NOWE SWOISTE CECHY PRZEBIEGU KLINICZNEGO ŁUSZCZYCY I ŁUSZCZYCOWEGO ZAPALENIA STAWÓW ORAZ NOWE OPCJE TERAPEUTYCZNE

Orysya O. Syzon, Marianna O. Dashko, Ulyana V. Fedorova

Danylo Halytsky Lviv National Medical University, Lviv, Ukraine

ABSTRACT

Introduction: Psoriasis affects about 2% of population. In 30-40% of occurrences arthropathic psoriasis (AP) is diagnosed and it leads to 11-19% of disability cases development.

Recent studies have shown that psoriasis is often synergistically combined with herpesvirus of the 1st and 2nd type, which, according to many scientists, determines the severity, frequency of recurrences, and the course of this dermatosis. Recently, new biomarkers, i.e. a system of small ribonucleic microRNA acids, have been described. Their role and interconnection in respect of regulation of congenital and acquired immunity activity in patients with herpesvirus infection at psoriasis has been defined.

The article analyses features of anamnesis, clinical, instrumental and laboratory tests related to arthropathic psoriasis, considers the relationship of probable mechanisms of disease aggravation and progression with the definition of a treatment method influencing the dynamics of a disease course.

The aim of our work was to improve the diagnostics of AP patients taking into account some indicators of the immune-endocrine system and features of the disease course to specify their role in AP pathogenesis and to develop the system of integrated therapy of patients whose locomotor system is affected due to psoriasis.

Materials and methods: A total of 178 AP patients have been systematically examined. We have examined AP patients with varying severity of process development, generalization and the severity of skin and osseous-articular apparatus damage, the presence of associated pathology. Additional instrumental studies, determination of biochemical, serological parameters and an assessment of stress-induced immune-endocrine system have been conducted in AP patients. The content of trigger cytokines (IL-1β, IL-8, IL-17, IL-22) in blood serum, stress hormones (ACTH, cortisol), cellular and humoral immunity condition (CD3 +, CD4 +, CD8 +, CD16 +, CD22 +, IgM and IgG levels) have been studied.

Results: The clinical course and characteristic features of AP instrumental tests are extremely versatile as well as the depth of their present study is insufficient. Regardless of the disease duration period, we have detected in blood serum of AP patients probable changes in concentrations of stress-response mediators (decreased parameters of cellular immunity (CD3+, CD4+, CD8+ of T-lymphocytes, CD22+ fraction of B-lymphocytes and compensatory increased CD16+ of T-cells, cytokines – IL-1β, IL-8, IL- 17, IL-22, stress hormones – cortisol, immunoglobulins IgM, IgG, and CIC), which indicate tension of their stress-induced mechanisms even despite occasional clinical stabilization of skin and articular process.

We have offered and tested regiments to treat AP patients, which involve differential application within the integrated therapy of nonsteroidal anti-inflammatory medications (Arcoxia 30-60 mg 1 time daily / Naklofen Duo 75 mg daily), disease-modifying medications (Sulfasalazine ЕН from 500 mg to 2 g daily / Methotrexate 7.5-10 mg/week), lyophilised dialysate of leukocytes.

Conclusions: The analysis of specific features of the AP clinical course and data of integrated studies allows identifying the probability of manifestation or persistence of the pathological psoriatic articular process. The improvement of AP patients diagnostics taking into account some indicators of the immune-endocrine system and specifics of the disease course contributed to the improved therapy and mended quality of life of patients.

 

Wiad Lek 2018, 71, 2 cz. I, -325

 

INTRODUCTION

At the present stage, psoriasis is considered to be a systemic disease that affects not only skin but also joints of patients and is accompanied by possible development of typical comorbid states (cardiovascular pathology, chronic inflammatory intestinal canal diseases, and metabolic syndrome). Psoriasis affects about 2% of population [1, 2, 3, 4]. In 30-40% of occurrences arthropathic psoriasis (AP) is diagnosed and leads to 11-19% of disability cases development [3, 5, 6].

Recent studies have shown that psoriasis is often synergistically combined with herpesvirus of the 1st and 2nd type, which, according to many scientists, determines the severity, frequency of recurrences, and the course of this dermatosis. Recently, new biomarkers, i.e. a system of small ribonucleic microRNA acids, have been described. Their role and interconnection in respect of regulation of congenital and acquired immunity activity in patients with herpesvirus infection at psoriasis has been defined.

The chronic-relapsing course of arthropathic psoriasis (AP) and steady progression of the disease associated with disability cases result in a significant deterioration in the quality of life of patients, which determines its medical and social significance [6, 7, 8]. Taking into account the importance of components of stress-induced immune-endocrine system at the AP development it is important to clarify the role of main indicators of the immune system and cortisol stress hormone in the disease pathogenesis [4, 9,10]. Substantial immunological changes (of humoral and cell sections of immunity), hormone and biochemical disorders, disorder of calcium-phosphorus balance naturally influence bone metabolism and cause systemic disorders in structural and functional state of bone and cartilage system in patients with AP [8, 9, 10]. No less actual is the relation of detected clinical-instrumental disorders, changes of some indices of hormone, immune and cytokine state [4, 10].

THE AIM

Objective is to improve the diagnostics of AP patients taking into account some indicators of the immune-endocrine system and features of the disease course to specify their role in AP pathogenesis and to develop the system of integrated therapy of patients whose locomotor system is affected due to psoriasis.

MATERIALS AND METHODS

A total of 178 AP patients have been systematically examined. We have examined AP patients with varying severity of process development, generalization and the severity of skin and osseous-articular apparatus damage, the presence of associated pathology. The diagnosis of AP was verified under the diagnostic criteria of the Institute of Rheumatology of RAMS. All patients with suspected or proved AP had their damaged joints examined radiologically (ultrasonography if necessary). Additional level of Т- and В-lymphocytes subpopulations in patients with AP was determined under the guidelines on the application of erythrocyte diagnostic preparations to detect human Т- and В-lymphocytes subpopulations “Anti-SD 3”, “Anti-SD 4”, “Anti-SD 8”, “Anti-SD 16”, “Anti-SD 22” produced by RDPF Granum LLC (Kharkiv). The concentration of general immuniblibulines of M (IgM) and G (IgG) classes in blood serum was determined by immune-enzyme analysis using “IgM (IgG) general – IFA – BEST” set produced by CJSC “Vector-Best –BEST”, Novosibirsk. The content of IL-1β, IL-8, IL-17, IL-22 in blood serum was studied in accordance with the techniques and guidelines using appropriate test systems (CJSC “Vector-Best –BEST”, Novosibirsk) which are based on the sandwich-method of solid phase immune-enzyme analysis. The quantitative determining of cortisol concentration in blood plasma was performed using the appropriate reagent sets, i.e. “Cortisol – IFA – BEST” which are based on the method of solid phase immune-enzyme analysis with the application of monoclonal antibodies.

RESULTS AND DISCUSSION

Based on the statistical data analysis, it was established that over the past 20 years the number of registered cases of psoriasis among the population of Lviv region has increased by 1.4 times against the growth by 2.2 times in respect of the newly established cases (fig. 1). An increase in the incidence rate by 1.3 times among children and adolescents and twofold prevalence of hospitalization of urban male population was determined. This situation may be caused by the accumulation of several factors such as bad ecological situation in Ukraine, insufficient level of material and living conditions that leads to psychoemotional stress and, as the result, to decreasing of clinical remission period in patient and more frequent relapses.

In 113 (63.5%) out of 178 examined AP patients joints were damaged in 5-15 years after the onset of skin psoriatic process. In 85 (47.8%) cases the dependence of the onset of joint damage with the subsequent manifestations of psoriatic skin rash was detected. According to medical history data, the examined patients typically associated the onset of psoriatic skin and joints damage with hereditary (15.2%), stress (35.4%), alcoholic and toxic (7.3%), tonsillar (6.2%), mono- and polytraumatic (15.7%) factors.

In 126 (70.8%) AP patients the prevalence of generalized skin psoriatic process with typical (84.3%), large plaque rash (38.2%), moderate infiltration degree (60.1%), moderate severity (65.2%), mixed type (62.9%), inpatient stage (57.9%) and frequent recurrent course (48.3%) was observed.

It has been established that in 113 (63.5%) AP patients joints damage occurred in 5-15 years after the onset of skin psoriatic process. In 70.8% of examined patients the prevalence of generalized skin psoriatic process with typical (84.3%), moderate infiltration degree (60.1%), frequent recurrent course (48.3%), nails psoriatic damage and polyarthritis complicated with the damage of small joints of hands or feet was observed (83.2%).

Upon conducting functional tests (in order to determine sacroilitis – Kushelevsky 1-2, Patrick, Mennel and spondylitis – Shober, Thomayer), sacroilitis has been revealed and further instrumentally confirmed in 7 (3.9%) cases and spondylitis of thoracic and lumbar sections in 12 (6.7%) cases. Using the RAIS index, in 89.4% of patients it has been verified moderate-severe and severe dermatosis course. A significant impact of AP on the quality of life of patients per the DLQI index has been recorded in 55.1%, and very significant in 43.8%. A pronounced correlation between the increase in joints functional deficiency, the AP course duration and the deterioration in the quality of life of patients has been established. A high degree of polyarthritis detection rate complicated with the damage of small joints of hands or feet associated with a functional insufficiency of average degree of activity (58.9%) though the preservation of professional ability has been diagnosed in 43.3% of patients.

In this context we have determined pathognomonic signs of AP, which include simultaneous psoriatic damage of skin (100%) and nails (73%); asymmetric (82%) mono- or oligoarthritis (68%) mainly of peripheral joints and especially associated with the hand DIPJ damage (92%); osteolysis (87%); negative reaction for rheumatoid factor (97%).

We have pathogenetically grounded the primary localization of pathological joint process in AP patients in the areas of increased traumatization of tendon-ligamentous apparatus and its relationship with nails psoriatic damage. Therefore, ultrasound diagnostics and MRI examination of joints for the purpose of determination of periarticular and articular damages is justified since in 10.7% of examined patients enthesopathy and osteitis in the absence of abnormal articular X-ray changes have been detected by ultrasound diagnostics and MRI. In our opinion, osteitis in psoriatic patients signals an early premonitory symptom of the AP development.

During radiological examination of patients with AP it was detected 88 (49.44 %) cases of AP and 66 (37.08 %) cases of deforming AP, at that, in 120 (67.42 %) of cases AP was the dominant disease on clinical picture in the form of poly- or periarthritis of distal interphalangeal joints, at that, in 19 (10.67 %) of cases it was associated with axial affection of spine. At early stages of AP development using radiological examination the following facts were accurately defined more frequently than the others: non-uniform narrowing of joint gap, osteoporosis in bone epimetaphys area, erosions of distal flanges of feet and hands. In the case of progressing – partial or total destruction of closing plates with prevailing osteo-destructive (osteolysis, ankylosis) and osteo-proliferated (hyperostosis, periostitis) pathological processes over osteoporosis.

In 107 (60.1%) AP patients the presence of inflammatory biochemical serum and cholecystobiliary syndromes has been testified, which indicates metabolic character of the disease course. The analysis of laboratory examinations indicates the decreased number of thrombocytes, expressed hypoalbuminemia, hypergammaglobulinemia. In 1/3 of patients with AP anaemia was identified as well as increasing of BSR within the limits of 15-20 mm/h, from 21 to 40 mm/h – in 37 (20.8 %) of patients, more than 40 mm/h – 20 (11.2 %). The increased glucose level was identified in 44 (24.7 %) of patients, cholesterol and LDL – in 120 (67.4 %), creatinine – in 83 (46.6 %). Alkaline phosphatase (AP) and its bone izoenzyme activity were within the limits of normal values except the patients who have been suffering from the disease for more than 20 years. This means that AP activity exceeds the norm more than 2.3-2.5 times and bone izoenzyme AP decreased in 2.6-2.7 times. Creatinine content in blood serum was lower than the norm in 86 (48.3%) of patients notwithstanding the duration of the disease.

Calcium concentration in blood serum was within the norm limits. Phosphorus content tended to be increased in 1.2-1.3 times notwithstanding the duration of AP, thus testifying the disorder in catabolic and synthetic reactions.

Indices of С-reactive protein were as follows: negative “–“ – in 54 (30.3%) of patients, “+”– in 77 (43.3%), “++” – in 31 (17.4%), “+++” – in 11 (6.2%) and “++++” – in 5 (2.8%) of cases.

It has been determined that the occurrence of pathological immune-endocrine process in all variants of AP course was triggered by a possible blood serum decrease (p<0.01) of immunocompetent cells of phenotype CD3+ by 50 %, CD 22+ or В- lymphocytes by 46.6 %, moderate decrease of CD4+ by 12.9%, CD8+ by 19.6 % and increased content of CD16+ by 18.4 %; increased levels of cytokines IL-1β by 5-11 times, IL-8 by 60 times, IL-17 by tenfold, IL-22 by 5 times, cortisol stress hormone by twofold, IgG by 5 times and immunoglobulins IgМ by threefold, which testify the fact of tension of stress-induced mechanisms in patients even at the stage of clinical stabilization of skin and joint process. A statistically significant increase of the above cytokine concentration in blood serum (by more than 2-3 times) and in synovial fluid (by more than 2-5 times against the respective values in blood serum (p <0.05)) during the first months starting from the PD joint syndrome onset can serve as an additional diagnostic criterion for early AP diagnostics.

It has been set that the character of correlation between changed indicators of immune-endocrine system in AP patients indicated the autoimmune nature of the disease chronicity and development. It has been justified that decreased levels of cytokines IL-1β, IL-8, IL-17, IL-22, cortisol, IgМ, IgG are the key mediators of the stress-induced immune-endocrine system since they cause inflammation and osteolysis on the one hand and regulate the processes of articular contractions formation on the other hand.

In addition, there is a need to assess immunoregulatory effects of the miR146a system, 155 on the formation of immune response in such patients. There is no structured integrated and differentiated approach to the treatment tactics. This illustrates the feasibility of further studying of immunopathogenetic mechanisms of psoriasis in order to determine the links that are subject to therapeutic correction and the pathogenetic role of immune factors in triggering the inflammatory process at psoriasis.

We have offered and tested regiments to treat AP patients, which involve differential application within the integrated therapy of nonsteroidal anti-inflammatory medications (Arcoxia 30-60 mg 1 time daily / Naklofen Duo 75 mg daily), disease-modifying medications (Sulfasalazine ЕН from 500 mg to 2 g daily / Methotrexate 7.5-10 mg/week), lyophilised dialysate of leukocytes. This allows increasing the efficacy of treatment under statistically significant recovery of changed indicators of clinical, laboratory and instrumental examination (р<0.05), controlling of AP progression, preserving of workability and improving of the quality of life of patients. It is recommended to administer Methotrexate as a part of integrated therapy in the event of mild cases, especially central AP, and comorbid cardiovascular pathology. In the event of moderate severity of peripheral AP complicated with pronounced contractures and digestive tract pathology it is recommended to administer Sulfasalazine.

CONCLUSIONS

The analysis of specific features of the AP clinical course and data of integrated studies allows identifying the probability of manifestation or persistence of the pathological psoriatic articular process. The improvement of AP patients diagnostics taking into account some indicators of the immune-endocrine system and specifics of the disease course contributed to the improved therapy and mended quality of life of patients.

REFERENCES

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2. Belyaev G.M.: Psoriasis, psoriatic arthropathy. Moscow, Med. Press-inform, 2005.

3. Vakiryak N.P.: Diagnostics of state changes in psoriatic arthropathy patients. Journal of dermatology and cosmetology named after M.O. Torsuyev. 2007; 1–2 (14): 60–68.

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7. Molochkov V.A., Badokin V.V., Albanova V.I., Volnuhin A.V.: Psoriatic arthritis and psoriasis. Red. Molochkov V,A., Мoscow, 2007.

8. Skripnichenko S.V., Bulavina V.P., Bilous A.V.: Special aspects of etiology, course and treatment of psoriatic arthritis. Medical aspects of woman’s health. 2008; 4(13): 82-85.

9. Veale D., Ritchlin C., Fitz O.: Gerald Immunopathology of psoriasis and psoriatic arthritis. Ann. Rheum. Dis. 2005; 64: 26-29.

10. Plotnikoff N.P., Faith R.E., Murgo A.G., Good R. A.: Cytokines: Stress and Immunity. Second Edition, CRC,2006

ADDRESS FOR CORRESPONDENCE

Orysya Syzon

Department of Dermatology, Venereology

Danylo Halytsky Lviv National Medical University

Konovalets str., 1, Lviv, 79014, Ukraine,

e-mail: syzon-orysya@ukr.net

Received: 20.02.2018

Accepted: 10.04.2018

Fig. 1. Dynamics of psoriasis morbidity cases in Lviv region for 2008- 2017.