Leprosy [Hansen's disease]: clinical guidelines

List of Abbreviations

BI — bacteriological index;

ENL — erythema nodosum leprosum;

ESR — erythrocyte sedimentation rate;

TTp — polar tuberculoid type of leprosy;

TTs — subpolar tuberculoid type of leprosy;

BT — borderline tuberculoid form of leprosy;

BB — borderline form of leprosy;

BL — borderline lepromatous form of leprosy;

LLs — subpolar lepromatous type of leprosy;

LLp — polar lepromatous type of leprosy;

I — indeterminate form of leprosy;

M. leprae – Mycobactrium leprae;

M. lepromatosis – Mycobacterium lepromatosis.

Terms and Definitions

Leprosy (syn.: Hansen's disease, hansenosis, hanseniasis, leprosy, Crimean disease, Phoenician disease, affliction disease, black malady, scabies leaves, Saint Lazarus disease, etc.) is a chronic generalized granulomatous infectious disease from the group of mycobacterioses, caused by Mycobacterium leprae (M. leprae) and Mycobacterium lepromatosis (M. lepromatosis), characterized by clinically diverse lesions of the skin, upper respiratory tract mucosa, peripheral nervous system, musculoskeletal system, and internal organs [1].

Remission – a period of the disease course characterized by significant amelioration or complete disappearance of symptoms, including data from laboratory and instrumental diagnostic methods.

Relapse – return of clinical manifestations of the disease, including according to laboratory and instrumental research methods.

Exacerbation (reactions, reactive phases) refers to reactive states characterized by varying degrees of increased skin manifestations, involvement of the peripheral nervous system, transformation of the disease into another classification group, or activation of an existing form of the disease (reactions of the ENL [erythema nodosum leprosum] and Lucio phenomenon type).

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Leprosy is a chronic generalized human infectious disease caused by Mycobacterium leprae and Mycobacterium lepromatosis, characterized by a long incubation period, clinically diverse granulomatous lesions of the skin, upper respiratory tract mucosa, peripheral nervous system, musculoskeletal system and internal organs, and sometimes the anterior chamber of the eye [1, 2].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

Leprosy (Hansen's disease) is a chronic infectious disease and granuloma caused by human-pathogenic Mycobacterium leprae and Mycobacterium lepromatosis, primarily affecting the skin, mucous membranes, and peripheral nervous system [3–5].

The oldest paleontological finds showing evidence of this disease have a wide geographical distribution and date back to various periods—ranging from the Bronze and Iron Ages to the Modern era, demonstrating a clear example of pathogen-host coevolution [6].

In the Russian Federation, cases of the disease are rare and sporadic in nature. Endemic foci include the Lower Volga region, the North Caucasus, Siberia, and the Far East [4, 7].

Mycobacterium leprae was considered the only known etiologic agent of leprosy until PCR analysis identified another closely related species, Mycobacterium lepromatosis, in patients of Mexican descent who died from diffuse lepromatous leprosy [8]. According to current data, M. lepromatosis is localized mainly in North and Central America [9].

Both mycobacteria are closely related: they are obligate intracellular parasites, cannot be cultivated on artificial nutrient media, and cause similar pathological conditions. However, despite genome conservation, they belong to separate species due to certain differences in DNA nucleotide sequences. M. lepromatosis de novo sequencing revealed nucleotide polymorphisms, leading to the hypothesis that M. leprae and M. lepromatosis diverged from a common ancestor more than 13 million years ago [2]. Since the divergence, both species have gradually lost gene fragments from different regions of the genome, and furthermore, according to P. Singh et al. (2015), M. leprae has a more recent origin [10]. Through phylogenetic analysis, the authors established that M. lepromatosis has lost several enzymes required for amino acid synthesis, whereas M. leprae exhibits defects in heme synthesis regulation. Like M. leprae, M. lepromatosis also possesses neuropathogenic properties, which consist of the ability to infect Schwann cells of the peripheral nervous system [10].

A distinctive feature of M. leprae is that approximately 2% of its genome consists of specific repetitive sequences from four families: RLEP (39 copies), REPLEP (15 copies), LEPREP (8 copies), and LEPRPT (5 copies). This feature allows them to be used as genetic targets in diagnostic studies [11].

Genome-wide analysis of the pathogen has revealed numerous pseudogenes that determine the metabolic strategy of M. leprae for survival in the host organism during the long incubation period [12].

The issues of leprosy pathogenesis remain largely unclear. Despite the low contagiousness of the disease, there is strong evidence of an increased risk for people living in close contact with patients due to "infectious aerosols" generated by coughing and sneezing, as a large number of mycobacteria are found in nasal mucus and the secretions of the pharynx and larynx. Transmission of leprosy can also occur via fomites and damaged skin [13, 14].

The pathogenesis of leprosy is closely related to the state of the host immune system, involving mechanisms of both innate and adaptive immunity. Host susceptibility to infection is determined by a genetically predisposed susceptibility to pathogen invasion into human tissues, congenital defects in the macrophage link, and host T-lymphocytes [4, 15, 16].

Macrophages are among the most common cells interacting with mycobacteria. Phagocytosis of M. leprae by monocyte-derived macrophages can be mediated by complement receptors CR1 (CD35), CR3 (CD11b / CD18), and CR4 (CD11c / CD18) and is regulated by protein kinase [17].

Leprosy mycobacteria invade vascular endothelial cells and settle in Schwann cells of cutaneous nerves. This tropism is explained by the similarity of antigens between M. leprae and peripheral nerve tissue, where a prolonged period of adaptation and replication takes place [2, 18].

M. leprae-induced demyelination results from direct bacterial binding to the neuregulin receptor, activation of ErbB2 and Erk1/2, and subsequent signaling and MAP kinase proliferation [17].

Along with a decrease in the immunological resistance of the body against M. leprae, an increase in leprosy incidence may also be promoted by possible changes in the biological properties of the pathogen itself, including the emergence of drug-resistant strains or strains with increased virulence and pathogenicity.

It is believed that HIV coinfection may worsen the pathogenesis of leprosy lesions or lead to increased susceptibility, as observed with tuberculosis. However, to date, it has not been reported that HIV infection increases susceptibility to leprosy, affects the immune response to M. leprae, or significantly impacts the pathogenesis of nerve or skin lesions.

Currently, the variability of candidate leprosy-susceptibility genes involved in the host immune response to the infectious agent is of great interest to researchers. Genome-wide association studies have identified 4 chromosomal regions linked to leprosy: 6p21, 17q22, 20p13, and 10p13 [21, 22].

For a long time, leprosy was considered an exclusively anthroponotic disease. A prerequisite for the development of the disease was prolonged contact with an infected person. J. Pedley (1967) proposed a hypothesis regarding the alimentary route of leprosy transmission, as the pathogen is detected in breast milk [23]. The possibility of sexual transmission of leprosy was also considered, since mycobacteria were found in the testes of patients with the lepromatous form of the disease [24]. Nevertheless, modern scientific data largely point to the airborne droplet route of pathogen transmission [25, 26].

However, in a review by T. Ploemacher et al. (2020) on environmental pathogen dissemination, the authors emphasize that human-to-human transmission is not the only way to contract leprosy [14].

Blood-sucking insects and flies have been considered potential vectors of leprosy because mycobacteria have repeatedly been found in their bodies. However, experimental data confirming this hypothesis have not yet been presented [27].

There are reports of red squirrels being infected with M. lepromatosis or M. leprae in England and Scotland [14, 28, 29, 30].

According to R. Sharma et al. (2020), nine-banded armadillos are highly susceptible to leprosy, and approximately 16% of wild armadillos in the southern United States are affected by M. leprae. Given the similarity between M. leprae and M. lepromatosis, it is quite likely that armadillos can also be infected with M. lepromatosis [8]. Furthermore, in most human cases, the pathogen shares the same genotypes as those found in infected armadillos in the region [9].

Other studies indicate the presence of the pathogen in various natural habitats within leprosy-endemic regions. M. Tio-Coma et al. (2019) identified M. leprae DNA in soil samples collected in Bangladesh, Suriname, and the British Isles using PCR and Sanger sequencing [31].

Studies by P. Mohanty et al. (2016) revealed similarities in the genotypes of leprosy mycobacterium strains found in skin scrapings of patients at a leprosarium in Ghatampur (India) and in soil samples collected on the leprosarium grounds. The authors suggest that these findings are promising for understanding and further studying the transmission routes of the pathogen [32].

1.3 Epidemiology of the Disease or Condition

Thanks to advances in modern medicine, there is a steady global decrease in the number of newly registered leprosy cases.

According to WHO data, the number of new cases decreased from 763,000 in 2001 to 249,000 in 2008 [34, 35]. In 2013, 215,656 new cases of leprosy were registered, in 2014 – 213,899, in 2015 – 215,973, and in 2017 – 193,118 [33–35].

In 2018, a total of 208,641 new cases of leprosy were registered worldwide (an incidence rate of 2.74 per 100,000 population), of which 20,500 were in Africa (1.93 per 100,000 population), 30,957 in the Americas (3.08 per 100,000 population), 50 in Europe (0.01 per 100,000 population), and 148,495 in Southeast Asia (7.49 per 100,000 population) [33].

The highest incidence rate per 100,000 population in 2018 was recorded in Somalia at 17.3, followed by Brazil at 13.6, Nepal at 10.2, India at 8.8, Mozambique at 8.2, Sri Lanka at 6.9, Indonesia at 6.3, Congo at 3.9, Ethiopia at 2.9, and Bangladesh at 2.0. By comparison, in China, with a population of 1.5 billion, 521 new cases of leprosy were registered in 2018 (0.03 per 100,000 population). Global statistics show that 95.6% of new leprosy cases were detected in 23 countries worldwide [33].

Migration flows play a significant role in the spread of leprosy in modern conditions. For example, out of 168 leprosy cases registered in Spain in 2013, 40 (24.6%) were detected among native Spaniards, while 128 (76.2%) were among migrants living in the country, mainly from Brazil, Paraguay, and Bolivia [36]. In Denmark, between 1980 and 2010, 15 leprosy patients were identified, 13 of whom were migrants from South and Southeast Asia [37]. In Italy, between 1990 and 2009, the number of new leprosy cases among the native population was 12, whereas among migrants it was 159 [38].

According to WHO data, 50 new cases of leprosy were registered across Europe in 2018, which accounted for 0.01 per 100,000 population. France registered 9 new cases of leprosy (0.01 per 100,000 population), Portugal 5 (0.04 per 100,000 population), Spain 7 (0.01 per 100,000 population), Sweden 11 (0.11 per 100,000 population), the United Kingdom 7 (0.10 per 100,000 population), Italy 5 (0.008 per 100,000 population), and Russia 3 (0.002 per 100,000 population) [33]. As can be seen from the data presented, the leaders in absolute numbers and per 100,000 population are prosperous Sweden and the United Kingdom, with the majority of new cases detected among the non-native population.

The incidence of leprosy in Russia has long been stable and sporadic in nature. Thanks to the successes of domestic healthcare, the total number of registered leprosy patients in the Russian Federation has decreased over the past 20 years from 711 in 2000 to 143 in 2020. At the same time, an increase in the number of new cases has been noted in recent years. Thus, over the past decade (2010–2020), 15 new cases of leprosy were detected in the Russian Federation, with 13 (86.6%) of the total newly detected cases being residents of the Lower Volga region (primarily Astrakhan Oblast). The newly detected patients are predominantly elderly individuals with multibacillary leprosy, which is the most unfavorable from an epidemiological standpoint.

It should be noted that currently in the Russian Federation there are no separate accounting and reporting statistical forms for leprosy, which makes it difficult to obtain reliable data.

1.4 Features of Coding the Disease or Condition

Other bacterial diseases (A30–A49)

A30 Leprosy [Hansen's disease]: infection caused by Mycobacterium leprae

A30.0 Indeterminate leprosy (I leprosy)

A30.1 Tuberculoid leprosy (TT leprosy)

A30.2 Borderline tuberculoid leprosy (BT leprosy)

A30.3 Borderline leprosy (BB leprosy)

A30.4 Borderline lepromatous leprosy (BL leprosy)

A30.5 Lepromatous leprosy (LL leprosy)

A30.8 Other forms of leprosy

A30.9 Leprosy, unspecified

Sequelae of infectious and parasitic diseases (B90–B94)

B92 Sequelae of leprosy.

The concept of "sequelae" includes conditions specified as such, as well as residual manifestations of a disease classified in the categories mentioned above, provided it is evident that the causal disease is no longer present.

1.5 Classification of the disease or condition

There are three classifications of leprosy: the Madrid Classification adopted in 1953, its subsequent modification proposed by D.S. Ridley and W. Jopling and recommended for use since 1973, and the classification proposed by the WHO in 1993 [1, 39].

According to the Madrid Classification, two polar types of leprosy are distinguished—tuberculoid and lepromatous—and two intermediate types: indeterminate and borderline (dimorphous) [39].

The modern Ridley-Jopling leprosy classification is based on dividing patients according to their state of immunological reactivity to M. leprae, which is reflected in clinical manifestations as well as histopathological, bacterioscopic, and immunobiological study data. The leprous process is viewed as a continuous spectrum of immunopathological changes between the tuberculoid and lepromatous types of leprosy, termed polar types, with the identification of three borderline forms and one indeterminate form [1, 40, 41].

The following designations for clinical forms of leprosy are adopted:

TTp — polar tuberculoid type of leprosy;

TTs — subpolar tuberculoid type of leprosy;

BT — borderline tuberculoid form of leprosy;

BB — borderline form of leprosy;

BL — borderline lepromatous form of leprosy;

LLs — subpolar lepromatous type of leprosy;

LLp — polar lepromatous type of leprosy;

I – indeterminate form of leprosy.

The use of this classification required morphological and bacterioscopic studies.

The WHO concluded that a clinical classification was necessary, without the use of bacterioscopic examinations, and proposed distinguishing the following groups:

- MB multibacillary forms of leprosy;

- PB paucibacillary forms of leprosy.

The MB group includes polar (LLp) and subpolar lepromatous (LLs), borderline-lepromatous (BL), and borderline (BB) forms of leprosy, while the paucibacillary group includes the borderline-tuberculoid (BT), subpolar tuberculoid (TTs), and polar tuberculoid (TTp) forms [42].

1.6 Clinical presentation of the disease or condition

The main signs of leprosy include:

- characteristic skin lesions;

- thickening of affected peripheral nerves (greater auricular, facial, ulnar, median, peroneal, etc.);

- impairment of superficial types of sensitivity (pain, tactile, temperature);

- presence of acid- and alcohol-fast rod-shaped bacteria in smears from skin scarifications, nasal mucosal scrapings, or biopsy specimens [42, 45].

Clinical syndromes in leprosy:

• Intoxication syndrome

Not pronounced; fever is generally absent. Symptoms of the prodromal period may appear in leprosy, manifesting as brief low-grade fever, edema, and neuralgic pain along peripheral nerves. The onset of intoxication syndrome (elevation of body temperature, headache, arthralgia, neuralgia) combined with skin changes (increased redness in both the marginal zone and the entire lesion, development of edema, and formation of a urticarial-type lesion) is characteristic of reactive states (reactive phases, exacerbations) in the form of erythema nodosum leprosum (ENL). The development of ENL is the result of autoimmune mechanisms in the pathogenesis of the leprous process and always worsens the patient's condition [48, 49].

• Skin lesion syndrome

Early manifestations of leprosy are characterized by skin mottling that does not disappear upon warming, and persistent cyanosis (acrocyanosis) upon cooling, especially in the plantar surfaces of the feet and palms. Initial manifestations in all types of leprosy have much in common and are characterized mainly by macular elements.

The most frequent early manifestations of the lepromatous type of leprosy are erythematous macules. They are either pale pink or red-cyanotic. The size and shape of the macules vary, and their borders are indistinct, gradually blending into the surrounding outwardly unchanged skin. Numerous small hypopigmented macules and papules with blurred edges may be present; the nerves at this stage are only slightly thickened, and involvement of the nasal mucosal lesion in the pathological process is frequently noted. Localization: buttocks, torso, extensor surfaces of the arms, thighs, lower legs, and face. In addition to erythematous macules, erythematosquamous or erythematopigmented macules occur. They most frequently appear on outwardly unchanged skin, both primarily and in the process of evolution of erythematous macules. In the process, the latter acquire the yellowish-brown color typical of lepromatous leprosy (a "rusty" shade). Subsequently, erythematous and erythematopigmented macules can turn into superficial and deep diffuse infiltrates [48, 51, 54].

The lepromatous type of leprosy, even in the early stages of its development, is characterized by symmetry of lesions. Increased sebaceous gland function in the area of macules and infiltrates makes the skin "greasy", shiny, and glossy. Enlargement of the follicles of vellus hair and the excretory ducts of sweat glands gives the skin an "orange peel" appearance [54].

With diffuse infiltration of the facial skin, natural skin folds become deeper and coarser, the superciliary arches protrude sharply, the nose is thickened, the earlobes enlarge, and the cheeks, lips, and chin acquire a lobular appearance (leonine facies – facies leonina). Infiltrates do not develop in the so-called "immune" zones (elbow and popliteal fossae, armpits, inner parts of the eyelids). Single or multiple papules and nodes (lepromas), ranging in size from 1–2 mm to 2–3 cm, appear in the areas of infiltration as early as the initial stages of the leprotic process. Lepromas are most frequently localized on the face (superciliary arches, forehead, nasal alae, chin, cheeks, earlobes), as well as on the skin of the hands, forearms, lower legs, and less commonly on the thighs, buttocks, back, and knee joints. They are sharply demarcated from the surrounding skin and painless. Lepromas can be dermal or hypodermal, depending on the depth of the infiltrate. The most common outcome of leproma development is ulceration. Eyelashes and eyebrows thin out and fall out, especially in the lateral zone [13, 54].

In tuberculoid leprosy, single and sparse elements with a unilateral arrangement are characteristic, most commonly spots, papules, and plaques with a clearly defined, elevated border resembling a "curb". This type of the disease is frequently characterized by reddish-brown papular plaques with an uneven or smooth surface and clearly defined edges ranging from 1 cm in diameter to the size of a palm. Localization includes the trunk, upper and lower extremities, buttocks, and less commonly the face. The surface of the plaques is often covered with fine scales, and vellus hair is sparse or absent [51]. As they develop, plaques may acquire figured outlines or an annular shape with a sharply demarcated, roller-like elevated border consisting of grouped papules. The central part is usually slightly hypopigmented and atrophic. Sometimes the peripheral papular rim is interrupted in places, and the eruptions appear as open rings. Papular eruptions may be preceded by erythematous spots. In addition to papular eruptions, elements resembling "sarcoidal nodes" are found on the face and extensor surface of the extremities; they are reddish-bluish with a brownish tint, 0.5–2.0 cm in diameter, and of a dense consistency.

Early atypical manifestations of tuberculoid leprosy include hypochromic, erythemo-hypochromic, and erythematous spots that are clinically almost indistinguishable from manifestations of indeterminate leprosy. Unlike lepromatous-type spots, they have clear borders, and a sensory disturbance can sometimes be determined within them. These manifestations may subsequently transform into typical tuberculoid lesions [50, 51].

Borderline leprosy is characterized by numerous plaque-like skin lesions with a slightly elevated surface, as if punched out in the center ("stamped-out") in the manner of "Swiss cheese", located symmetrically. The elements have a shiny surface and indefinite borders [51, 52].

In indeterminate leprosy, macular eruptions are also encountered. They may present as erythematous (ranging from pale pink to reddish-blue), hypopigmented, and erythemo-hypopigmented spots. The latter may have a hypopigmented central part with a narrow erythematous rim at the periphery. The borders of these spots are usually clear, but may also transition imperceptibly into the surrounding, seemingly unaffected skin. Their outlines are typically round, the surface is smooth, and localization includes the buttocks, trunk, shoulders, and thighs [13, 53].

• Peripheral Nervous System Lesion Syndrome

is one of the early manifestations of the leprotic process and presents with thickening of nerve trunks, impairment of superficial sensory modalities, as well as motor and autonomic disorders. Most commonly and primarily affected are the ulnar nerve, followed by the peroneal, radial, tibial, median, great auricular, and facial nerves. Nervous system involvement may be limited to one or several nerves with the development of polyneuropathy.

A distinctive feature of neuritis is its bacterial (specific) ascending nature. One of the early clinical signs of leprotic neuritis is the formation of thickenings along the course of nerve trunks, which can be detected in areas accessible to palpation [13, 44].

In lepromatous leprosy, thickenings of the nerve trunks have a "spindle-like" shape, whereas in the tuberculoid type, they resemble "rosary beads". They are often painful upon compression. Symmetric involvement of peripheral nerve trunks is characteristic of lepromatous leprosy, whereas mononeuropathy more frequently develops initially in tuberculoid and indeterminate forms.

Sensory disorders manifest in a strict, regular sequence. Temperature sensitivity weakens first and then disappears, followed by pain sensitivity, and finally tactile sensitivity. All types of sensitivity may be absent on the distal parts of the extremities, only temperature and pain sensitivity at the wrist joint, and only temperature sensitivity on the forearm. The "insular" ("ramuscular") type of sensory disturbance, most characteristic of leprosy, is caused by the destruction of nerve endings in the skin and is usually detected over eruptions. Sometimes this type of sensory disturbance can spread to extensive areas of skin, including outwardly healthy-looking skin. Sensory changes may present as hypesthesia, anesthesia, or hyperesthesia (at the onset of the disease). During exacerbations of leprotic neuropathy, hyperpathia, synesthesialgia, and causalgia appear. In leprotic polyneuropathy, decreased sensitivity is observed in the distal extremities in the form of "gloves", "socks", or "stockings", extending to the elbow and popliteal fossae. In tuberculoid leprosy, hypesthesia usually appears fairly early and is detected not only within the lesion but also beyond its borders as a rim 0.5 to 2 cm wide. In lepromatous leprosy, tactile sensitivity may be weakened in areas of massive infiltration within the affected site. In indeterminate leprosy, sensory disturbances in the lesions sometimes cannot be detected [13, 55, 56].

Decreased deep sensory modalities (muscle-joint sense, vibration sense, pressure sense) are uncharacteristic of leprosy and can be detected exclusively in severe leprotic polyneuropathies.

Motor disorders join the previously developed sensory disorders and affect the muscles innervated by the corresponding nerves. The decrease in muscle strength is proportional to the degree of amyotrophy. Facial amyotrophy, although symmetric, is expressed unevenly on both sides. The face becomes mask-like, expressing no emotions. Motor function of the facial and trigeminal nerves is rarely impaired. Paresis is characteristically localized in the distal extremities (fingers, ankle joints, wrist joints). In leprotic neuritis, not all muscles innervated by a given nerve are affected to the same degree. Thus, in facial nerve neuritis, paresis of the orbicularis oculi muscle occurs first, manifested by the "eyelash sign", followed by lagophthalmos, and considerably later, paresis of the frontal muscle and the corrugator supercilii muscles develops. Isolated involvement of a single upper branch of the facial nerve is a largely pathognomonic symptom of leprosy. In ulnar nerve neuritis, the first symptom of motor impairment is limited extension of the terminal and middle phalanges of the 5th and then 4th fingers, later causing the hand to acquire a "claw hand" shape. When the median nerve is involved in the leprotic process, the patient cannot pick up an object, such as a pencil from a table; difficulty in opposition of the thumb occurs, along with atrophy of the thenar and hypothenar muscles, and the hand resembles an "ape hand". Radial nerve neuritis in leprosy is accompanied by paresis of the fingers and wrist extensors, leading to wrist drop. When the peroneal nerve is affected, foot extensor paresis occurs. Initially, patients often "trip", clumsiness in walking appears, then a "drop foot" develops with atrophy of the peroneal muscles, and the gait acquires a "steppage" character [55, 56].

A peculiarity of reflex changes is noted in leprosy. Some of the superficial reflexes (plantar, corneal, conjunctival) decrease and disappear relatively early, even in patients without clinically pronounced neuritic manifestations.

In severe cases, amyotrophies, trophic ulcers, and deforming osteoarthropathies occur, which are also characteristically localized in the distal extremities. Bowel and bladder dysfunction, trophic disorders on the sacrum, buttocks, perineum, and external genitalia do not occur in leprosy [55, 56].

In the innervation zones of the affected peripheral nerves, autonomic vasomotor disorders are observed in the form of hypo- or anhidrosis, loss of vellus hair, weakened pilomotor reflex, changes in local and reflex dermographism, impaired sebaceous gland function, dryness, flaking, and thinning of the skin, as well as transverse ridging and dullness of the nails. Initial autonomic skin disorders in leprosy are topographically identified in two variants or their combinations: in the form of localized disorders at the sites of macules, papules, and infiltrates, and in the form of diffuse disorders, most commonly in the distal extremities.

The course of leprous neuritis is divided into chronic and acute phases. The chronic course is characterized by a slow progression of neurological symptoms and the absence of pronounced pain syndrome, even with significant thickening of nerve trunks. All types of sensitivity are reduced, up to complete anesthesia. Paresis in the distal extremities and facial mimic muscles develops and slowly progresses. The slowly progressive development of neuritis can exacerbate. The acute phase of leprous neuritis sharply worsens the patient's condition and is accompanied by severe causalgic pain, significant thickening of nerve trunks, marked nerve tenderness upon palpation, and the appearance or rapid increase of sensory, motor, and trophic disorders. Sensitivity changes in the first days present as hyperesthesia, hyperpathy, and synesthesialgia, subsequently replaced by hypesthesia and anesthesia. Rapidly progressing motor disorders may precede the onset of muscle atrophy. The acute phase of leprous neuritis varies in duration, sometimes dragging on for several months [44, 47, 48, 55, 56].

Musculoskeletal system involvement syndrome is accompanied by significant osteoarticular deformations and functional impairments. The quantitative and qualitative characteristics of these changes directly depend both on specific violations of bone integrity and on peripheral nervous system involvement accompanied by neurotrophic disabling complications of the leprous process (amyotrophy, contractures, mutilation, trophic ulcers). Involvement of the bones of the distal upper and lower extremities is characteristic of all types of leprosy, with the development of complications such as pathological fractures or dislocations. Changes in the feet are more severe and diverse: destruction of the terminal and main phalanges, fractures, dislocations, and shortening of the toes, resorption of bone tissue leading to the rejection of phalanges and entire toes, and the development of specific osteomyelitis. Hand lesions manifest as diffuse osteoporosis, osteolysis, concentric atrophy, focal semicircular bone defects, thinning of the cortical layer, and beak-like tapering of the phalangeal bones. In the lepromatous type of leprosy, manifestations of an inflammatory hyperplastic nature predominate, along with focal destructions of the spongy and cortical bone layers, as well as foci of specific destruction (lepromas). It is important to note a characteristic feature of bone lesions in leprosy: the polymorphism of these changes occurring in the same patient. Most frequently, leprosy affects the muscles of the distal extremities, namely: the abductor hallucis/digiti minimi muscles of the hand, the extensor digitorum brevis of the feet, and the interosseous muscles of the hands and feet. In second place are: the flexor digitorum superficialis of the hand, the tibialis anterior and fibularis muscles of the leg, and the gastrocnemius muscles [55, 56].

Syndrome of external nose and upper respiratory tract involvement. Lepromatous changes of the nose are diverse and almost never observed in isolation. They are combined with changes in other facial areas, namely the superciliary arches, cheeks, lips, chin, auricles, eyebrows, and eyelashes. Various deformations of the external nose very often represent the consequences of leprous changes in the nasal cavity and, first and foremost, processes in the nasal septum. Changes in the external nose, as well as in the vestibule, are expressed by infiltration of the skin, the presence of lepromas, their breakdown and ulceration followed by scarring, and finally, various gross deformations of the entire external nose and its individual parts. The most frequent deformation of the external nose is the so-called flat-sunken nose. This deformation is based on the destruction or resorption of the anterior parts of the quadrilateral cartilage plate. In such cases, the nose appears flattened, spread out, wide, and thickened. The flat-sunken nose is accompanied by a depressed nasal tip in 80% of cases. The next most frequent deformation of the external nose is the so-called saddle nose. This shape is characterized by the formation of a variable-degree depression in the middle part of the nasal bridge and the destruction of the nasal septum. Specific leprous infiltrates and lepromas are localized predominantly in the cartilaginous part of the external nose. Depending on the degree of development, infiltrates and lepromas cause thickening of the alae and tip of the nose, turning them into tuberous formations, which often causes significant disfigurement of these areas of the external nose [55, 56].

The nasal cavity is affected extremely frequently in leprosy, earlier than any other segment of the upper respiratory tract, and in some cases earlier than the skin and peripheral nerves. Some patients, long before the appearance of the first overt manifestations of leprosy, experience dryness and crusting in the nose, impaired nasal breathing, and suffered from nosebleeds, which were observed especially frequently when trying to remove formed crusts from the nose. These changes should be regarded as initial signs of leprosy. Specific changes in the nasal cavity are expressed in the development of lepromas, mucosal infiltration, ulcerative processes, and, consequently, the destruction of the cartilaginous and bony framework. Along with this, there is dryness of the nasal mucosa, crusting and scarring changes, impaired nasal breathing, and sensory disorders. In leprosy, unlike other diseases, cicatricial narrowing of the nasal cavity entrance is often observed in the form of concentric tightening and a decrease in the size of the entrance openings. However, in the majority of patients suffering from the lepromatous type of leprosy, the disorder of nasal breathing does not reach a sharp degree, at least subjectively. Olfaction is rarely impaired in leprosy. This is exclusively explained by the localization of the leprous process at a significant distance from the olfactory zone of the nose [55, 56].

The spread of the specific process to the laryngeal area leads to voice and external respiration disorders due to the formation of lepromas.

Visceral involvement syndrome. The most frequent manifestations of visceral involvement are specific lesions of the liver (hepatitis), eyes (episcleritis, keratitis, keratoscleritis, iritis, corneoscleral lepromas, secondary lens lesions with cataract development), and testes (orchiepididymitis). Cases of fertility impairment and gynecomastia due to changes in neurohumoral regulation as a consequence of endocrine gland damage are not uncommon.

Lymph node involvement syndrome is characteristic mainly of the active period of multibacillary forms of leprosy and is accompanied by enlargement of the inguinal lymph nodes. Exacerbations of chronic foot osteomyelitis and the relapsing course of a chronic wound process (neurotrophic ulcers) may also be accompanied by regional lymphadenitis [55, 56].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the diagnosis/condition:

Clinical manifestations of leprosy are diverse; the disease can affect various organs and tissues. The main condition for the correct diagnosis of leprosy is a comprehensive patient examination and analysis of laboratory research methods.

The diagnosis of leprosy is considered probable if there are clinical signs suspicious of leprosy and positive results of functional tests (superficial sensation disorder).

The diagnosis of leprosy is considered established if the patient has clinical signs of the disease and laboratory confirmation by microscopic examination (bacterioscopy) and/or pathomorphological examination (histology).

2.1 Complaints and Anamnesis

Complaints of skin changes, sensory disturbances in individual parts of the body, including the fingers and toes, a feeling of «numbness» in the fingertips, their cooling and/or «crawling sensations», persistent mild nasal congestion, ulcers in the foot area, joint pain and a feeling of heaviness in the limbs, contractures of the fifth, fourth, and third fingers of the upper extremities, decreased muscle strength and incipient muscle atrophy in the fingers, frequent burns resulting from decreased or complete loss of skin sensitivity. Patients often complain of a feeling of coldness, severe paroxysmal pain, especially at night, shifting from one nerve to another, and facial and extremity edema and skin dryness.

The history of present illness is typically prolonged with a gradual, slow period of increasing clinical manifestations (often over several years). The presence of nonspecific complaints, especially in the early stages of the disease, prompts patients to consult specialists in various fields (general practitioner, dermatovenerologist, neurologist, otorhinolaryngologist, surgeon, rheumatologist), who misdiagnose other conditions and prescribe ineffective therapy.

An epidemiological history is extremely important for establishing a diagnosis of leprosy. The significance of data regarding a "family" contact with a leprosy patient cannot be overstated. It should be noted that leprophobia is the reason why, in most cases, the fact of having leprosy patients among relatives is concealed not only from physicians, but also from relatives themselves, neighbors, and acquaintances. Information about visiting leprosy-endemic countries may also contribute to the early diagnosis of the disease [55, 56].

2.2 Physical Examination

An examination of the patient's entire skin is performed in daylight, using a magnifying glass if necessary. Attention is paid to changes in skin pigmentation, especially on the face, the condition of the eyebrows and eyelashes (sparse, falling out), the presence of erythema, acrocyanosis, rash, polyadenitis, edema and pastosity of the face, the backs of the hands and feet, trophic disorders (impaired sweating and sebum secretion, dryness, "ichthyosis", thickening and brittleness of the nails), burn scars on the lower legs and forearms ending in scars, nerve paresis and limb deformities (most commonly contracture of the V, IV, and III fingers of the hand), atrophy of the muscles of the hands and feet, non-healing felon, osteomyelitis, neuritis, polyneuritis with involvement of the upper branch of the facial nerve, and chronic foot ulcers.

Palpation in peripheral nervous system disorders in leprosy: the ulnar nerve is palpated in the medial ulnar sulcus with the forearm positioned at a right angle to the arm, in the cubital region, in the popliteal fossa near the head of the fibula and near the lateral malleolus (fibular nerve), in the middle of the popliteal fossa and near the medial malleolus of the lower leg (tibial nerve); the greater auricular nerve is identified visually and during maximum head rotation to the side opposite to the one being examined along its course – from the auricle downward and posteriorly, crossing the sternocleidomastoid muscle [55, 56].

Examination of the sensory and motor spheres in peripheral nervous system pathology in leprosy is assessed using functional tests:

Assessment of temperature sensitivity is performed using two test tubes filled with hot (45–50° C) and cold (18–20° C) water. Applying the hot and cold test tubes alternately to the examined skin area, the patient is asked about their sensations: "hot?" or "cold?". It is necessary to check the patient's ability to distinguish temperature differences between pathologically altered and visibly healthy skin areas.

To determine tactile sensitivity, monofilaments (surgical threads) are used, alternately touching the surface of the affected area and visibly unchanged skin. The physician asks the patient, who cannot see the skin area being examined, to count the stroke touches: "one", "two", "three", etc.

Pain sensitivity is determined using a needle or a regular medical needle. A light touch ("prick") should be alternated with the sharp and blunt ends of the needle both on the altered area and on healthy skin. The patient must also not see the area where sensitivity is being assessed and should characterize only their subjective sensation as "sharp", "sharper" (on healthy skin), "less sharp" (within the rashes), or "blunt". It is recommended to start needle touches from the center of the lesion toward the periphery, moving onto healthy skin.

To more clearly identify poorly distinguishable or even invisible elements, a test with #nicotinic acid is used, which involves the intravenous administration of 5–10 ml (depending on the body weight of the patient) of a 1% nicotinic acid solution. After 1–2 minutes, the face flushes, and simultaneously or even earlier, redness appears in the affected areas on the trunk and limbs, which have clear bright pink borders, sometimes slightly raised above the surrounding skin. After the general erythematous reaction disappears, the redness in the areas of leprosy lesions persists. This test also allows for the topographic selection of the most suitable site for further studies (taking a scarification, biopsy, etc.) [200–202].

2.3 Laboratory Diagnostics

Laboratory tests are performed to detect changes that may be caused by the course of leprosy or be a manifestation of adverse effects of drug therapy.

Comments: patients with leprosy may develop anemia, neutropenia, lymphopenia [203–205]. The erythrocyte sedimentation rate (ESR) is not a sensitive and/or specific diagnostic method, as it is elevated in 50% of leprosy patients, especially with the development of erythema nodosum leprosum (ENL) [16]. Monitoring complete blood count parameters is necessary during #dapsone** therapy to detect laboratory signs of anemia and agranulocytosis [59, 60, 206–209].

Comments: monitoring the parameters of the general routine blood biochemistry test is necessary due to the development of protein and carbohydrate dystrophy in hepatocytes in leprosy, with impaired enzymatic processes and significant changes in Kupffer cells [64] both as a result of the disease itself and the use of combination therapy [65, 66]. This may manifest as an increase in the activity levels of alanine aminotransferase and aspartate aminotransferase in the blood [61]. Anemia in patients with leprosy is accompanied by a decrease in blood iron levels [203–205]. In renal involvement in patients with leprosy, an increase in blood creatinine and urea levels may be detected [62, 63, 68]. A decrease in serum albumin and cholesterol levels is possible [205]. The general routine blood biochemistry test is performed with the determination of blood glucose levels; determination of blood albumin levels, determination of blood cholesterol levels, determination of alanine aminotransferase activity in the blood; determination of aspartate aminotransferase activity in the blood; determination of gamma-glutamyltransferase activity in the blood; determination of alkaline phosphatase activity in the blood; determination of blood iron levels, determination of blood urea levels; determination of blood creatinine levels; determination of C-reactive protein levels in blood serum. An elevation of C-reactive protein in blood serum is characteristic during the development of leprosy reactive states [16, 67]. Adverse events may develop during systemic therapy in patients, which can be detected by performing a general routine blood biochemistry test. Toxic liver damage may develop during dapsone** therapy [206–209].

Comments: patients with leprosy may develop renal involvement in the form of acute or chronic glomerulonephritis, interstitial nephritis, secondary amyloidosis, or pyelonephritis, which may manifest as hematuria, proteinuria, and possibly leukocyturia and cylindruria [211]. Monitoring urinalysis parameters is necessary to rule out renal involvement during the disease and to monitor the safety of antileprosy therapy [61, 68, 206–209].

Comments: staining is preferably carried out at room temperature rather than by heating. AFBs are stained bright red with carbol fuchsin and stand out distinctly against the methylene blue background. Mycobacterium leprae appear as homogenous bacilli or granular forms, singly and in typical clusters forming balls or "cigar packets". At least 100 fields of view should be examined in each smear. The number of AFBs in smears is evaluated using a 6-point grading system; the bacteriological index (BI) is calculated for each smear, and the arithmetic mean of the BIs (from 6 smears taken from different skin areas) is determined for the patient. The BI calculation is based on a logarithmic scale where 0 indicates the absence of AFBs; 1+ represents 1–10 AFBs per 100 fields; 2+ indicates 1–10 bacilli per 10 fields; 3+, 4+, 5+, and 6+ represent the identification of 1–10, 10–100, 100–1000, and > 1000 AFBs per field of view, respectively [72]. To evaluate treatment efficacy, testing for the presence of AFBs and BI calculation should be performed at 3, 6, and 12 months of treatment. In addition, to assess treatment outcomes, the morphological index—the ratio of homogenous to granular forms of M. leprae—is calculated and its proportion is indicated. Microscopy generally provides low sensitivity, especially in paucibacillary forms of leprosy, and does not allow for the differentiation of M. leprae from other Mycobacterium species [74]. It should be taken into account that non-lepramotous AFBs (such as paratuberculous, tuberculous, M. ulcerans, M. avium, M. fortuitum, etc.) morphologically indistinguishable from M. leprae may be present in the skin and nasal mucosa [75].

It has been demonstrated that PCR can facilitate the early diagnosis of leprosy even in the absence of confirmation by other diagnostic tests [80, 81]. The diagnosis of paucibacillary forms of the disease is always challenging, but PCR can serve as a useful tool for this purpose [77, 82, 83]. PCR can also help differentiate leprosy from other conditions presenting with hypopigmented or granulomatous lesions, such as leishmaniasis, cutaneous tuberculosis, sarcoidosis, and other mycobacterioses. Furthermore, the detection of M. leprae by PCR in leprosy patients indicates that the patient is a bacillary shedder and poses a risk to others, significantly increasing the likelihood of disease development in close contacts [84, 85]. Currently, a domestic test system has been developed in the Russian Federation for in vitro laboratory diagnostic testing for the qualitative detection of Mycobacterium leprae DNA in clinical material using real-time polymerase chain reaction, designated "M. leprae Real-Time PCR", and patents have been obtained for methods of identifying M. leprae using PCR analysis targeting RLEP sequences and 16S rRNA [88, 89]; an EAEU registration certificate was issued on October 30, 2024 (MU-RUKZ-000113).

Comments: to study the morphological picture, sections are stained with hematoxylin and eosin [76]. If multiple lesions are present, the freshest one is biopsied; if the morphological picture varies, taking biopsies from at least 2 skin sites is permitted. Follow-up (control) examinations should preferably be performed on the same or similar lesions. The volume of the biopsy specimen must be at least 1.0 cm² including the subcutaneous adipose tissue. When taking the biopsy, an imprint smear is made on a glass slide for bacterioscopy. To detect AFBs, histological sections are stained using the Ziehl-Neelsen method, the Fite-Faraco method [77], or by fluorescence staining [78, 79].

Pathomorphological changes in various forms of leprosy can differ significantly. In tuberculoid leprosy (TT), typical epithelioid cell granulomas are formed, with an abundance of Pirogov-Langhans giant cells and lymphocyte clusters. Signs of hypersensitivity are pronounced with a characteristic arrangement of granulomas in the subepidermal zone; there may be foci of fibrinoid necrosis in the dermis, and deep within the dermis, there is an enlargement of the nerve bundle surrounded by lymphocytes within the perineurium. With this type of leprosy, the destruction of both small and large nerve trunks running along the course of blood vessels, infiltrated by epithelioid and lymphoid cells, occurs. M. leprae are detected very rarely, mainly as single specimens located in epithelioid cells and nerve fibers. In borderline tuberculoid leprosy (BT), granulomas only partially involve the subepidermal zone and do not destroy the epidermis; the giant cells in them are more similar to foreign-body type cells and contain fewer lymphocytes. Nerves are moderately thickened due to the granuloma, and lymphocytes usually infiltrate the perineurium, causing its distinct separation. However, the nerves are always recognizable, and only proliferation of Schwann cells is found in them. M. leprae are more common. In borderline leprosy (BB), infiltration of the dermis by epithelioid cells with varying degrees of differentiation is characteristic.

The subepidermal zone remains free of infiltrate. Lymphocytes and plasma cells are present in small numbers. Nerve thickening is slight or absent; splitting of the perineurium by invading epithelioid cells may occur. Mycobacteria are found in the cytoplasm of epithelioid cells, usually as short, thick, and intensely stained bacilli. Immunologically, the process in BB is characterized by instability: in the absence or inefficacy of treatment, it progresses toward LL or BL, whereas with treatment it may approach TT, transforming into BT with a predominance of elements characteristic of these types. In borderline-lepromatous leprosy (BL), a defining feature is the accumulation of epithelioid cells among macrophagic granulomas. In lepromatous leprosy (LL), granulomas are formed without epithelioid cells, consisting of histiocytes at various stages of transformation into classic Virchow lepra cells containing M. leprae, neutral fats, fatty acids, and their esters. M. leprae predominantly form intracellular clusters resembling "cigar packets" or "globio"; however, a large number of M. leprae can also be found extracellularly within collagen fibers, beneath the epidermis, in smooth muscle fibers, around small blood vessels, and in the secretion of sebaceous and sweat glands.

Homogenous forms predominate in earlier granulomas, whereas granular forms prevail in older, regressing ones. Unlike TT and BT, granulomas in LL do not involve the subepidermal zone, leaving a narrow strip of collagen fibers between them and the basal layer. Splitting may be detected in the nerves without prominent infiltration, or the nerves may remain unchanged. In indeterminate leprosy (I), the morphological picture is characterized by an inflammatory infiltrate in the dermis consisting of lymphocytes, histiocytes, plasmacytes, occasionally neutrophilic and eosinophilic granulocytes, located perivascularly and perifollicularly, as well as around fine nerve fibers and larger bundles along small blood and lymphatic vessels. M. leprae are detected very rarely, although they can occasionally be found within nerve bundles. The presence of a significant number of M. leprae is a sign of disease progression. Groups of epithelioid cells and isolated small epithelioid foci may appear.

2.4 Instrumental Diagnostics

Comments: instrumental examinations of peripheral nerves (ultrasonography of peripheral nerves (one anatomical region), stimulatory electroneuromyography of a single nerve, needle electromyography (one nerve), magnetic resonance neurography) such as the ulnar, median, and peroneal nerves, provide an objective assessment of their damage, information on the exact location of the enlarged segment, and morphological changes in the nerve, which is most informative when the disease manifests solely as neuropathies in the absence of cutaneous symptoms (neural leprosy) [111–115].

Comments: in leprosy, bone tissue changes occur in the distal parts of the upper and lower extremities. Leprosy-specific changes are characterized by foci of inflammatory destruction, most frequently localized in the spongy (less commonly cortical) substance of the phalanges, metacarpal, and metatarsal bones. Neurotrophic bone changes are characterized by osteoporosis, atrophy, and resorption of bone tissue. Leprosy is characterized by concentric atrophy of the phalanges with a characteristic bone deformation known as the "opera-glass hand/foot" (or "chess pawn") appearance. Periostitis and hyperostosis of the metatarsal, metacarpal, and less frequently long tubular bones of the forearms and legs may also develop [118].

2.5 Other Procedures

Leprosy is characterized by involvement of not only the skin, but also the peripheral nerves. Involvement of other organs is possible. Therefore, patients with leprosy may require additional examination for diagnostic purposes and to prescribe appropriate therapy – consultations with specialists: a neurologist, general practitioner (internist), endocrinologist, ophthalmologist, urologist, otorhinolaryngologist, surgeon, and physical therapy doctor for the diagnosis and treatment of specific lesions of various organs and systems, as well as comorbidities that may affect the course of the leprosy process and the choice of therapy.

Comments: leprosy is characterized by the development of peripheral neuropathies requiring appropriate treatment.

Comments: leprosy may be accompanied by damage to various internal organs, developing either due to M. leprae bacteremia or as a result of a leprosy reaction [218]. Involvement of the respiratory, cardiovascular system, liver and kidneys, blood and lymph nodes may be observed [217, 218].

Comments: endocrine system involvement in leprosy is a consequence of either direct damage to endocrine gland tissue or immune response disorders [219]. The most significant include thyroid disorders and hypogonadism [219, 220].

Comments: meibomian gland dysfunction, dry eye syndrome, and cataracts are most frequently detected in patients with leprosy [221, 222].

Comments: testicular involvement is observed in 10–50% of patients with leprosy [223].

Comments: involvement of the pharynx and larynx is possible in patients with leprosy [217, 218].

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1 Conservative Treatment

Treatment is carried out in accordance with the standard of specialized medical care for active-stage leprosy, approved by Order of the Russian Ministry of Health No. 1681n dated December 29, 2012, which includes dapsone** 100 mg daily and rifampicin** 600 mg once a month for 6–12 months [121].

Due to drug resistance to ongoing chemotherapy in some patients [122], alternative chemotherapy regimens using fluoroquinolones are currently proposed.

Alternative leprosy treatment regimens include: rifampicin** 600 mg once a month, #ofloxacin** 400 mg daily, #minocycline 100 mg daily (ROM) [123–125] and #rifapentine 600 mg once a month, #moxifloxacin** 100 mg daily, #minocycline 100 mg daily (RMM) [123, 125].

#Rifapentine for adults and children over 15 years of age 600 mg once a month + #Moxifloxacin** for adults and children over 15 years of age 400 mg daily + #Minocycline for adults and children over 15 years of age 100 mg daily.

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Treatment of Exacerbations (Leprosy Reactions)

Comments: a #prednisolone** dose tapering schedule is proposed after 3–6 months of therapy at an initial dose of 30 or 40 mg daily (Table 1)

Table 1. Treatment regimen for patients with leprosy in the event of signs of exacerbation of the leprosy process in the form of leprosy reactions [212]

When using #methotrexate**, it is necessary to regularly perform a complete blood count (CBC), test blood total bilirubin levels, and determine the activity of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase in the blood.

Systemic corticosteroids remain the leading drugs for the treatment of reversal reactions. Below are the WHO-recommended regimens for the use of #prednisolone** in leprosy reactions [126].

#Prednisolone** 40 mg once daily for 2 weeks;

#Prednisolone** 30 mg once daily for 2 weeks;

#Prednisolone** 20 mg once daily for 2 weeks;

#Prednisolone** 15 mg once daily for 2 weeks;

#Prednisolone** 5 mg once daily for 2 weeks.

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: #Prednisolone** and other systemic corticosteroids are used in accordance with the prednisolone equivalent. Systemic corticosteroid therapy is administered at a dose of no more than 1 mg per kg of the patient's body weight for 3 weeks, less commonly 4 weeks or more. The daily dose of the drug is taken strictly in the morning hours (before 11:00 AM) after a meal. The drug should be discontinued after a gradual dose reduction.

3.2 Surgical Treatment

Leprosy patients with contractures, deformities of the fingers and toes, or neurotrophic foot ulcers complicated by osteomyelitis may require surgical treatment.

Comments: nerve damage in leprosy may be accompanied by edema, leading to tunnel neuropathy manifested by pain and neurological deficit, which requires surgical intervention.

3.3 Other Treatment

In accordance with Order of the Russian Ministry of Health No. 1681n "On Approval of the Standard of Specialized Medical Care for Patients with Leprosy, Active Stage" and domestic clinical experience [197–199], physiotherapy may be prescribed to leprosy patients.

Comments: general contraindications for electrophoresis are conditions and diseases in which physiotherapy methods are contraindicated.

Comments: general contraindications for UHF therapy are conditions and diseases in which physiotherapy methods are contraindicated.

Comments: general contraindications for SMT current treatment are conditions and diseases in which physiotherapy methods are contraindicated.

Comments: general contraindications for ultrasound therapy are conditions and diseases in which physiotherapy methods are contraindicated. Ultrasound exposure is contraindicated during pregnancy and thrombophlebitis.

Comments: during laser therapy procedures, shielding of the patient's eyes and medical personnel is mandatory. Contraindications for laser therapy include benign neoplasms in the irradiation zones and individual intolerance to the physical factor.

Comments: number of procedures per course is 15–30. General contraindications for SCENAR procedures are conditions and diseases in which physiotherapy methods are contraindicated.

Comments: contraindications for microwave therapy are conditions and diseases in which physiotherapy methods are contraindicated.

Comments: contraindications to d'arsonvalization include conditions and diseases for which physiotherapy methods are contraindicated. The treatment course consists of 10–15 procedures; repeated courses can be carried out after 1–2 months.

Comments: general contraindications for the procedures include conditions and diseases for which physiotherapy methods are contraindicated. During laser therapy procedures, mandatory shielding of the eyes of the patient and medical personnel is required. Contraindications for laser therapy include the presence of benign neoplasms in the irradiation areas and individual intolerance to the factor.

For ulnar nerve neuritis, paraffin is applied in the form of high gloves; for peroneal nerve neuritis, in the form of long socks or stockings. After the procedure, the patient undergoes massage and exercise therapy (physiotherapy exercises) [197, 198, 199].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: contraindications for paraffin therapy of diseases of the peripheral nervous system include conditions and diseases for which physiotherapy methods are contraindicated.

Comments: 10–15 procedures are performed per course. Repeated courses can be administered after two to three months.

Comments: the treatment course consists of 20 procedures; repeated sessions can be performed at an interval of one month.

Comments: general contraindications for low-intensity laser irradiation of the skin are conditions and diseases for which physiotherapy methods are contraindicated. During laser therapy procedures, mandatory shielding of the eyes of the patient and medical staff is required.

Constant attention should be paid to the prevention and rehabilitation of progressive musculoskeletal deformities through exercise therapy, occupational therapy, prosthetics [198], and, in severe cases, surgical correction of disorders [131].

Medical Nutrition Therapy

When receiving specialized medical care in an inpatient setting, patients regardless of the stage and form of the disease are prescribed a high-protein diet with technological modifications for comorbid conditions and in accordance with the orders of the Russian Ministry of Health No. 330 dated August 5, 2003, "On measures to improve therapeutic nutrition in healthcare institutions of the Russian Federation" and No. 395n dated June 21, 2013, "On approval of therapeutic nutrition standards" [132, 133].

Pain Management

Nervous system involvement in leprosy may be accompanied by pain. Spontaneous pain occurs periodically, varies in intensity, and evoked pain can be triggered by palpation, compression of a skin fold or superficial peripheral nerves, or percussion of the nerve in the area of its thickening [227].

In the acute phase of neuritis, or during an exacerbation in the form of erythema nodosum leprosum, leprosy patients are prescribed non-steroidal anti-inflammatory and antirheumatic drugs in therapeutic dosages according to the instructions, with the aim of reducing and eliminating pain.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Medical rehabilitation of leprosy patients is a crucial part of the overall patient treatment.

Comments: general medical massage, upper limb medical massage, lower limb medical massage, mechanotherapy for peripheral nervous system diseases, and exercise therapy for peripheral nervous system diseases aim to increase muscle strength and the range of motion in limb joints. In the treatment of contractures, the effectiveness of these procedures increases when combined with preliminary paraffin therapy. the treatment course usually prescribes from 20 to 30 massage sessions. General contraindications for general medical massage, upper and lower limb medical massage, mechanotherapy for peripheral nervous system diseases, and exercise therapy for peripheral nervous system diseases include conditions and diseases for which physiotherapy methods are contraindicated.

Comments: prosthetics and orthotics are performed according to indications in specialized prosthetic and orthopedic institutions, with the development of an applied kinesotherapy rehabilitation program taking into account individual psychomotor ontogenesis. For patients with pronounced foot deformities, orthopedic shoes are custom-made.

Sanatorium-resort treatment is not indicated for leprosy patients due to the infectious nature of the disease. In accordance with Order of the Ministry of Health of the Russian Federation No. 216 dated April 29, 2015, "On approval of the list of medical contraindications due to the presence of which a citizen or recipient of social services may be denied, including temporarily, the provision of social services in an inpatient form, as well as the form of the conclusion of an authorized medical organization on the presence of such contraindications," leprosy (A30) is included in the List of medical contraindications due to the presence of which a citizen or recipient of social services may be denied, including temporarily, the provision of social services in an inpatient form.

5. Prevention and Dispensary Observation

Primary prevention aims at preventing the occurrence and development of leprosy in the population.

Comments: Currently, there is no vaccine against leprosy in the world. Evidence of the effectiveness of the #tuberculosis vaccine** for the prevention of leprosy is well known [149], but the magnitude of its effect has varied significantly [4, 143, 144].

Secondary prevention is a set of measures aimed at preventing the onset and development of the disease in individuals in contact with leprosy patients.

Comments: the risk of developing leprosy is increased in children under 14 years of age and in the elderly [224].

Tertiary prevention is a set of measures aimed at preventing exacerbations, relapses, and complications of the leprosy process.

Comments: dispensary follow-up of leprosy patients is carried out once a year for life [225]. During dispensary follow-up, a comprehensive examination of leprosy patients is performed to identify the high-risk group for disease relapse. Relapse cases have been described both shortly after the end of combination therapy and several decades later [162, 163]. At the same time, despite full antimycobacterial therapy, some patients experience relapses, even multiple ones, while others never do. This indicates the role of hereditary factors in the occurrence of disease relapses [168]. Along with non-adherence to therapy, one of the main factors contributing to the development of relapses in the leprosy process is the emergence of drug-resistant forms of M. leprae [171, 172]. To exclude drug resistance to rifampicin**, dapsone**, #ofloxacin**, a test system based on PCR with hybridization is used, which allows the detection of mutant M. leprae strains resistant to these drugs. Currently, using whole-genome sequencing of M. leprae, it has become possible to distinguish relapse cases from reinfection [169] and to determine mutations in M. leprae genes responsible for drug resistance [173]. If drug-resistant strains of M. leprae are identified, the use of second-line drugs is recommended.

Comments: the cause of most disabling complications of the leprosy process is damage to the peripheral nervous system, manifested by mono- and polyneuritis and trophic ulcers, which is associated with the long-term persistence of M. leprae in Schwann cells within nerves [185] and in trophic ulcers [177]. Treatment of these complications must be carried out in antileprosy institutions with the participation of neurologists. Early detection of complications of the leprosy process is possible using immunogenetic criteria [178]. Thus, it has been shown that the severe course of leprosy polyneuritis can be predicted with a high degree of probability by the presence of the HLA-DRB1-15-DQA1-0102-DQB1-0602/8 haplotype in the patient's genotype [179].

Comments: the patient should avoid skin trauma on the hands and feet; avoid hot objects, choose comfortable footwear (custom-made), perform muscle exercises, regularly moisturize palms and soles, and protect the eyes from dryness [179].

Comments: patients transferred to dispensary follow-up are examined once a year at dermatovenereological dispensaries. The need for long-term dispensary care is associated with the risk of relapse in leprosy, especially in the lepromatous type, which may be due to the persistence of viable M. leprae in the organs and tissues of the leprosy patient [183, 184], as well as irregular or insufficiently effective treatment. According to various estimates, the relapse rate is 0.65 to 3.0% for multibacillary forms of leprosy and 0.02 to 0.8% for paucibacillary leprosy [185]. The examination should include inspection of the skin and mucous membranes, assessment of temperature and tactile sensitivity, and microscopic examination of biopsy (surgical) material or punctate for acid-fast mycobacteria (Mycobacterium spp.) [69] to detect M. leprae.

Comments: upon the development of progressive complications of the leprosy process, patients, in addition to physiotherapeutic and general therapeutic procedures, must receive a course of specific antimycobacterial therapy under medical supervision, taking into account that M. leprae persist in internal organs and nerves, and the progression of complications may indicate their multiplication [175].

6. Organization of Medical Care

As part of the provision of primary medical and sanitary care, general practitioners, family physicians, neurologists, and surgeons, upon detecting characteristic skin rashes, thickening of affected peripheral nerves, impaired superficial sensitivity, or symptoms/signs of leprosy, refer the patient to a dermatovenereological medical organization to receive primary health care. If medical care cannot be provided within the framework of primary health care and there are medical indications, the patient is referred to a medical organization providing specialized medical care.

Specialized, including high-tech, medical care for leprosy patients is provided in specialized antileprosy medical organizations subordinate to the Russian Ministry of Health.

Control over the outpatient treatment of leprosy patients, dispensary follow-up of registered leprosy patients and their contacts, and the implementation of health education and preventive work are carried out by the dermatovenereologist of the dermatovenereological dispensaries responsible for antileprosy measures.

Treatment of comorbid somatic diseases in leprosy patients is carried out in medical institutions at the patient's place of residence.

Hospitalization and treatment of leprosy patients

Hospitalization in antileprosy institutions is subject to:

- all patients with a newly established diagnosis;

- patients discharged to dispensary follow-up upon the occurrence of a relapse or suspected relapse.

Discharge of patients from antileprosy institutions

Inpatient treatment is the first and main stage of medical rehabilitation for patients. After achieving clinical regression, patients may be discharged for outpatient treatment (if necessary) and/or dispensary follow-up.

Indications for patient discharge

Patients with lepromatous, borderline-lepromatous, or borderline leprosy are discharged when a partial or complete regression of rashes is achieved, along with negativity of bacterioscopic indicators of nasal mucosa scrapings, skin scarifications, and skin biopsies for 6 months (3 times). Histological examination of skin biopsies by the time of discharge should show regressive changes manifested by the replacement of the specific granuloma with a nonspecific infiltrate showing signs of tissue fibrosis; in polar lepromatous processes, a small number of vacuolated lipid-containing leprosy macrophages may be detected. The presence of solitary granular mycobacteria is permissible.

Patients with tuberculoid, borderline-tuberculoid, and indeterminate leprosy who are bacteriologically positive upon admission may be discharged for outpatient treatment after the disappearance of active disease manifestations and upon obtaining two consecutive negative bacteriological test results over the past 6 months.

Patients hospitalized for a leprosy relapse may be discharged after 6 months of bacteriological negativity, provided that the clinical manifestations of the disease have regressed.

Transfer to dispensary follow-up

Indications for transferring patients from outpatient treatment to dispensary follow-up include:

- absence of active leprosy manifestations on the skin over the past year;

- negative results of repeated bacteriological examinations of nasal mucosa scrapings and skin scarifications over the past 12 months (once every 3 months);

- presence of pronounced connective tissue fibrosis without leprosy bacilli in skin histological specimens at the site of specific infiltrates;

- stable condition of existing neurotrophic changes over the past 12 months (sensory disturbances, amyotrophy, contractures, paresis, etc.).

7. Additional Information

Risk factors for an unfavorable prognosis in leprosy include older age, late diagnosis [116], severe disease course, non-adherence to treatment, relapsing disease course, presence of hereditary predisposition factors to leprosy [186], and M. leprae resistance to antileprotic drugs [122].

Leprosy patients transferred to outpatient treatment have no restrictions in choosing a civilian profession based on epidemiological indications, but they are not recommended to engage in work related to direct service to children or in public catering establishments. When developing employment recommendations for outpatients, it is necessary to consider the presence of complications of the leprous process and facilitate employment in industries that exclude the possibility of injuries, burns, hypothermia, occupational hazards, and excessive physical exertion.

Severe neurotrophic complications of the leprous process are a factor that negatively affects the outcome of the disease, hindering the medical and social rehabilitation of leprosy patients [187].

Leprosy patients are indicated for a high-protein diet. Modification of the high-protein diet variant is possible depending on existing concomitant diseases (diabetes mellitus, hepatitis, etc.).

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Kubanov Alexey Alekseevich – Academician of the RAS, Doctor of Medical Sciences, Professor, Director of the State Research Center of Dermatovenereology and Cosmetology of the Russian Ministry of Health, President of the Russian Society of Dermatovenereologists and Cosmetologists.

2. Shelepova Tatyana Nikolaevna – Candidate of Medical Sciences, Member of the Russian Society of Dermatovenereologists and Cosmetologists.

3. Saroyants Lyudmila Valentinovna – Doctor of Medical Sciences, Member of the Russian Society of Dermatovenereologists and Cosmetologists.

4. Nabieva Antonina Ramazanovna – Candidate of Medical Sciences, Member of the Russian Society of Dermatovenereologists and Cosmetologists.

5. Shats Evgeny Ilyich – Candidate of Medical Sciences, Member of the Russian Society of Dermatovenereologists and Cosmetologists.

6. Yushin Mikhail Yurievich – Candidate of Medical Sciences, Member of the Russian Society of Dermatovenereologists and Cosmetologists.

7. Naumov Valentin Zakharovich – Candidate of Medical Sciences, Member of the Russian Society of Dermatovenereologists and Cosmetologists.

8. Lutsenko Anna Viktorovna – Candidate of Biological Sciences, Member of the Russian Society of Dermatovenereologists and Cosmetologists.

9. Plakhova Ksenia Ilyinichna – Doctor of Medical Sciences, Scientific Secretary, State Research Center of Dermatovenereology and Cosmetology of the Russian Ministry of Health, Member of the Russian Society of Dermatovenereologists and Cosmetologists. No conflict of interest.

10. Karamova Arfenya Eduardovna – Candidate of Medical Sciences, Head of the Department of Dermatology, State Research Center of Dermatovenereology and Cosmetology of the Russian Ministry of Health; Member of the Russian Society of Dermatovenereologists and Cosmetologists.

11. Chikin Vadim Viktorovich – Doctor of Medical Sciences, Senior Researcher at the Department of Dermatology, State Research Center of Dermatovenereology and Cosmetology of the Russian Ministry of Health; Member of the Russian Society of Dermatovenereologists and Cosmetologists.

Conflict of Interest: The authors declare no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Medical specialists: dermatovenereologist, general practitioner (family physician), neurologist.

2. Residents and trainees of continuing professional education cycles in the specified specialties.

Table 1. Levels of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2. Scale for grading levels of evidence (LoE) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, rehabilitative interventions)

Table 3. Scale for grading grades of recommendation (GoR) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, rehabilitation interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

These clinical guidelines were developed taking into account the following regulatory legal documents:

1. Order of the Ministry of Health of the Russian Federation No. 1681n dated December 29, 2012, "On Approval of the Standard of Specialized Medical Care for Leprosy, Active Stage".

Table A3.1 Differential diagnosis of leprosy.

Appendix B. Physician Action Algorithms

Appendix B1. Physician Action Algorithms

Appendix B2. Physician Action Algorithms (relapse of leprosy)

Appendix C. Patient Information

Specific anti-leprosy treatment requires regularity in taking combination therapy.

At the first signs of neurotrophic complications or exacerbation of the disease, it is necessary to promptly contact a leprosarium or a local dermatologist-venereologist.

Patients need to follow a high-protein diet during the acute period of the disease.

What you should know about leprosy (patient information leaflet):

Leprosy is a chronic infectious disease known to humanity since ancient times. The disease is still widespread in certain regions of the world (Southeast Asia, Africa, Latin America), and sporadic cases can occur in any country.

The disease mainly affects the skin, mucous membranes of the upper respiratory tract, peripheral nerves, and, if left untreated, involves the musculoskeletal system, eyes, and other organs, leading to severe disability. Leprosy is usually transmitted through prolonged contact with an infected person. The risk of infection increases with poor personal hygiene, unsatisfactory quality of life, increased population migration, and low sanitary culture. However, only a small fraction of the population develops the disease, which is explained by the presence of congenital immunity to this illness in most people.

It should be noted that leprosy usually begins insidiously, with an incubation period from infection to the appearance of the first signs averaging 2–4 years, and sometimes longer. The main initial signs of the disease are varied (non-painful, non-itching) skin patches with clear or unclear borders, loss of sensitivity (pain, temperature, and tactile), darkening and thickening of the skin on the face and extremities, and painful or thickened nerves. Sometimes patients complain of weakness, nosebleeds, a "crawling sensation" (paresthesia), or numbness in the extremities.

If you or your loved ones have any skin rashes, if you have developed dark or light patches on your skin with loss of sensitivity, if your facial features have changed, your hands are swelling, your joints are not working properly, if you do not feel burns or already have signs of paralysis and non-healing ulcers, you should urgently consult a physician, preferably a dermatologist-venereologist. Modern medicine has highly effective drugs for the treatment and rehabilitation of leprosy patients. Timely and adequate treatment ensures complete recovery and prevents disability.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Rating scales, questionnaires, and other assessment tools for evaluating the condition of patients with leprosy have not been developed.