RU2703313C1 - Method of treating disseminated lichen acuminatus associated with chronic granulomatous periodontitis - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to dermatology and can be used for treating the patients with common lichen acuminatus associated with chronic granulomatous periodontitis. For 4 weeks, systemic immunosuppressive therapy with hydroxychloroquine is administered orally 200 mg twice a day in courses of 5 days with two-day interruptions in a combination with external anti-inflammatory therapy of mometasone furoate 0.1 % in the form of ointment once a day on lesions for occlusion dressing. Simultaneously with drug therapy removal or resection of tops of teeth having signs of chronic granulomatous periodontitis is performed.

EFFECT: method enables prolonging remission and reducing the number of recurrences.

1 cl, 1 tbl, 3 ex

Description

The invention relates to medicine, namely to the field of dermatology, and can be used to treat common lichen planus associated with chronic granulomatous periodontitis (CGP).

Lichen planus is a non-contagious disease with a subacute or chronic course, affecting the skin and mucous membranes, clinically characterized by a rash of monomorphic itchy papular elements. The etiology of dermatosis is currently unknown. Various infectious agents, contact allergens, drugs, stress, endocrinopathies, diseases of the gastrointestinal tract, and insolation are considered as provoking factors. A certain role is played by a hereditary predisposition (Dermatovenerology: a textbook; edited by A.V. Samtsova, V.V. Barbinova. - M.: GEOTAR-Media, 2016. - 432 p.).

An additional factor that can worsen the course of skin diseases, including CPL, is the presence of foci of chronic infection (ACI) in the body. They stimulate the development of immunological reactions, using various mechanisms: molecular mimicry, the release of pro-inflammatory cytokines, and the release of bacterial exo- and endotoxins into the blood, some of which are superantigens and non-specifically activate T-lymphocytes (Patrushev A.V., Sukharev A.V., Ivanov AM, Samtsov A.V.The role of foci of infection in various skin diseases.Vestn. dermatol. And venereol. 2015; (5): 34-42). Therefore, measures aimed at the diagnosis and treatment of acute intestinal infections should be given due attention.

The basic theory of pathogenesis is to change epidermal antigens under the influence of viruses, drugs or allergens and activate cytotoxic CD8 ⁺ T cells. T-lymphocytes migrating into the skin damage the basal keratinocytes (trigger apoptosis) and lead to the development of an inflammatory reaction (Weston G., Payette M. Update on lichen planus and its clinical variants. Int. J. Womens. Dermatol. 2015; 1 (3) : 140-149).

There is a traditional treatment regulated by the professional community, which provides for the administration of systemic drugs for common forms of dermatosis (derivatives of aminoquinoline - chloroquine, hydroxychloroquine or corticosteroids - prednisolone, betamethasone) and external anti-inflammatory therapy in the form of topical glucocorticosteroids. In limited forms, only external therapy is indicated. A treatment option using physical factors is possible, namely various phototherapy options (narrow-band medium-wave therapy with a wavelength of 311 nm, PUVA therapy) (Olisova O.Yu., Chikin VV, Mineeva AA Red lichen plan. Federal clinical recommendations Dermatovenerology 2015: Skin diseases. Sexually transmitted infections. - M.: Delovoy express, 2016. - P. 212-226).

Improving the provision of medical care for patients with CPL went in several directions: the inclusion in the treatment regimen of immunomodulators, antimicrobials and drugs acting on the central nervous system (tranquilizers, nootropics).

Thus, there is a known method of treating patients with CPL, including the additional administration of an immunoregulatory preparation of immunofan intramuscularly in 1.0 ml doses with the active component arginine-alpha-aspartyl-lysyl-valyl-tyrosyl-arginine 50 μg every other day for 10 days (RF patent No. 2564907, A61K 38/08, A61K 38/32, A61P 37/02, publ. 10.10.2015). The scheme is applied with the inclusion of Panavir (intravenously 200 μg every other day in the amount of 5 injections), which is the original domestic drug that stimulates the production of interferon (RF patent No. 2367445, A61K 31/715, A61K 31/573, A61P 17/00, publ. September 20, 2009). A treatment method has been developed, including the appointment of an antiviral agent (0.2 g acyclovir five times a day for 7-10 days) and a neovir immunostimulating drug from day 1 to 2 ml intramuscularly every other day, for a course of treatment of 5-10 injections ( RF patent No. 2192250, А61К 31/19, А61Р 17/00, publ. 06/20/2002).

The treatment options are proposed when anxiolytic agents are administered against the background of the standard complex drug treatment: selank in the form of 0.15% nasal drops daily 2 drops in each nostril 3 times a day for 10 days (RF patent No. 2629601, A61K 38/08, A61P 17/04, publ. 08/30/2017); noofen in a dose of 250-500 mg, three times, after meals (RF patent No. 2627456, A61K 31/197, A61P 17/00, publ. 08.08.2017). In the second case, a course (6-12 procedures) of transcranial electrostimulation is also carried out, which has a synergistic autoregulatory and stress-protective effect.

Improving the effectiveness of physical methods is also associated with the appointment of immunocorrective drugs. A known method of treating CPL, including PUVA therapy using external photosensitizers, when against the background of PUVA baths, 5 injections of Panavir at a therapeutic dose of 200 μg every other day are administered simultaneously (RF patent No. 2443439, A61N 5/00, A61K 31/37, A61K 31/7028, A61P 17/00, published on 02.27.2012).

All the proposed methods can improve the effectiveness of therapy by reducing treatment time and increasing the period of remission. However, they have significant drawbacks: firstly, they do not solve the main problem - preventing or reducing the number of relapses of the disease, and secondly, there is the possibility of developing a number of side effects (allergic, hepatotoxic, disorders of the gastrointestinal tract, etc.) and thirdly, from the point of view of the modern concept of the pathogenesis of the disease (activation of certain parts of the immune system), the appointment of immunostimulants is not shown.

We carried out work to study the role of foci of chronic infection (ACI) on the development and course of immuno-mediated dermatoses, which showed that association with chronic granulomatous periodontitis (CGP) is a significant factor for CPL. CGP was diagnosed in 30.2% of patients, which is significantly higher than in the general population (Patrushev A.V., Samtsov A.V., Ivanov AM, Sukharev A.V., Asfendiarov D.D. The prevalence of foci of chronic infection in patients with T-cell-mediated dermatoses. Vestn. dermatol. and venereol. 2018. 94 (3): 30-38).

The basis of the invention is the creation of a method for the treatment of common lichen planus associated with chronic granulomatous periodontitis, using adequate systemic and external anti-inflammatory therapy in combination with radical rehabilitation of the focus of chronic infection, which would be effective, leading to prolonged clinical remission of the disease and reduce the number relapses.

The technical result is achieved in that the treatment of patients with lichen planus is carried out by the integrated use of the topical corticosteroid mometasone furoate 0.1% in the form of an ointment 1 time per day on the lesions under an occlusive dressing for 2 hours and the systemic drug hydroxychloroquine orally 200 mg 2 times per day in courses of 5 days with two-day intervals for 4 weeks, additional treatment of foci of odontogenic infection is carried out in the form of extraction or resection of the apices of the roots of problem teeth. The method allows to achieve a quick resolution of rashes (within 3-6 weeks), reduce the number of relapses and achieve long-term clinical remission.

Mometazone furoate is a synthetic non-fluorinated glucocorticosteroid for external use that has anti-inflammatory, antipruritic, epidermostatic effects (Russian Drug Register, 2018). The inclusion of a furoate ring in the molecule, significantly increased the duration of the drug and move to a more convenient treatment regimen (1 time per day). Mometazone furoate in comparison with other corticosteroids (hydrocortisone, prednisone, betamethasone) significantly inhibits the synthesis of such pro-inflammatory cytokines as interleukin-1 and 6. The use of recommended doses does not suppress the hypothalamic-pituitary-adrenal system (Sadykova D.A. Comparative assessment therapeutic efficacy of mometasone furoate (momezone-F) in patients with atopic dermatitis. Vestnik KSMA named after IK Akhunbaev. 2011. (2): 42-47).

Hydroxychloroquine is an antimalarial drug from the 4-aminoquinoline group with additional beneficial effects that are used in the treatment of lichen planus: immunosuppressive, anti-inflammatory, analgesic, antiplatelet, antimicrobial, antiproliferative and antioxidant (Lisitsyna T.A., Kosheleva N. therapy for systemic lupus erythematosus: past, present, future, modern rheumatology. 2010. 4 (2): 81-88.). Side effects when taking hydroxychloroquine are rare and, as a rule, are not severe. The most significant complications are changes in the eyes - clouding of the cornea and retinopathy. In this regard, before prescribing the drug and during treatment (1 time in 3 months), an ophthalmologist is required to consult (Rational pharmacotherapy of skin diseases and sexually transmitted infections, under the general editorship of A.A. Kubanova, V.I. Kisina, Moscow: Litter. 2005: 62-66).

Full-fledged rehabilitation of the focus of odontogenic infection in the form of chronic granulomatous periodontitis involves the removal or resection of the tops of the roots of problem teeth. Such an intervention eliminates the negative effect of OXI on the patient’s immune system, reduces the level of pro-inflammatory cytokines and normalizes the imbalance in the subpopulations of lymphocytes.

From the analysis of the scientific, technical and patent literature of the claimed combination of properties, leading to a significant increase in therapeutic effectiveness due to correction of the immune status, improvement of quality of life and reduction in the number of relapses of the disease, it is not revealed, which allows us to conclude that the claimed technical solution meets the criteria of "novelty" and inventive level. "

The method is as follows.

Patients with a common form of lichen planus, in which a preliminary examination suggests the presence of chronic granulomatous periodontitis (based on the performance of an orthopantomogram), undergoes a clinical, laboratory and instrumental examination in a specialized medical institution with the obligatory consultation of a dentist or maxillofacial surgeon to confirm the presence of a lesion odontogenic infection and receiving recommendations on the need for surgical treatment in lans order. During a clinical examination, indicators characterizing the severity of the course of dermatosis and the quality of life are necessarily determined.

The severity of dermatosis is assessed on the basis of a scale developed by us - the KPL severity index (ITKPL) or LPASI (Lichen Planus Area and Severity Index) (rationalization proposal No. 14400/5 of 11/09/2016, issued by the Military Medical Academy). When calculating this indicator, the following criteria are taken into account: the prevalence of the pathological process, the severity of clinical manifestations on the skin, the presence and severity of damage to the oral mucosa, the severity of subjective sensations (itching, soreness). The minimum value is 0 points, the maximum is 82 points. A mild severity of CPL is diagnosed with LPASI values of less than 10 points, medium - from 10 to 20 points, severe - more than 20 points.

The quality of life is determined using the Vitebsk Dermatosis Patient Questionnaire (VOBD), which is a list of questions characterizing the physical and psychosocial spheres, as well as the level of independence and social relations. The answer to each question is evaluated on a five-point scale: no - 0 points, rarely - 1 point, sometimes - 2 points, often - 3 points, always - 4 points. The maximum number of points (152) indicates the highest level of influence of skin disease on the patient's quality of life. The minimum number of points (0) is observed in healthy individuals.

From laboratory tests, general blood and urine tests, a biochemical blood test are performed, and the titer of antistreptolysin-O is determined. Instrumental examination methods include ultrasound examination of the thyroid gland, organs of the abdominal cavity and small pelvis, radiography of the paranasal sinuses to exclude concomitant pathology and other significant OXI. Consultation is being conducted by an ophthalmologist in order to resolve the issue of the possibility of prescribing hydroxychloroquine, consultation by an otolaryngologist to exclude ACh from the ENT organs.

At the first stage, systemic immunosuppressive therapy with hydroxychloroquine orally 200 mg 2 times a day and external anti-inflammatory therapy with mometasone furoat in the form of an ointment under an occlusive dressing are performed for 4 to 3 weeks. As an occlusive dressing, a conventional food-grade plastic film is used, which is fixed on top of the applied ointment for 2 hours. This method allows to increase the effectiveness of the topical preparation due to the full and deeper penetration of the active substance into the skin.

The second stage consists in the rehabilitation of the focus of odontogenic infection. Intervention can be carried out simultaneously with the treatment of CPL or after discharge from a dermatological hospital. The patient is referred to the dentist (maxillofacial surgeon), where a tooth (several teeth) is removed in a dental office. According to indications, the operation can be replaced by a resection of the tops of the roots of the teeth. In the future, the patient requires dynamic monitoring with a dermatologist examination once every 6 months.

Additionally, the immunological status of patients can be investigated before treatment and during follow-up after 12 weeks to assess the effectiveness of the treatment. Basic and narrowly targeted subpopulations of lymphocytes, cytokine profile (interleukins (IL) 1β, 2, 4, 6, 8, 10, interferons (INF) α and γ, tumor necrosis factor (TNF) α, circulating immune complexes (CEC), spectrum are determined immunoglobulins).

The proposed treatment method is easily reproducible, accessible and feasible in medical institutions.

We present clinical examples that demonstrate the capabilities of the proposed method of treatment.

Example 1. Patient T., 19 years old. Diagnosis: common lichen planus, typical form, moderate, acute stage. Concomitant diagnosis: chronic granulomatous periodontitis of 36 teeth. Sick for 1 month, the disease began with the appearance of rashes in the wrists, which gradually spread to the skin of the forearms, shoulders, lower limbs, trunk. He was hospitalized at the Clinic for Skin and Sexually Transmitted Diseases of the Military Medical Academy for examination and treatment in November 2016. On examination: skin lesions are widespread symmetrical in nature with localization in the trunk, upper and lower extremities, where against the background of a dry, flesh-colored color with preserved turgor skin, there are rashes in the form of polygonal flat miliary and lenticular papules of violet color with a navel-like impression in the center of the elements. The positive Kebner phenomenon is determined. Dermographism is red, unstable. The appendages of the skin are not changed. LPASI index - 20 points, VOBD - 7 points.

According to the results of the examinations: general blood and urine tests, a biochemical blood test (glucose, ALT, ACT, total bilirubin, creatinine, total protein) without pathology. The titer of antistreptolysin-O is normal - 101 IU / ml (reference range 0-200 IU / ml). Immunological parameters: increase in the relative number of NK cells (CD3 ^- CD56 ⁺ ) - 20.3% (reference range - 8-18%), increase in the level of TNF-α - 11 pg / ml (reference range - 0-6 pg / ml ) and IL-8 - 34 pg / ml (reference range - 0-10 pg / ml), immunoglobulins A, G and M, CEC were within normal limits. Ultrasound of the thyroid gland, abdominal organs and small pelvis - without pathology. Radiography of the sinuses - no pathology. Orthopantomogram - granuloma at the root of 36 tooth is determined.

The patient underwent the following treatment: in a dermatological hospital (16 days) - oral therapy with hydroxychloroquine 200 mg 2 times a day for 5 days with two-day breaks, external therapy of mometasone with furoat 0.1% in the form of an ointment 1 time per day for lesions under occlusive dressing for 2 hours. The patient was discharged with improvement and recommendations to continue the prescribed therapy for another 12 days, as well as the need for sanitation of the focus of odontogenic infection in a planned manner. 7 days after discharge in a dental clinic, 36 teeth were removed.

Control examinations showed the following results: after 4 weeks, the LPASI index decreased to 5.2 points; after 12 weeks, the LPASI index was 0 points (rashes were completely resolved), immunological parameters were normalized - the relative number of NK cells was 15.8% o, the level of TNF-α was 5 pg / ml, IL-8 was 7 pg / ml; after 1 year, rashes were absent (LPASI index = 0 points, no recurrence of dermatosis), IAP = 2 points (quality of life improved more than 3 times).

Example 2. Patient K., 20 years old. Diagnosis: common lichen planus, typical form, moderate, acute stage. Concomitant diagnosis: chronic granulomatous periodontitis 21, 11 teeth. Deep caries 38 tooth. Sick for 1 month, the disease began with the appearance of rashes in the penis, which gradually spread to the skin of the forearms, shoulders, hips. He was hospitalized at the Clinic for Skin and Sexually Transmitted Diseases of the Military Medical Academy for examination and treatment in October 2017. On examination: skin lesions are common with localization in the head and body of the penis, inner surface of the forearms, shoulders, hips, where the background is dry , flesh-colored with preserved skin turgor, there are rashes in the form of polygonal flat miliary and lenticular papules of violet color with a central umbilical depression. The positive Kebner phenomenon is determined. Dermographism is red, unstable. The appendages of the skin are not changed. LPASI Index - 10.2 points; VOBD - 8 points.

According to the results of the examinations: general blood and urine tests, a biochemical blood test (glucose, ALT, ACT, total bilirubin, creatinine, total protein) without pathology. The titer of antistreptolysin-O is normal - 94 IU / ml (reference range 0-200 IU / ml). Immunological indicators: signs of activation of cytotoxic T-lymphocytes (CD3 ⁺ CD8 ⁺ ) were detected, characterized by an increase in their relative number - 38.5% (reference range - 20-30%), an increase in the number of T cells with expression of markers of natural killers was also noted ( CD3 ⁺ CD16 ⁺ CD56 ⁺ ) - 14.0% (reference range - 1.7-8.6%), imbalance in the content of the main subpopulations of T cells (CD3 ⁺ CD4 ⁺ / CD3 ⁺ CD8 ⁺ = 0.86 at normal from 1.2 to 2.5), an increase in the level of TNF-α is 13 pg / ml (reference range is 0-6 pg / ml) and IL-8 is 27 pg / ml (reference range is 0-10 pg / ml ), immunoglobulins A, G and M, the CEC were within normal limits. Ultrasound of the thyroid gland, abdominal organs and small pelvis - without pathology. Radiography of the sinuses - no pathology. Orthopantomogram - granuloma at the root of the 11th tooth is determined, the periodontal gap at the root of the 21st tooth is expanded, the defect of the crown of the 38th tooth.

The patient underwent the following treatment: in a dermatological hospital (11 days) - oral therapy with hydroxychloroquine 200 mg 2 times a day for 5 days with two-day breaks, external therapy of mometasone with furoat 0.1% in the form of an ointment 1 time per day for lesions under occlusive dressing for 2 hours. The patient was discharged with improvement and recommendations to continue the prescribed therapy for another 17 days, as well as the need for sanitation of the focus of stomatogenic infection in a planned manner. 10 days after discharge in the conditions of the Department of Maxillofacial Surgery, resection of the apices of the roots of 11.21 teeth and removal of 38 teeth was performed.

Control examinations showed the following results: after 4 weeks, the LPASI index decreased to 6.1 points; after 12 weeks, the LPASI index was 0 points (rashes were completely resolved), immunological parameters returned to normal - the relative number of cytotoxic T cells was 27.4% o, T cells with expression of natural killer markers 7.2%, the ratio CD3 ⁺ CD4 ⁺ / CD3 ⁺ CD8 ⁺ = 1.4, the level of TNF-α is 4 pg / ml, IL-8 -9 pg / ml; after 1 year there were no rashes (LPASI index = 0 points, no recurrence of dermatosis), IOBI = 1 point (quality of life improved 8 times).

Example 3. Patient A., 63 years old. Diagnosis: common lichen planus, typical form, severe course, acute stage. Concomitant diagnosis: chronic granulomatous periodontitis of 43 teeth. Sick for 1 year, there were 2 exacerbations of the disease, fresh rashes appeared 10 days ago. She was hospitalized at the clinic of skin and venereal diseases of the Military Medical Academy for examination and treatment in March 2018. On examination: skin lesions are common with localization in the forehead, scalp, trunk, upper and lower extremities, where the background is dry, flesh-colored with preserved skin turgor, there are rashes in the form of polygonal flat miliary and lenticular papules of violet color with a central umbilical depression. The positive Kebner phenomenon is determined. Dermographism is red, unstable. The appendages of the skin are not changed. LPASI Index - 32 points; VOBD - 31 points.

According to the results of the examinations: general blood and urine tests, a biochemical blood test (glucose, ALT, ACT, total bilirubin, creatinine, total protein) without pathology. The titer of antistreptolysin-O is normal - 69 IU / ml (reference range 0-200 IU / ml). Immunological parameters: activated T-lymphocytes (CD3 ⁺ HLA-DR ⁺ ) are significantly increased - 28.7% (reference range - 1.3-10%) and T-lymphocytes expressing the IL-2 receptor α-chain - 20.6 % (reference range - 3.3-12.5%)), an increase in the level of TNF-α - 18 pg / ml (reference range - 0-6 pg / ml), INF-α - 6 pg / ml (reference range - 0-5 pg / ml) and IL-8 - 63 pg / ml (reference range - 0-10 pg / ml), immunoglobulins A, G and M, CEC were within normal limits. Ultrasound of the thyroid gland, abdominal organs and small pelvis - without pathology. Radiography of the sinuses - no pathology. Orthopantomogram - granuloma at the root of the 43 tooth is determined.

The patient underwent the following treatment: in a dermatological hospital (10 days) - oral therapy with hydroxychloroquine 200 mg 2 times a day for 5 days with two-day intervals, external therapy with mometasone furoat 0.1% in the form of an ointment 1 time per day for lesions under occlusive dressing for 2 hours. The patient was discharged with improvement and recommendations to continue the prescribed therapy for another 18 days, as well as the need for sanitation of the focus of stomatogenic infection in a planned manner. 14 days after discharge in a dental clinic, 43 teeth were removed.

Control examinations showed the following results: after 4 weeks, the LPASI index decreased to 13 points; after 12 weeks, the LPASI index was 0 points (rashes were completely resolved), immunological parameters returned to normal - activated T-lymphocytes (CD3 ⁺ HLA-DR ⁺ ) - 9.7%, T-lymphocytes expressing the α-chain of IL-2 receptor - 10 , 2%, the level of TNF-α - 5 pg / ml, INF-α - 3 pg / ml, IL-8 - 4 pg / ml; after 1 year, rashes were absent (LPASI index = 0 points, no recurrence of dermatosis), IAP = 10 points (quality of life improved more than 3 times).

The indicated scheme was used in the treatment of 12 patients with common lichen planus associated with chronic granulomatous periodontitis. Comparison group (11 people) - patients who received traditional therapy without sanitizing the focus of stomatogenic infection. Comparative data of the methods according to the invention and the prototype (traditional treatment) are shown in table 1.

As can be seen from the table, the proposed treatment option allows to increase the duration of remission and reduce the number of relapses of the disease, which is accompanied by a significant increase in the quality of life of patients.

Claims (1)

A method of treating common lichen planus associated with chronic granulomatous periodontitis, characterized in that during exacerbation in the conditions of the dermatological department, adequate immunosuppressive therapy with hydroxychloroquine is administered orally 200 mg 2 times a day for 5 days with two-day breaks for 4 weeks in combination with external anti-inflammatory therapy of mometasone furoat 0.1% in the form of an ointment 1 time per day on the lesions under an occlusive dressing; simultaneously with the prescribed treatment, the removal or resection of the apices of the roots of the teeth with signs of chronic granulomatous periodontitis is carried out in a planned manner.