Romatoid artritli ve ankilozan spondilitli hastalarda adalimumab ve infiliksimab'ın etkinliğinin, klinik parametreler yanında akut faz reaktanları, inflamatuvar sitokinler, kollajen yıkım ürünü MMP-3 aracılığı ile karşılaştırılması
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Date
2009
Authors
Serin, Sibel
Journal Title
Journal ISSN
Volume Title
Publisher
Uludağ Üniversitesi
Abstract
Romatoid Artrit (RA) ve Ankilozan spondilit (AS) primer olarak eklemleri tutan, etyolojisi tam olarak bilinmeyen, kronik, sistemik, inflamatuvar kökenli hastalıklardır. Bu hastalıkların tedavisinde ağrı ve inflamasyonun kontrolü, eklem fonksiyonunun korunması temel amaçtır. Önceki dönemlerde mevcut ilaçların kombine edildiği protokollerle genel bir immünsupresyon yapılmaktayken, geçtiğimiz 10 yılda patogenezdeki immün basamakları spesifik olarak bloke eden biyolojik tedaviler gündeme gelmiştir. Bunlardan TNF-α inhibitörlerinin birçok sistemik inflamatuvar hastalıkta klinik ve radyolojik sonuçlarda önemli iyileşmelere neden olduğu gösterilmiştir. Bu çalışmada, daha önce almış oldukları tedaviler ile hastalık aktivitesi kontrol altına alınamamış RA’li ve AS’li hastalarda, TNF-α inhibitörlerinden monoklonal antikor yapısındaki adalimumab (ADA) ve infliksimabın (İNFİ) kullanımı ile elde edilen etkinliğin klinik parametreler yanında akut faz reaktanlarından (AFR); ESH, CRP, SAA, inflamatuvar sitokinlerden; IF-γ, IL1β, IL-6 ve kollajen yıkım ürünü; MMP-3 aracılığı ile karşılaştırılması amaçlandı. Çalışmaya Eğlül 2007-Haziran 2008 tarihleri arasında Uludağ Üniversitesi İç Hastalıkları Ana Bilim Dalı Romatoloji Bilim Dalı Polikliniğine başvuran katılma kriterlerine uygun 16’sı RA ve 15’i AS toplam 31 hasta alındı. RA’li hastaların yarısına ADA, diğer yarısına İNFİ, AS’li hastalardan 7’sine ADA 8’ine İNFİ verildi. Adalimumab hem RA’de hem AS’de 40 mg 14 günde bir s.c, İnfliksimab RA’de 3 mg/kg, AS de 5 mg/kg dozunda ve başlangıcı 0.,2.,6. haftalar, tekrar uygulaması ise, 8 haftada bir olmak üzere 2 saatlik i.v infüzyonlar şeklinde verildi. Hastalardan tedavi öncesi (0.hafta), 1., 4. ve 12. haftalarda kan örnekleri alındı. ESH ve CRP poliklinik kontrolleriyle eş zamanlı olarak çalışıldı. IF-γ, IL-1β, IL-6 , SAA ve MMP-3 ölçümleri için elde edilen serumlar takip sonunda ELİSA laboratuvarında çalışılmak üzere - 20°C’de saklandı. 0.,1.,4. ve 12. haftalarda hastalık aktiviteleri hastalığa özgü aktivite skoru veya indekslerine göre (RA’de DAS28, AS’de BASDAİ ve BASFİ) hesaplandı. Tedavi ile birlikte 1., 4., 12. haftalarda yanıt kriterlerine (RA de ACR20,50,70, AS’de ASAS 20,40,5/6 ) bakıldı. Hem RA hem de AS’li hastalarda ADA ve İNFİ grupları arasında demografik özellikler yönünden farklılık yoktu (>0,05). Her iki hastalıkta aktivite indeksleri ve tedaviye yanıt kriterleri ile yapılan klinik karşılaştırmada istatistiksel anlamlılığa rastlanmadı (>0,05). ESH, CRP ve SAA’ya göre yapılan kıyaslamada RA ve AS’de gruplar arasında farklılık saptanmadı (>0,05). IF-γ her iki hastalıkta tespit edilebilen düzeylerin altında olup, IL-6 ve IL-1β’nın ölçülebilen serum seviyelerinin özellikle RA’li hastalarda çok geniş bir aralıkta dağılması nedeniyle sitokinler her iki hastalıkta her iki ilaç grubunda istatistiksel değerlendirmeye alınamadı. MMP3 her iki hastalıkta her iki ilaç grubunda ESH ve CRP’e benzer şekilde azalırken, özellikle AS hastalarda ADA grubunda İNFİ grubuna göre anlamlı olarak daha fazla baskılandı(<0,05). Çalışmamızda RA ve AS’li hastalarda ADA ve İNFİ gruplarının hastalık aktivite skoru/indeksleri ve cevap kriterleri açısından yapılan klinik karşılaştırmasında iki ilacın birbirine üstünlüğüne rastlanmadı. ESH, CRP ve SAA’ya göre yapılan kıyaslamada RA ve AS’de gruplar arasında anlamlı farklılık saptanmadı. İnflamatuvar sitokinlerin ilaçlar, travma ve lokal yada sistemik enfeksiyonlar gibi bir çok faktörden direkt yada dolaylı olarak etkilenmesi nedeniyle tedaviye yanıtın takibinde kullanılmasının objektif değerlendirme sağlamayacağı düşünüldü. MMP-3, her iki hastalıkta her iki ilaç grubunda ESH ve CRP’ye benzer bir seyir gösterdi. Bununla birlikte MMP-3’ün özellikle AS’de ADA grubunda İNFİ grubuna göre anlamlı olarak daha fazla baskılanması, AS’li hastalarda ADA’ın etkinliğinin İNFİ’a göre daha fazla olduğunu gösterdi. Bu sonuç, MMP-3’ün kronik inflamatuvar artritlerin hastalık aktivitesini belirlemede ve tedaviye yanıtın takibinde sitokinlere göre daha kararlı bir belirteç olabileceğini, ESH ve CRP gibi daha sık kullanılması durumunda ek katkılar sağlayabiliceğini düşündürmektedir.
Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) are chronic and systemic inflammatory diseases that affect primarily joints and have an unknown etiology. Pain and inflammation control and joint function preservation are the primary goal of the treatment. In the past, available medications were combined to provide systemic immunosuppression. In the last ten years, biological agents that block the specific immunologic process of the disease have come into question. It has been determined that TNF-α inhibitors provide both clinical and radiologic improvements in many systemic inflammatory diseases. In this study we aimed to show the clinical response and serum APR (ESR, CRP, SAA), inflammatory cytokine (IF-γ, IL-1β, IL-6) and collagen degradation product (MMP-3) levels to TNF-alpha inhibitors (adalimumab (ADA) and infliximab (INFI)) in RA and AS patients that have uncontrolled disease with classical treatments. Totally 31 patients (16 with RA, 15 with AS) who applied to the Uludag University Faculty of Medicine, Rheumatology patients clinic between September 2007- June 2008 that fulfill the admission criteria have been taken to this study. We randomized seven of 15 AS patients and eight of 16 RA patients with ADA therapy, eight of 15 AS and 16 RA patient with INFI therapy. We use to 40 mg of ADA subcutaneously every 14 days in both group RA and AS patients. INFI administered 3 mg/kg in RA patients and 5 mg/kg in AS patients at 0, 2, 6th weeks and repeated doses every eight weeks with two hours infusion. Blood samples were taken at 0, 1, 4, 12th weeks. ESR and CRP studied during outpatient clinic follow. SAA, IF-γ, IL-1β, IL-6 and MMP-3 stored in -20°C in the ELİSA laboratory and studied at the end of the follow up. Disease activity measurements applied at 0, 1, 4, 12th weeks for each disease with their own activity score and indexes (DAS28 in RA, BASDAI and BASFI in AS). We determine the response to the therapy at 4, 12th weeks with its own response criteria (ACR20, 50, 70 in RA, ASAS20, 40, 5/6 in AS). There is no significant demographic features difference between RA and AS patients both ADA and INFI groups (>0,05). No statistically significant differences were noted in the activity indexes, response to therapy criteria, ESR, CRP, SAA between RA and AS (>0,05). IF-γ was under the measurable levels in both diseases but IL-6 and IL-1β levels were not used for statistical evaluation because of wide variety of measurements particularly in RA. MMP-3 levels were found to be decreased as CRP and ESR in both RA and AS with both of two drugs. Particularly in AS patients with ADA treatment MMP-3 levels decreased more than the patients with INFI group. This finding was statistically significant (<0, 05). No significant differences in activity score/indexes between ADA and INFI treated groups in both RA and AS were noted in our study. There was no difference between AS and RA according to ESR, CRP, SAA measurements. We thought that inflammatory cytokines were not suitable for the objective assessment to estimate the response to the therapy. Because these cytokines are directly or indirectly effected from drugs, trauma and local/systemic infections. MMP-3 levels were measured similarly as ESR, CRP. Nonetheless MMP-3 levels were measured lower in AS patients treated with ADA than AS patients treated with INFI. This finding shows that, ADA treatment in AS patients is more efficient than the INFI treatment. These results show us that MMP-3 level is more stable marker than inflammatory cytokines for chronic inflammatory arthritis follow up to estimate disease activity and response to the treatment. So, we think that the use of MMP-3 level as frequently as ESR, CRP may have additive benefits.
Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) are chronic and systemic inflammatory diseases that affect primarily joints and have an unknown etiology. Pain and inflammation control and joint function preservation are the primary goal of the treatment. In the past, available medications were combined to provide systemic immunosuppression. In the last ten years, biological agents that block the specific immunologic process of the disease have come into question. It has been determined that TNF-α inhibitors provide both clinical and radiologic improvements in many systemic inflammatory diseases. In this study we aimed to show the clinical response and serum APR (ESR, CRP, SAA), inflammatory cytokine (IF-γ, IL-1β, IL-6) and collagen degradation product (MMP-3) levels to TNF-alpha inhibitors (adalimumab (ADA) and infliximab (INFI)) in RA and AS patients that have uncontrolled disease with classical treatments. Totally 31 patients (16 with RA, 15 with AS) who applied to the Uludag University Faculty of Medicine, Rheumatology patients clinic between September 2007- June 2008 that fulfill the admission criteria have been taken to this study. We randomized seven of 15 AS patients and eight of 16 RA patients with ADA therapy, eight of 15 AS and 16 RA patient with INFI therapy. We use to 40 mg of ADA subcutaneously every 14 days in both group RA and AS patients. INFI administered 3 mg/kg in RA patients and 5 mg/kg in AS patients at 0, 2, 6th weeks and repeated doses every eight weeks with two hours infusion. Blood samples were taken at 0, 1, 4, 12th weeks. ESR and CRP studied during outpatient clinic follow. SAA, IF-γ, IL-1β, IL-6 and MMP-3 stored in -20°C in the ELİSA laboratory and studied at the end of the follow up. Disease activity measurements applied at 0, 1, 4, 12th weeks for each disease with their own activity score and indexes (DAS28 in RA, BASDAI and BASFI in AS). We determine the response to the therapy at 4, 12th weeks with its own response criteria (ACR20, 50, 70 in RA, ASAS20, 40, 5/6 in AS). There is no significant demographic features difference between RA and AS patients both ADA and INFI groups (>0,05). No statistically significant differences were noted in the activity indexes, response to therapy criteria, ESR, CRP, SAA between RA and AS (>0,05). IF-γ was under the measurable levels in both diseases but IL-6 and IL-1β levels were not used for statistical evaluation because of wide variety of measurements particularly in RA. MMP-3 levels were found to be decreased as CRP and ESR in both RA and AS with both of two drugs. Particularly in AS patients with ADA treatment MMP-3 levels decreased more than the patients with INFI group. This finding was statistically significant (<0, 05). No significant differences in activity score/indexes between ADA and INFI treated groups in both RA and AS were noted in our study. There was no difference between AS and RA according to ESR, CRP, SAA measurements. We thought that inflammatory cytokines were not suitable for the objective assessment to estimate the response to the therapy. Because these cytokines are directly or indirectly effected from drugs, trauma and local/systemic infections. MMP-3 levels were measured similarly as ESR, CRP. Nonetheless MMP-3 levels were measured lower in AS patients treated with ADA than AS patients treated with INFI. This finding shows that, ADA treatment in AS patients is more efficient than the INFI treatment. These results show us that MMP-3 level is more stable marker than inflammatory cytokines for chronic inflammatory arthritis follow up to estimate disease activity and response to the treatment. So, we think that the use of MMP-3 level as frequently as ESR, CRP may have additive benefits.
Description
Keywords
Romatoid artrit, Ankilozan spondilit, Adalimumab, İnfliksimab, AFR, Sitokinler, MMP-3, Rheumatoid arthritis, Ankylosing spondylitis, İnfliximab, APR, Cytokines
Citation
Serin, S. (2009). Romatoid artritli ve ankilozan spondilitli hastalarda adalimumab ve infiliksimab'ın etkinliğinin, klinik parametreler yanında akut faz reaktanları, inflamatuvar sitokinler, kollajen yıkım ürünü MMP-3 aracılığı ile karşılaştırılması. Yayınlanmamış uzmanlık tezi. Uludağ Üniversitesi Tıp Fakültesi.