cause the same clinical disease [2].

Leprosy is an important global health concern, yet is widely misunderstood. Leprosy is not highly contagious (contrary to popular belief), and effective treatment is available [3,4]. Nonetheless, leprosy carries a heavy burden of stigma [5]. Early diagnosis and treatment are necessary to minimize the likelihood of irreversible nerve damage leading to permanent disability involving the hands, feet, and eyes [6].

Not all patients have access to appropriate therapy, and not all countries have adequate infrastructure to support leprosy control efforts [7]. Worldwide, the number of dedicated leprosy programs is declining, and international migration is bringing patients with leprosy to nearly every region [8].

The treatment and prevention of leprosy are reviewed here. The epidemiology, microbiology, clinical manifestations, and diagnosis of leprosy are discussed separately. (See "Leprosy: Epidemiology, microbiology, clinical manifestations, and diagnosis".)

CLASSIFICATION — 

Leprosy has been classified into the following categories based on the Ridley-Jopling classification (table 1):

●Tuberculoid (TT)

●Borderline tuberculoid (BT)

●Mid-borderline (BB)

●Borderline lepromatous (BL)

●Lepromatous (LL)

●Indeterminate (I)

The classification of leprosy is discussed in further detail separately. (See "Leprosy: Epidemiology, microbiology, clinical manifestations, and diagnosis", section on 'Classification and terminology'.)

ANTIMICROBIAL THERAPY

General approach — Leprosy is not highly contagious. Therefore, isolation of individuals suspected or confirmed to have leprosy is not necessary.

Treatment of leprosy consists of multidrug therapy (MDT) to minimize the likelihood of emergence of resistance; single-drug therapy should always be avoided [9]. First-line medications include dapsone, rifampin, and clofazimine. These agents are effective for treatment of leprosy due to M. leprae and M. lepromatosis [10-15]. The efficacy of these individual agents for treatment of leprosy has been demonstrated clinically, in animal studies, and in vitro [16-18].

No controlled trials comparing drug combination regimens have been performed. Relapse rate is an important criterion for efficacy, but evaluation of relapse rate requires a long observation period (approximately 15 to 20 years).

Within the United States — Our treatment approach is in alignment with the United States National Hansen's Disease Program (NHDP), as follows (table 2 and table 3) [19]:

●Tuberculoid disease (TT, BT types; the WHO refers to these as paucibacillary [PB]) – Dapsone and rifampin for 12 months

●Lepromatous disease (BB, BL, LL types; the WHO refers to these as multibacillary [MB]) – Dapsone, rifampin, and clofazimine for 24 months

The NHDP approach follows World Health Organization (WHO) guidance issued in 1982 [20], which differs from the WHO 2018 guidelines with respect to the following:

●Longer duration of therapy – The NHDP has maintained a conservative approach in the absence of robust data to support shortened duration of treatment.

●Frequency of rifampin administration – The NHDP approach consists of daily rifampin (monthly rifampin for patients on prednisone); the WHO approach consists of monthly rifampin [19].

●Administration of daily rifampin is supported by a study including 158 patients with leprosy (123 with MB disease) treated with regimens including daily rifampin and followed for 10 to 15 years; only one case of relapse was observed (in a patient with MB disease who was treated with a two-drug regimen rather than a three-drug regimen) [21]. While this relapse rate is similar to that of the WHO, the WHO rate is based on a shorter follow-up period (5 years).

●Role of clofazimine – The NHDP excludes clofazimine for treatment of PB disease. (See 'Outside the United States' below.)

In the United States, medication for treatment of leprosy is provided free of charge by the NHDP (1-800-642-2477) [8].

Outside the United States

●Standard approach - The 2018 WHO guidelines treatment approach is as follows (table 2 and table 3) [9]:

•Tuberculoid (TT-BT; PB) disease: Dapsone, rifampin, and clofazimine for 6 months.

•Lepromatous (BB-BL-LL; MB) disease: Dapsone, rifampin, and clofazimine for 12 months.

Compared with NHDP, use by the WHO of a shorter treatment duration and less frequent rifampin administration (monthly rather than daily) partly reflects cost considerations.

Use of clofazimine for patients with PB disease is controversial because treatment with dapsone and rifampin (without clofazimine) has been successful. However, it has been proposed that routine use of clofazimine reduces the likelihood of undertreating patients with MB disease who may be misclassified as having PB disease. In the United States, the classification of all cases includes histopathologic assessment of a skin biopsy, including documentation of the bacterial load, and misclassification is not an issue.

The WHO distributes medications through the Ministry of Health in each country [22].

●Investigational approach – Bedaquiline, an antimycobacterial agent with a mode of action that differs from other drugs (inhibition of mycobacterial ATP synthase), has demonstrated consistent bactericidal activity against M. leprae in animal models and greater bactericidal activity than rifampin [23].

In an open-label, proof-of concept study including nine patients with previously untreated multibacillary leprosy in Brazil, patients were treated with bedaquiline for eight weeks, followed by standard multidrug therapy (as defined by the WHO) [24]. After four weeks of treatment, no growth of M. leprae in mouse footpads was observed, and PCR for M. leprae viability in patient skin biopsies was undetectable. After eight weeks of treatment, improvement in the appearance of skin lesions (compared with baseline) was observed in all patients. Leprosy reactions developed while receiving bedaquiline in 36 percent of patients. No serious adverse events were observed during bedaquiline treatment. 

Antimicrobial agents

Preferred agents — Preferred agents for treatment of leprosy include dapsone, rifampin and clofazimine.

●Dapsone – Dapsone is a bacteriostatic agent that is generally well tolerated in the doses used for the treatment of leprosy.

•Adverse effects – Adverse effects include dapsone hypersensitivity syndrome (associated with HLA-B*13:01), methemoglobinemia, and agranulocytosis. Shortened red cell survival is common; 90 percent of patients treated with dapsone demonstrate a decline in hemoglobin concentration (by 1 to 2 g/dL); however, severe hemolytic anemia is uncommon except in those with severe glucose-6-phosphate dehydrogenase (G6PD) deficiency (activity <30 percent). (See "Methemoglobinemia" and "Drug-induced neutropenia and agranulocytosis" and "Drug-induced hemolytic anemia".)

•G6PD screening – Patients should be screened for G6PD deficiency before receiving dapsone:

Most individuals with G6PD activity ≥30 percent will tolerate dapsone; monitoring is described below. (See 'Clinical response and follow-up' below.)

For patients who are unable to tolerate dapsone (due to G6PD <30 percent or other intolerance), consultation with experts is warranted regarding substituting dapsone with minocycline or clarithromycin. (See 'Alternative agents and regimens' below.)

●Rifampin – Rifampin is the most bactericidal drug that is routinely used for the treatment of leprosy.

Rifampin toxicity correlates with the dose and the interval between doses. The standard doses for leprosy are relatively nontoxic; occasional cases of renal failure, bone marrow suppression, flu-like syndrome, and hepatitis have been reported.

Daily administration of rifampin has major effects on drug metabolism by the liver cytochrome 3A4 (CYP3A4), which greatly affects metabolism other medications such as oral contraceptives, corticosteroids, and human immunodeficiency virus (HIV) protease inhibitors, among many others. (See "Rifamycins (rifampin, rifabutin, rifapentine)".)

●Clofazimine – Clofazimine is weakly bactericidal against M. leprae, but the combination of clofazimine and dapsone is much more active than either drug alone [25].

The major adverse effect of clofazimine is skin pigmentation (especially within skin lesions) since the drug is lipophilic and accumulates in the lipid-rich cell wall of M. leprae. At higher doses (200 mg daily), hyperpigmentation may be noticeable within four weeks; at lower doses, hyperpigmentation may be observed in four to six months. Clofazimine causes phototoxicity, which can accelerate darkening of the skin with sun exposure. This pigmentation usually clears within one to two years after treatment is discontinued. It is important to counsel patients on the pigmentation associated with use of clofazimine prior to initiation. Alternative antimicrobial agents should be used in patients who deem pigmentation unacceptable.

The higher doses of clofazimine (up to 300 mg daily) sometimes used for the control of immunologic reactions may occasionally produce gastrointestinal side effects.

For patients who are unable to tolerate clofazimine, ofloxacin is a potential alternative agent. (See 'Alternative agents and regimens' below.)

Clofazimine is not commercially available in the United States; it is classified by the US Food and Drug Administration (FDA) as an investigational drug. Requests for clofazimine for treatment of leprosy should be directed to the NHDP (an agency within the Department of Health and Human Services), which holds the investigational new drug protocol for this indication, at 1-800-642-2477 (phone) [26].

Alternative agents and regimens — The following agents are bactericidal for M. leprae but have not been evaluated in adequately powered clinical trials; they should be used in consultation with clinicians experienced in treatment of leprosy.

●Alternative agents

•Minocycline – Minocycline is the only tetracycline with significant activity against M. leprae. This may be due to its lipophilic properties, which allow the drug to penetrate cell walls. It is bactericidal for M. leprae to a somewhat greater degree than clarithromycin but much less so than rifampin.

Side effects of minocycline include teeth discoloration in children, pigmentation of the skin and mucous membranes, gastrointestinal complaints, and central nervous system toxicity including dizziness and unsteadiness. There are also uncommon cases of hepatotoxicity and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome.

•Clarithromycin – Several macrolides have been evaluated for activity against M. leprae; clarithromycin is the only effective agent. Clarithromycin has potent bactericidal activity but is less bactericidal than rifampin. At a dose of 500 mg daily, 99 percent of M. leprae are killed in 28 days and 99.9 percent by 56 days [27].

Gastrointestinal irritation, nausea, vomiting, and diarrhea are the most common adverse effects, but they do not usually necessitate drug discontinuation. Clarithromycin can cause QT prolongation and has been associated with cardiovascular events. (See "Azithromycin and clarithromycin".)

•Fluoroquinolones – Fluoroquinolones with bactericidal activity against leprosy include ofloxacin, levofloxacin, and moxifloxacin. Adverse effects of fluoroquinolones are discussed separately. (See "Fluoroquinolones".)

-Ofloxacin – Ofloxacin has good antibacterial activity and is the most widely accepted fluoroquinolone for treatment of leprosy [25]. It acts by interfering with bacterial DNA replication by inhibiting the A subunit of DNA gyrase. A single 400 mg dose has bactericidal activity against M. leprae, although less than that demonstrated by a single dose of rifampin, and two doses are capable of killing more than 99 percent of viable M. leprae.

-Levofloxacin – Levofloxacin, the active L-racemer of ofloxacin, has replaced ofloxacin in many United States formularies.

-Moxifloxacin – Moxifloxacin is also highly bactericidal against M. leprae; further study of rifampin and moxifloxacin as combination short-term therapy is needed [28,29].

●Alternative regimens – Limited data are available on the following alternative regimens for treatment of tuberculoid (paucibacillary) leprosy:

•Monthly rifampin, ofloxacin, and minocycline – In a trial including 268 patients with paucibacillary leprosy randomly assigned to receive either six months of once-monthly rifampin, ofloxacin, and minocycline or standard treatment (daily rifampin and dapsone) cure rates at two years were similar (99 versus 97 percent), and relapse rates at 5 to 8 years were similar (0.435 versus 1.10 per 100 person years) [30]. Cure are relapse were diagnosed clinically; loss to follow-up was an important study limitation

•Monthly rifampin, moxifloxacin, and minocycline – This regimen has been evaluated in case series and small nonrandomized studies [31,32]; further study is needed.

Clinical response and follow-up

●Clinical response – The exact time to noninfectiousness is not known since M. leprae cannot be grown in culture; however, treatment likely renders the patient noninfectious within a few days.

Treatment response is assessed clinically based on improvement of skin lesions. The erythema and induration of skin lesions generally diminish within a few months of initiating therapy. It may take a few years for cutaneous lesions to resolve fully, depending on the initial number of lesions and severity of infection. Most lesions heal without scarring.

Once killed, dead bacilli are removed from the tissues very slowly; some may persist in the tissues for several years (picture 1) [33]. Since M. leprae and M. lepromatosis cannot be cultured and their viability cannot be assessed in routine biopsies, a definitive bacteriologic endpoint for treatment is not available. The presence of bacilli in smears or biopsies during and after treatment does not, in itself, indicate treatment failure or drug resistance. There is no evidence that prolonged antimicrobial treatment enhances the removal of dead M. leprae from tissues.

Given the lack of a definitive therapeutic endpoint, ensuring treatment adherence is especially important in assessing completeness of treatment. Laboratory evidence indicates that M. leprae are killed rapidly after exposure to rifampin and the other drugs used [34]. Experience with multidrug therapy has provided good evidence of cure with very few relapses using NHDP or WHO protocols with one to two years of treatment [35]. Therefore, with good adherence to the well-established MDT protocols, killing of the bacilli and resolution of the lesions can be expected.

●Follow-up during treatment

•Clinical reassessment – While on treatment, we schedule the first follow-up visit in two to four weeks to evaluate for side effects of medications.

After that, we schedule routine follow-up visits every three months. Patients should be asked about any new skin lesions, sensory or motor loss, eye symptoms, systemic symptoms, or other complaints. Visits should consist of a clinical examination, including assessment of the skin, nerves, and limbs. (See "Leprosy: Epidemiology, microbiology, clinical manifestations, and diagnosis", section on 'Clinical evaluation'.)

In addition, eye examination should include assessment of lid closure, cornea, and conjunctiva [36]. Complex eye problems should be referred to a specialist; corneal anesthesia and lagophthalmos require protective measures and corrective surgery.

•Laboratory follow-up – Routine laboratory studies to assess drug toxicity while on treatment include a complete blood count, creatinine, and liver function tests (table 4). Drug toxicity is relatively uncommon after the first year of treatment, and serious toxicity may manifest clinically before it is detected in the laboratory. Asymptomatic liver enzyme elevation of up to three times normal is acceptable. Depending on the severity of drug toxicity, it may be necessary to modify dosing or switch to an alternative agent on a case-by-case basis. (See 'Alternative agents and regimens' above.)

•Patient education – Patient education is an essential part of each visit. Patients should be counseled on the importance of strict adherence to treatment to avoid disease progression or development of resistance. In addition, it should be reinforced that patients are no longer considered infectious within a few days of starting treatment,

Patients should be taught to perform daily inspection of the eyes, hands, and feet, especially areas where sensation has been lost. Patient should also be educated on use of protective mitts for handling hot cookware and use of appropriate footwear, and should be counseled to obtain treatment properly for injuries.

•Neuropathy – Neuropathic pain is a common long-term complication of leprosy (prevalence 11 to 66 percent) [37] with an important impact on quality of life [38,39]. Issues related to management of neuropathic pain are discussed separately. (See "Overview of pharmacologic management of chronic pain in adults".)

Special protective shoes may be needed to avoid injury or ulceration. Motor loss resulting in deformities (eg, claw hand, foot drop) may require corrective surgery.

●After completion of treatment – After completion of treatment, annual follow-up for three more years is warranted for patients with tuberculoid disease, and annual follow-up for 10 more years is warranted for patients with lepromatous disease. Relapses are uncommon in patients who are adherent to treatment. Most relapses occur 5 to 10 years or more after completion of treatment [40]. Patients should be advised to return for evaluation if new lesions or other problems develop.

PROGRESSION OF SIGNS OR SYMPTOMS

Evaluation

●Timing of presentation

•Disease progression during treatment — For patients with disease progression during treatment, the most common cause is development of an immunologic reaction. Nonadherence is another possible cause. Drug resistance is a less common cause. (See 'Clinical response and follow-up' above.)

•Disease progression after treatment – For patients with disease progression after completion of treatment, the most likely cause is an immunologic reaction. Disease relapse is an alternative consideration.

●Initial approach – In some cases, immunologic reaction may be diagnosed based on clinical features; in such cases, we proceed with empiric treatment. (See 'Immunologic reactions' below.)

For patients who do not respond to empiric treatment for immunologic reaction, and for patients whose presentation is not consistent with an immunologic reaction, we pursue biopsy to evaluate for drug resistance or disease relapse; these are discussed further below.

•Immunologic reaction – The development of new lesions during or after completion of treatment is most commonly attributable to an immunologic reaction. These are systemic inflammatory complications that can occur during or after completion of treatment; they affect 30 to 50 percent of patients with leprosy [41].

Characteristic clinical features are usually sufficient to make the diagnosis of an immunologic reaction. These may include fatigue, malaise, fever, neuritis (nerve enlargement, tenderness, or loss of function), arthritis, iritis, and nasopharyngeal symptoms. The associated inflammation can lead to severe nerve injury with subsequent paralysis and deformity. Immunologic reactions are discussed further separately. (See "Leprosy: Epidemiology, microbiology, clinical manifestations, and diagnosis", section on 'Immunologic reactions'.)

If there is uncertainty about the diagnosis of immunologic reaction, a biopsy may be helpful. Polymorphonuclear leukocytes are a hallmark of type 2 reactions (T2Rs); no reliable histologic criteria have been identified for type 1 reactions (T1Rs), so this remains a clinical diagnosis. (See "Leprosy: Epidemiology, microbiology, clinical manifestations, and diagnosis", section on 'Biopsy'.)

The approach to management of T1R and T2R is discussed below. (See 'Immunologic reactions' below.)

•Disease relapse

-Epidemiology – The World Health Organization (WHO) estimated relapse rates at nine years following multidrug therapy for multibacillary (MB) and paucibacillary (PB) leprosy are 0.77 and 1.07 percent, respectively [4]. However, relapse rates in different countries range from 0.7 to 19 percent [42].

Most relapses occur 5 to 10 years or more after completion of treatment [40]. Risk factors for relapse include incomplete treatment and very high bacterial load at the onset of treatment [43].

-Diagnosis – Skin biopsy demonstrating an increase in bacteriologic index (BI) from 0 to 2 or more indicates probable relapse. However, since treatment response is primarily determined based on clinical assessment, and biopsies are not routinely performed at the end of treatment, it is difficult to establish evidence of rise in BI. (See "Leprosy: Epidemiology, microbiology, clinical manifestations, and diagnosis", section on 'Biopsy'.)

The approach to management of disease relapse is discussed below. (See 'Disease relapse' below.)

•Drug resistance

-Epidemiology – In a WHO surveillance study that evaluated the rate of M. leprae antimicrobial resistance among more than 1900 patients in 19 countries between 2009 and 2015, overall rates of drug resistance for rifampin and dapsone were 3.8 and 5.3 percent, respectively [44]. The rate of rifampin resistance in new cases was 2 percent and in relapsed cases was 5 percent. The rate of rifampin resistance was highest among new cases in Brazil and India (15 and 8 percent, respectively) and among relapsed cases in Colombia and Mozambique (24 and 20 percent, respectively).

-Diagnosis – Skin biopsy with PCR allows detection of mutations associated with drug resistance [45]. The rpoB gene of M. leprae and other mycobacteria is associated with rifampin resistance [45,46]. Mutations in the dihydropteroate synthase gene (folP1) predicted dapsone resistance in a survey of 38 M. leprae strains isolated from skin biopsies of patients with multibacillary leprosy [44].

In the United States, the Molecular Biology Laboratory of the National Hansen's Disease Program (NHDP) provides testing for drug resistance mutations.

-Management – Management of drug resistance is discussed below. (See 'Drug resistance' below.)

Management

Immunologic reactions

Type 1 reaction (T1R, reversal reaction) — T1R typically occurs in patients with borderline tuberculoid (BT), mid-borderline (BB), or borderline lepromatous (BL) disease. Clinical manifestations of T1R are described separately. (See "Leprosy: Epidemiology, microbiology, clinical manifestations, and diagnosis", section on 'Type 1 reaction (T1R, reversal reaction)'.)

Antimicrobial therapy should be continued in the setting of an immunologic reaction, and patients should be reassured that the symptoms are not a reaction to the medications.

●Mild reactions – Mild reactions (edema and erythema of existing skin lesions, in the absence of neuritis [nerve enlargement, tenderness, or loss of function] or skin ulceration) may be managed with analgesics such as nonsteroidal anti-inflammatory drugs [8]. Such patients must be observed closely for deterioration of nerve function, which requires more aggressive treatment.

●Severe reactions – Severe reactions (including neuritis [nerve enlargement, tenderness, or loss of function], skin ulceration, fever, and/or joint pain) warrant prompt treatment to avoid permanent nerve damage [47]. The mainstay of treatment for T1R consists of corticosteroids; potential alternative agents include cyclosporine and methotrexate.

•Corticosteroids

-Clinical approach – There is no consensus on the optimal dose or duration of corticosteroids for treatment of immunologic reactions [4]. Our approach consists of prednisone 40 to 60 mg daily (maximum 1 mg/kg); the duration is typically at least 12 weeks (or longer, depending on individual circumstances) followed by a taper, depending on the severity of the reaction and the response to treatment. Rapid improvement of nerve function occurs most often in situations when the lesion is of recent onset (less than six months).

-Rifampin dose adjustment – Coadministration of rifampin with prednisone accelerates metabolism of prednisone; for patients receiving prednisone, we reduce the rifampin dose from 600 mg daily to 600 mg monthly. After prednisone has been discontinued, daily rifampin should be resumed.

-Efficacy – The benefit of steroids is uncertain. In a 2016 review [48], moderate-quality evidence from two randomized trials including 179 patients with longstanding or mild nerve function impairment demonstrated no superior effect of corticosteroids over placebo with respect to nerve function improvement; however, a third trial including 334 patients with T1R demonstrated benefit from a 20-week steroid regimen over a 12-week regimen; at the end of 12 months, additional steroid treatment was required more frequently among patients who received the shorter course (46 versus 31 percent) [49]. In a subsequent randomized trial including more than 800 patients with leprosy and nerve function impairment, the efficacy of a 20-week prednisone course was comparable to that of a 32-week course for improving or restoring nerve function (78 percent) [50].

-Adverse effects – Prolonged use of corticosteroids entails the risk of many serious side effects. (See "Major adverse effects of systemic glucocorticoids".)

For patients receiving ≥20 mg of prednisone daily for one month or longer, considerations are warranted for prevention of adverse effects including Pneumocystis infection, strongyloidiasis, and steroid-induced osteoporosis. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis' and "Strongyloidiasis", section on 'Preventive treatment' and "Prevention and treatment of glucocorticoid-induced osteoporosis", section on 'Candidates for pharmacologic therapy'.)

-No role for prophylaxis – No long-term benefit has been associated with prophylactic corticosteroid treatment for prevention of nerve function impairment.

In a randomized trial including 636 patients with newly diagnosed multibacillary (MB) leprosy, patients were randomly assigned to receive antimicrobial therapy with or without prednisolone (20 mg/day for three months, followed by taper). Those who did not receive prednisolone had a higher likelihood of nerve function impairment at four months (15 versus 4 percent; relative risk 3.9, 95% CI 2.1 to 7.3); however, the benefit was not maintained at one year (relative risk 1.3, 0.9 to 1.8) [51].

•Other agents

-Cyclosporine – Cyclosporine may be a useful second-line treatment for severe T1R in patients who do not respond to or who are unable to take corticosteroids [3]. It has been demonstrated to improve sensory nerve impairment and skin lesions in small numbers of patients in Brazil, Ethiopia, and Nepal [52,53]. Further study is needed to determine optimal dosing and to compare efficacy and toxicity with corticosteroids.

-Methotrexate – Methotrexate is a potential steroid sparing agent that can be used to minimize the dose of corticosteroids; further study is needed [45].

Type 2 reaction (T2R, erythema nodosum leprosum [ENL]) — T2R occurs in patients with BL and lepromatous (LL) disease. Clinical manifestations of T2R are described separately. (See "Leprosy: Epidemiology, microbiology, clinical manifestations, and diagnosis", section on 'Type 2 reaction (T2R, ENL)'.)

Antimicrobial therapy should be continued in the setting of immunologic reactions, and patients should be reassured that the symptoms are not a reaction to the medications.

●Mild reactions – Mild reactions (low-grade fever, mild skin lesions, mild nerve pain without loss of function) may be managed with rest, analgesics such as nonsteroidal anti-inflammatory drugs, and topical corticosteroids [8].

●Severe reactions – Severe reactions (including fever, acute neuritis [nerve enlargement, tenderness, or loss of function], skin ulceration, loss of sensation or muscle weakness [hands, feet, or eyes], joint pain, eye pain and redness [uveitis, scleritis], and/or orchitis) warrant prompt treatment to avoid permanent nerve damage.

The treatment of choice for T2R is thalidomide, based on limited evidence [46,48]; if thalidomide is contraindicated or unavailable, systemic corticosteroids are the mainstay treatment. Alternative approaches include methotrexate and clofazimine.

•Thalidomide – We favor thalidomide for treatment of T2R if feasible [4]; teratogenicity limits its use in women of childbearing age.

Our approach consists of initial treatment with 100 to 200 mg daily; frequently, this regimen controls the reaction within 48 hours. Subsequently, we continue a maintenance level of 100 mg daily. It may be necessary to continue thalidomide for several years to control chronic erythema nodosum leprosum (ENL); every few months, we attempt to taper off the drug, with some patients taking as little as 100 mg once weekly. In our experience, a few patients with severe, prolonged T2Rs have continued use of thalidomide for up to ten years.

Compared to long-term use of systemic corticosteroids, thalidomide has a much more favorable adverse effect profile. Apart from teratogenicity, adverse events of thalidomide therapy include sedation, peripheral neuropathy, and deep vein thrombosis (particularly when used in combination with systemic corticosteroids) [54].

Data comparing thalidomide with corticosteroids are limited; in one randomized study including 60 patients with ENL, treated with thalidomide (300 mg/day for one week followed by gradual reduction) or prednisone (40 mg daily for two weeks), thalidomide was associated with faster resolution of cutaneous symptoms than prednisone (5.5 versus 13.2 days) [55]. In a five-year retrospective review including 102 patients with ENL treated with thalidomide, improvement was observed in 67 percent of cases; recurrence occurred in 16 percent with a mean duration of 14 months [56].

In the United States, thalidomide is FDA-approved for the treatment of T2R. The drug is approved for marketing only under a special restricted distribution program approved by the FDA called "Risk Evaluation and Management Strategy" (REMS). Under this program, only prescribers and pharmacists registered with the program are allowed to prescribe and dispense the drug. In addition, patients must be advised of, agree to, and comply with the requirements of the REMS program in order to receive the drug.

•Use of corticosteroids – Use corticosteroids for treatment of T2R is as discussed above for T1R. (See 'Type 1 reaction (T1R, reversal reaction)' above.)

•Other agents – Other immunomodulatory drugs have been evaluated for management of T2Rs [3].

-Methotrexate – For patients with ENL and acute neuritis who are not candidates for thalidomide or corticosteroids, methotrexate (10 to 25 mg weekly) with or without low-dose corticosteroids (1 to 7.5 mg daily) is a potential alternative regimen [45,57,58]. The duration of treatment may range from 12 to 24 months, guided by individual status of the immune reaction. Further study of methotrexate for management of leprosy reactions is ongoing [59].

Patients treated with methotrexate should have baseline laboratory testing and receive coadministration of folic acid; these issues are discussed separately. (See "Therapeutic use and toxicity of high-dose methotrexate" and "Major adverse effects of low-dose methotrexate", section on 'Prevention of adverse effects with folate'.)

-Clofazimine – Clofazimine is not useful for the management of acute T2R but may be used as an alternative regimen for chronic T2R in patients who are unable to be treated with thalidomide or high-dose corticosteroids [48].

Clofazimine may be increased to a dose of 300 mg daily for four weeks and tapered slowly after response to 100 mg/day within 12 months. Gastrointestinal complaints may limit the use of higher doses.

The clofazimine component of the MB regimen may have some protective effect in preventing reactions since T2R appears to have become less common with inclusion of this agent in the treatment regimen.

In the United States clofazimine can be obtained through the National Hansen's Disease Program (NHDP; phone 1-800-642-2477).

-Other medications – Anecdotal reports of the use of biologics (TNF-alpha inhibitors) and apremilast have been published [60,61]; further study of these agents for management of immunologic reactions is needed.

Lucio phenomenon — Lucio phenomenon (necrotizing vasculopathy in patients with longstanding untreated lepromatous leprosy) is a rare, severe, and potentially life-threatening reaction. Management requires antimicrobial therapy and corticosteroids as well as skin and wound care comparable with that given for extensive burns [62,63]. Such patients should be managed in consultation with a clinician experienced with the treatment of Lucio reactions.

Isolated neuritis — Some patients with leprosy have progressive sensory or motor loss in hands or feet, in the absence of nerve pain or other signs of immunologic reaction. For patients with deteriorating nerve function for less than six months who are adherent to antimicrobial treatment, we favor treatment with corticosteroids. The approach is as discussed above for treatment of immunologic reactions. (See 'Type 1 reaction (T1R, reversal reaction)' above.)

Neuritis may persist for months or years; there are no rigorous data on its responsiveness to treatment [41].

Drug resistance — Issues related to diagnosis of drug resistance are discussed above. (See 'Evaluation' above.)

The approach to treatment should be guided by skin biopsy PCR test results for mutations associated with drug resistance [64].

Alternative agents for treatment of leprosy include minocycline, clarithromycin, and fluoroquinolones (ofloxacin, levofloxacin, and moxifloxacin); their use for treatment of leprosy has not been evaluated in controlled trials.

We are in agreement with the WHO guidelines for treatment of drug-resistant leprosy, as follows (table 5) [9,65]:

●Patients whose isolate demonstrates rifampin resistance may be treated using at least two of the following second-line drugs: clarithromycin, minocycline, or a fluoroquinolone (ofloxacin, levofloxacin, or moxifloxacin) plus clofazimine daily for 6 months, followed by clofazimine plus one of the second-line drugs daily for an additional 18 months.

●Patients whose isolate demonstrates resistance to both rifampin and fluoroquinolones may be treated with the following drugs: clarithromycin, minocycline, and clofazimine for 6 months followed by clarithromycin or minocycline plus clofazimine for an additional 18 months.

Disease relapse — Issues related to diagnosis of disease relapse are discussed above. (See 'Evaluation' above.)

The optimal approach to treatment of relapse is uncertain. In general, treatment consists of restarting the same regimen used for initial therapy [66]. Patients who presented initially with PB disease but relapse with MB leprosy should be retreated with a MB regimen. (See 'General approach' above.)

SPECIAL POPULATIONS

Patients with HIV infection — There has been no increase in leprosy in regions where human immunodeficiency virus (HIV) is prevalent. In patients coinfected with M. leprae and HIV, initiation of antiretroviral therapy may trigger a T1R as a manifestation of the immune reconstitution inflammatory syndrome [67]. (See "Overview of immune reconstitution inflammatory syndromes".)

The response to leprosy treatment in individuals with HIV infection appears to be comparable with the response in individuals without HIV infection [68].

Pregnant patients — Immunologic reactions occur more frequently in pregnant and postpartum patients than in nonpregnant patients [69-71]. In two small series, such reactions were observed in up to 38 percent of patients [72,73]. T2Rs were observed more frequently during pregnancy; T1Rs were observed more frequently in the postpartum period.

Management of leprosy during pregnancy and breastfeeding is the same as described above for other patients. (See 'Antimicrobial therapy' above.)

For pregnant patients with T1R or TR2, corticosteroids may be used; however, thalidomide is contraindicated.

Disability due to leprosy — Physical disability is a major complication of leprosy.

●Classification – Disability due to leprosy is classified by WHO as follows [74]:

•Grade 0: No impairment

•Grade 1: Sensory impairment but no visible impairment

•Grade 2: Visible impairment, such as claw hand, foot drop, or lagophthalmos

●Management – For patients with Grade 2 disability, surgery may be beneficial for mechanical improvement and rehabilitation, as well as to reduce stigma. Examples include skin grafts for large ulcerations, tendon transfer for claw hand or foot drop, and tarsorrhaphy for lagophthalmos.

PREVENTION

●General principles – Control measures for leprosy include clinical management of active cases as well as contact management. Household contacts should be evaluated annually for evidence of leprosy for at least five years, and should be educated to seek immediate attention if skin or neurologic manifestations develop.

●Prophylaxis

•Within the United States – Within the United States, our approach to prevention of leprosy aligns with the United States National Hansen's Disease Program (NHDP) which does not advise prophylaxis. The incidence of leprosy in the United States is very low (<1 per million population) and there has been no documentation of human-human transmission in the United States for several decades.

For household contacts (defined as a person living in the same house as a patient with leprosy for ≥6 months, within six years before diagnosis to one month after initiation of therapy) of patients with multibacillary leprosy and high bacterial load (eg, bacterial index of 5 or 6), administration of a single-dose rifamycin for prophylaxis is a reasonable alternative (table 6). Data supporting use of rifamycins for prophylaxis are discussed below.

•Outside the United States

-Social contacts – A social contact is defined by the World Health Organization (WHO) as an individual who has been exposed to a patient with infectious leprosy for at least 20 hours per week for at least three months per year; this may include neighbors and associates at work or school [75].

For social contacts of patients with leprosy, the WHO recommendation is to use a single dose of rifampin for adults and children ≥2 years of age (table 6) [9]. For children <2 years of age, monitor clinically for signs of leprosy.

This approach was evaluated in a cluster-randomized controlled trial including more than 28,000 contacts of 1037 patients with newly diagnosed leprosy in Bangladesh treated with single-dose rifampin or placebo; the protective effect was 57 percent (95% CI 33-72 percent) and lasted only for two years [76]. However, the least benefit was observed among household contacts (the participants at highest risk).

-Household contacts – Leprosy household contacts are generally defined as individuals living in the same dwelling or sharing the same kitchen as the index case. These include family members but also domestic staff, aids, co-workers, or others sharing the same accommodation. A family member living elsewhere should not be considered as a household contact [75,77,78]. In some studies a household contact has been defined more precisely as a person living in the same house as a patient with leprosy for a cumulative total of at least six months, within the period from six years before diagnosis to one month after initiation of multidrug therapy in the patient [77,78].

For household contacts of patients with leprosy, postexposure prophylaxis with rifapentine for individuals ≥10 years of age has been proposed; dosing is outlined in the table (table 6). Pending further data, household contacts <10 years of age may be managed as social contacts (discussed above).

This approach is supported by a cluster-randomized trial including 7450 household contacts (≥10 years of age) of patients with newly diagnosed leprosy in China treated with rifapentine (single dose), rifampin (single dose), or no intervention. The incidence (intention-to-treat analysis) of new leprosy cases over four-year follow-up was lower in the rifapentine group than the control group (0.09 versus 0.55 percent; incidence ratio 0.16, multiplicity-adjusted 95% CI 0.03-0.87); the cumulative incidence did not differ significantly between the rifampin group and the control group [77]. The benefit of rifapentine was observed through all four years of follow-up.

●Vaccination – Vaccination with Bacillus Calmette-Guérin (BCG) is partially protective for leprosy; a single dose appears to be 50 percent protective, and two doses further increase protection [79,80]. BCG is administered at birth in most countries with high rates of leprosy; vaccination for prevention of leprosy in other regions is not economically feasible except in areas with an extremely high incidence of the disease [81].

Development of an improved BCG vaccine, BCG booster, or alternate vaccine strain is an important research goal that could benefit control of both tuberculosis and leprosy. Skin test antigen studies and the identification of the appropriate protective M. leprae genomic DNA sequence could also lead to an improved vaccine for leprosy [82].

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Leprosy".)

SUMMARY AND RECOMMENDATIONS

●General principles – Leprosy (also known Hansen's disease) is an infectious disease caused by Mycobacterium leprae or M. lepromatosis that involves the skin and peripheral nerves. Classification is summarized in the table (table 1). Leprosy is an important global health concern; early diagnosis and treatment are important for preventing neuropathy and disability. (See 'Introduction' above and 'Classification' above.)

●Treatment

•Within the United States – Within the United States, our approach to treatment of leprosy aligns with the United States National Hansen's Disease Program (NHDP), as follows (table 2 and table 3) (see 'Within the United States' above):

-For patients with tuberculoid (paucibacillary [PB]; TT, BT) disease, we suggest treatment with dapsone and daily rifampin for 12 months (Grade 2C).

-For patients with lepromatous (multibacillary [MB]; LL, BL, BB) disease, we suggest treatment with dapsone, daily rifampin, and clofazimine for 24 months (Grade 2C).

•Outside the United States – Outside the United States, countries follow the World Health Organization (WHO) approach, as follows (table 2 and table 3) (see 'Outside the United States' above):

-For patients with tuberculoid (PB; TT, BT) disease, treatment consists of dapsone, monthly rifampin, and clofazimine for 6 months.

-For patients with lepromatous (MB; LL, BL, BB) disease, treatment consists of dapsone, monthly rifampin, and clofazimine for 12 months.

●Monitoring and follow up – During antimicrobial treatment, we schedule routine follow up every three months. Visits should include clinical examination (including assessment of the skin, nerves, limbs, and eyes) as well as laboratory studies to evaluate for drug toxicity. Patient education is essential to ensure treatment adherence. (See 'Clinical response and follow-up' above.)

●Progression of signs or symptoms: Evaluation (See 'Evaluation' above.)

•Timing of presentation

-For patients with disease progression during treatment, the most common cause is development of an immunologic reaction. Nonadherence is another possible cause. Drug resistance is a less common cause.

-For patients with disease progression after completion of treatment, the most likely cause is an immunologic reaction. Disease relapse is an alternative consideration.

•Initial approach – In some cases, immunologic reaction may be diagnosed based on clinical features; in such cases, we proceed with empiric treatment. For patients who do not respond to empiric treatment for immunologic reaction, and for patients whose presentation is not consistent with an immunologic reaction, we pursue biopsy to evaluate for drug resistance or disease relapse.

●Progression of signs or symptoms: Management

•Immunologic reactions – Immunologic reactions are systemic inflammatory complications that occur before, during, or after antimicrobial treatment of leprosy. (See 'Immunologic reactions' above.)

-Clinical approach – Mild reactions without neuritis or skin ulceration can be managed with supportive care. For patients with severe type 1 reaction (T1R) with neuritis, we suggest treatment with prednisone (Grade 2C); the optimal dose and duration are uncertain and should be individualized. For patients with type 2 reaction (T2R), we suggest treatment with thalidomide in regions where available (Grade 2C), but teratogenicity limits its use in women of childbearing age. Other agents for treatment of immunologic agents are discussed above.

-Continuation of antimicrobial therapy – Antimicrobial therapy should be continued in the setting of an immunologic reaction, and patients should be reassured that the symptoms are not a reaction to the medications. During prednisone administration, rifampin should be administered monthly rather than daily.

•Isolated neuritis – For patients with deteriorating nerve function for less than six months who are adherent to antimicrobial treatment, we suggest treatment with corticosteroids (Grade 2C); the optimal dose and duration are uncertain and should be individualized. (See 'Isolated neuritis' above.)

•Drug resistance – The approach to treatment should be guided by skin biopsy PCR test results for mutations associated with drug resistance. We are in agreement with the WHO guidelines for treatment of drug-resistant leprosy, summarized in the table (table 5). (See 'Drug resistance' above.)

•Disease relapse – The optimal approach to treatment of relapse is uncertain; in general, treatment consists of repeating the same regimen used for initial therapy. Patients who presented initially with PB disease but relapse with MB leprosy should be retreated with a MB regimen. (See 'Disease relapse' above.)

●Prevention

•Prophylaxis (See 'Prevention' above.)

-Within the United States – Within the United States, we suggest against prophylaxis (Grade 2C), in alignment with the NHDP, given very low incidence of leprosy.

For household contacts (defined as a person living in the same house as a patient with leprosy for ≥6 months, within six years before diagnosis to one month after initiation of therapy) of patients with multibacillary leprosy and high bacterial load (eg, bacterial index of 5 or 6), administration of a single-dose rifamycin for prophylaxis is a reasonable alternative (table 6).

-Outside the United States – For social contacts of patients with leprosy, the WHO recommends administration of rifampin (single dose) for individuals ≥2 years of age (table 6). For household contacts of patients with leprosy, postexposure prophylaxis with rifapentine has been proposed; rifampin may be used as an alternative agent. Contacts who are not treated should be monitored for signs of infection.

•Vaccination – Vaccination with Bacillus Calmette-Guérin (BCG) is partially protective for leprosy. (See 'Prevention' above.)

ACKNOWLEDGMENTS — 

The UpToDate editorial staff acknowledges Barbara Stryjewska, MD, and David Scollard, MD, PhD, who contributed to earlier versions of this topic review.