Leprosy (FL INITIAL Autonomous Practice- Pharmacology)

Drawing observations from published reviews on leprosy transmission, it appears the exact mode of transmission in humans currently lacks sufficient evidence. Modes of transmission documented in different submissions range from tattooing to household contacts and exposure to armadillos. Household contact reportedly accounts for about 28% of new cases, with many of these contacts described as M. leprae by PCRs that were positive on skin and nasal swabs (Makhakhe, 2021). M. leprae infections also occur through air droplets expelled from infected individuals. In lepromatous leprosy patients, infected tissues reportedly house up to seven billion bacilli, making these individuals highly infectious. Experimental models of transmission and infection suggest that the main entry route and dissemination point of the bacilli is the upper respiratory tract. However, there seems to be wide variabilities in these two points in different infected persons. These variabilities have made it difficult to pinpoint an exact, generalized mode of transmission of the causal organisms. In many cases, the identification of leprosy transmission is also hindered by the long incubation period of the causal organisms, as clinical manifestation can take up to 10-15 years in infected individuals (Bhandari et al., 2022).

Zoonotic transmissions also appear important in many regions where leprosy is considered endemic. In cases attributed to M. leprae in Mexico, zoonotic transmissions were suspected. Two affected individuals reportedly had direct contact with armadillos. Since this documentation, a history of contact with armadillos is now considered a valid investigation when presenting cases with clinical manifestations suggest leprosy. M. leprae samples have also been reportedly isolated from red squirrels in the British Isles. Isolated samples reportedly closely resemble those found in medieval human remains from Denmark and England (Schaub et al., 2020).

The pathophysiology of leprosy is properly documented in infected individuals with special cases of susceptibility to causal organisms. In active cases of infection, the bacilli primarily cause physiological deficiencies in the macrophage, keratinocytes, and histocytes of the skin. Simultaneously, active infections cause axonal dysfunction and demyelination in the Schwann cells of the peripheral nerves as the clinical presentation continues to emerge. In infected Schwann cells, cellular de-differentiation and reprogramming consequently lead to degeneration of the peripheral nerves as local senses of touch and pressure significantly diminish (De Oliveira Brugger et al., 2023).

Schwann cell axons are surrounded by lamina that interact with receptors to regulate cell activity and facilitate signal transduction in the central nervous system. Active cases of leprosy usually involve the rapid binding of the causal organism with laminin-2 isoforms – a key component of basal lamina consisting of alpha-2, beta-1, and gamma-1 chains. Early experimental models investigating this binding suggest that the neuronal tropism of M. leprae is mediated by laminin alpha-2 chain with the binding affinity to laminin alpha-1 chains despite its wide distribution in tissues (De Oliveira Brugger et al., 2023).

As part of bacilli invasion into healthy tissues, clinical studies identified alpha-Dystroglycan as the cell membrane receptor facilitating bacterium entry on Schwann cells. Similarly, beta-Dystroglycan has been identified to modulate cellular invasion in cytoskeletal proteins domiciled on peripheral nerves and muscles containing dystrophin. As documented by subsequent etiological studies, M. leprae appears to express a multi-dimensional approach to cell invasion in an active infection. Glycolipids and phthiocerol acids on the cell wall of M. leprae reportedly contain M. leprae-specific trisaccharides known to mediate binding on the laminin alpha-2 chain in the basal lamina of Schwann cells. In a typical physiological setup, Schwann cells have been demonstrated to depend on neuronal ligands for functionality and survival. The interdependence is mediated by an interaction facilitated in the binding of neuregulin to epidermal growth factor receptors ErbB2/ErbB3 – a receptor tyrosine kinase complex. To a large extent, this binding is considered primarily important in the differentiation and proliferation of Schwann cells. By binding and activating ErbB2, M. leprae induces early demyelination and, subsequently, downstream signaling pathways dependent on ErbB2. Deregulation of the Schwann cell axon signaling system leads to the eventual physiological collapse of the myelin sheath – a situation that directly initiates nerve injury and demyelination (Mungroo et al., 2020).

Clinical evidence documenting how M. leprae reprograms Schwan cells through epigenetic modification of key genes has slowly accumulated over the past few years. Schwann cell reprogramming follows a complex transcriptional process that produces multiple stem-like progenitor cells that ultimately facilitate the spread of the causal organism to other susceptible tissues. Beyond merely explaining how M. leprae infects muscle fibers and fibroblasts in humans, studies have also documented how the propagation of infection in fibroblasts is more efficient when M. leprae originates from reprogrammed Schwann cells compared to non-reprogrammed ones. By reprogramming Schwann cells, M. leprae ultimately improves its chances of continued survival and propagation in infected individuals (White & Franco-Paredes, 2015).

Diagnosed as the early stage of bacilli invasion, indeterminate leprosy is characterized by prodromal symptoms almost unnoticed in many patients until the appearance of cutaneous lesions. In most cases, it presents primarily as numbness followed by loss of sensitivity to temperature extremes and light pressure as the earliest signs of sensory impairment. Variables in the level and type of sensory loss experienced first have been reported to be linked with the type of disease that is slowly evolving. However, in most cases, the dermatological presentation of indeterminate leprosy is similar across infected individuals.

A solitary, hypopigmented macule is often the first lesion noticed as it merges perfectly into the surrounding healthy skin patch. Erythematous macules may be present in some cases. Both clinical presentations are likely to be noticed on the cheeks, upper arm, thigh region, and buttocks. Sensory functions on these macules may be minimal or completely impaired, and compared to other forms, the macules may contain only a few or no bacilli on biopsy. From this form, the disease may evolve into either tuberculoid or borderline lepromatous leprosy.

In this form of leprosy, the presenting lesions are solitary, asymmetrically distributed, and may be five or fewer. On close physical examination, lesions appear dry, scaly, hairless, and hypopigmented. In some cases, a few lesions may be erythematous. Clinical studies have also reported typical large erythematous plaque-like presentations with elevated, rounded edges that slope down to a flattened atrophic center. Compared to those formed in indeterminate leprosy, lesions may also appear macular, erythematous, or hypopigmented in the early stages. The distinguishing feature, however, is the presence of palpable indurations accompanied by a completely altered neurological function at the site of lesion formation. In tuberculoid leprosy, the most common location for the formation of dermatological symptoms includes the trunk, limbs, and face.

In most cases, the groin, perineum, axilla, and scalp are not involved. Another presentation often reported in this form of leprosy is the enlargement or tenderness of superficial peripheral nerves serving or proximal to the lesions. In the same vein, the peroneal nerve and the greater auricular nerve may also present as enlarged or tender (Jariyakulwong et al., 2022).

Nerve involvement in tuberculoid leprosy implicates and initiates characteristic changes in the physiology of muscle groups in the affected region. The interosseous muscles of the hand may atrophy, leading to contracture of the fingers and wasting of the thenar and hypothenar eminences. Eventually, paralysis of the facial muscles may occur. As facial nerve paralysis progresses, the risk of vision loss and many ocular dysfunctions significantly increases. Although the emergence of lesions may be slow, spontaneous remission of dermatological presentation has been reported, and remission may be faster with adequate therapy.

Hand Wasting

Clinical presentations of borderline leprosy share multiple similarities with those of tuberculoid leprosy. The distinguishing factor, however, is that lesions in the borderline form are more numerous and are often reported as smaller in size. A typical presentation often reported is the appearance of satellite lesions around larger macules or plaques. If erythematous infiltrates are present, they form with prominent borders sharply demarcated and arranged asymmetrically. Sensory dysfunction and motor nerve involvement may also be present, although less pronounced than tuberculoid leprosy. Histologically, granulomatous infiltrates may extend to the cutis, and only a few bacilli are detected on biopsy.

Borderline borderline leprosy is characterized by numerous but countable skin lesions formed conspicuously with reddish plaques of no regular shape. The larger plaques may be surrounded by small satellite lesions largely distributed asymmetrically. Compared to those formed in tuberculoid leprosy, the lesions in this form are poorly defined. Nerve involvement presents as thickened and tendered nerves with moderate loss of sensory functions. Depending on the lesion, the biopsy may reveal a few or numerous bacilli. Normal hair growth and sweat gland function are primarily unaffected, and granulomas are often not reported in many cases.

The most reported clinical presentation of borderline lepromatous leprosy is the formation of lesions that are too numerous to count, formed on unaltered skin patches, and distributed asymmetrically. Papules, nodules, and infiltrated plaques are usually present as numerous, hypopigmented, and poorly demarcated. Sweating and hair growth in the affected skin region are hardly affected. In this form of leprosy, there is an extensive, symmetric involvement of peripheral nerves as they become enlarged and tender. Although dermatological symptoms may be slightly different in a few patients, they usually do not show the features of full-blown lepromatous leprosy as presentations such as leonine facies, loss of eyebrows, nasal ulceration, and keratitis are hardly present (Arunraghav et al., 2021).

As with tuberculoid leprosy, patients with clinical presentation of indeterminate leprosy may develop lepromatous leprosy. Often, a downgrade from borderline leprosy forms may also develop into lepromatous leprosy. Typically, lesions of lepromatous leprosy present with pale macules and diffuse infiltration of the skin distributed asymmetrically over the body. Unlike tuberculoid macules, the ones in lepromatous macules are numerous, smaller in size, and poorly defined with skin texture changes. Textural configuration and skin tone may remain intact, making the lesion blend perfectly with the surrounding skin. Sensory functions are not lost, sweating may be unaffected, and there is little to no peripheral nerve involvement. Hair loss may occur slowly and progressively from the outer third of the eyebrows to the lashes and the body. Hair on the scalp may remain largely unaffected (De Sousa Oliveira et al., 2019).

A standard procedure for diagnosis is the physical examination of lepromatous infiltrations in suspected cases. These infiltrations are divided into three types – nodular, diffuse, and plaque types. The diffuse types are presented as diffuse infiltrations of the face with a waxy and shiny appearance noticeable on the forehead. In all cases of lepromatous leprosy, recent clinical studies suggest nerve involvement invariably occurs, proceeding slowly in a bilaterally symmetrical pattern. Considering the pattern of involvement, loss of sensory function in this case may be misdiagnosed as diabetic neuropathy in many active leprosy cases.

Type 1 reactions of leprosy are described as hypersensitivity reactions to M. leprae cellular invasion occurring suddenly and clinically characterized by an onset of leprous skin reactions and urticarial swellings. In many cases, there is clinical evidence of loss of sensory and motor functions as affected peripheral nerves develop abscesses and become noticeably thickened. Type 1 reaction's most reported possible triggers include comorbidities, therapies, and pregnancies. In therapies, it may occur within the first twelve weeks of starting a therapy plan for patients with borderline borderline leprosy, borderline lepromatous, and borderline tuberculoid (Luo et al., 2021).

Type 2 reactions, also known as erythema nodosum leprosum, develop as an immune complex vasculitis (Coombs and Gell type 3 reaction) presenting histological resemblance with leukocytoclastic vasculitis, and manifesting as systemic reactions with iridocyclitis, orchitis, lymphadenitis, and glomerulonephritis. Dermatologically, there is a clinical presentation of painful erythematous-violaceous nodules occurring cutaneously or subcutaneously. Nodules spread rapidly across the body and may become neurotic or ulcerate. Patients presenting with type 2 reactions have these features predominantly on the face and the trunk. In older patients, myalgia, osseous pain, and arthralgia have been reported as accompanying symptoms. Considering recent evidence from clinical surveys, type 2 reactions are common in patients with borderline lepromatous forms as therapy is first initiated.

Recently, the Lucio phenomenon has been primarily studied as a type of leprosy reaction. It is generally observed in patients with untreated lepromatous leprosy and characterized by extensive violaceous patches and bullous infiltrates. On histological examination, endothelial proliferation and extensive vasculitis with hemorrhages, cutaneous infarctions, and thromboses are common in the advanced stages of this reaction. Areas of the body affected ulcerate and become neurotic, and histological examination of endothelial cells may be positive for M. leprae bacilli (Ya et al., 2021).

Synthesized in Italy from Amycolatopsis rifampycinica – a gram-positive soil bacteria, rifampicin has been commercially available since 1965. Pharmacologically, it exerts bioactivity by inhibiting bacteria RNA polymerase in mycobacteria. It is considered very active in leprosy cases as it significantly reduces bacteria count detectable in mucosal and cutaneous lesions of the leprosy types after a few days of administration. With a resistance rate currently estimated at 5%, rifampicin is not recommended as a monotherapy. High doses may cause severe side effects, including nausea, vomiting, and diarrhea. In patients who abuse alcohol while taking rifampicin, elevated liver function tests, intrahepatic cholestasis, and hepatotoxicity have been reported. In first-time users, erythematous macules on the face and scalp may occur within three hours of use. Noticeably, rifampicin causes a red-orange discoloration of the body fluids, including tears, urine, and saliva. Its teratogenic effects make it prohibited for use in pregnancy (Thangaraju & Venkatesan, 2019).

Synthesized in Dublin in 1954 and first used as a leprosy treatment in Nigeria in 1959, clofazimine is considered in many anti-leprosy drug regimens for its anti-inflammatory and bactericidal effects. Many countries consider it a first-choice drug in treating multibacillary leprosy. It has also shown huge clinical results in treating type 2 leprosy reactions, making it an important component of the WHO treatment strategy. Typically, especially in Caucasians, clofazimine produces red-brown hyperpigmentation of leprosy lesions as the skin tone slowly changes. These effects are reversed over a few months or years once clofazimine is discontinued. Other side effects commonly reported include discoloration of the conjunctiva and body fluids, xerosis, and the accumulation of clofazimine crystals in the intestinal mucosa, causing multiple gastrointestinal symptoms (Riccardi et al., 2020).

Dapsone was first synthesized in Germany in 1908 and used as monotherapy for leprosy for the first time in 1941. It exerts bacteriostatic effects on M. leprae by inhibiting folic acid synthesis. It is widely considered a first-line drug for leprosy in many treatment regimens and is reported to have demonstrated significant clinical benefits in leprosy patients. It has no known teratogenic effects and can be used in pregnancy. Popularly reported side effects include fatigue, headache, gastrointestinal symptoms, hemolysis, and methemoglobin formation pronounced in patients with a clinical deficiency of glucose-6-phosphate dehydrogenase. Other rare side effects of dapsone include drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, hepatitis, agranulocytosis, urticaria, and phototoxic reactions (Kurien et al., 2023).

The Hansen Disease Program (NHDP) is commonly used in the United States. It is particularly popular for its longer treatment period and its exclusion of clofazimine in treating paucibacillary leprosy.

In both treatment strategies, comorbidities, drug-drug interactions, and patient-specific contraindications might force the introduction of a second-line therapy agent. The most commonly used agents in this class include minocycline, ofloxacin, and clarithromycin. As a standard for measuring treatment efficacy, the parameters considered during therapy include:

1. The rapid decline in the infectivity of patients with an active leprosy disease
2. Low rate of recurrence and reactions
3. Prevention of resistance to dapsone