hansen’s disease (leprosy) current and future

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Hansen’s Disease (Leprosy): Current and FuturePharmacotherapy and Treatment of Disease-Related

Immunologic Reactions

Davey P. Legendre, Pharm.D., Christina A. Muzny, M.D., and Edwin Swiatlo, M.D., Ph.D.

Hansen’s disease, also known as leprosy, remains an important public healthproblem throughout the world, including North America. The causativemicrobe in Hansen’s disease is Mycobacterium leprae, an acid-fast organism thatis difficult to grow in vitro. The nine-banded armadillo is the major animal

reservoir in the United States. Manifestations of disease vary based on hostimmune response and can range from tuberculoid to lepromatous leprosy(paucibacillary to multibacillary disease). Hansen’s disease typically affects theskin, nerves, and eyes, and patients may present with skin lesions, weakness,numbness, eye pain, or loss of vision. Definitive diagnosis is based on a combi-nation of physical examination findings and skin biopsy and/or smear. Modernantibacterial therapy typically consists of combinations of dapsone and rifampinwith or without clofazimine. Clofazimine is available only as an investigationaldrug through the National Hansen’s Disease Program. Other options includemoxifloxacin, ofloxacin, minocycline, and clarithromycin. Hansen’s disease isassociated with type 1 (reversal) and type 2 (erythema nodosum leprosum)

immunologic reactions, during which the disease process appears to worsendramatically. These reactions may occur at any time before, during, or aftertreatment. Antibacterial therapy should usually be continued during thesereactions. Treatment options for these reactions differ based on clinical manifes-tations and include corticosteroids, thalidomide, pentoxiphylline, tumor necrosisfactor inhibitors, and T cell inhibitors. Prompt diagnosis, antimicrobial ther-apy, and treatment of reactions dramatically reduce complications of the disease.Key Words: Hansen’s disease, leprosy, reversal reaction, erythema nodosumleprosum, ENL.(Pharmacotherapy 2012;32(1):27 – 37)

OUTLINE

EpidemiologyMicrobiologyPathogenesisClinical ManifestationsDiagnosisImmunologic ReactionsTreatment of the Disease

Dapsone

Rifampin

Clofazimine

Fluoroquinolones

Minocycline

Clarithromycin

Future Therapy

Prevention

Treatment of Immunologic ReactionsCorticosteroids

Thalidomide

Pentoxiphylline

Tumor Necrosis Factor Inhibitors

T-Cell Inhibitors

Adjunctive Therapy

Conclusion

R E V I E W S O F T H E R A P E U T I C S


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Hansen’s disease, also known as leprosy, is anancient infectious disease, with references datingback to Biblical times.1 Recent research suggeststhat individuals have been afflicted with thisdisease dating back as early as 1550 B.C.2

Throughout the course of history, Hansen’s dis-

ease has played a significant role in the lives of mankind as a feared, misunderstood, and disfig-uring disease for which no treatment was avail-able.2 Infected persons were forced to live insecluded “leper colonies,” until the 1940s whenmodern antibacterial therapy became available,due to concern for contagiousness and lack of effective treatment.2 Mycobacterium leprae, thecausative agent of this disease and the firsthuman pathogen to be described, was identifiedin 1873 by Dr. Armauer Hansen of Norway.2

Because of Hansen’s discovery, successful efforts

to characterize the disease and find treatmentsthat would slow or eliminate its progressionwere pursued.

Epidemiology

Hansen’s disease occurs in both tropical andsubtropical temperate climates. Worldwide, itremains an important public health problem,especially in Asia, Africa, and South America,including India, Brazil, Indonesia, DemocraticRepublic of the Congo, Bangladesh, Nepal,

Angola, China, Madagascar, Mozambique, Nige-ria, the Philippines, and the United Republic of Tanzania.3 Nevertheless, the annual case detec-tion rate of new infections with M. leprae hasdeclined over the past decade as a result of moreintensive infection control programs and the useof multidrug therapy.3 In the United States,immigrants from endemic countries constitutethe vast majority of cases diagnosed annually(85 – 95%).4 Endemic foci do exist, however,mainly in parts of Texas, Louisiana, Florida, andCalifornia.5 A total of 150 endemic cases in theUnited States were reported to the National Han-

sen’s Disease Registry in 2008.5 The annualnumber of endemic cases reported in the UnitedStates has remained relatively stable since 1988.The incidence of disease peaks in the age groupsof 10 – 15 and 30 – 60 years, and the male:femaleratio of infection is ~ 2:1.1 No racial predilection

for acquisition of this disease is known.Humans are the primary reservoir for M. leprae.

Besides man, only wild nine-banded armadillos(Dasypus novemcintus) are known to be naturalhosts of M. leprae.6 Several cases of suspectedzoonotic transmission from armadillos to humanshave been reported.7 – 10 Infected armadillos havebeen found in Alabama, Arkansas, Louisiana, Mis-sissippi, Texas, and Mexico.11 Whole-genomesequencing of M. leprae from infected wild arma-dillos and patients with leprosy in the UnitedStates has revealed a unique M. leprae genotype

(3I-2-v1) that has not been reported elsewhere inthe world, lending further evidence to the hypoth-esis that M. leprae is a zoonosis in this region.12

Microbiology

Although M. leprae cannot be cultured insynthetic laboratory media, it does infect nine-banded armadillos and multiplies in mouse foot-pads. These animal hosts have providedsufficient quantities of bacteria for microbiologicinvestigations. The organism is an aerobic rod-

shaped bacterium that is acid fast with carbolfuchsin and other commonly used bacterialstains.

The cell wall of M. leprae is structurally simi-lar to that of most Mycobacterium species. Thepolymers that lie adjacent to the cytoplasmicmembrane comprise a complex amalgam of polysaccharides and glycolipids. Mycolic acidsconstitute up to 60% of the cell wall by weightand are thought to be primarily responsible forthe acid-fast staining characteristic of mycobac-teria. The outer surface of the cell wall containssurface-exposed proteins that are unique to eachspecies. The complex mixture of polysaccharidesand glycolipids renders mycobacterial cellsimpermeable to most solutes without specifictransport mechanisms. Resistance to both cellu-lar and humoral immune responses is attributed,in large part, to the complex cell wall of patho-genic mycobacteria.13

Little is known about the physiology of M. leprae, but its doubling time of nearly14 days in vivo is the longest of any knownpathogen. The complete genome of a strain of M. leprae isolated in the Indian state of Tamil

From the Pharmacy Division, Health ManagementAssociates, Woodstock, Georgia (Dr. Legendre); the Divisionof Infectious Diseases, University of Alabama at Birmingham,Birmingham, Alabama (Dr. Muzny); and the Division of Infectious Diseases, University of Mississippi Medical Center, Jackson, Mississippi (Dr. Swiatlo).

For reprints, visit https://caesar.sheridan.com/reprints/ redir.php?pub=10089&acro=PHAR. For questions or com-ments, contact Davey P. Legendre, Pharm. D., BCPS-AQID,Health Management Associates, Pharmacy Division, 5811Pelican Bay Blvd., Suite 500, Naples, FL 34108.

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Nadu has been published.14 The genome is~ 3.2 Mbp and has a G + C content of 57.8%,compared with a G + C content of 65.6% in Myco-bacterium tuberculosis. Although M. leprae and M.tuberculosis appear to have originated from acommon ancestor, the M. leprae genome is ~ 30%

smaller and contains over 1000 pseudogenesthat have functional full-length homologues inM. tuberculosis. It appears that less than half thegenome of M. leprae is protein-coding sequence.Many metabolic pathways found in other Myco-bacterium species, including respiratory electrontransport systems, are lacking in M. leprae, andits ability to generate energy in the form of adenosine triphosphate (ATP) is severely com-promised.14

Pathogenesis

The mode of transmission of M. leprae has notbeen absolutely proven; however, the most com-mon mechanism is thought to occur through therespiratory route in a manner similar to that of tuberculosis. Inoculation of bacilli through bro-ken skin and other close physical contact has alsobeen implicated. In the southeastern UnitedStates, armadillos carry M. leprae, and contactwith these animals is presumed to cause someinfections in this region. Most people are resis-tant to infection with M. leprae; however, certain

genotypes are increasingly recognized as risk fac-tors for leprosy. Both human leukocyte antigen(HLA) and non-HLA alleles have been linked tosusceptibility to infection.15 A recent genome-wide association study in eastern China associ-ated variant genes in the NOD2 signalingpathway with susceptibility to infection withM. leprae.16

The pathogenesis of infection with M. lepraeis poorly understood, but most evidence suggeststhat clinical manifestations of infection resultprimarily from host immune responses to theleprosy bacillus. Classified on the basis of theRidley-Jopling scale or by the World HealthOrganization (WHO), the immune response toM. leprae varies over a large continuum and isthought to be responsible for the heterogeneousclinical appearance of leprosy.17 – 19 The Ridley- Jopling scale combines clinical, immunologic,and histopathologic evidence and recognizes fiveforms of leprosy: tuberculoid, borderline tuber-culoid, midborderline, borderline lepromatous,and lepromatous leprosy. The WHO classifica-tion scheme is superimposed on the Ridley- Jopling scale to fit two distinct multidrug

therapy regimens and consists of two broad cate-gories: paucibacillary disease, which includes thetuberculoid and borderline tuberculoid forms,and multibacillary disease, which includes themidborderline, borderline lepromatous, andlepromatous forms (Figure 1).

At the paucibacillary tuberculoid end of thespectrum, skin and nerve lesions have character-istics of well-developed T helper cell type 1 (Th1) – mediated immune responses and possess fewacid-fast bacilli that signify presence of the organ-ism. This form of leprosy typically is associatedwith a low burden of organisms and few skinlesions. In contrast, at the multibacillary leproma-tous end of the spectrum, Th2-type cellularimmune responses predominate, with numerousskin lesions containing many acid-fast bacilli.This form of infection results in multiple progres-

sive skin lesions and may extensively involveperipheral nerves. Between these two phenotypicextremes is a highly variable continuum of clini-cal disease that is marked by dynamic immuno-logic responses to M. leprae.

The clinical manifestations of infection in anindividual may evolve in a waxing and waningmanner dependent on the predominant immuno-logic response at any time. These clinical formsof infection have been studied in the context of gene expression profiling,20 and this approachhas uncovered new insights into the mechanisms

underlying the regulation of disparate immuneresponses to M. leprae.

Clinical Manifestations

Because of the large variability in hostimmune response to M. leprae, patients present

BF A IMC

Unstable clinical presentation

TT BB BL LLTB

Borderline disease

yrallicabitluMyrallicabicuaP

Figure 1. Relationships of bacterial burden, immuneresponse, and clinical classification schemes. The five formsof leprosy based on the Ridley-Jopling Scale are tuberculoid(TT), borderline tuberculoid (BT), midborderline (BB),borderline lepromatous (BL), and lepromatous (LL).CMI = cell-mediated immunity; AFB = acid-fast bacilli.

TREATMENT OF HANSEN’S DISEASE Legendre et al 29


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with heterogeneous clinical manifestations of disease. The period between infection and overtdisease varies widely from several months to 30 – 40 years.1 The disease typically affects the skin,nerves, and eyes, and patients may present withskin lesions, weakness or numbness, eye pain,

or loss of vision. The clinical diagnosis of lep-rosy should always be suspected in someonewith skin lesions and/or enlarged nerves accom-panied by sensory loss.17 – 19

At the paucibacillary tuberculoid end of thespectrum of disease, patients can have one to sev-eral large asymmetric skin lesions, typically ma-cules or plaques, with sharply defined bordersand hypopigmented, anesthetic centers. In bor-derline tuberculoid, the most common form of leprosy, skin lesions resemble those of tubercu-loid leprosy but are more frequent and variable

in appearance with less well-demarcated borders.Asymmetric enlargement of peripheral nervesand progressive nerve damage are common, andpatients may present with muscle weakness ortrauma secondary to sensory impairment. Pro-gressing toward the multibacillary lepromatousend of the spectrum, patients with the midbor-derline form are immunologically unstable andmay shift rapidly toward the borderline tubercu-loid end of the spectrum during a reversal reac-tion (Figure 1). Skin lesions are numerous; varyin size, shape, and distribution; and may be hyp-

opigmented or erythematous.A characteristic “target lesion,” typically pres-ent in patients with the midborderline form of leprosy, has a broad, erythematous border with avague outer edge and a punched-out pale centerwith sensory impairment. Patients with the bor-derline lepromatous form also have numerousskin lesions, generally with intact sensation,although occasionally lesions may exhibithypoesthesia. Patients at the lepromatous endof the disease spectrum have extensive diseaseand widespread involvement of the skin andother organs. Generalized infiltration of thedermis may cause the skin to have a smooth,shiny appearance. Numerous skin lesions(macules, papules, or nodules) are symmetri-cally distributed, but with retained sensation.Progressive thickening of the skin causescoarse facial features and thickening of theear lobes. Eyebrows and eyelashes are thinnedout, and infiltration of the nasal mucosa mayoccur, resulting in discharge and obstruction.Erosion of the cartilage and nasomaxillarybones can result in perforation of the nasalseptum, collapse of the nose, and saddle-nose

deformity. Extension into the eye can causekeratitis and iritis. Infiltration of dermalnerves can cause peripheral sensory loss.17, 18

Diagnosis

More than 125 years after the discovery of M.leprae, the bacillus is yet to be cultivated in vitro.The diagnosis of leprosy is based on a combina-tion of physical examination findings and skinbiopsy and/or smear.17, 18 Slit-skin smears canbe performed by making a shallow incision inthe skin at standard sites (bilateral earlobes,elbows, and knees), as well as from several typi-cal skin lesions. After the incision is made, theinner surface of the wound is scraped with ablade held at a right angle to the incision. Uponscraping, tissue fluid and dermal tissue are

obtained and transferred to a clean microscopicslide where a circular smear is made. After theslide is stained with Ziehl – Neelsen carbol-fuch-sin and counterstained with methylene blue, thenumber of acid-fast bacilli viewed under themicroscope per oil immersion field is deter-mined and expressed as a “bacteriologic index.”This technique may be used to guide multidrugtherapy by assessing the bacterial load beforeand during therapy.

In addition, a full-thickness skin biopsyspecimen from the margin of an active lesion

can be obtained and the Fite stain used to visu-alize acid-fast bacilli in the tissue. If anothermycobacterial infection is suspected, culture of tissue biopsy material can be performed; growthwill exclude M. leprae. Also, a rapid molecularassay using real-time polymerase chain reactionto identify and quantify M. leprae DNA in tissuesamples can be performed at laboratory facilitiesequipped to perform this test, such as theNational Hansen’s Disease Program (NHDP)Laboratory in Baton Rouge, Louisiana.21, 22

Immunologic ReactionsImmunologic reactions to M. leprae antigens

are generally classified as either type 1 (reversal)or type 2 (erythema nodosum leprosum[ENL]) and reflect the predominant immuno-logic response locally in either nerves or skin.An example of a type 1 (reversal) reaction isshown in Figure 2. Approximately one third of patients with borderline leprosy are at risk fortype 1 reactions, whereas type 2 reactions affect50% of patients with the lepromatous formand 10% of those with the borderline leproma-



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tous form of leprosy. These reactions may be apresenting feature of the disease or occur duringor after multidrug therapy.23 These reactionshave also been described in patients with humanimmunodeficiency virus as part of the immunereconstitution inflammatory syndrome.24 Promptrecognition and treatment of inflammatory reac-tions are necessary to minimize progressivenerve damage that can occur with sustainedinflammatory responses.

Type 1 reactions are characterized by a shift

to Th1-type immune responses in the host andare associated with locally elevated levels of interferon-c, tumor necrosis factor-a (TNF-a),interleukin-12, and inducible nitric oxide syn-thase.25 This type of reaction can be seen inany type of leprosy but is uncommon in thetuberculoid form of the disease as an appropri-ate Th1-type immune response already exists.The diagnosis of type 1 reactions is generallymade clinically; however, skin biopsy is oftenuseful. Histologic criteria for type 1 reactionsare not standardized, but common findingsinclude dermal edema, large epithelioid granu-lomas, and plasma cells.26 Skin lesions maybecome larger and more erythematous and mayulcerate. New or worsening symptoms of neuri-tis may appear and can include both motor andsensory nerve dysfunction.23 Generalized edemamay occur, but systemic symptoms are notcommon.

Type 2 reactions, also known as ENL, are dis-tinguished clinically by fever, malaise, and therapid appearance of new subcutaneous nodulesthat are erythematous and quite painful.17 Theselesions are typically found on the face and exten-

sor surfaces of the limbs, but any site of the bodycan be affected.23 Painful neuritis is a commoncomplication. Erythema nodosum leprosum isthought to be an immune complex disease withconsequent activation of complement. Circulat-ing levels of TNF-a and interferon-c are ele-

vated.27 Widespread immune complex depositioncan occur and cause polyarthritis, iridocyclitis,orchitis, lymphadenitis, and glumerulonephritis.17

Peripheral leukocytosis with neutrophils is a com-mon laboratory finding. Patients with borderlineor the lepromatous form of leprosy are at highestrisk for ENL because they have a higher bacterio-logic index.23

A rare but potentially life-threatening reactionto M. leprae is erythema necroticans or Lucio’sphenomenon.28 This reaction is distinct fromtype 1 and 2 reactions and is characterized by

necrotizing vasculitis that has been ascribed toinvasion of vascular endothelium with M. leprae.Clinical manifestations include bluish or violace-ous and hemorrhagic plaques, followed bynecrotic ulcerations. These symptoms typicallyoccur in the absence of systemic complaints orleukocytosis. The precise role of dysregulatedimmune responses in this reaction has not beenfully studied.

Treatment of the Disease

Before the advent of sulfone treatment, therapyfor Hansen’s disease consisted of potassiumiodide, arsenic, antimony, copper, sera, vaccines,aniline dyes, thymol, strychnine, baths, X-rays,radium, and electrical current.29 Chaulmoograoil, a product of the seeds of several species of the Hydnocarpus tree, was a hallmark of therapyin the late 19th and early 20th centuries, withvarying reports of documented success andindifferent results. The oil was mixed with lardand applied locally as well as taken orally sev-eral times/day.30 Commercial preparations of chaulmoogric acid became available in 1909 byBayer and Company under the name Antileproland later Chaulmestrol (Winthrop ChemicalCompany).31 Oral therapy appeared to be themost effective, but the dosage had to be titratedover time primarily because of nausea. The drugwas also prepared as an injection, but theadverse effects of fever, local reactions, andabscess made therapy difficult to tolerate.

In his book Alone No Longer , Stanley Stein, apharmacist who contracted Hansen’s disease,filled capsules of “foul smelling oily liquid” thatleft him “so nauseated that [he] quickly recorked

Figure 2. Example of a type 1 (reversal) reaction totherapy for Hansen’s disease (leprosy) appearing as skinlesions on the patient’s back.



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the bottle.”32 Ironically, he distributed pills inthe cafeteria at the leprosarium in Carville, Loui-siana. He also described a chaulmoogra oil injec-tion combined with olive oil and benzocaine that

left “painful suppurating abscesses” and resultedin several hospitalizations.32

Although modern recommendations for ther-apy differ between the U.S. Public Health ServiceNHDP and the WHO, antibacterials targetingM. leprae are the mainstay of therapy. Table 1shows recommendations for therapy, noting WHO suggestions for directly observed ther-apy.33 – 35 Pharmacokinetic properties of theantibacterials are listed in Table 2.36 – 38

Dapsone

Sulfones have long been the cornerstone fortreatment of Hansen’s disease. Dapsone exertsweakly bactericidal activity against M. leprae byinhibiting dihydropteroate synthase, ultimatelypreventing folic acid synthesis. In a mouse foot-pad model, oral dapsone therapy killed 99.4% of viable organisms as evidenced by a lag of anaverage of 78 days for M. leprae growth curvesin dapsone-treated versus control animals.39 It istaken orally once/day with or without meals,with nearly complete absorption and peak serumconcentrations of 2 – 8 hours. There is no dosage

adjustment needed for patients with renaldysfunction, but patients with hepatic impair-ment should be monitored closely. Dapsone maycause hepatitis and cholestatic jaundice, but no

dosage adjustment guidelines are available forthose with liver disease.Dapsone was initially used as monotherapy,

but resistance, estimated at 2 – 10%, has becomeproblematic.40 One proposed mechanism of resistance is a mutant folP1 gene, which encodesa resistant dihydropteroate synthase capable of folic acid synthesis under a variety of extremeconditions.41 In an effort to prevent the emer-gence of resistance expected with monotherapy,multidrug therapy is the standard of care.

The adverse effects of dapsone can be quitelimiting with the most profound being methemo-globinemia and hemolysis related to glucose-6-phosphate dehydrogenase (G6PD) deficiency.42

All patients should be screened for G6PD defi-ciency before starting dapsone, and those withmild G6PD deficiency may be started at 25 mg/ day with close monitoring.35 Dapsone is usedin pregnant patients, although it is a categoryC drug. It is excreted substantially in breast milkand is potentially harmful to nursing infants withG6PD deficiency. Cutaneous manifestations thatmay be confused with worsening disease are alsopossible, sometimes accompanied with lymphade-

Table 1. Recommended Therapy According to the World Health Organization33 and the National Hansen’s Disease Pro-gram34

WHOClassification of Disease NHDP Recommendation WHO Recommendation

Single-lesion

paucibacillary

Dapsone 100 mg/day + rifampin 600 mg/

day for 12 mo

Rifampin 600 mg once + ofloxacin 400 mg once+

minocycline 100 mg once

a

Paucibacillary Dapsone 100 mg/day + rifampin 600 mg/ day for 12 mo

Dapsone 100 mg/day (unsupervised) + rifampin 600 mg/mo(supervised) for 6 mo

Multibacillary Dapsone 100 mg/day + rifampin 600 mg/ day + clofazimine 50 mg/day for 24 mo

Dapsone 100 mg/day (unsupervised) + rifampin 600 mg/mo(supervised) + clofazimine 300 mg/mo (supervised) for24 mo

WHO = World Health Organization; NHDP = National Hansen’s Disease Program.aThis regimen is not recommended in the United States and is associated with clinical failure.

Table 2. Pharmacokinetic Properties of Antibacterials36 – 38

Antibacterial Bioavailability (%) Half-Life (hrs) Metabolism Route of Elimination

Dapsone 80 – 99 30 Acetylation 20% urineRifampin 60 – 99a 3 – 5 Deacetylation 60% feces, 30% urine

Clofazimine 20 –

70b

70 days Not available FecesOfloxacin 98 4 – 8 Hepatic 95% urine, 5% fecesMoxifloxacin 86 15 Glucoronidation, sulfation 20% urine, 25% fecesMinocycline 100 14 – 18 Hepatic 20% urineClarithromycin 55 3 Hepatic 30% urineaFood decreases absorption.bFood increases absorption.



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patients with intolerance, resistance, or clinicalfailure to primary therapy. Fluoroquinolones areactive against M. leprae by inhibiting DNA gyraseand inhibiting DNA replication and transcrip-tion.48 Agents, such as moxifloxacin, exhibit pow-erful bactericidal activity similar to that of rifampin,

with one dose producing substantial kill. In onestudy, no viable organisms remained after 3 weeksof daily therapy.49 Ofloxacin has substantial activityand is recommended as a single dose withother drugs for single-lesion disease, but due to aslightly increased failure rate compared with stan-dard therapy, this regimen should be limited tocountries with limited resources or operationaldifficulties.50, 51 Other agents in this class, such asciprofloxacin, show little to no activity.52 Fluoroqu-inolone resistance occurs primarily through muta-tions in gyrA but is not associated with mutations in

gyrB.53

Minocycline

Minocycline is the only tetracycline with intrinsicactivity against M. leprae. Minocycline is a lipo-philic molecule that passively enters the bacterialcells and exerts its action on the 30S ribosomalsubunit. Although not as active as rifampin, mino-cycline remains an effective and useful alternativein the treatment of Hansen’s disease.54, 55 It is partof single-lesion therapy recommended by the

WHO, and it has been used to successfully treatpatients with lepromatous leprosy at a dose of 100 mg/day.56 Adverse effects, even with long-term treatment, are usually very mild, althoughskin pigmentation, gastrointestinal symptoms,and central nervous system symptoms have beenreported. Minocycline should not be used in chil-dren or during pregnancy because it may depositin tooth enamel and discolor teeth.

Clarithromycin

Clarithromycin is a semisynthetic macrolideantibiotic with bactericidal activity against M. lepraegreater than other macrolides although less bacteri-cidal than minocycline.54 Its mechanism may bedue to reduction of ATP in the bacteria.57 It is use-ful as an alternative to primary therapy due toeither resistance or intolerance and has been usedto treat lepromatous leprosy as monotherapywith success, although higher doses lead to somegastrointestinal distress.58 Clarithromycin 500 mg/ day has been paired successfully with minocy-cline.56

Future Therapy

There is little in terms of novel therapy beingexplored for future treatment of Hansen’s disease,and the same is true for many diseases caused byMycobacterium species. The diarylquinolone,

R207910, is a promising new drug with bacterici-dal activity comparable to that of moxifloxacinand rifapentine.59 Its novel mechanism is believedto be inhibition of ATP synthase.60 In a murinemodel, R207910 retained bactericidal capabilitieseven when dosed once/month.61 Although it mustbe studied in humans, this drug remains an excit-ing option for the future.

Prevention

Vaccines are effective at preventing infectiousdiseases and epidemics. There is no vaccine forM. leprae, but bacillus Calmette-Guérin (BCG),often used as a tuberculosis vaccine, also offerssome protection against M. leprae, with a singledose providing 50% protection. Some have advo-cated adding killed M. leprae to the BCG vaccinefor increased immunologic response, but trialsof this strategy conducted in Malawi have notproved effective.62 Using BCG for prevention of Hansen’s disease alone is not recommended atthis time, and BCG is generally not recom-mended for any indication in the United States.

Treatment of Immunologic Reactions

Immunologic reactions are medical emergen-cies that must be evaluated and treatedimmediately to prevent long-term sequelae. Anti-microbial therapy should continue throughoutthe type 1 (reversal) reaction, although many cli-nicians will stop rifampin, especially in the pres-ence of active neuritis. Cutaneous manifestationsof a type 1 reaction generally do not require addi-tional therapy. However, if the patient experi-ences loss of sensation or other peripheral nerve

symptoms, corticosteroids should be startedimmediately to prevent permanent damage. Type2 reactions may not respond to corticosteroidsalone, and the addition of drugs such as thalido-mide may be useful in these cases. Patients notresponding to any therapy may benefit from clof-azimine if not already taking this drug.

Corticosteroids

Corticosteroids provide symptomatic relief from a reversal (type 1) reaction frequently within



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1 week. Prednisone 1 mg/kg up to 80 mg/daytapered over several months can be used. Thedose may be increased by 20 mg/day if symptomspersist after initiation of therapy. Prednisolone isavailable as an oral solution that may be used inplace of prednisone. Long-term use of high-dose

corticosteroids certainly has complications associ-ated with adrenocortical atrophy and hypoalbu-minemia. Myopathy, osteoporosis, ocular effects,hyperglycemia, and skin reactions are just a fewof the major adverse effects that must be moni-tored and addressed throughout the treatment.Some practitioners will also prescribe a bis-phosphonate, such as alendronate, to preventosteoporosis.

Thalidomide

The mechanism of action of thalidomide inpatients with Hansen’s disease is not fully under-stood, but it does reduce systemic concentrationsof TNF-a, a cytokine involved in systemicinflammation. Thalidomide is useful for treat-ment for ENL when corticosteroids are not effec-tive or are contraindicated. The initial dose is100 – 300 mg/day. Once symptoms subside, ther-apy can be tapered by 50 mg every 2 – 4 weeks.Thalidomide is known to cause birth defects andis a pregnancy category X drug. In this case, cor-ticosteroids are the hallmark of therapy. Breast-

feeding is also contraindicated while takingthalidomide. Those who wish to prescribe ther-apy must be licensed through the System forThalidomide Education and Prescribing Safety(STEPS) program, and pharmacists are alsoresponsible for complying with these regulations.

Pentoxiphylline

This methylxanthine’s mechanism of action isunknown, but oral pentoxiphylline 400 – 800 mg 3times/day appears to decrease levels of TNF-a.63

The major adverse effects are related to thegastrointestinal tract and central nervous sys-tem, but these effects are reduced by usinga controlled-release formulation. Thalidomideoutperformed pentoxiphylline in a randomizedclinical trial in patients with type 2 reactions,in terms of limb edema and systemic symp-toms, but 62.5% of patients in the pentoxiph-ylline group had symptom relief. Althoughthis drug is not first line, it is a useful optionwhen other therapies are ineffective or contrain-dicated.64

Tumor Necrosis Factor Inhibitors

Since the mechanism of action of several drugsis proposed to inhibit TNF-a concentrations,biologic TNF inhibitors are a promising optionfor treatment of refractory type 2 reactions.

Various case reports show successful treatment of difficult reactions with etanercept and inflix-imab.65, 66 However, these drugs are known toexacerbate infectious complications, and severalcase reports show development or worsening of disease with agents such as infliximab and ada-limumab.67, 68 It is interesting to note that twopatients who developed disease when starting inf-liximab also developed a type 1 reaction after itsdiscontinuation. The true efficacy and safety of these drugs in type 2 reactions are still unknown,but these drugs may be useful in situations whenall other therapies are ineffective and the patientdesperately needs relief of symptoms.

T Cell Inhibitors

There is some evidence that drugs that disruptT cell activation and function can provide relief during a reaction. Oral cyclosporine resulted incomplete response in 3 of 4 patients, with theremaining patient achieving a partial response.69,70 However, M. leprae grew more readily inBALB/c mice infected with M. leprae who weretreated with extended courses of cyclosporine.71

Sixty-seven patients, with 20 experiencingchronic neuritis while receiving prednisone,were treated with cyclosporine 5 mg/kg reducedover 12 months.72 Therapy resulted in reduc-tions of antibodies to nerve growth factor tonormal levels and improvement of sensoryimpairment. One published case reporteddramatic improvement of skin lesions afterdaily topical administration with tacrolimus0.1%.73 Cyclosporine and other drugs that inhi-bit T cells are another option for patients notresponding to standard treatment of a reaction.

Adjunctive Therapy

There is little evidence that directly supportsthe use of nonsteroidal antiinflammatory drugs,but they are commonly used in very high doses totreat reactions, because of their antiinflammatoryeffects. Amitriptyline and gabapentin have alsobeen used to mitigate neuropathy despite littleevidence to demonstrate effect. Some evidencepoints to the utility of leukotriene inhibitors,such as zafirlukast, in the treatment of ENL.74



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The Leprosy Mission in Bangladesh proposed aclinical study in 2006 to test montelukast. In Ban-gladesh, thalidomide is unavailable and clofazi-mine is difficult to obtain. However, no patientshave been enrolled in this trial to date.

Conclusion

Hansen’s disease (leprosy) remains problem-atic in the United States and throughout theworld. Transmission of bacteria from person toperson is uncommon, and armadillos remain themajor reservoir in the United States. There is noefficient way to grow the organism in culture,which makes research efforts difficult. Promptrecognition of disease and treatment reducesdisease signs and symptoms, such as anestheticlesions, loss of vision, and amputation. The

discovery of antibacterial therapy targetingM. leprae has dramatically improved thoseinfected with Hansen’s bacillus. Patients benefitfrom comprehensive care involving numeroushealth care professionals. Astute pharmacistswho effectively manage antibacterial and reac-tion therapy will notice improved patient out-comes and quality of life. Major complicationstoday involve immunologic reactions and drugresistance due to lack of compliance. Clinicianscan recognize these issues early and adjust treat-ment appropriately to limit long-term complica-

tions from this disease.

Acknowledgments

The authors would like to thank Barbara Stry- jewska, M.D., and Jackie Lea, R.Ph., from the NHDPfor helpful discussions regarding the manuscript.

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