Uticaj različitih terapijskih modaliteta, citokina i aktivnosti bolesti na bihevioralni status bolesnika sa reumatoidnim artritisom

Abstract

Uvod: Reumatoidni artritis (RA) je hronična progresivna sistemska bolest koju karakteriše simetrični perzistirajući sinovitis perifernih zglobova. Patološki proces, praćen upalom i posledičnim uništavanjem hrskavice i kostiju, prate u daljem toku oštećenja različitih tkiva uključujući tetive, ligamente i krvne sudove. Reumatoidni artritis mogu da prate i vanzglobne manifestacije koje predstavljaju faktore loše prognoze. Zabeležena je incidenca od približno 3 slučaja na 10000 stanovnika, a stopa prevalencije iznosi od 0,46% - 1%. Mnogi od odgovora imunog sistema koji su povezani sa RA su povezani sa depresivnom simptomatologijom koja je kod ovih pacijenata višestruko češća nego u opštoj populaciji. Odnos između depresije i RA je multifaktorski bilo da je depresija posredovana socioekonomskim faktorima vezanim za RA ili je posledica bola, funkcionalnih ograničenja ili je povezana sa dejstvom proinflamatornih citokina. Ova hronična autoimuna bolest koju karakteriše postepeno pogoršanje funkcije zglobova može dovesti do smanjenja adaptivnih sposobnosti osobe, samim tim se smanjuje kvalitet života, a gubitak funkcionalnosti umanjuje njihove radne sposobnosti. Glavni cilj lečenja RA je zaustavljanje upale, ublažavanje simptoma, sprečavanje oštećenja zglobova i organa, poboljšanje fizičkog funkcionisanja i sprečavanje ili smanjenje dugoročnih komplikacija. Optimalno lečenje pacijenata sa RA sastoji se od integrisanog pristupa koji uključuje nefarmakološku i farmakološku terapiju. Primena nebioloških i bioloških DMARD, bilo kao monoterapija ili u kombinovanoj terapiji, predstavlja najvažniju meru u uspešnom lečenju RA. Navodi se da depresija smanjuje odgovor na biološku terapiju kod RA i može ili pojačati bol ili samu aktivnost bolesti ili smanjiti verovatnoću za remisiju RA.Cilj: Cilj 1. Ispitati učestalost i stepen depresivne simptomatologije kod bolesnika sa RA. Cilj 2. Ispitati povezanost serumskih nivoa TNF-α i IL-6 sa pojavom i stepenom depresivne simptomatologije kod bolesnika sa RA. Cilj 3. Ispitati povezanost serumskih nivoa TNF-α i IL-6 sa funkcionalnim statusom, stepenom aktivnosti bolesti, stepenom umora i kvalitetom sna kod bolesnika sa RA. Cilj 4. Uporediti uticaj različitih terapijskih pristupa (konvencionalni sintetski lekovi koji modifikuju tok bolesti i biološki lekovi koji modifikuju tok bolesti) primenjenih u tretmanu bolesnika sa RA na stepen aktivnosti bolesti, funkcionalni status, stepen hroničnog umora, kvalitet sna i stepen depresivne simptomatologije. Cilj 5. Uporediti uticaj različitih bioloških lekova (TNF-α inhibitori i IL-6 receptor antagonisti) na funkcionalni status bolesnika i učestalost depresivne simptomatologije. Materijali i metode: Istraživanje je sprovedeno kao studija preseka, prospektivnog karaktera i obuhvatila je 84 bolesnika koji su bili hospitalizovani ili se ambulantno prate na Klinici za nefrologiju i kliničku imunologiju, Univerzitetskog Kliničkog centra Vojvodine. Od ukupnog broja ispitanika ženskog pola je bilo 95,2%, dok je preostalih 4,8 % ispitanika bilo muškog pola. Starost se kretala u intervalu od 19-75 godina, pri čemu je prosečna starost celokupnog uzorka iznosila M=53,19 godina (SD=13,09). Kod svih bolesnika je prethodno postavljena dijagnoza RA prema kriterijumima Američkog koledža za reumatologiju i Evropske lige protiv reumatizma. Svi bolesnici su ispitivani u odnosu na prisustvo i stepen depresivne simptomatologije korišćenjem standardizovanog upitnika Bekova skala depresivnosti (Beck Depression Inventory – BDI), funkcionalnog statusa upotrebom Upitnika o proceni zdravstvenog stanja-indeks onesposobljenosti (HAQ-QI), stepena hroničnog umora korišćenjem Upitnika za procenu zamora u hroničnim bolestima (FACIT-F- Functional Asessment of Chronic Illness Therapy-Fatigue), kvaliteta sna putem Pitsburškog indeksa kvaliteta spavanja (Pittsburgh Sleep Quality Index – PSQI) i stepena aktivnosti bolesti kroz Indeks aktivnosti bolesti koji inkorporira sedimentaciju eritrocita (Disease Activity Score-28 for Rheumatoid Arthritis with ESR -DAS28-ESR), Indeksa aktivnosti bolestikoji inkorporira CRP - DAS28-CRP indeks, i Klinički indeks aktivnosti bolesti (Clinical Disease Activity Index- CDAI). Takođe je jednokratno određena koncentracija IL-6 i TNF-α u serumu svih bolesnika koji su najmanje 6 meseci od momenta uključivanja u istraživanje na stabilnim dozama aktuelne terapije (isključivo konvencionalnim sintetskim lekovima koji modifikuju tok bolesti ili kombinacijom ovih lekova sa biološkim lekom koji se ispituje). Rezultati: Od celokupnog uzorka, 82% obolelih od RA je bilo seropozitivno, a od pridruženih bolesti, kao najčešći komorbiditet je navođena hipertenzija, koja je prisutna kod oko 31% ispitanika Bez komorbiditeta je bilo oko 30% ispitanog uzorka. Prosečna dužina trajanja bolesti iznosi M=12,74 godine (SD=7,38). Kada su u pitanju konvencionalni sistemski lekovi najveći procenat ispitanika koristi metotreksat (oko 47%), dok u vrlo sličnom procentu uzimaju sulfasalazin i antimalarik. NJih oko 18% ne uzima konvencionalnu terapiju. Najfrekventnija terapija iz grupe biološke prema dobijenim podacima je terapija koja uključuje TNF-α inhibitore, a koju dobija oko 48% ispitanika, naspram 33% koji dobijaju IL-6 receptor antagoniste. Iz grupe ispitanika koja se leči biološkim lekovima, jedan medikament uzima oko 84% ispitanih, dok preostalih 16% uzima dva. Kada je u pitanju dužina trajanja aktuelne biološke terapije ona u proseku iznosi M= 5,37 godina, dok je raspon korišćenja od 0,5 do12 godina. Jutarnju ukočenost kao simptom nema oko 40% ispitanih. U odnosu na kategorije ukupnog skora na Indeksu aktivnosti bolesti, može se uočiti da je u remisiji oko 40% ispitanog uzorka, dok kada je bolest aktivna, najveći procenat ispitanika ima umeren stepen aktivnosti bolesti 42%. Prema drugom pokazatelju aktivnosti bolesti, Kliničkom indeksu aktivnosti bolesti - CDAI, u remisiji je oko 18% ispitanog uzorka, a najveći broj ispitanika se nalazi u kategorijama umerenog i niskog stepena aktivnosti bolesti (redom, 36% i 40%). Prema Upitniku o proceni zdravstvenog stanja najveći procenat ispitanika pripada kategoriji koja funkcioniše bez ograničenja (oko 60%), a zatim sledi kategorija umereno ograničenog funkcionisanja (oko 34%). Procene aktivnosti bolesti na osnovu CRP i SE statistički se značajno razlikuju te je vrednost DAS28 skora veća u slučaju kada se u proceni koristi SE u odnosu na procenu u kojoj se koristi CRP parametar. Najveći procenat ispitanika nema simptome depresije (75%) procenjene Bekovom skalom depresije. S druge strane, među onima koji ispoljavaju simptome depresije relativno ujednačen broj ispitanika ispoljava znake blage depresije i depresije koja se po intenzitetu svrstava u smetnje umerenog stepena (13% i 11%). U odnosu na kategorije ukupnog skora na Bekovoj skali anksioznosti, može se uočiti da najveći procenat ispitanih, njih oko 82%, pripada kategoriji niske anksioznosti, dok oko 2% ispitanih izveštava o visokom stepenu prisutne anksioznosti. Najveći procenat ispitanika (47%) pripada kategoriji umerenog stepena zamora odnosno ekstremnog zamora (34%). Najveći procenat ispitanika (70%) navodi simptome koji ih svrstavaju u kategoriju lošeg kvaliteta sna. Beleži se statistički značajna korelacija pozitivnog smera i visokog intenziteta (r=0,842 i r=0,634) između serumskog nivoa interleukina 6 i stepena depresivnosti i anksioznosti. Postoje statistički značajne korelacije koje su po intenzitetu visoke ( 0,535 do 0,732) dok su po smeru i pozitivne i negativne između visine serumskog nivoa interleukina 6 i različitih parametara koji se tiču stepena aktivnosti bolesti, stepena umora i kvaliteta sna. Ispitanici koji imaju umeren i visok stepen aktivnosti bolesti, umereno i teško ograničenje funkcionisanja, loš kvalitet sna imaju više vrednosti faktora nekroze tumora alfa. S druge strane, ispitanici koji imaju lak zamor procenjen FACIT upitnikom imaju više vrednosti tumor nekrozis faktora alfa. Statistički značajne razlike postoje između ispitanika koji uzimaju konvencionalnu terapiju sa dodatkom TNF-α inhibitora u odnosu na ispitanike koji uzimaju konvencionalnu terapiju sa dodatkom IL-6 receptor antagonista. Osobe koje imaju prisutne simptome depresivnosti imaju viši nivo aktivnosti bolesti, viši nivo onesposobljenosti, kao i veći broj bolnih zglobova, viši stepen bola procenjen od strane i pacijenta i lekara. Sve dobijene razlike govore u prilog tome da osobe koje imaju prisutne simptome depresivnosti imaju viši nivo aktivnosti bolesti, veći stepen anksioznosti, lošiji kvalitet sna i viši stepen hroničnog umora u odnosu na pacijente koji nemaju depresiju u okviru kliničke slike.U predviđanju ishoda depresivnosti značajni prediktori pokazali su se DAS 28 CRP (p=0,009) i dužina trajanja bolesti (p=0,025). Zaključak: Rezultati ovog istraživanja pokazuju da najveći broj pacijenata sa RA (75%) nema simptome depresije procenjene pomoću BDI upitnika, dok je kod preostalih ispitanika podjednako zastupljena blaga depresija i depresija umerenog intenziteta. Hronični zamor, umerenog stepena ima skoro polovina ispitanika. Čak dve trećine ispitanika ima loš kvalitet sna, a jedna trećina ispitanika ima umereni stepen onesposobljenosti. Najveći broj ispitanika prijavljuje nizak stepen anksioznosti. Pacijenti koji imaju dokazano prisustvo depresivne simptomatologije imaju viši stepen aktivnosti bolesti, veći stepen anksioznosti, lošiji kvalitet sna i viši stepen hroničnog umora i onesposobljenosti. Prisustvo depresivne simptomatologije kod pacijenata sa RA povezano je sa većim brojem bolnih zglobova, višim stepenom bola izraženim na vizuelno analognoj skali kako od strane pacijenta, tako i od strane lekara. Dužina trajanja bolesti i stepen aktivnosti bolesti iskazan kroz DAS-28 CRP predstavljaju moguće prediktore nastanka depresivne simptomatologije kod pacijenata sa RA. Postoji povezanost između vrednosti IL-6 i TNF-α u serumu sa stepenom depresivne simptomatologije. Povišene serumske vrednosti IL-6 i TNF-α povezane su takođe sa većim stepenom aktivnosti bolesti, prisustvom anksioznosti, izraženijim umorom, smanjenom funkcionalnošću i lošijim kvalitetom sna. Terapija konvencionalnim sintetskim lekovima koji modifikuju tok bolesti se pokazala jednako efikasnom u odnosu na biološku u pogledu kontrole stepena aktivnosti bolesti, funkcionalnog statusa, umora i pojave depresivne simptomatologije. Primena IL-6 receptor antagonista i TNF-α inhibitora u lečenju pacijenata sa RA dovodi do postizanja boljeg funkcionalnog statusa, smanjenja hroničnog umora, boljeg kvaliteta sna, manjeg stepena kako depresivne simptomatologije tako i anksioznosti, i smanjenja aktivnosti osnovne bolesti. U odnosu na tip biološke terapije IL-6 receptor antagonisti su se pokazali efikasnijim u kontroli osnovne bolesti, ostvarivanju boljeg funkcionalnog statusa, manjeg stepena hroničnog umora, boljeg kvaliteta sna i ređe pojave depresivne simptomatologije u odnosu na TNF-α inhibitore.

Introduction: Rheumatoid arthritis is a chronic progressive systemic disease characterized by symmetrical persistent synovitis of peripheral joints. The pathological process accompanied by inflammation and consequent destruction of cartilage and bones is followed, in further course, by damage to various tissues, including tendons, ligaments and blood vessels. Rheumatoid arthritis can be accompanied by extra-articular manifestations, which are poor prognostic factors. An incidence of approximately 3 cases per 10,000 inhabitants was recorded, and the prevalence rate was 0.46% - 1%. Many of the immune system responses which occur in RA, are associated with depressive symptoms that are much more common in these patients than in the general population. The relationship between depression and RA was multifactorial, on the one hand that depression is mediated by socioeconomic factors related to RA and could be a consequence of pain, functional limitations, or is associated with the action of proinflammatory cytokines. This chronic autoimmune disease, which is characterized by a gradual deterioration of joint function, can lead to a decrease in the adaptive abilities of persons, thus reducing the quality of life, whereby the loss of functionality reduces their working abilities. The main goal of RA treatment is to stop inflammation, alleviate symptoms, prevent damage to joints and organs, improve physical functioning and prevent or reduce long-term complications. The optimal treatment of patients with RA consists of an integrated approach that includes non-pharmacological and pharmacological therapy. The use of non-biological and biological DMARDs, whether as monotherapy or in combination therapy, is the most important action in the successful treatment of RA. Depression is said to reduce the response to biologic therapy in RA and may either increase pain or disease activity itself or reduce the likelihood of RA remission. The goal: Objective 1. To examine the frequency and degree of depressive symptoms in patients with RA. Objective 2. To investigate the association of serum levels of TNF-α and IL-6 with the occurrence and degree of depressive symptoms in patients with RA. Objective 3. To investigate the association of serum levels of TNF-α and IL-6 with functional status, degree of disease activity, degree of fatigue and quality in patients with RA. Objective 4. To compare the impact of different therapeutic approaches (conventional synthetic drugs that modify the course of the disease and biological drugs that modify the course of the disease) used in the treatment of patients with RA on disease activity, functional status, chronic fatigue, sleep quality and depressive symptoms. Objective 5. Compare the influence of different biological drugs (TNF-α inhibitors and IL-6 receptor antagonists) on the functional status of patients and frequency of depressive symptoms. Materials and methods: The study was conducted as a cross-sectional study, prospective in nature and included 84 patients who were hospitalized or monitored on an outpatient basis at the Clinic of Nephrology and Clinical Immunology, University Clinical Center of Vojvodina. Of the total number of respondents, 95.2% were female, while the remaining 4.8% were male. The age ranged from 19-75 years, with the average age of the entire sample being M = 53.19 years (SD = 13.09). All patients were previously diagnosed with RA according to the criteria of the American College of Rheumatology and the European League Against Rheumatism. All patients were examined for the presence and degree of depressive symptomatology using the standardized Beck Depression Inventory (BDI), functional status using the Health Assessment Questionnaire (HAQ-QI), chronic fatigue rate using the Assessment Questionnaire. fatigue in chronic diseases (FACIT-F-Functional Assessment of Chronic Illness Therapy-Fatigue), sleep quality through the Pittsburgh Sleep Quality Index (PSQI) and the degree of disease activity through the Index of Disease Activity Incorporating Sedimentation Eng. Disease Activity Score-28 for Rheumatoid Arthritis with ESR-DAS28-ESR), the Index of Disease Activity Incorporating CRP - DAS28-CRP Index, and the Clinical Disease Activity Index (CDAI). The serum IL-6 and TNF-α concentrations were also determined singlehanded in all patients who were at least 6 months from the time of enrollment on stable doses of current therapy (exclusively conventional disease-modifying synthetic drugs or a combination of these drugs with a biologics). Results: Of the total sample, 82% of RA patients were seropositive, and of the associated diseases, the most common comorbidity was hypertension, which is present in about 31% of subjects. About 30% of the sample was free of comorbidities. The average duration of the disease was M = 12.74 years (SD = 7.38). When it comes to conventional synthetic drugs which modify the course of the disease, the largest percentage of respondents use methotrexate (about 47%), while a very similar percentage take sulfasalazine and antimalarials. About 18% of them do not take conventional therapy. The most frequent therapy from the biological group according to the obtained data is TNF-α inhibitors, which was received by about 48% of the subjects, compared to 33% who receive IL-6 receptor antagonists. From the group of respondents who are treated with biological drugs, about 84% of the respondents take one medication, while the remaining 16% take two. When it comes to the duration of current biological therapy, it averages M = (5.37 years), while the range of use is from 0.5 to 12 years. About 40% of respondents do not have morning stiffness as a symptom. In relation to the categories of the total score on the Disease Activity Index, it can be noticed that about 40% of the examined sample is in remission, while, when the disease is active, the largest percentage of respondents has a moderate degree of disease activity 42%. According to the second indicator of disease activity, the Clinical Index of Disease Activity - CDAI, about 18% of the examined sample is in remission, and the largest number of respondents is in the categories of moderate and low degree of disease activity (36% and 40%, respectively). According to the Questionnaire on Health Assessment, the largest percentage of respondents belongs to the category that functions without restrictions (about 60%), followed by the category of moderately limited functioning (about 34%). Estimates of disease activity based on CRP and SE differ statistically significantly, and the value of DAS28 is almost always higher in the case when SE is used in the assessment compared to the assessment in which the CRP parameter is used. The largest percentage of respondents do not have symptoms of depression (75%) as assessed by the Beck Depression Scale. On the other hand, among those who show symptoms of depression, a relatively uniform number of respondents show signs of mild depression and depression, which is classified as moderate in severity (13% and 11%). In relation to the categories of the total score on the Beck anxiety scale, it can be noticed that the largest percentage of respondents, about 82%, belong to the category of low anxiety, while about 2% of respondents report a high degree of anxiety. The largest percentage of respondents (47%) belong to the category of moderate fatigue or extreme fatigue (34%). The highest percentage of respondents (70%) cite symptoms that place them in the category of poor sleep quality. There were statistically significant correlations of positive direction and high intensity (r = 0.842 and r = 0.634) between serum interleukin 6 levels and the degree of depression and anxiety. There are statistically significant correlations that are high in intensity (0.535 to 0.732) while in direction both positive and negative between the level of serum interleukin 6 and various parameters concerning the degree of disease activity, fatigue and sleep quality. Subjects who have moderate and high levels of disease activity, moderate and severe limitation of functioning, poor sleep quality, have higher values of tumor necrosis factor alpha. On the other hand, subjects who have mild fatigue assessed by the FACIT questionnaire have higher values of tumor necrosis factor alpha. There are statistically significant differences between subjects taking conventional therapy with the addition of TNF-α inhibitors compared to subjects taking conventional therapy with the addition of IL-6 receptor antagonists. People who have symptoms of depression have a higher level of disease activity, a higher level of disability, as well as a higher number of painful joints, a higher degree of pain assessed by both the patient and the doctor. All the differences suggest that people who have symptoms of depression have a higher level of anxiety activity, poorer quality of sleep and a higher degree of chronic fatigue compared to patients who do not have depression within the clinical picture. DAS28-CRP (p=0,009) and disease duration (p=0,025) have been identified as significant predictors of depression outcome. Conclusion: The results of this study show that the largest number of patients with RA (75%) do not have symptoms of depression assessed using the BDI questionnaire, while the remaining subjects have equally mild depression and depression of moderate intensity. Almost half of the respondents have chronic fatigue of a moderate degree. As many as two thirds of respondents have poor sleep quality, and one third of respondents have a moderate degree of disability. Most respondents report low levels of anxiety. Patients who have a proven presence of depressive symptoms have a higher degree of disease activity, a higher degree of anxiety, poorer quality of sleep and a higher degree of chronic fatigue and disability. The presence of depressive symptoms in patients with RA is associated with a greater number of painful joints, a higher degree of pain expressed on a visually analogoue scale by both the patient and the physician. The duration of the disease and the degree of disease activity expressed through DAS-28 CRP are possible predictors of the development of depressive symptoms in patients with RA. There is an association between serum IL-6 and TNF-α values with the degree of depressive symptomatology. Elevated serum levels of IL-6 and TNF-α are also associated with higher disease activity, the presence of anxiety, more pronounced fatigue, decreased functionality, and poorer sleep quality. Therapy with conventional synthetic drugs that modify the course of the disease has proven to be equally effective in relation to biological in terms of controlling the degree of disease activity, functional status, fatigue and the occurrence of depressive symptoms, better functional status, reduction of chronic fatigue, better quality of sleep, lower degree of both depressive symptoms and anxiety, and reduced activity of the underlying disease. Compared to the type of biological therapy, IL-6 receptor antagonists have been shown to be more effective in controlling the underlying disease, achieving better functional status, lower chronic fatigue, better sleep quality and less frequent depressive symptoms compared to TNF-α inhibitors.