RU2806053C2 - Method for combination therapy of rosacea - Google Patents

Abstract

FIELD: dermatovenereology; physiotherapy; cosmetology.

SUBSTANCE: used to treat rosacea. The drug minocycline is taken at a dosage of 50 mg per day from 8 to 12 weeks with mild and moderate severity, 100 mg per day for 14 days with a further transition to 50 mg per day for up to 10 weeks in severe forms. At the same time, an external preparation is used: for the erythematous form - 0.5% brimonidine tartrate, for the papulo-pustular form - 1% ivermectin cream. Then, after stopping the acute inflammatory skin process, a physiotherapeutic effect on the area of telangiectasias is carried out with a neodymium laser with a wavelength of 1064 μm, 1 pulse of 8 ms, with a fluence of 100-120 J/cm², spot diameter is 2.5 mm. Next, IPL exposure is carried out with a course of 3-4 procedures on the area of residual vascular changes with the first passage of two pulses with a wavelength of 560 μm, the first pulse is 3.5 ms with a fluence of 11 J/cm² and the second pulse is 4.5 ms with a fluence of 8 J/cm², with a cooling period of 30 ms, the second pass with the contact of the cooling light guide with the skin, with a wavelength of 515 μm, 1 pulse, duration of 4 ms, with a fluence of 14-15 J/cm².

EFFECT: method allows to correct aesthetic defects, improve skin quality, reduce the frequency of relapses, prolongs the period of remission, allows for an individual approach to therapy depending on the clinical form and severity of the disease, while reducing its duration and increasing the efficiency and safety, due to the combination of methods of the claimed inventions.

1 cl, 4 dwg, 8 tbl, 4 ex

Description

The present invention relates to the field of medicine, in particular to dermatology, cosmetology, physiotherapy, and can be used in dermatological and venereal disease clinics, in medical organizations that have a physiotherapeutic, dermatological department in their structure, in specialized departments of dermatological and cosmetology institutions.

Currently, the main difficulties in the treatment of rosacea are the limited possibilities of using combined treatment regimens, the implementation of a personalized approach taking into account the diversity of clinical manifestations, since to date no optimal treatment algorithms have been found for the treatment of various forms of rosacea. Creating an individual algorithm for the treatment of rosacea is a serious medical and socially significant task due to the prevalence of this disease among other dermatoses, the torpidity of the pathological process to therapy, a significant decrease in the quality of life of patients due to the chronic, recurrent course of the disease and the aesthetic imperfections of the facial skin accompanying this process.

Rosacea (acne rosacea, gutta rosacea, erythrosis facialis, cuperosis) is a chronic, recurrent disease, mainly of the facial skin, based on a different etiological nature and characterized by a staged course [Rosacea. Etiology, clinical picture, therapy. N.N. Potekaev. M-SPb. "Binom Publishing", "Nevsky Dialect", 2000]. Based on its clinical features, the variety of clinical forms from transient erythema to severe papulopustular, conglobate and phymatous manifestations, as well as the important role of trigger factors in the etiology of rosacea, we can draw conclusions about the complex multifactorial genesis of this disease with the participation of various regulatory systems. Despite the fact that in recent years many studies have shed new light on the pathophysiology of rosacea, there is no clear and accurate data on the interaction of the immune, vascular, and nervous systems in the formation of this inflammatory disease of the facial skin [New insights into rosacea pathophysiology: a review of recent findings. Martin Steinhoff, Jurgen Schauber, James J Leyden. J Am Acad Dermatol. Dec 2013; 69(6 Suppl 1): S15-26. doi: 10.1016/j.jaad.2013.04.045.]. The main key links in triggering the cascade of inflammatory reactions in rosacea are known: a violation in the innate and adaptive immune system, a violation of the skin barrier, where exogenous trigger factors play an important role, as well as neurovascular dysregulation, since in essence rosacea is an angiotrophoneurosis in the zone of innervation of the trigeminal nerve [ Rosacea: Molecular Mechanisms and Management of a Chronic Cutaneous Inflammatory Condition. Yu Ri Woo, Ji Hong Lim, Dae Ho Cho and Hyun Jeong Park. Int J Mol Sci. 2016 Sep 15; 17(9). New insights into rosacea pathophysiology: a review of recent findings. Steinhoff M., Schauber J., Leyden J.J. J. Am. Acad. Dermatol. 2013. Vol. 69. No. 6. Suppl. 1. P. S15-26].

Modern approaches to the treatment of rosacea are based on local treatment in mild stages of the pathological process and systemic treatment of moderate and severe forms. Traditionally, three groups of drugs are used for the systemic treatment of severe forms of rosacea: antibiotics (most often tetracycline), antiparasitic imidazole derivatives (metronidazole, ornidazole, etc.) and retinoids. A widely used regimen for the treatment of moderate and severe forms of rosacea is isotretinoin in low dosages, from 0.2 to 0.4 mg per kg of body weight per day, depending on the severity of clinical manifestations, the duration of therapy is at least 4-6 months. The principle of action of systemic retinoids is based on reducing the expression of pathogen-associated receptors (TLRs) and disorganizing the functioning of the pilosebaceous follicles [Emerging therapies in rosacea. Layton A., Thiboutot D. J. Am. Acad. Dermatol. 2013. Vol. 69. No. 6. Suppl. 1. P. S57-65. 18. Diagnosis and treatment of rosacea: state of the art. Baldwin H.E. J. Drugs. Dermatol. 2012. Vol. 11. No. 6. P. 725-730., New insights in the pathogenesis and treatment of rosacea. Palatsi R., Kelha'la" H.-L., Ha"gg P. Duodecim 2012; 128: 2327–2335].

Tetracycline antibiotics are still considered the most effective antibacterial drugs in the treatment of rosacea. These drugs inhibit angiogenesis, reduce the production of inflammatory cytokines and nitric oxide, suppress neutrophil chemotaxis, and inhibit the activation of proteolytic enzymes - metalloproteases MMP-2 and MMP-9 [Parish, L.C. Acne rosacea and Helicobacter pylori betrothed /L.C. Parish, J.A. Witkowski // Int J Dermatol. - 1995. - Vol 34. - No. 4. - P. 237-238]. The starting dose of doxycycline varies from 200 mg to 100 mg per day. Treatment is usually long-term, up to 12 weeks [Parish, L.C. Acne rosacea and Helicobacter pylori betrothed /L.C. Parish, J.A. Witkowski // Int J Dermatol. - 1995. - Vol 34. - No. 4. - P. 237-238. Gupta, A.K. Rosacea and its management: an overview / A.K. Gupta, M.M. Chaudhry // J Eur Acad Dermatol Venereol. - 2005. - Vol. 19. - P. 273-285]. A widely used scheme is the long-term use of “subantibiotic doses” of doxycycline, the principle of which is to prescribe the drug from 40 to 100 mg per day for 6-12 weeks. Such doses of the drug have an anti-inflammatory effect, in particular, by inhibiting the enzymes of the protease system. The effectiveness of the use of “anti-inflammatory doses” of doxycycline for rosacea has been shown in separate studies [Valentin S, Morales A, Sanchez J, Abimael R. Safety and efficacy of doxycycline in the treatment of rosacea // Clin Cosmet Investig Dermatol. 2009; 2: 129-140. Del Rosso JQ. Anti-inflamatory dose doxycycline in the treatment of rosacea // Journal of Drugs in Dermatology: JDD, 01 Jul 2009, 8(7):664-668].

An alternative drug for treating rosacea is minocycline. A large randomized study compared the effectiveness of minocycline 100 mg and doxycycline 40 mg. The study found that minocycline 100 mg was noninferior to doxycycline 40 mg in effectiveness over a 16-week treatment period. RosaQoL and PaGA follow-up showed that minocycline was superior to doxycycline in providing statistically significant clinical improvement in patients with severe rosacea, and that treatment with minocycline 100 mg resulted in longer-lasting remission. This study found no significant differences in the safety of these drugs, however, based on the literature, minocycline has a lower risk-benefit ratio than doxycycline [Clinical Trials. DOMINO, doxycycline 40 mg vs. minocycline 100 mg in the treatment of rosacea: a randomized, single-blinded, noninferiority trial, comparing efficacy and safety. M.M.D. van der Linden A.R. van Ratingen D.C. van Rappard S.A. Nieuwenburg Ph.I. Spuls. British Journal of Dermatology Volumel76, Issued. June 2017. Pages 1465-1474]. Other studies have shown good efficacy of a new form of extended-release minocycline at a dosage of 45 mg in combination with topical treatment with azelaic acid [Efficacy of extended-release 45 mg oral minocycline and extended-release 45 mg oral minocycline plus 15% azelaic acid in the treatment of acne rosacea . Jackson JM, Kircik LH, Lorenz DJ. Journal of Drugs in Dermatology: JDD, 01 Mar 2013, 12(3):292-298 PMID: 23545911]. There is evidence that systemic therapy with minocycline leads to a significant reduction in erythema, normalization of seboregulation, skin pH levels and the degree of hydration in patients with rosacea [Epidermal hydration levels in patients with rosacea improve after minocycline therapy. S. Ni Raghallaigh F.C. Powell. British Journal of Dermatology. Volumel71, Issue2. August 2014. Pages 259-266]. A little later, data appeared on the external form of minocycline in the form of foam, the results of which in patients with severe papulopustular rosacea turned out to be effective, allowing one to achieve the results of “clear” and “almost clear skin” according to IGA. The drug has shown good tolerability, safety and ease of use, which creates high treatment compliance in patients [A Phase II, Randomized, Double-Blind Clinical Study Evaluating the Safety, Tolerability, and Efficacy of a Topical Minocycline Foam, FMX103, for the Treatment of Facial Papulopustular Rosacea. Ulrich Mrowietz, Tai Hetzroni Kedem, Rita Keynan, Meir Eini, Dov Tamarkin, Dror Rom & Mitchell Shirvan. American Journal of Clinical Dermatology volume 19, pages 427-436(2018)].

Given current research data on efficacy and good tolerability, minocycline is a promising drug for the treatment of severe forms of rosacea, however, further research is required on the use of minocycline in various forms of rosacea in large samples of patients to better understand the effect of the drug on the pathophysiological aspects of rosacea and its benefits in prolonging period of remission of this dermatosis.

Among topical drugs, 1% ivermectin cream and 0.5% brimonidine tartrate gel have shown their advantage in many studies. Ivermectin belongs to the avermectin group, which exerts anti-inflammatory effects by suppressing the production of proinflammatory cytokines induced by lipopolysaccharides. Ivermectin also acts against Demodex folliculorum mites primarily through selective binding and high affinity to 5 glutamate-regulated chloride channels found in invertebrate nerve and muscle cells. The efficacy and safety of ivermectin 1% cream, administered once daily, was studied in patients with moderate to severe papulopustular rosacea aged 18 years or older in two multicenter, randomized, placebo-controlled, double-blind, 12-week studies. research in the USA and Canada. The effectiveness of using 1% ivermectin cream once a day in comparison with 15% azelaic acid gel when used twice a day has also been shown. Study results showed a statistically significant superiority of ivermectin 1% cream over placebo in terms of efficacy and continuous clinical improvement with long-term use of ivermectin 1% cream (for 40 weeks), as well as a favorable safety profile of ivermectin 1% cream over 52 weeks of rosacea treatment. There was also a statistically significant superiority of ivermectin cream 1% once daily compared to metronidazole cream 0.75% twice daily in 962 patients aged 18 years and older with moderate to severe papulopustular rosacea. . When prolonging the study, patients achieved a statistically significant longer remission with topical use of ivermectin compared to metronidazole [Efficacy and safety of ivermectin 1% cream in treatment of papulopustular rosacea: results of two randomized, double-blind, vehicle-controlled pivotal studies. Stein L, Kircik L, Fowler J, Tan J et al. Journal of Drugs in Dermatology : JDD 2014, 13(3):316- 323. Superiority of ivermectin 1% cream over metronidazole 0-75% cream in treating inflammatory lesions of rosacea: a randomized, investigator-blinded trial. Taieb Al, Ortonne JP, Ruzicka T, Roszkiewicz J, Berth-Jones J, Peirone MH, Jacovella J; Ivermectin Phase III study group. Br J Dermatol. 2015 Apr; 172(4):1103-10. doi: 10.111 l/bjd.13408. Epub 2015 Feb 11. Long-term safety of ivermectin 1% cream vs azelaic acid 15% gel in treating inflammatory lesions of rosacea: results of two 40-week controlled, investigator-blinded trials. Stein Gold L, Kircik L, Fowler J, Jackson JM, Tan J, Draelos Z, Fleischer A, Appell M, Steinhoff M, Lynde C, Sugarman J, Liu H, Jacovella J, Ivermectin Phase 3 Study Group Journal of Drugs in Dermatology 2014, 13(11):1380-1386].

Brimonidine tartrate is a highly selective alpha2-adrenergic receptor agonist. The principle of action of this drug is to reduce erythema due to direct vasoconstriction of the blood vessels of the dermis. In two identical multicenter, randomized, double-blind, placebo-controlled phase III studies conducted in the United States and Canada, brimonidine tartrate 0.5% gel demonstrated efficacy significantly superior to that of placebo in adult patients with erythematous and erythematous papular rosacea. In an open-label, multicenter, phase III study conducted in the United States in 449 patients with moderate to severe facial erythema, brimonidine tartrate 0.5% gel was effective in long-term treatment of patients for 12 months with an acceptable safety profile. It should be noted that data from clinical studies show that the use of 0.5% brimonidine tartrate gel induces a decrease in the intensity of erythema after 30 minutes with the maximum effect achieved after approximately 3 hours and the duration of the maximum decrease in the intensity of erythema for approximately 6 hours after a single dose of the drug [ Efficacy and safety of once-daily topical brimonidine tartrate gel 0.5% for the treatment of moderate to severe facial erythema of rosacea: results of two randomized, double-blind, and vehicle-controlled pivotal studies. Fowler J Jr, Jackson M, Moore A, Jarratt M, Jones T et al. Journal of Drugs in Dermatology 2013,12(6):650-656. Once-daily topical brimonidine tartrate gel 0-5% is a novel treatment for moderate to severe facial erythema of rosacea: results of two multicentre, randomized and vehicle-controlled studies Fowler, J., Jarratt, M. Moore, A., Meadows , K., Pollack, A., Steinhoff, M., Liu, Y., Leoni, M. and on behalf of the Brimonidine Phase II Study Group (2012). British Journal of Dermatology, 166: 633-641. Brimonidine gel 0.33% rapidly improves patient-reported outcomes by controlling facial erythema of rosacea: a randomized, double-blind, vehicle-controlled study. Layton, A.M., Schaller, M., Homey, B., Hofmann, M.A., Bewley, A.P., Lehmann, P., Nohlgard, C., Sarwer, D.B., Kerrouche, N. and Ma, Y.M. J Eur Acad Dermatol Venereol, 2015. 29: 2405-2410].

It is worth noting that the disadvantage of both systemic treatment and external therapy, and often their combination, is the lack of effectiveness in relation to significant aesthetic defects of the skin both in the acute inflammatory period and after relief of inflammatory manifestations, as well as an unpredictable period of remission. Even after effective treatment with systemic and external drugs, telangiectasias remain on the facial skin of patients; facial erythema of a transient or persistent nature, as well as post-inflammatory phenomena, may persist. According to survey data in numerous studies, about half of patients with rosacea note a significant decrease in quality of life precisely due to the characteristic localization of rashes on the skin of the face, on a “cosmetically significant” area of the skin. Moreover, the severity of depressive symptoms in most cases correlates with the number of aesthetic defects and the area of skin lesions [Gupta MA, Gupta AK, Chen SJ, et al. Comorbidity of rosacea and depression: an analysis of the National Ambulatory Medical Care Survey and National Hospital Ambulatory Care Survey - Outpatient Department data collected by the U.S. National Center for Health Statistics from 1995 to 2002. Br J Dermatol. 2005;153(6):l 176-1181]. Therefore, these treatments may not have a significant impact on the quality of life of patients with rosacea.

Considering this, much attention is currently paid to hardware methods for treating rosacea. An important advantage of device-based treatments for rosacea is that therapeutic and cosmetic effects are usually observed within a limited number of treatment sessions, which contrasts with the need for daily treatment with topical and oral agents for long periods of time. After achieving the final clinical result of treatment, remission can persist for several years. Concurrent drug therapy is often used as maintenance therapy [Update on the Management of Rosacea from the American Acne & Rosacea Society (AARS). James Q. Del Rosso, DO, FAOCD, FAAD et all. J Clin Aesthet Dermatol. 2019 Jun; 12(6): 17-24]. Pulsed dye laser (PDL) is widely used to treat telangiectasia and facial erythema. Later generations of PDL have a new pulse format that greatly reduces the vascular hematomas often seen after treatment with earlier versions of PDL. Providing high effectiveness in treating telangiectasia and facial erythema in rosacea, this laser continues to remain relevant in the treatment of rosacea [Update on the Management of Rosacea from the American Acne & Rosacea Society (AARS). James Q. Del Rosso, DO, FAOCD, FAAD et all. J Clin Aesthet Dermatol. 2019 Jun; 12(6): 17- 24. Flash lamp pumped dye laser for rosacea-associated telangiectasia and erythema. Lowe NJ, Behr KL, Fitzpatrick R, Goldman M, Ruiz-Esparza J.J Dermatol Surg Oncol. 1991 Jun; 17(6):522-5.].

Broadband pulsed light (IPL) machines have also been used successfully to treat both facial erythema and facial dilation associated with rosacea [Update on the Management of Rosacea from the American Acne & Rosacea Society (AARS). James Q. Del Rosso, DO, FAOCD, FAAD et all. J Clin Aesthet Dermatol. 2019 Jun; 12(6): 17-24. Effective treatment of rosacea using intense pulsed light systems. Schroeter CA, Haaf-von Below S, Neumann HA. Dermatol Surg. 2005 Oct; 31 (10): 1285-9.]. Studies have shown comparable effectiveness of the updated PDL and IPL devices. Both led to a significant reduction in the clinical manifestations of rosacea, such as erythema and telangiectasia, while being safe. There were no significant differences between PDL and IPL treatments, so these devices can be effectively used in the treatment of rosacea [Comparative efficacy of nonpurpuragenic pulsed dye laser and intense pulsed light for erythematotelangiectatic rosacea. Isaac M Neuhaus 1, Lee T Zane, Whitney D Tope. Randomized Controlled Trial. Dermatol Surg. 2009 Jun;35(6):920-8.].

Early studies with long-pulse 532-nm neodymium-doped yttrium aluminum garnet (Nd:YAG) lasers showed effectiveness in treating telangiectasia [Long pulse 532-nm laser treatment of facial telangiectasia. Adrian RM, Tanghetti EA. Dermatol Surg. 1998 Jan; 24(1):71-4]. More recent studies using a more powerful 532 nm laser have shown excellent results in the treatment of telangiectasias and diffuse erythema in patients with rosacea, which were comparable to the results obtained with the PDL device [A split-face comparison study of pulsed 532 -nm KTP laser and 595-nm pulsed dye laser in the treatment of facial telangiectasias and diffuse telangiectatic facial erythema. Uebelhoer NS, Bogle MA, Stewart B, Arndt KA, Dover JS. Dermatol Surg. 2007 Apr; 33(4):441-8.].

It is important that the use of lasers, IPL and PDL devices showed excellent results in the treatment of telangiectasia compared with the results achieved with drug treatment of diffuse facial erythema in rosacea [The pulsed-dye laser for treatment of cutaneous conditions. Bernstein EF G Itai Dermatol Venereol. 2009 Oct; 144(5):557-72].

Laser technologies have already won a significant niche in the correction of aesthetic imperfections on the facial skin in patients with rosacea, however, there is no reliable data on the effect of hardware techniques on pathophysiological processes, therefore, at the moment, laser technologies are mainly used after a course of treatment with systemic or external drugs, in post-inflammatory conditions period.

Combination therapy is a common treatment option for rosacea and has become the preferred treatment option for patients with varying clinical manifestations of moderate to severe papulopustular and erythematous rosacea. When targeting multiple disease symptoms simultaneously, combination therapy may be preferable to monotherapy [E.J. van Zuuren, Z. Fedorowicz, V. Carter, et al. Interventions for rosacea Cochrane Database Syst Rev, 4 (2015), p. CD003262].

The effectiveness of combination therapy with topical ivermectin 1% and systemic modified-release doxycycline 40 mg in 273 patients with severe rosacea was demonstrated in a phase 3b/4 randomized trial. The combined use of ivermectin and doxycycline demonstrated superior efficacy in reducing inflammation (80.3%) compared with 1% topical ivermectin monotherapy (73.6%). Because doxycycline and ivermectin may have different or common molecular targets in the inflammatory cascade in rosacea, it is known that their combined use can lead to improved treatment efficacy and optimize clinical outcomes [M. Steinhoff, M. Vocanson, J.J. Voegel, et al. Topical ivermectin 10 mg/g and oral doxycycline 40 mg modified-release: current evidence on the complementary use of anti-inflammatory rosacea treatments. Adv Ther, 33 (9) (2016), pp. 1481-1501].

Currently, much attention is paid to the study of the combined use of external and systemic drugs with laser and light technologies. A study on mice demonstrated the effectiveness of combined local anti-inflammatory and laser treatments. When the LL-37 peptide was introduced into the skin of mice, a sharp dilation and congestion of blood vessels of both the arterial and venous links developed, the integrity of the walls of microvasculature vessels in the dermis and hypodermis was disrupted, as a result of which multiple small hemorrhages were detected in the tissues. Having thus induced rosacea-like dermatitis, a scheme of combined local anti-inflammatory and laser effects was used (Ivermectin cream 1% after each injection of the peptide, 60 hours after the first injection, treatment was carried out on a PDL device with a wavelength of 595 nm), resulting in infiltration of dermal leukocytes and hypodermis decreased, endothelial dysfunction was observed in the dermis. The authors concluded that the proposed combined effect, taking into account the morphological picture, is promising and requires additional study in patients with rosacea without the use of invasive research methods [Evaluation of the effect of the combined effect of local anti-inflammatory therapy (Ivermectin) and pulsed dye laser (595 nm ) on LL-37-initiated rosacea-like inflammation in mice. E. N. Glagoleva, D. R. Fayzullina, G. A. Plisko, E. G. Sukhorukova, G. Yu. Yukina, E. R. Arabian, E. V. Sokolovsky, N. N. Petrishchev “Regional blood circulation and microcirculation" Vol. 19, No. 2 (2020)]. Thus, in a randomized comparative study of the effectiveness and safety of the use of pulsed dye laser (585 nm PDL) and its combination with topical ivermectin 1% in the treatment of rosacea, the greater effectiveness of the combined treatment regimen was demonstrated in comparison with motor therapy. More significant clinical improvements in the dermoscopic picture and clinical assessment of the severity of the skin process were observed in 15 patients in the group that received 4 times the application of 585 nm PDL with an interval of 4 weeks against the background of topical application of 1% ivermectin cream [Pulsed dye laser alone versus its combination with topical ivermectin 1% in treatment of Rosacea: a randomized comparative study. Mai Abdelraouf Osman, Hisham A. Shokeir, Arwa Mohamed Hassan & Marwa Atef Khalifa Received 28 Jan 2020, Accepted 22 Feb 2020, Accepted author version posted online: 06 Mar 2020, Published online: 12 Mar 2020].

Having analyzed the current methods of combined treatment of rosacea, we can conclude that there is no optimal treatment method aimed at relieving both inflammatory and non-inflammatory, but aesthetically significant manifestations on the facial skin of patients with rosacea. Existing methods do not take into account the clinical features of rosacea forms and do not have correction options depending on the individual characteristics of the course of dermatosis. Based on the results of these studies, combinations of systemic, external and hardware therapy for rosacea open up new prospects in creating an optimal treatment algorithm for severe and difficult-to-treat forms of rosacea.

The therapy method closest to the proposed method of treatment is described in the article “Assessment of the dynamics of indicators of the dermatological index of the symptom scale and the dermatological index of quality of life under the influence of complex phototherapy in patients with a combination of subtypes of rosacea” by Novikova K.A., Tamrazova O.B., Matushevskaya Yu. I., the research results of which were published in 2021. This work took into account the synergism of the physiotherapeutic effects exerted by intense pulsed light and submillisecond neodymium 1064 nm laser radiation, as well as the increased destruction of pathologically altered vessels, observed with the sequential use of both procedures.

The purpose of the study was to evaluate the effect of complex phototherapy on changes in the dermatological index of the symptom scale and the dermatological index of quality of life, reflecting the influence of the therapy on the clinical manifestations of the disease and the subjective assessment of the skin condition by the patient himself. The study included 130 patients with a combination of rosacea subtypes. All patients were divided into 4 groups. In each separate group, the following types of therapy were used: in group I - laser therapy and 1% metronidazole cream; in group II - phototherapy and 1% metronidazole cream; in group III - complex photolaser therapy and 1% metronidazole cream; in the comparison group (IV), patients received only 1% metronidazole cream. The treatment included 6 sessions with an interval of 2 weeks, with a total duration of 3 months. The developed complex method of therapy demonstrated maximum effectiveness in the group receiving complex photo-laser therapy, which was reflected in the maximum (55.21%) reduction in the diagnostic index of the symptom scale in group III compared to the other three groups.

These studies confirm improved treatment results when combining 1064 nm neodymium laser and broadband pulsed light in patients with a combination of rosacea subtypes.

The difference between this method and the proposed method of treatment is the use of combined hardware treatment in combination with external 1% metronidazole, which, according to numerous comparative studies, is inferior in effectiveness to 1% ivermectin. This method was used only in patients with a combination of papulopustular and erythematous types of rosacea, who also did not receive systemic therapy. At the end of the course of treatment with the proposed method in patients with a combined type of rosacea, the number of pustular elements decreased by only 67%, and the number of telangiectasias by only 50%. This work also does not take into account the period of remission after completion of the course of treatment.

The technical result of the proposed method of treatment is the effective and safe use of combination therapy, including a course of systemic treatment with minocycline with dose titration depending on the severity of the skin process, external therapy with 1% ivermectin and 0.5% brimonidine tartrate depending on the clinical form of the disease, and combined laser treatment of rosacea depending on the type of rosacea. This combination of the most effective treatment methods allows us to cover the largest number of pathogenesis links and influence a larger number of symptoms of this polymorphic disease, and also allows us to shorten the time for the onset of clinical results and prolong the period of remission, which significantly affects the quality of life of patients.

This technical result is achieved by the fact that the patient, depending on the severity and clinical form of the disease, at the first stage of treatment is orally prescribed the drug minocycline according to the following scheme: in the case of mild to moderate severity of papulopustular and erythematous forms of rosacea - at a dose of 50 mg per day in one dose for 12 weeks, in case of severe forms of rosacea - 50 mg 2 times a day for 14 days, then 50 mg 1 time a day for 10 weeks. At the same time as taking minocycline, external treatment is prescribed: for the papulopustular form, 1% ivermectin cream 1 time per day for rashes during the entire course of treatment (8-12 weeks), for the erythematous form - 0.5% brimonidine tartrate gel for thin areas of erythema layer 1 time per day in the morning. At the second stage of therapy, 20-30 days from the start of systemic and external treatment, with complete or partial relief of acute inflammatory phenomena, a laser correction procedure with a neodymium laser (Nd:Yag with a wavelength of 1064 nm) is prescribed in the presence of large telangiectasias - 1 or 2 procedures per depending on the number of telangiectasias, then after 2 weeks a course of 4 IPL (broadband pulsed light) procedures with a wavelength of 560 and 515 nm with an interval of 2 weeks.

The expediency of the primary use of a neodymium laser is explained by the fact that correction of vascular changes using technologies using broadband pulsed light in the presence of large-caliber telangiectasias has undesirable effects in the form of the formation of hematomas and petechial elements due to trauma to the vascular wall. These side effects are temporary and usually self-limited within 3-7 days, however, a longer period of rehabilitation in the post-procedure period negatively affects the psychological comfort and compliance of patients. The use of a neodymium laser is the most effective method for correcting local telangiectasias, which does not cause discomfort in the patient and has the shortest rehabilitation periods. After the procedure, slight hyperemia may be present at the site of exposure, which will subside on its own within 1-2 days. The use of broadband pulsed light has a more diffuse effect and has a more pronounced therapeutic effect. Broadband pulsed light radiation has a coagulating effect on skin vessels throughout the entire depth of the dermis.

The principle of the biological effect of IPL on vascular skin is the absorption of photons by chromophores located in different layers of the skin, where, in the case of vascular changes, hemoglobin acts as a chromophore. In addition, IPLs cause coagulative necrosis of Demodex fol., which plays an important role in the pathogenesis of rosacea, which expands the therapeutic capabilities of this technology. Side effects of using IPL systems for the correction of vascular changes are transient erythema and edema, as well as small petechial elements, which resolve on their own within 7 days.

The combined use of minocycline and ivermectin/brimonidine tartrate has a powerful long-lasting anti-inflammatory effect, has a synergistic effect and simultaneously affects the main targets of the pathogenesis of rosacea. The addition of laser technologies to such therapy enhances and accelerates the onset of clinical response, makes it possible to more effectively cope with aesthetic imperfections of the skin, affects a greater number of symptoms of the disease, increases patient compliance, and has a preventive role, prolonging the period of remission.

Description of the method.

A combined three-component two-stage method for treating rosacea is carried out as follows:

At the first stage of therapy, the drug minocycline (the first component) is prescribed according to the following scheme: in the case of mild to moderate papulopustular and erythematous forms of rosacea - at a dose of 50 mg per day in one dose for 12 weeks, in the case of severe forms of rosacea - 50 mg 2 times a day (once every 12 hours) for 14 days, then 50 mg 1 time a day for 10 weeks.

Note. In some cases, when treating severe forms of papulopustular rosacea, with particularly torpid skin processes, the dose of minocycline can be increased to 200 mg per day in 2 doses for the first 2 weeks of therapy. Next, the dose of the drug is titrated according to a gradual reduction scheme, the next 2 weeks - 100 mg per day, then 8 weeks - 50 mg per day. In cases of mild forms of rosacea, the course of systemic therapy with minocycline at a dose of 50 mg per day can be reduced to 8 weeks with a rapid and durable clinical response.

The severity of the skin process with rosacea is assessed using the Rosacea Diagnostic Rating Scale (RDS).

The scale includes:

- qualitative assessment of erythema (0-not noticeable, 1-mild, 2-moderate, 3-severe);

- determination of the number of papules and pustules (0 - less than 10, 1 - from 11 to 20, 2 - from 21 to 30, 3 - more than 30).

- presence of telangiectasia (0-absent, 1-occupied less than 10% of the face, 2-from 11 to 30%, 3-more than 30%)

Secondary signs are also assessed:

- dry skin and the presence of peeling (0 - absent, 1 - weak, 2 - moderate with slight peeling, 3 - severe with pronounced peeling);

- subjective sensations (a feeling of “burning” and tingling of the skin, the presence of facial swelling) (O-absent, 1 - weak, 2 - moderate, 3 - strong).

- severity of symptoms of ophthalmic rosacea (0 - absent, 1 - slight hyperemia (blepharitis), 2 - conjunctivitis, 3 - keratitis, corneal ulcer).

The maximum score is 21.

A score from 1 to 7 points corresponds to mild severity of rosacea, 8-14 - moderate, 15-21 - severe.

Simultaneously with taking minocycline, at the first stage, external treatment is prescribed (second component): for the papulopustular form, 1% ivermectin cream is applied once a day to the lesions during the entire course of treatment (12 weeks), for the erythematous form - gel 0.5 % brimonidine tartrate is applied to areas of erythema in a thin layer once a day in the morning for 12 weeks, except for days of hardware procedures.

At the second stage, 20-30 days from the start of the first stage of therapy, laser and IPL technologies (3 components) are added.

Hardware procedures are carried out with the patient lying on a couch in a laser room that meets the requirements of San Pin, using certified emitters.

Before each hardware procedure, the patient’s skin is treated with a skin antiseptic solution of chlorhexidine bigluconate 0.05% using sterile gauze pads and dried thoroughly. The patient's eyes are covered with special protective lead glasses. Next, a medical transparent ultrasound gel of medium viscosity is applied to the skin.

If the patient has telangiectasias with a diameter of 1 mm or more, a correction procedure is first performed with a neodymium laser (Nd:Yag with a wavelength of 1064 nm) according to the following parameters: 1 pulse 8 ms, with a fluence of 100-120 J/cm ² , diameter spots - 2.5 mm. If the total area of telangiectasias is more than 5x5 cm on one side of the face, the procedure is carried out in 2 stages with an interval of 2 weeks between them.

2 weeks after correction with a neodymium laser, a course of 4 procedures of the IPL system (broadband pulsed light) follows.

Conduction parameters: first pass with contact of the cooling light guide with the skin, two pulses with a wavelength of 560 nm, the first pulse of 3.5 ms with a fluence of 11 J/cm ² and the second pulse of 4.5 ms with a fluence of 8 J/cm ² , with a period cooling 30 ms. The second pass with contact of the cooling light guide with the skin, with a wavelength of 515 nm, 1 pulse, duration 4 ms, with a fluence of 14-15 J/cm ² .

After completion of the procedure, the gel is carefully removed from the patient’s skin using sterile gauze wipes, and the skin is wiped with a solution of chlorhexidine bigluconate 0.05%. Next, the patient’s skin is cooled using an ice compress or cryoblowing for 2-5 minutes in order to reduce the patient’s subjective sensations, then a cream with dexpanthenol is applied to the treated skin.

4 IPL procedures are performed with an interval of 2-3 weeks.

Treatment protocols depending on the type of clinical form of rosacea and the severity of the pathological process:

1. Erythematous form of rosacea of mild to moderate severity without telangiectasias

Systemic therapy External therapy Hardware therapy Minocycline
50 mg 1 time per day - 12 weeks. Brimonidine tartrate
Apply a thin layer of 0.5% gel to areas of erythema once a day for 12 weeks. IPL 560, 515 nm
4 procedures with
at intervals of 2 weeks.

2. Erythematous form of rosacea of mild to moderate severity with the presence of telangiectasia

Systemic therapy External therapy Hardware therapy Minocycline
50 mg 1 time per day - 12 weeks. brimonidine tartrate 0.5% gel
apply a thin layer on chagi erythema once a day for 12 weeks. Nd:Yag laser 1064 nm
1-2 procedures with an interval of 2 weeks.
Further:
IPL 560, 515 nm
4 procedures with
at intervals of 2 weeks.

3. Severe erythematous rosacea without telangiectasia

Systemic therapy External therapy Hardware therapy Minocycline
50 mg 2 times a day - 14 days, then 50 mg 1 time a day - 10 weeks. brimonidine tartrate 0.5% gel
apply a thin layer to areas of erythema once a day for 12 weeks. Nd:Yag laser 1064 nm
1-2 procedures with an interval of 2 weeks.
Further:
IPL 560, 515 nm
4 procedures with
at intervals of 2 weeks.

4. Severe erythematous form of rosacea with the presence of telangiectasia.

Systemic therapy External therapy Hardware therapy Minocycline
50 mg 2 times a day - 14 days, then 50 mg 1 time a day - 10 weeks. brimonidine tartrate 0.5% gel
apply a thin layer to areas of erythema once a day for 12 weeks. Nd:Yag laser 1064 nm 1-2 procedures with an interval of 2 weeks. Further:
IPL 560, 515 nm
4 procedures with
at intervals of 2 weeks.

5. Papulopustular form of rosacea of mild to moderate severity without telangiectasias

Systemic therapy External therapy Hardware therapy Minocycline
50 mg 1 time per day - 12 weeks. 1% ivermectin cream
apply a thin layer on the rash 1 time per day for 12 weeks. IPL 560, 515 nm
4 procedures with
at intervals of 2 weeks.

6. Papulopustular form of rosacea of mild to moderate severity in the presence of telangiectasia

Systemic therapy External therapy Hardware therapy Minocycline
50 mg 1 time per day - 12 weeks. 1% ivermectin cream
apply a thin layer on the rash 1 time per day for 12 weeks. Nd:Yag laser 1064 nm 1-2 procedures with an interval of 2 weeks. Further:
IPL 560, 515 nm
4 procedures with
at intervals of 2 weeks.

7. Severe papulopustular rosacea without telangiectasia

Systemic therapy External therapy Hardware therapy Minocycline
50 mg 2 times a day - 14 days, then 50 mg 1 time a day - 10 weeks. 1% ivermectin cream
apply a thin layer on the rash 1 time per day for 12 weeks. IPL 560, 515 nm
4 procedures with
at intervals of 2 weeks.

8. Papulopustular form of severe rosacea with the presence of telangiectasia

Systemic therapy External therapy Hardware therapy Minocycline
50 mg 2 times a day - 14 days, then 50 mg 1 time a day - 10 weeks. 1% ivermectin cream
apply a thin layer on the rash 1 time per day for 12 weeks. Nd:Yag laser 1064 nm
1-2 procedures with an interval of 2 weeks.
Further:
IPL 560, 515 nm
4 procedures with
at intervals of 2 weeks.

The total duration of combination therapy is individual and ranges from 3 to 4 months.

Examples of application of the method

Example No. 1. Patient M., 57 years old. Diagnosis: Rosacea, papulopustular form, severe.

Concomitant diseases: stage 2 hypertension, chronic Cholecystitis, remission, chronic disease. Bronchitis without exacerbation.

History of the disease: considers himself sick for 10 years, when he first noticed the appearance of rashes on the skin of the face, which he associates with stress. The skin process is wavy, often recurrent, with gradual spread and an increase in the number of rashes.

Over the past 2 years, the patient has noted persistent redness of the facial skin, subjective sensations in the form of a feeling of “flushing, heat, burning,” as well as signs of conjunctivitis. Repeatedly consulted dermatologists, received courses of systemic and external treatment with metronidazole, external therapy with azelaic acid - with minor short-term improvement. Dermatological status: the skin process is acutely inflammatory in nature, localized on the skin of the face, represented by multiple papules and pustules of red color against a background of diffuse pink erythema, also on the skin of the face, multiple small telangiectasias are present within the lesion (Fig. 1A). The patient was prescribed combination therapy:

1. Minocycline according to the regimen: the first 2 weeks, 50 mg, 1 capsule, 2 times a day (100 mg per day) - 14 days, then 10 weeks, 50 mg, 1 capsule. per day - 10 weeks.

2. Topically apply 1% ivermectin cream on rashes in a thin layer once a day in the evening.

3. Subsequent laser correction of telangiectasias with Nd:Yag laser with a wavelength of 1064 nm - 1 procedure. Then, after 3 weeks, the patient received 3 IPL 560, 515 nm procedures with an interval of 2 weeks.

Results of the treatment: as a result of the treatment, 3 months after the start of therapy, positive dynamics were noted in the form of complete regression of the rashes, as well as relief of subjective sensations. The severity of rosacea according to the SDOR decreased from 13 points to 0. Complete clinical remission was stated (Fig. 1B). Observation of the patient for 12 months showed no relapse.

Example No. 2. Patient N., 54 years old. Diagnosis: Rosacea, erythematous form, moderate severity.

Concomitant diseases: stage 2 hypertension, uterine fibroids. History of the disease: considers herself sick for 5 years, when she first noticed redness of the facial skin, accompanied by subjective sensations in the form of “hot flashes, heat, burning.” The patient associates the onset of the disease with the onset of menopause. The skin process is persistent and progressive. She repeatedly turned to dermatologists and cosmetologists, received courses of external therapy with metronidazole, tacrolimus, and cryomassage procedures - with little short-term effect.

Dermatological status: the skin process is localized on the skin of the face, mainly in the central part, represented by bright diffuse erythema without clear boundaries, stagnant red color. Against the background of erythema in the cheek area, single small red papules are visualized (Fig. 2A).

The patient was prescribed combination therapy:

4. Minocycline according to the regimen: the first 2 weeks 50 mg, 1 capsule. 2 times a day (100 mg per day) - 14 days, then 10 weeks 50 mg, 1 capsule. per day - 10 weeks.

5. Topically apply a thin layer of brimonidine tartrate gel 0.5% to areas of redness once a day in the morning.

6. Subsequent IPL therapy: 4 procedures of IPL 560, 515 nm with an interval of 2 weeks.

Results of the treatment: as a result of the treatment, positive dynamics were noted in the form of complete regression of the rashes, as well as relief of subjective sensations. The severity of rosacea according to the SDOR decreased from 9 points to 0. Complete clinical remission was stated (Fig. 2B). Observation of the patient for 12 months showed no relapse.

Example No. 3. Patient A., 59 years old. Diagnosis: rosacea, papulopustular form, moderate severity.

Concomitant diseases: hr. gastritis, remission. Hypertension, stage 1, chronic. tonsillitis.

History of the disease: considers herself sick for 8 years, when she first noticed redness of rashes on the skin of the face, accompanied by slight itching. The patient associates the onset of the disease with poor diet and stress factors. The skin process is persistent and progressive. She repeatedly consulted dermatologists, received courses of systemic therapy with doxycycline, metronidazole, external therapy with azelaic acid, 1% ivermectin for 14 days, tacrolimus for 1 month - without effect.

Dermatological status: the skin process is acutely inflammatory in nature, localized on the skin of the face, mainly in the lower third, represented by multiple small papules and pustules against a background of diffuse pink erythema, in places the rashes merge into extensive lesions with fine-plate peeling and single hemorrhagic crusts (Fig. 3 A). The patient was prescribed combination therapy:

1. Minocycline according to the regimen: 50 mg, 1 drop, per day - 12 weeks.

2. Topically apply ivermectin 1% cream on the rash with a thin layer once a day in the evening.

3. Follow-up IPL therapy: 4 IPL 560, 515 nm procedures with an interval of 2 weeks.

Results of the treatment: as a result of the treatment, positive dynamics were noted in the form of complete regression of the rashes, as well as relief of subjective sensations. The severity of rosacea according to the SDOR decreased from 11 points to 0. Complete clinical remission was stated (Fig. 3B). Observation of the patient for 12 months showed no relapse.

Example No. 4. Patient V., 45 years old. Diagnosis: Rosacea, erythematotelangiectatic form, mild severity. Concomitant diseases: Obesity 2 tbsp.

History of the disease: considers himself sick for 4 years, when he first noticed the appearance of rashes on the skin of the face, associated with stress. The skin process is persistent with a gradual increase in the area of skin damage. The patient notes periodic attacks of redness of the facial skin, accompanied by subjective sensations in the form of a feeling of “heat, burning” in response to exposure to high temperatures, psycho-emotional experiences, and alcohol consumption. I visited a dermatologist for the first time; I had not received any previous treatment. Dermatological status: the skin process is sub-inflammatory in nature, localized on the skin of the face, represented by foci of pink erythema on the skin of the cheeks and an extensive network of pink and cyanotic telangiectasia, most of which are 1 mm in diameter or more (Fig. 4A).

The patient was prescribed combination therapy:

1. Minocycline according to the regimen: 50 mg, 1 drop per day for 8 weeks.

2. Topically apply brimonidine tartrate gel 0.5% in a thin layer on the rash in the morning once for 12 weeks.

3. Subsequent laser correction of telangiectasias with Nd:Yag laser with a wavelength of 1064 nm - 2 procedures. Then, after 3 weeks, the patient received 2 IPL 560, 515 nm procedures with an interval of 2 weeks.

Results of the treatment: as a result of the treatment, after 2 months. From the start of therapy, positive dynamics are observed in the form of complete regression of rashes, as well as relief of subjective sensations. The severity of rosacea according to the SDOR decreased from 6 points to 0. In this case, the course of therapy was reduced to 8 weeks due to the rapid clinical response and effective correction of vascular changes using hardware methods.

Complete clinical remission was stated (Fig. 4B). Observation of the patient for 12 months showed no relapse.

The proposed method of treatment was used in 40 patients with papulopustular and erythematous rosacea of varying severity. The average course of treatment using the proposed method was 3 months.

All patients tolerated treatment with the proposed method well, no side effects were observed. All patients showed a pronounced positive dynamics of the main symptoms of the disease: by the end of the course of treatment, clinical remission was noted in the form of complete regression of rashes and subjective sensations in 93% of patients (37 patients), a significant improvement in the form of almost complete regression of rashes occurred in 7% of patients (3 patient). The proposed method of combined treatment made it possible to achieve improvement in both objective criteria of the disease and the subjective state of patients due to the rapid onset of clinical and aesthetically significant effect from the treatment, improvement of the course of the disease and extension of the period of remission, which was at least 1 year. The patients did not make any complaints during the course of treatment or after.

The indication for this treatment method is papulopustular and erythematous forms of rosacea of both mild, moderate and severe severity with a variety of clinical manifestations within these forms of rosacea.

The proposed method for treating rosacea has a number of advantages compared to previously known methods. Combination therapy for rosacea using systemic minocycline, topical ivermectin, 1% brimonidine tartrate, followed by exposure to aesthetic skin defects with a neodymium laser and a broadband pulsed light system allows simultaneous impact on various pathophysiological processes underlying the pathogenesis of the disease, making it possible to implement a personalized approach to therapy in depending on individual characteristics and differences in clinical variants of rosacea. The use of minocycline in low, subclinical dosages has a prolonged anti-inflammatory effect. The administration of minocycline in a dosage of 50-100 mg is safe for patients, eliminates the occurrence of unwanted side effects, makes it possible to use in patients with concomitant somatic pathology, makes therapy effective, easily tolerated and comfortable for sick. The ability to choose an external drug depending on the form of the disease is a necessary addition to systemic therapy, since different components of external agents (1% ivermectin or 0.5% brimonidine tartrate) due to the synergism of the anti-inflammatory effect make it possible to specifically influence the prevailing symptoms and take into account the individual characteristics of the manifestation diseases.

Laser technology using a neodymium laser with a wavelength of 1064 nm and a broadband pulsed light system using a wide range of wavelengths (515-560 nm) can effectively correct the aesthetic imperfections of the skin in patients with rosacea, cover vascular changes at different depths of the skin, and combined use These technologies make it possible to safely treat vessels of different sizes, which accelerates the onset of clinical effect, while increasing patient compliance with treatment.

The combined use of low doses of minocycline, brimonidine tartrate/ivermectin and laser technologies allows you to quickly and safely increase therapeutic effectiveness, influencing a greater number of pathogenesis links, which allows you to relieve the maximum number of symptoms, achieve lasting clinical results, more effectively cope with aesthetic imperfections of the skin, and reduces the incidence of relapses, increases the period of remission, significantly improves the quality of life of patients.

Claims (1)

A method of combined treatment of rosacea, including the use of a systemic drug, a topical drug, as well as the influence of a physical factor, characterized in that at the first stage, depending on the severity of rosacea, the drug minocycline is used in a dosage of 50 mg per day from 8 to 12 days. ten weeks for mild to moderate severity, 100 mg per day for 14 days, followed by a further transition to 50 mg per day for up to 10 weeks for severe forms; also, depending on the clinical form of rosacea, an external preparation is simultaneously used: in the case of the erythematous form - 0.5% brimonidine tartrate, in the case of the papulopustular form - 1% ivermectin cream; at the second stage, after stopping the acute inflammatory skin process, physiotherapeutic effects of a neodymium laser on the area of telangiectasias are added to the therapy, regardless of the clinical form of the disease, namely 1-2 Nd:Yag procedures with a wavelength of 1064 nm according to the following parameters: 1 pulse 8 ms, s fluence 100-120 J/cm ² , spot diameter - 2.5 mm, then with an interval of at least 2 weeks, IPL treatment is carried out in a course of 3-4 procedures on the area of residual vascular changes with an interval between procedures of 2 weeks according to the following parameters: first passage with contact of the cooling light guide with the skin, two pulses with a wavelength of 560 nm, the first pulse is 3.5 ms with a fluence of 11 J/cm ² and the second pulse is 4.5 ms with a fluence of 8 J/cm ² , with a cooling period of 30 ms, the second pass with contact of the cooling light guide with the skin, with a wavelength of 515 nm, 1 pulse, duration 4 ms, with a fluence of 14-15 J/cm ² .