ROMATOİD ARTRİT TEDAVİSİNDE

ROMATOİD ARTRİT TEDAVİSİNDE
YENİ NELER VAR ? Prof. Dr. Murat Birtane Trakya Ü Tıp F FTR AD

EULAR 2013 Tedavi Önerileri
Genel Tedavi stratejisindeki gelişmeler Yeni DMARD strateji çalışmaları Glukokortikoid tedavide yeni nüanslar Tedavi yönlendirmede ultrason Patofizyolojiden tedaviye RA & periodontit Deneysel tedaviler Biyolojikler için yeni tbc önleme stratejisi RA & kardiyovasküler sistem ACR 2015 RA tedavi önerileri

EULAR 2013 RA TEDAVİ ÖNERİLERİ

Yeni ilaç tasnif terminoloji önerisi
DMARD Sentetik (sDMARD) Konvansiyonel (csDMARD) Mtx, lef,ssz Hedefe yönelik (tsDMARD) Tofacitinib Biyolojik (bDMARD) Biyolojik orijinal (boDMARD) Biyosimilar (bsDMARD) Smolen JS, van der Heijde D, Machold KP, et al. Proposal for a new nomenclature of disease-modifying antirheumatic drugs. Ann Rheum Dis 2014;73:3–5.

Birinci Basamak Metotreksat kontrendikasyonu yok Klinik romatoid
artrit* tanısı Metotreksat kontrendikasyonu var Metotreksat veya konvansiyonel sentetik DMARD kombinasyonuna1 başlayın Leflunomid veya Sülfasalazini tek başına veya kombine2 başlayın Kısa süreli düşük doz glukokortikoidler ile kombine edin 6 ay içinde hedefe ulaşıldı mı?** Tedaviye devam edin 1. basamak başarısız, 2. basamağa geçin. HAYIR EVET * 2010 ACR-EULAR sınıflandırma kriterleri erken teshisin yararını desteklemektedir. **Tedavi hedefi ACR-EULAR tanımlamasına göre klinik remisyona ulaşmaktır. Eğer remisyona ulaşılamayacak durumda ise hedef en azından düşük hastalık aktivitesine 6 ay sonunda erişmek olmalıdır. Ama eğer 3 ay içinde bir iyileşme görülmez ise tedavi değiştirilmelidir. 1En sık kullanılan kombinasyon metotreksat, sülfasalazin ve hidroksiklorokini kapsamaktadır. 2Sülfasalazin ya da leflunomidin metotreksat dışındaki kombinasyonları yeterince araştırılmamıştır. Referanslar: 1. Kremer JM et al. Ann Intern Med 2006;144: Schiff M. Abatacept and anti-TNF monoclonal antibadies: Efficacy and safety comparisons. EULAR 2013 poster no: FRI Schiff M, et al. Ann Rheum Dis 2013;0:1–9. doi: /annrheumdis Weinblatt ME et al. J Rheumatol.2013; 40(6): Alten R, et al EULAR 2013 poster no: SAT Genovese MC et al., The Journal of Rheumatology 2012; 39:8; doi: /jrheum Schiff M., Rheumatology 2011;50:437–449 doi: /rheumatology/keq287.

DMARD stratejisine geçin: Biyolojik ajan ekleyin1
İkinci Basamak 1. basamakta Başarısızlık etkisizlik ve/veya toksisite Olumsuz prognostik faktörler var‡ Olumsuz prognostik faktörler yok İkinci konvansiyonel DMARD stratejisine geçin: Leflunomid, Sülfasalazin ya da Metotreksatı, tek başına veya kombine2 olarak başlayın (glukokortikosteroidler eklenerek) Biyolojik ajan ekleyin1 TNF inhibitörü veya Abatasept veya Tosilizumab (belirli koşullarda*** Rituksimab) HAYIR 6 ay içinde hedefe ulaşıldı mı?* 6 ay içinde hedefe ulaşıldı mı?* 2. basamak başarısız, 3. basamağa geçin EVET Tedaviye devam edin HAYIR ‡ Çok yüksek hastalık aktivitesi; erken eklem hasarı; RF/ACPA yüksek düzeylerde *Tedavi hedefi ACR-EULAR tanımlamasına göre klinik remisyona ulaşmaktır. Eğer remisyona ulaşılamayacak durumda ise hedef en azından düşük hastalık aktivitesine 6 ay sonunda erişmek olmalıdır. Ama eğer 3 ay içinde bir iyileşme görülmez ise tedavi değiştirilmelidir. 1Bu durumlar metinde detaylandırılmıştır. 2Sülfasalazin ya da leflunomidin metotreksat dışındaki kombinasyonları yeterince araştırılmamıştır. *** TB, lenfoma, demiyelizan hastalıklar Referanslar: 1. Kremer JM et al. Ann Intern Med 2006;144: Schiff M. Abatacept and anti-TNF monoclonal antibadies: Efficacy and safety comparisons. EULAR 2013 poster no: FRI Schiff M, et al. Ann Rheum Dis 2013;0:1–9. doi: /annrheumdis Weinblatt ME et al. J Rheumatol.2013; 40(6): Alten R, et al EULAR 2013 poster no: SAT Genovese MC et al., The Journal of Rheumatology 2012; 39:8; doi: /jrheum Schiff M., Rheumatology 2011;50:437–449 doi: /rheumatology/keq287.

Biyolojik tedaviyi değiştirin.
Üçüncü Basamak Diğer biyolojik ajanlar + konvansiyonel DMARD 2. basamakta başarısızlık etkisizlik ve/veya toksisite Tofasitinibe geçin2 (±DMARD) (en az 1 biyolojikten sonra) Biyolojik tedaviyi değiştirin. Abatasept veya Rituksimab veya (ikinci) TNF inhibitörü1 veya Tosilizumab 6 ay içinde hedefe ulaşıldı mı?* 6 ay içinde hedefe ulaşıldı mı?* EVET Tedaviye devam edin HAYIR Diğer biyolojik ajanlar + konvansiyonel DMARD Kinaz inhibitörü + konvansiyonel DMARD *Tedavi hedefi ACR-EULAR tanımlamasına göre klinik remisyona ulaşmaktır. Eğer remisyona ulaşılamayacak durumda ise hedef en azından düşük hastalık aktivitesine 6 ay sonunda erişmek olmalıdır. Ama eğer 3 ay içinde bir iyileşme görülmez ise tedavi değiştirilmelidir. 1Adalimumab, serolizumab, etanersept, golimumab, infliximab ya da üzerinde yeterince çalışma yapılan ve FDA/EMA tarafından kabul edilmiş diğer biyobenzerleri 2Türkiye’de ruhsatlandırılmamıştır. Referanslar: 1. Kremer JM et al. Ann Intern Med 2006;144: Schiff M. Abatacept and anti-TNF monoclonal antibadies: Efficacy and safety comparisons. EULAR 2013 poster no: FRI Schiff M, et al. Ann Rheum Dis 2013;0:1–9. doi: /annrheumdis Weinblatt ME et al. J Rheumatol.2013; 40(6): Alten R, et al EULAR 2013 poster no: SAT Genovese MC et al., The Journal of Rheumatology 2012; 39:8; doi: /jrheum Schiff M., Rheumatology 2011;50:437–449 doi: /rheumatology/keq287.

TEDAVİ STRATEJİNE GENEL BAKIŞ
Rheumatoid arthritis (RA) is regarded as an incurable chronic disease; its aetiology is unknown and, therefore, no causal treatment is available. In the treatment of other incurable chronic diseases, such as diabetes mellitus or hypertension, the aim of treatment is usually a particular target that is associated with prevention of organ damage,1–6 but one would not ordinarily stop treatment upon normalization of the respective disease markers. On the contrary, such restitution of health ‘on drug’ is regarded to reflect therapeutic success and, thus, is an indication to continue therapy. At a time when such a targeted strategy was already long studied and implemented in these other diseases, the approach to treating RA still employed a slow step-up strategy;7 the notion that the disease process in RA could be modified emerged gradually,8 and only relatively recently (around the mid‑1990s) did it become clear that early intervention improves outcomes.9,10 However, despite early intervention with conventional synthetic DMARDs, progression of joint damage and suboptimal functional outcomes were still seen, and even after biologic agents had long been available, clinical trial data revealed that patients were being maintained on insufficiently effective conventional synthetic DMARD therapies for many years.

Hastalar gerçekte yetersiz tedavi alıyor
9 yıldan uzun süreli RA hastaları bile görülmüş ki: Sadece 2 ya da daha az DMARD kullanmış Indeed, even in a trial that enrolled patients in 2008–2010, almost 60% of patients with RA of mean duration 9 years had received only two or fewer DMARDs at baseline. Thus, the treatment target for RA, and the strategy for reaching this target, had not been sufficiently elucidated and communicated with patients and/or caretakers, with the consequence that outcomes of the disease were frequently poor, and often still are. Efforts to change this situation led to the development of recommendations for optimizing treatment outcomes in RA by using a treat-to-target (T2T) approach. For patients with RA who do achieve the desired disease state, biologic-free and even drug-free strategies have been investigated repeatedly in recent years. The overall results of these efforts vary slightly, but they seem to follow certain patterns. Tedavi optimizasyonu için son yıllarda T2T stratejisi önemseniyor, hedefe özel biyolojik ilaçlar kullanılıyor, ilaçsız remisyon aranıyor… Weinblatt Rheumatology (Oxford) 51, 2204–2214 (2012).

gelişen hedefli tedaviler
RA’da yeni milenyumda gelişen hedefli tedaviler (Targeted therapies)

Güncel olarak vurulan hedefler
TNF alfa IL 6 reseptörü IL 1 B hücreleri T hücre kostimulasyonu JAK yolağı Targeted therapies for RA The therapeutic approach to RA has changed dramatically over the past two decades. Beyond improvements in the assessment of RA in the context of clinical trials and clinical practice around the turn of the millennium, and in optimizing the use of conventional synthetic DMARDs, the efficacy of a biologic agent in RA was first shown in a randomized controlled clinical trial published 20 years ago, eliciting unparalleled progress in the development of novel therapies for RA. As of 2015, five biologic agents and one biosimilar targeting TNF are approved for the treatment of RA, as are other therapies that target the IL‑6 receptor,21 IL‑1, B cells22 and T‑cell co-stimulation; meanwhile, a targeted synthetic DMARD that interferes with a pivotal signal transduction pathway is licensed in many countries, and other targeted therapies are on the horizon. Of note, it should be acknowledged that—with the exception of TNF and IL‑6 inhibition—the mode of action of some targeted therapies for RA is not fully understood. Indeed, whereas abatacept targets T‑cell co-stimulation and rituximab leads to B‑cell depletion, other agents supposed to interfere with the same target cell populations, namely T cells or B cells, respectively, do not have significant clinical efficacy. This finding raises some doubt that the presumed mechanisms of these drugs are, in effect, primarily responsible for the observed clinical benefit, and, indeed, alternative explanations have been provided for some of these agents. Likewise, it had been assumed that interference with the TNF-signal transduction cascade, particularly with p38 mitogen-activated protein kinase pathways, would be highly effective, but in reality this is not the case, in contrast to targeting Janus kinases.clinically Mantıkla beklenen ancak elde edilen yarar her zaman eşdeğer olmayabilir.

Derin remisyon elde etmek halen zordur
Perplexingly, irrespective of the biological target, all effective therapies achieve similar therapeutic effects in patients with RA, with none of them able to induce remission in a majority of patients. The benchmarks for efficacy of the various approaches are shown in Figure 1 and seemingly differ by prior drug experience, as depicted in Figure 2. Although the major goal of therapy is now remission or at least low disease activity (LDA), the latter of which is reflected quite well by achievement of the ACR criteria for 70% improvement (ACR70 response), such ‘deep’ responses are relatively rare and difficult to obtain in patients with established disease, even in clinical trials of biologic agents (Figure 1). Biyolojik hedef ne olursa olsun yanıtlar benzer ve en idealin uzağında

başarılı olmak zorunda ya da daha az yan etkiye sahip olmalı
Kinlik oranında önemlidir Önceki ilaç, etkinlik oranında önemlidir In clinical trials of abatacept, golimumab, tocilizumab and rituximab, higher proportions of methotrexate-naive patients responded to treatment with a biologic agent plus methotrexate, in terms of clinical and functional outcomes, than methotrexate-experienced or TNF-inhibitor-experienced individuals (Figure 2a,b); only progression of joint damage was inhibited to a similar extent irrespective of prior drug experience (Figure 2c). A new drug that does not reach these established levels of response has little place in future treatment armaments, unless it is effective in a population particularly refractory to existing treatments or it elicits comparably fewer adverse events. In patients who have failed to respond to anti-TNF therapy, agents that interfere with truly different target mechanisms would be expected to be highly effective; alas, all agents hitherto tested, irrespective of their molecular target, have lesser efficacy in anti-TNF-experienced than anti-TNF-naive patients. Yeni bir ilaç yer bulmak istiyorsa diğer tedavilere dirençli hastalarda başarılı olmak zorunda ya da daha az yan etkiye sahip olmalı Smolen, J. S. & Aletaha, D. Nat. Rev. Rheumatol. advance online publication 17 February 2015;

Mtx ile % 25’lere yakın ASAS70 yanıtı elde edilir
MTX hala temel ilaçtır Notably, combinations of biologic agents acting on different therapeutic targets usually do not increase efficacy but are more toxic. Of further note, methotrexate continues to be the ‘anchor’ drug in RA therapy and, indeed, in methotrexate-naive patients with early RA, methotrexate monotherapy conveys ACR70 response rates of up to 25% (Figure 2a,d). This good response to methotrexate could account, to a large extent, for the difference in response to anti-TNF plus methotrexate between methotrexate-naive patients and those with an insufficient response to methotrexate and long-standing disease (Figure 2a,d); thus, initial treatment with biologic agents plus methotrexate leads to overtreatment in a substantial proportion of patients who would respond very well to methotrexate monotherapy. Moreover, when methotrexate is combined with low-dose glucocorticoids the proportions of patients reaching LDA are even higher Mtx ile % 25’lere yakın ASAS70 yanıtı elde edilir Daha başlangıçtaki biyolojik + Mtx kombinasyonu bazıları için ‘overtreatment’ olabilir

Biyolojik yeni ilaçlarda öngörü yanıltır
IL 17 ve IL12/23 blokerleri A TNF’ler RA’da A TNF rezistan hastalarda çok etkin değil IL 17 inh, pSA’da oldukça etkili, RA’da orta düzeyde etkili IL 17 AS’de etkinlik RA’ya göre daha iyi, ancak Chron alevlenmesi yapar Secukinumab Chron’da iyidir. Hemen hemen her hastalıkta etkili TNF belki de her mekanizmanın üzerinde hiyerarşik bir dominansa sahip olabilir IL 6 Blokerleri Furthermore, as seen with alternative TNF-blockers, rituximab and abatacept,39,40,42 both IL‑17 and IL‑12/23 inhibition seem to be less efficacious in patients with RA or psoriatic arthritis (PsA) who previously had an insufficient response to TNF-blockers than in those naive to such therapy.62,63 These findings can be interpreted in several ways. For instance, all the cytokines or cell populations targeted by these agents might act, at least partly, via induction of TNF and/or other proinflammatory cytokines, or TNF might be hierarchically above all or most of these cytokines. Alternatively, the targeted molecules could have numerous functions and the functions perceived as being of primary importance are mostly independently associated with the disease and are not major drivers of the inflammatory response. Determining the optimal treatment for a patient with RA is, therefore, challenging, considering the aforementioned clinical observations. Additional insights have come from the differential efficacy of various biologic therapies in different immune-mediated inflammatory diseases. Whereas TNF-blockers quite pronouncedly improve PsA, ankylosing spondylitis (AS), psoriasis and—with the exception of etanercept66—inflammatory bowel disease, IL‑6 inhibition, for example, is ineffective in AS67 and has only limited efficacy (at high doses) in Crohn disease.68 IL‑17 inhibition seems to be highly effective in psoriasis69 and seems to convey good efficacy in PsA,70 but is only moderately effective in RA;25,62,71 in AS it might be proportionally more efficacious than in RA when related to the efficacy of various approved agents,72,73 whereas Crohn disease has even worsened following anti-IL‑17 therapy.74 Ustekinumab, an inhibitor of IL‑12 and IL‑23, is likewise highly effective in psoriasis,75 has significant efficacy in PsA (although proportionally less than TNF-inhibitors),76 and has good efficacy in Crohn disease.77 Who could have predicted all that? The fact that all these targeted therapies have differential efficacy in various disorders, whereas TNF inhibition works well in all of them, suggests that different cells and cytokines drive the different disease processes, but that all of them activate TNF as a common pathway of the inflammatory response that leads to the clinical manifestations of the disease. This does not preclude the notion that TNF might act upstream of some cytokines, such as IL‑1 and IL‑6. RA’da etkin AS’de inefektif Çok yüksek dozlarda Chron hast.’da sınırlı etki

Optimum sonuç alabilmek

Tedaviyi kişiselleştirmek
Hedefe tedavi (treating to target) Fırsat penceresi (window of opportunity) Sıkı hastalık kontrolü (tight disease control) Optimizing response to therapy In this section, we discuss the current concepts guiding treatment decisions in RA. Rather than being ‘individualized’ on a molecular level, RA treatment is ‘personalized’ on clinical grounds by using the well-established T2T strategy to achieve the best therapeutic outcome. Before going into further detail of the T2T approach, we first address some important aspects related to what constitutes a good outcome and how the achievement of treatment goals depends on these definitions, as well as the hypothesized ‘window of opportunity’ for RA therapy.

Sonuçları iyi tartabilmek
Alternatif hedef Remisyon* Düşük hastalık aktivitesi** Aktif RA Uzun süreli remisyon Uzun süreli düşük hastalık aktivitesi 1-3 ayda bir hastalık aktivitesini değerlendirin 3-6 ayda bir hastalık aktivitesini değerlendirin Temel hedef Tedaviyi hastalık aktivitesine göre düzenleyin Kötüleşme olursa tedaviyi düzenleyin Erken hastalık Comorbidite İlaç etkileşimleri Defining ‘good outcomes’ DAS28-defined remission rates are often higher than ACR70 response rates, which is a clear-cut contradiction given that ‘remission’ cannot possibly be more prevalent than 70% improvement. Therefore, future publications focusing on remission should solely use the ACR–EULAR definition of remission. Indeed, regulators regard DAS28 <2.6 as a reflection of LDA.90 From now on, when treatment adaptations or withdrawal of biologic DMARDs are studied, one must consider these different definitions. Importantly, stringent remission according to the ACR–EULAR definitions is not rare in clinical practice, being achieved by ~25% of patients. An initial systematic literature review yielded four studies, foremost the TICORA trial,107 that clearly addressed the success of targeted therapy using tight control and corresponding treatment adaptations, and several other trials that provided supportive evidence. The 4 overarching principles and 10 recommendations of T2T in RA advocate remission as the optimum target, especially for patients with very early disease who are initiating therapy with DMARDs, and LDA as an alternative second-best target, especially for patients with longer-standing disease. In summary, adherence to the T2T concept leads to better outcomes than ever previously achieved in RA. Importantly, however, this conclusion pertains to the group level. In clinical practice, at the level of the individual patient, many factors have to be considered, especially once LDA has been achieved. Comorbidity, which has already been mentioned in this context, can limit the intensity with which one can implement or amend therapy. Also, one has to consider drug-related risks, financial costs and the potentially low magnitude of additional benefit when trying to move a patient from a state of LDA to one of stringent remission. For example, the therapeutic goal for a patient who has already achieved LDA might be influenced by whether achieving stringent remission would necessitate increasing the dose of methotrexate slightly or adding another, in particular a biologic, agent. Such decisions will of course also depend on the particulars of residual joint involvement, functional impairment and risk of damage progression. Therefore, in the context of the realization of the T2T approach in clinical practice, it is important to be particularly aware of recommendation #9: “The choice of the (composite) measure of disease activity and the level of the target value may be influenced by consideration of co-morbidities, patient factors and drug-related risks.” This important item, which is also discussed in detail in the original publication of the T2T recommendations, is usually insufficiently appreciated, or even overlooked, in reviews on T2T OKUMA The various criteria for the modern therapeutic goals of remission and LDA merit consideration. LDA is defined by cut-off points of composite measures. When employing various versions of the disease activity score (DAS), for example, the cut-off point for LDA is <3.2 for 28‑joint DAS (DAS28) and <2.4 for 44‑joint DAS (DAS44).15 When using the simplified or clinical disease activity indices (SDAI, CDAI), the LDA cut-off points are ≤11 and ≤10, respectively. LDA is a state in which progression of joint damage is minimal and physical function, quality of life and work capacity are largely preserved.78,79 Inherently, LDA implies some residual inflammation, albeit at a low intensity. Importantly, differences in the proportions of patients who achieve LDA according to its various definitions are small.38,80 This similarity in LDA rates is not paralleled by the remission-definitions of these composite measures. DAS-based definitions of remission allow for substantial residual swollen joint counts and other abnormalities, including progression of joint damage.81–85 By contrast, the definition of remission provided by the ACR and EULAR in 2011 is based on Boolean as well as SDAI and CDAI criteria, and attaining any of these states is associated with optimal structural and functional outcomes.86 DAS28-based definitions of remission were excluded by virtue of their failure to differentiate sufficiently between ‘good’ and ‘bad’ structural outcomes as related to the general understanding of clinical remission, which was confirmed in studies that showed substantial ultrasonography-detected residual disease activity in patients in DAS28-defined remission, with little difference compared with those not in DAS28-defined remission.87,88 Thus, when publications allude to ‘clinical remission’, it needs to be borne in mind that a significant proportion of patients who achieve DAS28-defined ‘remission’ (that is, DAS28 <2.6) do not fulfill stringent remission criteria; Uzun süreli hastalık DAS 28 remisyonu tartmak açısından bonkördür ve ACR 70 yanıtından daha fazla remisyon bulur ACR EULAR remisyon tanımı baz alınsa iyi olur ki bu ölçekle remisyon %25 civarındadır.

6 ay 3 ay Hedefe yürürken zamanlama
Hastalık aktivitesinde ilaçla ilk 3 ayda elde edilen başarı ya da başarısızlık uzun dönemde paralel gelişmelerin habercisi olabilir. İlaç rejimi ile hedef 6 ayda tutturulmalı ancak 3 ayda major gelişme yoksa rejim gözden geçirilir ve değiştirilir Treating to target Risk factors for progression of joint damage have long been known and it has also been well established that effective therapy slows progression of joint damage and improves physical function and that damage is halted when stringent remission is achieved (even by use of conventional synthetic DMARDs). Moreover, early change in clinical disease activity (during the first 3 months) as assessed by composite measures was found to be associated with attainment of remission or LDA at subsequent time points (6 months to 1 year) and, more importantly, even despite some clinical improvement, maintenance of a high disease activity state by such composite measures at 3 months predicts the unattainability of LDA or remission with continual therapy (including biologic agents). Finally, attaining stringent remission according to ACR–EULAR criteria is associated with less comorbidity and normalization of cardiovascular risk factors and of quality of life. Taking all these RA‑related data together, and considering the successful prevention of organ damage in patients with diabetes mellitus, hypertension and hyperlipidemia by aiming for respective targets, an international task force developed a set of T2T recommendations for optimizing structural and functional outcomes in RA. The basis of T2T is regular assessment of disease activity and adaptation of therapy at least every 3 months if the treatment target has not been reached, with the proviso that other factors, such as comorbidity or drug-related risk, do not preclude such adjustments. Importantly, the recommendations make clear that the target should be reached within ~6 months, but that “in patients in whom the disease activity did not show major improvement within 3 months, changing the drug regimen may have to be considered at that early point in time”. Since the T2T recommendations also advocate the involvement of the patients in decision-making, a version for patients was also developed The T2T concept was incorporated into the 2010 EULAR recommendations for the management of RA and is also included in the 2013 update; the latest ACR recommendations also set the target of treatment in accordance with the T2T recommendations.

Fırsat Penceresi Bu nedenle T2T prensiplerini uygulamaya olabildiğince
Exploiting the ‘window of opportunity’ Two decades ago we learned that early DMARD therapy enables early interference with inflammation as well as cartilage and bone destruction and the development of irreversible disability, thus improving the overall long-term outcome in patients with RA. Such observations confirmed the need to treat RA early and intensively rather than using the ‘start low, go slow’ pyramid approach. As the activation of the destructive processes of RA requires higher levels of proinflammatory cytokines than required for the induction of inflammation, even incomplete inhibition of the signs and symptoms of inflammation will have profound protective effects on cartilage and bone. Hence, reducing the inflammatory load that induces joint damage will interfere with the early destructive processes of RA or, if it is halted early enough, prevent joint damage from developing at all—a conceived ‘window of opportunity’ to alter the natural history of the disease (Box 1). In this respect, close adherence to the principles of T2T as early as possible (in the first 12–16 weeks after symptom onset or diagnosis) seems especially important; essentially, all study data show an impressive effect of T2T on radiographic progression and overall prognosis, particularly in patients with early RA. Bu nedenle T2T prensiplerini uygulamaya olabildiğince erken başlamak (ilk 3-4 ay içinde) mükemmel olur.

Hedefe tedavi ve fırsat penceresi
ADA + MTX kombo Acaba önceki tedavilere göre azalan yanıt, zaman kaybından mı? The T2T recommendations have meanwhile been validated in several studies. Importantly, however, T2T trials now enable revisiting of the phenomenon of diminishing responsiveness with increasing previous drug experience, as discussed above and shown in Figure 2. Specifically, it was never absolutely clear whether the lower efficacy of biologic therapy plus methotrexate in patients with active disease despite methotrexate therapy, relative to the efficacy of this combination in methotrexate-naive patients, was a consequence of prior drug experience or rather of longer disease duration. In the OPTIMA trial,113 patients with very short disease duration (~4 months) who were treated with methotrexate and did not achieve the target of stable LDA within 6 months received additional adalimumab and had response rates that were very similar to the response rates of patients who received this combination therapy from the outset of this study or in another trial that enrolled methotrexate-naive patients. Indeed, the response to the addition of adalimumab in this ‘methotrexate failure’ OPTIMA population (disease duration now ~10 months) was much greater than in previous trials (such as DE019) in patients with long-standing disease of several years (usually >5 years) that was active despite methotrexate therapy (Figure 2d).50 Thus, when treatment is rapidly adjusted early in the disease course, biologic therapy plus methotrexate is just as successful in those who initially received methotrexate monotherapy (and still had moderate to high disease activity) compared with those who received biologic therapy plus methotrexate from the start and, therefore, rather than methotrexate experience, it seems to be longer disease duration, or long-term use of ineffective therapy, that elicits a treatment-refractory state. Thus, amending therapy within a short period, such as after 6 months in a treatment approach aimed at LDA or remission, will maximize good outcome. In other words, the aforementioned ‘window of opportunity’ does not close if methotrexate monotherapy is introduced instead of a combination regimen that incorporates biologic agents for patients newly diagnosed with RA, but it might close if stepping up of therapy in those who need it occurs too late, further suggesting some ‘imprinting’ of the disease process with increasing disease duration. Eğer optimada olduğu gibi MTX yanıtsızlığını 6 ayda saptayıp ek olarak ADA verirseniz MTX naif hastalardaki etkinliğe ulaşırsınız. Yani T2T burada önemli, yoksa etkisiz ilaçta zaman kaybedersiniz. Ama MTX ile başlama şansınız da sürer…. Smolen, J. S. the randomised controlled OPTIMA trial. Lancet 383, 321–332 (2014).

sonuçları koruyabilmek (Tedaviye kesin devam etmek zorunda mıyız?)
Elde edilen sonuçları koruyabilmek (Tedaviye kesin devam etmek zorunda mıyız?) One key question, and the other major focus of this article, pertains to clinical strategies for the treatment of patients who achieve a good response with appropriate therapy, and who often ask whether they will have to continue that therapy indefinitely. Data have accrued over the past few years that provide some supportive, and some even conclusive, evidence for at least a few facets of these strategies. In this section, we address the evidence for tapering of therapy according to several aspects: the type of DMARD (conventional synthetic versus biologic DMARDs); the duration of RA (established versus early disease); and the type of the biologic agent. In addition, we consider these strategies in the context of the ‘window of opportunity’ hypothesis.

Daha küçük çaplı çalışmalarda bu oran % 80-100 vs % 20’dir
. Remisyonu sürdürmek zordur Remisyonda iken aldığı csDMARD kesilenlerde 1 yıldaki relaps % 40 tır ve kesilmeyenlere göre 2 kat fazladır Daha küçük çaplı çalışmalarda bu oran % vs % 20’dir ten Wolde, S. et al. Lancet 347, 347–352 (1996). One of the most comprehensive studies in this regard was performed almost two decades ago by ten Wolde et al., who randomly assigned patients who had achieved stringent remission (as defined at the time) to continue any of the employed conventional synthetic DMARDs or exchange them for placebo. Within 1 year, flares had occurred in ~40% of patients from whom active drugs were withdrawn, almost twice the frequency as among those who continued therapy. Indeed, in previous smaller trials, all of 5 patients who discontinued methotrexate therapy experienced flares, and 15 of 19 (80%) of patients undergoing withdrawal of penicillamine (compared with 20% who continued treatment) flared. The ten Wolde et al. study further demonstrated that restoration of remission is difficult, as 70% continued to have some disease activity despite reinstitution of the originally effective conventional synthetic DMARDs, although most experienced some improvement. Thus, although drug-free remission might be viable in some patients, withdrawing therapy is quite risky in terms of both losing the state of remission and difficulties in regaining a good outcome after a post-withdrawal flare. A 2010 systematic review on this aspect reached a similar overall conclusion. İlaç kesildiği için atak geçirenlerde yeniden başlanan tedavi ile başarı oranı % 70’dir ten Wolde, S. Ann. Rheum. Dis. 56, 235–239 (1997).

Kombinasyondaki MTX’i azaltmak
Regarding tapering of conventional synthetic DMARDs used in combination with a biologic agent, no formal studies are available. Indirect evidence exists for methotrexate in combination with adalimumab from the CONCERTO study. In this randomized study, the efficacy of methotrexate used at doses of 20 mg per week and 10 mg per week was comparable, whereas weekly doses of 5 mg and 2.5 mg were less efficacious. This result might indicate that, in patients achieving the treatment target on combination therapy, reduction of the methotrexate dose to 10 mg per week could be viable and safe. However, the results of this study might be specific to the interaction of methotrexate and adalimumab—and probably other TNF-blockers as well, given the greater efficacy of all of them in combination with methotrexate compared with monotherapy—but they might not be generalizable to the combination of methotrexate with other biologic agents. Indirek kanıt: ADA ile kombinasyondaki MTX’i 5 veya 2.5 mg/haftaya düşürmek etkisiz.. Burmester, G. R. the randomised CONCERTO trial. Ann. Rheum. Dishttp://dx.doi.org/ /annrheumdis

Biyolojik ilaçları azaltmak
bDMARD MTX ile kombine kullanılır. Tamamını bırakmaktan ziyade bDMARD kesilmeye çalışılabilir. Erken başlanan bDMARD’ı bırakmak daha olasıdır. Tam remisyonda bırakmak daha olumludur. Withdrawal of biologic DMARDs When considering withdrawal of biologic DMARDs, one may have to take various factors into consideration. Firstly, biologic DMARDs are usually combined with conventional synthetic DMARDs because of the enhanced efficacy of such combinations and, therefore, withdrawing the former but continuing the latter could lead to different results than stopping all DMARDs. Secondly, the use of biologic DMARDs early in the course of RA could modify inflammatory events and prevent chronicity, by interfering within the hypothetical ‘windows of opportunity’ when the inflammatory events could still be modified and chronicity prevented (Box 1); thus, the results of stopping biologic therapy might differ depending on the time of their institution. Finally, one might consider that stopping a particular therapy should be attempted only if stringent remission, rather than residual disease activity (LDA), is achieved; by analogy, who would start reducing treatment in a patient with hypertension whose blood pressure did not yet consistently reach normotensive values?

Relaps oranı % 50-90 arasındadır
Oturmuş hastalıkta bDMARD’ı kesmek daha zordur Relaps oranı % arasındadır Established versus early disease Withdrawing biologic DMARDs in established RA A number of open-label withdrawal studies have been published (Table 1). In the RRR study, Tanaka et al. investigated withdrawal of infliximab in 114 patients who had achieved DAS28-defined LDA for >24 weeks by treatment with infliximab plus methotrexate.130 In 55% of the patients, LDA was maintained for >1 year after infliximab withdrawal, whereas 45% failed to maintain that target; however, almost 90% of patients in whom infliximab was restarted after flare regained a state of LDA. The probability of maintaining infliximab-free LDA increased with shorter disease duration, lower disease activity, and longer duration of LDA before withdrawal. Similar data were obtained from a study of adalimumab withdrawal in a similar study design.131 Somewhat different results were obtained in a study by Saleem et al.,132 in which only 3 of 20 patients (15%) with long-standing disease were able to maintain a good response (DAS28-defined remission) after stopping a TNF-inhibitor, and those whose disease flared had difficulty reassuming the good outcome upon reinstitution of therapy. However, among the 27 patients in the study who had received early anti-TNF therapy, 16 (59%) were able to maintain a good response even after withdrawal of biologic therapy. Also, in yet another study of long-standing disease, 15 of 20 patients (75%) in whom TNF inhibitors were withdrawn experienced a disease flare. Thus, overall, withdrawal of biologic agents in patients with established disease who had previously failed to respond to DMARDs, particularly methotrexate, is consistently associated with disease flares, in ~50–90% of patients across trials. In this respect, open-label and randomized controlled trials provide similar results, and these results are probably pertinent to all biologic agents. Importantly, however, dose reduction of biologic therapy seems to be viable, and doubling the interval between doses also seems to be an important option for clinical practice, at least in established RA. Çalışmalar daha çok Anti TNFlerle ilişkiidir. Ancak bir tocilisumab çalışmasında ve rituksimab ile deneyimler aynı yöndedir.

Başarılı bDMARD kesmenin kriterleri
Kısa hastalık süresi Düşük hastalık aktivitesi İlaçla uzun süren iyilik hali

bDMARD’larda dozu azaltmak
In all these trials, the biologic agents were discontinued in an open-label fashion. The PRESERVE trial, on the other hand, used a randomized double-blind design to compare withdrawal of etanercept with full-dose continuation or dose reduction after attainment of sustained LDA in patients with RA (duration ~7 years).134 As shown in Figure 3, LDA was lost in a large proportion of patients upon withdrawal of etanercept despite continuation of methotrexate, starting within 1 month of withdrawal. By contrast, there was little difference in the proportion of patients who maintained LDA with continuation of full-dose (50 mg weekly) or half-dose (25 mg weekly) etanercept therapy. Indeed, >80% of patients continuing etanercept maintained their LDA for 1 year, whereas this was the case in only ~40% of those who discontinued therapy, and stringent (SDAI-defined) remission was maintained in only one-third as many patients who discontinued etanercept than who continued with full-dose or half-dose etanercept (Figure 4). Moreover, progression of joint damage recurred in patients who discontinued etanercept.134 Thus, in accordance with the open-label studies mentioned above, withdrawal of biologic therapy was not feasible in most patients with established RA. However, the PRESERVE trial compared cessation and dose reduction for the first time, and reducing the etanercept dose by 50% enabled maintenance of response to a similar degree as continuing with the full dose. The best predictors of maintenance of remission despite etanercept withdrawal were longer duration of LDA (≥4 months) and lower disease activity at the time of withdrawal. bDMARD’ı kesmekten ziyade dozunu azaltmak daha başarılı görünüyor idamede…. Smolen, J. S. PRESERVE TRIAL Lancet 381, 918–929 (2013).

Erken RA’da ilaçsız devam konusu daha ümitvardır
Erken dönemde biyojik ilaç da içeren ilk basamak indüksiyon tedavisi, uzun dönemde biyolojik ilaç olmadan da %20-35 oranında iyilik hali sağlar Kısa dönem biyolojik ile indüksiyon, Mtx ile indüksiyona göre hastalarda % 70 oranında fazla biyolojik olamadan iyilik halini sürdürme şansı sağlar. It has long been suggested that interfering with RA in its early stages by using intensive ‘induction’ therapy might be beneficial by altering the disease process. Indeed, such a ‘window of opportunity’ has been discussed for several decades and, as mentioned in Box 1, cellular and molecular characteristics of RA might differ in the early and later stages of RA, promoting such thinking. Clearly, if the concepts of a window of opportunity and of the value of induction therapy apply in reality, we should see a large proportion of patients with early RA who receive a biologic agent plus methotrexate as a first-line treatment regimen being drug-fre, or at least biologic-free, in the long term. The results of several such trials are now available Slaytı oku Smolen, J. S. the randomised controlled OPTIMA trial. Lancet 383, 321–332 (2014). Allaart, C. F., Clin. Exp. Rheumatol. 31 (4 Suppl. 78), S14–S18 (2013).

Yeni bir paradigma mı doğuyor?
Çok erken RA’da biyojik ilaç da içeren ilk basamak indüksiyon tedavisi, Hadi inşallah Yeni bir paradigma mı doğuyor? Akabinde ilaçsız tedavi ile kür?

Ancak bu konuda çelişki gösteren çalışmalar da var
Figure 6 | Effect of dose reduction of etanercept, withdrawal of etanercept or withdrawal of both etanercept and MTX on remission and LDA in the PRIZE trial.144 After 1 year of combination therapy (MTX plus 50 mg etanercept) and achieved ‘remission’ (DAS28 <3.2 at 9 months and DAS28 <2.6 at 12 months) patients with RA were randomized to receive MTX plus 25 mg etanercept, MTX monotherapy or placebo (that is, withdrawal of both drugs) for 39 weeks. Data from the PRIZE trial. The PRIZE trial produced somewhat different results. In this study, methotrexate-naive patients with early RA (mean time from diagnosis ~3 months) initially received open-label treatment with methotrexate plus 50 mg etanercept weekly for 1 year; if they achieved ‘remission’ (DAS28 <3.2 at 9 months and DAS28 <2.6 at 1 year), they were randomized to receive a dose reduction of etanercept (to 25 mg weekly), withdrawal of etanercept but continuation of methotrexate, or withdrawal of both drugs; no patients maintained full-dose etanercept therapy for the second (39-week) phase. After withdrawal of etanercept and continuing methotrexate only, 60% of the patients lost their DAS28 <2.6 status, compared with 37% of those who received half-dose etanercept; indeed, 31% of those who discontinued etanercept and continued methotrexate had a DAS28 >3.2 despite having a lower score when etanercept was withdrawn, as compared with 11% who continued etanercept (Figure 6). On the other hand, upon withdrawal of both, etanercept and MTX, <40% of patients maintained DAS28 <2.6 at week 39 (and only 23% at week 68), and in most of them the disease activity increased to a moderate or high level. Thus, drug-free remission or drug-free LDA is infrequent even after an induction regimen with a TNF-inhibitor; even when methotrexate is continued, biologic-free remission is not sustained in a large proportion of patients. In all these respects, it needs to be borne in mind that treatment with etanercept was ongoing for a full year before withdrawal. Another important aspect of the PRIZE data is that if ACR–EULAR remission, whether using the Boolean-based or index-based criteria, is regarded as a cure-like state, then only about one in four patients attained drug-free remission 1 year after stopping etanercept plus methotrexate treatment. We obviously do not know if these patients with early RA achieved remission because of the therapy they received or did so spontaneously; data from the SAVE trial suggest that up to 25% of patients with very early arthritis might experience spontaneous remission at 1 year from the start of observation. How can one account for the different outcomes of OPTIMA or HIT HARD and PRIZE? One could hypothesize that the differences between the trials were either a play of chance or that an induction regimen using an antibody to TNF might differ from an induction regimen using the TNF-receptor construct etanercept, but this is speculative as long as the data from these trials are not confirmed. Thus, further data are needed to enable us to conclude if short-term induction therapy with a TNF-inhibitor plus methotrexate and subsequent withdrawal of the biologic agent should become a new paradigm. Finally, almost all studies addressing induction therapy including a biologic agent followed by withdrawal of the biologic agent focused on TNF-inhibitors. As it cannot be predicted if induction therapies with other biologic agents, such as tocilizumab, abatacept or rituximab, will show similar or different results, such studies should be performed. Erken dönemde indüksiyon alıp remisyona uğrayanlarda, MTX ile devam edilse bile %60 flare var. 1 yıl sonra ilaçsız devam edenşerde %25 oranında kür. Bunlar da spontane remisyona girenler olmasın?

Biyolojik tedaviyi bırakabilme algoritması

O zaman ilk soru kim bu sağlıklı insanlar ve ben onları nasıl bulurum?
Gelecek Perspektifi (Gerçek fırsat penceresi) Future challenges Despite exceptional success in treating RA compared with previous eras, some questions remain open. First, relating to achieving remission it remains enigmatic who will respond best to which therapy, or which factors are related, or not, to future success when introducing a particular therapy. Although these questions have remained resistant to answers at the molecular level, important information has been gleaned from the extent of early clinical responses, such as long disease duration rather than the number of previous treatment courses being a possible limiting factor. Additional insights from biological markers would be valuable. Several of the aforementioned challenging aspects related to patients with established disease who had a successful response to therapy and who, thus, often have achieved a cure-like state on therapy. Curing RA will depend on the recognition of the disease’s cause(s), which are currently unknown. However, we are aware of a preclinical phase of RA with characteristic abnormalities. During this preclinical phase, it should be possible to reverse the disease process by use of therapies that interfere with the abnormally triggered, but not yet pathogenic, immune response—a possibly ‘true’ window of opportunity to interfere in a disease-preventive way (Box 1). The challenge, then, will be to identify these individuals with preclinical RA within the healthy population. Population-level screening for autoantibodies might be too broad an activity, given the relatively high frequency of their presence with no incident arthritis cases within a few years. Innovative approaches in this respect will be needed to provide solutions, and these solutions will only be found by close collaboration between interested centres. Bu dönemde anormal ama patojenik olmayan tetik mekanizmalara müdahaleye ihtiyaç var. O zaman ilk soru kim bu sağlıklı insanlar ve ben onları nasıl bulurum?

Sonuç İlaçsız remisyon erken artritte bile hala uzaktadır ve bazı hastalar için umutvar çalışmaların rafine edilmesi gerekir. Bu çalışmalar devam ederken halen erken RA’da güncel kılavuzlardaki erken cs DMARD tedavi stratejisi devam ettirilecektir. Yerleşmiş RA’da bDMARD’ı bırakmak zordur. Doz azaltmak ve doz aralığını genişletmek olasıdır. Conclusions The data presented indicate that it is difficult to cure RA: drug-free remission is still far from reach, even in early arthritis, and we do not know if patients who have attained drug-free remission in the BeSt or PRIZE studies have done so by virtue of having been treated or as a spontaneous occurrence. In any case, it seems feasible that not only can the dose of a biologic agent be reduced and a good outcome be maintained, as in PRIZE and PRESERVE, but that it might also be possible to successfully withdraw the biologic agent, as in OPTIMA and HIT HARD. The finding in PRIZE that many patients experience a disease flare upon withdrawal of biologic therapy counterbalances the conclusions from OPTIMA and suggests that more information is needed to determine if such withdrawal is feasible in early RA. Until we know more, the way forward should be adherence to the EULAR management recommendations, namely starting treatment with csDMARDs in combination with glucocorticoids, followed by biologic therapy in the case of non-response to the initial regimen and the presence of markers of poor prognosis, and aiming for ACR–EULAR-defined remission (in early RA) or at least LDA (in established RA).57 Moreover, all these data do not support that ‘window of opportunity’ hypothesis which suggests that treatment of early, clinically manifest RA can reverse the disease (Box 1); it does not seem that intensive therapy ‘resets’ the immune-inflammatory system in most patients even when applied early, but rather that, once RA is clinically manifest, chronicity seems to be determined. However, preventive therapy as addressed above may become feasible once we learn how to recognize patients with a high likelihood to develop RA. On the other side of the spectrum, in patients with established RA, withdrawal of a biologic agent is not feasible; however, most of these patients can maintain a good response with a dose reduction or expansion of the interval between doses, as illustrated in the algorithm presented in Figure 7. This is good news for the patients and for the health-care budgets. Given that TNF-blockers in combination with methotrexate have profound effects in clinical practice, it is a bit disappointing that this treatment has to be maintained, especially in most patients with long-standing RA. However, these findings imply that the search for the cause, or causes, of RA must be intensified to enable the development of curative therapies. As much as we have achieved in improving outcomes over the past two decades, a cure for RA is still far from sight.

MTX ve DMARD KOMBO BAŞARISI

Kombine DMARD mı? Biyolojik mi
Methotrexate should be the first-line therapy for most rheumatoid arthritis patients and will produce the desired results in greater than one-third of the patients. When methotrexate is not adequate, triple DMARD therapy should be added which will result in control of approximately another one-third of the patients. Ultimately, and usually before 1 year of disease, the remainder of patients will require biological therapies usually added to conventional DMARDs. There is no evidence that this step-up approach results in any long term disadvantage and good evidence that it results in substantial cost savings. Bir görüş Mtx hastaların üçte birini iyi eder. Yetmezse üçlü DMARD kombo ile diğer üçte biri iyi olur 1 Yıl için de de kalanı biyolojiklere geçer

Bu geçiş zonundaki çalışmalar
Slaytları kısaca anlat….

Hasta özelinde tartmalı
Çalışmalardan çıkan bir genelleme Klinik, yaşam kalitesi Kombinasyon DMARD Biyolojik = Fırsat penceresinde indüksiyon? Radyolojik hasar Kombinasyon DMARD Biyolojik < CONCLUSION No rheumatologist who has been fortunate enough to practice where biologicals can be prescribed wants to go back to the prebiological world. If the biologicals were not expensive, much of the above discussion would be moot. We are certainly not arguing against the use of biologicals in RA; we are arguing for their use in the most appropriate patients. Extrapolation from the above studies suggests that approximately 30–40% of patients will not reach the target despite the best conventional combinations, and therefore should be candidates for the biologicals. If we can first optimize the use of conventional therapy, hopefully, healthcare budgets will continue to allow the increasing use of biologicals in those patients who will benefit the most. Radyolojik hasar ? Maliyet, yan etki Hasta özelinde tartmalı Kombinasyon DMARD Biyolojik >

Kısıtlı kafa kafaya yapılan çalışmalar

TEMPO, PREMIER, ADACTA VE AMPLE

Sonuçlar MTX diğer sDMARD’lara göre kar/zarar oranı en olumlu olan ve ilk basamak tedavide kullanılan bir ajandır. LEF ve SSZ alternatif. TCZ MTX’e bire bir üstünlüğü gösterilmiş tek bDMARD’dır. ADA ve ETN; MTX’e göre yapıyı daha etkin korur ancak anlamlı klinik fark yok. TCZ monoterapisi , ADA monoterapisine göre daha etkin. Güvenlik profilleri benzer. sc ABT ve ADA’nın her açıdan etkinliği benzer. Güvenlik profilleri de oldukça benzer ancak ABT lehine hafif bir kayma var… Conclusions The arsenal of therapeutic options for RA is vast, but knowledge on the optimal use of different drugs in individual patients in typical day-to-day practice remains poor. Over a period of more than 25 years, only 20 head-to-head RCTs comparing two different DMARDs have been performed, providing some preliminary but encouraging suggestion on how to deal with the complexity of the available therapeutic armamentarium. Key messages emerging from direct comparisons are as follows. It is hoped that future years will witness a radical shift in the way medical research is conceived and performed in RA. More direct comparisons and innovative trial designs will help achieving the final goal of treating the right patient at the right time with the right drug. …………………. Slayt bilgileri aşağıda (i) MTX overall risk/benefit ratio is the most favourable compared with other synthetic DMARDs, confirming its use as first line therapy and LEF or SSZ as an alternative treatment in newly diagnosed RA, as suggested by international guidelines [53]. (ii) TCZ is the only biologic DMARD with a demonstrated clinical superiority compared to MTX. ETN and ADA have been shown to be able only to slow damage progression better thanMTX, without significant differences in clinical response. (iii) TCZ monotherapy is superior to ADA monotherapy, with a similar safety profile. (iv) Clinical efficacy, damage progression, and kinetics of response of sc ABT and ADA are comparable. Safety profiles are quite similar, slightly in favour of ABT.

MTX’de toksisiteyi tahmin edebilir miyiz?

MTX toksisitesini etkileyen faktörler
Summary Low-dose MTX for RA treatment is the DMARD with the best efficacy/toxicity ratio. Although MTX-related ADRs are the main cause for MTX discontinuation, it is overall a well-tolerated drug. As a whole, clinical and biological factors are poor predictors of MTX-related toxicity, although clear recommendations can be made to all RA patients starting MTX, such as a gradual dose increase or concomitant folate supplementation at C5 mg/week. General or organ-specific comorbidities, such as obesity or preexisting liver, renal or pulmonary diseases for instance, might predispose to particular types of side effects and advise closer monitoring. On the other hand, older patients, with renal impairment and more comorbidities and concomitant drugs, should have increased surveillance and dose adjustments, as required. Continuous monitoring of the various organ systems is crucial, through clinical and laboratorial periodic assessments. So far pharmacogenetic data have not been consistent enough in order to be clinically useful. However, these data have provided further insight into mechanisms of MTX-associated toxicity and might soon contribute for helpful biomarkers, enabling personalized optimization of treatment. Consolidation of these data in future studies, as well as combination of clinical and biological variables with genetic polymorphisms in genes encoding for proteins involved in MTX action mechanism, will hopefully help to predict MTX-related toxicity, increasing long-term drug retention and, as such, improving RA patient’s care. OKUMA Clinical and biological predictors of methotrexate toxicity As previously discussed, identification of patient smore likely to develop MTX-associated side effects would be of great value in optimizing monitoring, while improving effectiveness and decreasing toxicity. Unfortunately, besides folate supplementation evidence for other clinicobiological predictors is weaker and less consistent, although some conclusions can be drawn for particular subtypes of drug toxicity. In a recent observational study, including 309 patients from an inflammatory polyarthritis inception cohort, %) and 46 (15 %) patients had discontinued MTX due to ADRs at 1 and 2 years, respectively [21]. In the first year, patients stopping MTX due to toxicity had higher baseline disability assessed by the health assessment questionnaire (HAQ, p = 0.02), higher tender joint count (TJC, 0 = 0.05) and lower baseline C-reactive protein(CRP, p = 0.04), whereas at 2 years, only lower CRP was associated with MTX side effects (p = 0.01). Female patients tended to discontinue MTX more frequently, although the difference was not statistically significant (79 vs. 64 % at 1 year, OR 2.2, 95 % CI 0.92–5.28). Multivariate logistic regression analysis demonstrated higher baseline HAQ to be predictive of ADRs only at 1 year (OR 1.87, 95 % CI 1.11–3.15), albeit prediction strength was weak on receiver operating characteristic (ROC) curve analysis (c-statistic 0.69, 95 % CI 0.60–0.79) [21]. Data from the open label CAMERA trial, comparing two RA treatment strategies with MTX ± cyclosporine (CSA), were analyzed regarding toxicity occurrence, and the authors reported that despite none of the baseline variables associated with MTX side effects in univariate analysis, a multivariate approach with 58 % of the patients identified an increased body mass index (BMI) as associated with toxicity-related MTX withdrawal (OR 1.21, 95 % CI 1.02–1.44) [26]. No baseline clinical variables were associated with an increase in alanine aminotransferase (ALT), which was only predicted by a previously increased ALT and creatinine prior to MTX start [26]. The impact of decreased renal function on MTX-related toxicity has been confirmed in a pooled analysis of 11 clinical trials (n = 496) that reported an association between low creatinine clearance with higher overall side effects and a fourfold increase in the odds of severe toxicity, while failing to show any impact of age [42]. Older age did not seem to be associated with increased risk of MTX-related toxicity in several other studies as well [17, 21, 66–69], although some smaller studies did find conflicting results [15, 70], which might be related to different studies methodologies, populations and outcomes definitions. The study conducted by Hoekstra et al. [69], with 411 RCT patients treated with MTX ± folate, confirmed the findings of the CAMERA trial regarding an association of higher BMI with hepatotoxicity and MTX withdrawal, but did not observe any significant influence of renal function on overall toxicity. Furthermore, the authors found prior GI events and younger age to be predictive of GI toxicity (diarrhea), while the former were also associated with MTX withdrawal, alongside female gender and the absence of folate supplementation [69]. Hepatotoxicity does seem to be associated with obesity/high BMI as shown by this and several other studies, in what might be a consequence of underlying hyperlipidemia and non-alcoholic fatty liver disease, as well as with alcohol intake, diabetes mellitus, previous hepatic disease, elevated baseline ALT, MTX dose and the absence of folate supplementation [18, 26, 59,60, 69, 71–74]. In fact, in a recently published retrospective cohort study with 659 rheumatic patients (60 % RA) treated with MTX, history of BMI C 30 kg/m2, raised AST/ALT and total cholesterol, biological treatment and lack of folate supplementation was associated with a 90 % chance of developing transaminases elevation (1.5–10 times) in the 7 months following MTX treatment start, compared to a \5 % probability if none of these factors were present [74]. On the other hand, the association of female gender with MTX-related toxicity withdrawal described by Hoekstra et al. [69] confirms the trend reported by Hider et al. [21], as well as the findings of another smaller study [71]. However, these findings might translate different distribution of risk factors that are gender-related and influence MTX-related toxicity and withdrawal, since they were not consistently confirmed in many other RCTs and observational studies [8, 9, 15, 17, 26, 67]. Myelotoxicity secondary to MTX use, in turn, has been associated with several factors, such as concomitant treatment with non-selective non-steroidal anti-inflammatory drugs (NSAIDs), acetylsalicylic acid or trimethoprim–sulfamethoxazole [75, 76]; hypoalbuminemia [16, 18]; decreased renal function [16] and concurrent infection [11,16]. Moreover, preexisting folate deficiency has also been described as a potential contributor to hematologic toxicity in MTX-treated patients, due to the importance of folic acid in myelopoiesis [59, 77–79], although the benefit of folate supplementation in the reduction in these ADRs has still not been clearly demonstrated in all large recent meta-analysis published, due to insufficient data [60, 62, 64]. Elevation of the mean corpuscular volume (MCV) has been initially suggested as a potential marker of myelotoxicity [78–80], but this has been a controversial subject with other studies failing to replicate these findings, and MCV probably is an insensitive marker of intracellular folate status that does not, alone, enable prediction of cytopenia [63, 81, 82]. As described above, preexisting lung disease characterized by interstitial infiltrates on chest radiographs has been shown to be associated with MTX-associated pneumonitis [14, 35, 36] and previously decreased renal function increases the chances of overall MTX-associated toxicity [42]. On the other hand, in a small study with 25 patients, central nervous system toxicity was more common in older patients with mildly elevated serum creatinine levels, although this has not been confirmed in larger studies [83]. Overall, clinical and biological factors related to patient and disease, including gender, ethnicity, inflammatory markers, RF and anti-citrullinated protein antibodies (ACPA) status, disease duration and disease activity, are poor predictors of general or organ-specific toxicity associated with low-dose MTX, as most studies failed to find any consistent association [11, 12, 17, 21, 26, 69]. Treatment-related variables such as MTX dose, concomitant drugs or folate supplementation are likely to influence MTX-associated side effects. In fact, a systematic literature review including 38 RCTs assessing various doses and formulations of low-dose MTX in RA concluded that starting doses of 25 mg/week, fast dose escalation and initial subcutaneous administration were associated with more ADRs, particularly GI, compared with doses of 5-15 mg/week, slow dose escalation and initial oral administration, respectively [84]. Besides GI toxicity, higher doses of MTX are also associated with increased myelo- and hepatotoxicity, the latter being intrinsically related to cumulative MTX dose over time [11, 12, 71, 72]. NSAIDs or trimethoprimsulfamethoxazole have been associated with increased risk of renal and hematologic ADRs [12, 75, 76]. Combination of MTX with other DMARDs has also been associated with increased toxicity, as revealed in two recent meta-analysis [85, 86]. In the review by Choy et al. combination therapy was associated with a 37 % increase risk of MTX-related toxicity (RR 1.37, 95 % CI 1.16–1.62), with combination of MTX with SSZ and/or HCQ presenting good efficacy/toxicity ratios (RR of toxicity = 0.81, p = 0.66) [85]. In the recent Cochrane Collaboration review by Katchamart et al. [86], combination therapy was more frequently associated with ADR-related withdrawal (RR 1.59, 95 % CI 1.2–2.12), particularly with the combination of MTX with CSA (RR 1.88, 95 % CI 1.02–3.5) or azathioprine (AZA, RR 5.18, 95 % CI 1.58–16.95). Total number of ADRs was higher with MTX ? AZA, but not with MTX ? LEF, which in turn increased GI and hepatotoxicity (RR 1.67 and RR 4.3, respectively, p\0.05). Combination with SSZ was associated with more GI side effects (RR 1.75, 95 % CI 1.14–2.67), but not with hepatic, mucosal or hematological toxicity [86]. However, when considering the gain in efficacy, the authors concluded that there was no significant advantage of one treatment regimen over another 5 mg/hafta folatın koruyuculuğu kanıta dayanır. Kadınlar ilacı daha fazla bırakıyor Obezlerde yan etki daha fazla Renal yetm riski arttırır. Kombinasyon yan etkileri arttırır. Pulmoner lezyonlar AC yan etki oranını arttırır.

GLUKOKORTİKOİD TEDAVİDE YENİLİKLER

Eular önerilerindeki değişiklikler

ACR 2015: Erken ve Oturmuş RA’da GK
Bu hastalar atak yaşarlarsa veya hastalık orta yüksek düzeyde kalırsa Ataklarda: Kısa dönem GK TEDAVİSİ Hala orta yüksek aktivite: Rejime ek düşük doz GK

TEDAVİ YÖNLENDİRMEDE ULTRASON

Remisyon belirlemede US bir şey katar mı?

Klinik remisyonda US ile bulunan aktif sinovit oranı
B MODE % 36 PD % 15 ConclusionThe main goal in the treatment of RA is to achieve remission and to prevent structural damage, which is a majorsource of future disability. Several scores are available to define remission. According to this review of the literatureon RA in remission and despite the heterogeneity of articlesincluded, US synovitis was present in patients in remission whatever the score used. US activity was found to be at least 36% with B-mode and 15% with PD depending on the study. Moreover, persistent synovitis was predictive of possible relapse and joint deterioration. Ideally all joints should be evaluated to assess RA activity. However, in daily clinical practice, this would be tedious and time-consuming. To date, there is no validated score that precisely defines the joints to be explored. However, a good correlation has been found between evaluation of the wrist and MCP joints ofthe dominant hand and RA activity on remission. Dominant el bileği ve MCP eklemler klinikte yol gösterebilir

Gelecekteki remisyon tanımlamalarında US yer bulabilir
Conclusion: US seems to be more effective than a clinical exam. True remission in RA must be defined. Moreover, the inclusion of this technique in the new definition of remission is being validated. Finally, the confirmation of remission by US seems necessary to determine the therapeutic strategy, avoid relapse and especially future structural progression. While waiting for new criteria of RA in remission, US should be performed more frequently in daily practice and repeated if necessary. Tanımlamaları beklerken klinikte fazlaca kullanmalıyız

PATOFİZYOLOJİDEN TEDAVİYE

HLA DR B1 PTPN22 TNFAIP3 STAT 4
Kısa ve kabaca özetlemek gerekirse…………….: Environment–gene interactions promote loss of tolerance to self-proteins that contain a citrulline residue, which is generated by post-translational modification. This anticitrulline response can be detected in T-cell and B-cell compartments and is probably initiated in secondary lymphoid tissues or bone marrow. Thereafter, localization of the inflammatory response occurs in the joint. Synovitis is initiated and perpetuated by positive feedback loops and in turn promotes systemic disorders that make up the syndrome of rheumatoid arthritis. Critical issues remain unresolved. Autoantibodies,such as rheumatoid factor and ACPA, are often (but not always) detected in patients before the development of arthritis (prearticular phase of rheumatoid arthritis); Why the systemic loss of tolerance is linked to a localized onset of inflammation in the joint is still unclear (transitional phase of rheumatoid arthritis). It is possible that biologic features of the targeted autoantigen (e.g., regulation of cellular metabolism in the case of α-enolase and glucose-6-phosphatase) may contribute. Other possible factors include local microvascular, neurologic, biomechanical, and microtrauma-related mechanisms.

Zaten romatoid artritin etyopatogenezini kısaca özetleyecek olursak:
Bu kabaca Adaptive and Innate Immune Processeslerin ortak hareket ettiği bir süreçtir: The costimulation-dependent interactions among dendritic cells, T cells, and B cells are shown as occurring primarily in the lymph node; these events generate an autoimmune response to citrulline-containing self-proteins. In the synovial membrane and adjacent bone marrow, adaptive and innate immune pathways integrate to promote tissue remodeling and damage. Positive feedback loops mediated by the interactions shown among leukocytes, synovial fibroblasts, chondrocytes, and osteoclasts, together with the molecular products of damage, drive the chronic phase in the pathogenesis of rheumatoid arthritis. …………………………………………………………………….. Zaten romatoid artritin etyopatogenezini kısaca özetlitecek olursak: Depo: B cell kaynaklı Ab üretimi (ACPA) form immun complexes and accumulate in joints activating compleman. This leads to recruitment of effector cells (Makrofaj, nötrofil) which secrete proinf. Sitokins, kemokins and activate osteoklastogenesis. NEJM, 2011;365:

RA’DA hedefli tedaviler
(Targeted Therapies) RA is a systemic autoimmune disease characterized by synovial inflammation and destruction of cartilage and bone. RA has a prevalence of 1% and affects three times more women than men. Although the exact etiology remains an active area of worldwide research, it is generally accepted that RA is a multifactorial disease in which both genetics as well as environmental factors have an important role. Genetic predispositions that affect T cell activation [such polymorphisms in the genes encoding major histocompatibility complex, class II, DR beta 1 (HLA-DRB1), protein tyrosine phosphatase, non-receptor type 22 (PTPN22), cytotoxic T-lymphocyte-associated protein 4 (CTLA4), and signal transducer and activator of transcription 4 (STAT4)] as well as the presence of autoantibodies, such as rheumatoid factor (RF) and anticitrullinated protein antibodies (ACPA) produced by plasma cells, indicate that in addition to the innate immune system, adaptive immune cells, such as T and B lymphocytes, also contribute to the disease pathogenesis

Hastalığı kür edebilmek gündemde yok
Curing RA is still out of our reach, and the induction of immunologic tolerance will not be achieved until the driving autoantigen(s) in RA have been fully identified. This search for autoantigens is increasingly complicated because it has become clear that the development of RA is characterized by an accumulation of multiple autoantibody specificities (so- called ‘epitope spreading’), which differs in individual patients with RA. However, there is a broad spectrum of antirheumatic drugs available to reduce painful symptoms and slow the progression of the disease. Current treatment strategies for RA include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, disease-modifying antirheumatic drugs (DMARDS) and biologic response modi- fiers (‘biologicals’). Previously, rheumatologists typically started treating patients with newly diagnosed RA with NSAIDs to reduce pain and joint swelling. Currently, such patients are treated more aggressively and joint damage is prevented with DMARDs, such as methotrexate (MTX), hydroxychloroquine, leflunomide, or sulfasalazine, and, depending on symptoms and stage of the disease, a combination of several DMARDs or a DMARD plus biological treatment has been demonstrated to be favorable for the disease outcome, resulting in 35% of patients with RA showing at least a 50% improvement in their American College of Rheumatology (ACR) criteria for treatment responses, and even 15% reaching the ACR70 response (indicating 70% improvement) Etkili olan oto antijenler tam bulunamadıkça ki bunlar kişisel bazda da değişebilir, immun tolerans sağlanamayacak, hastaların şimdi olduğu gibi % 15’i ACR 70; % 35’i de ACR 50 yanıtı sağlayacak en fazla…

Güncel tedavide neredeyiz ?
Hastaların %30’na kadarında ilk biyolojikten switch gerekir In contrast to the success of TNF blockade in arthritis, inhibitors of IL-1 (the IL-1 receptor antagonist anakinra and the anti-IL-1 monoclonal antibody canakinumab) have been regarded as inferior to TNF inhibitors in suppressing joint inflammation in patients with RA [3], although these IL-1 blockers are now effectively used in the clinical treatment of autoinflammatory syndromes as well as in patients with gout [4]. Over the past decade, the repertoire of biological drugs for RA has rapidly expanded, with new inhibitors targeting other pathways of the disease, including tocilizumab, abatacept, and rituximab (Figure 1). Tocilizumab was the first biological used to target the IL-6 pathway by binding to the IL-6 receptor, thereby prevent-ing the cell becoming activated by IL-6. Abatacept blocks the interaction of antigen-presenting cells (APCs) and T cells at the level of co-stimulatory signaling. This CTLA4-immunoglobulin (Ig) molecule binds to CD80 and CD86 receptors on the APC, selectively blocking the binding to CD28 on T lymphocytes and preventing the immunological response. Randomized trials have shown good clinical efficacy with this biological in RA [5]. Rituximab is an anti-CD20 antibody that depletes CD20-positive B cells by complement-mediated cytotoxicity, antibody-dependent cell-mediated cytotoxicity, or induction of apoptosis. Although TNF inhibitors are the first-in-line biological treatment for RA, these new biological therapies are considered to have similar efficacy and safety compared with TNF inhibitors; the current European League Against Rheumatism (EULAR) recommendation is that if the first biological fails in a patient with RA, any other biological may be used [6]. However, despite the success of these biological DMARDs, up to 30% of patients with RA still may not respond adequately and a change to other medication is required [8]. Ocrelizumab Ofatumumab Belimumab Tabalumab

JAK yolağı JAK inhibitors to fight RA Recent recommendations by expert rheumatologists pro-posed tofacitinib as a targeted synthetic DMARD (tsDMARD) to be used in the treatment of RA after the failure of at least one biological DMARD [6]. Tofacitinib is the first therapeutic compound that targets the intracellu-lar JAK signaling pathway. JAK is a family of intracellular tyrosine kinases that have a pivotal role in the transduction of cytokine-mediated signals via the JAK–STAT path-way (Figure 2). Tofacitinib Tofacitinib is a novel, oral JAK inhibitor and was the first US Food and Drug Administration (FDA)-approved small molecule for RA. It is a JAK inhibitor that preferentially inhibits JAK3 and JAK1. OKUMA Recent clinical trials demonstrat-ed that tofacitinib showed comparable efficacy to TNF inhibitor treatment in patients with RA who were also using MTX [11], and that this combination of tofacitinib plus MTX was also an effective alternative treatment for patients who were not responsive to TNF inhibitors [12]. Tofacitinib has even been suggested as a new first-line monotherapy, having superior efficacy over MTX in the treatment of RA [13,14]. In tofacitinib-treated patients, a clear reduction in synovial STAT1 and STAT3 phosphor-ylation was observed [15]. Interestingly, this JAK1/JAK3 inhibitor also affected the activity of human dendritic cells (DCs) by decreasing CD80/CD86 expression and T cell stimulatory capability through suppression of type I IFN signaling [16]. However, tofacitinib was not approved by the European regulatory agencies in 2013 because of its overall safety profile. The use of tofacitinib has been asso-ciated with an increased risk of serious infections, malig-nancy, and lymphoma. Tofacitinib treatment has also frequently been associated with an increase in both low-density and high-density lipoprotein cholesterol levels and with reductions in neutrophil counts [11]. However, serious infections and malignancies are not unique to JAK inhibi-tion and are also reported risks for biological therapies. New safety data claim that the overall risk of infections and mortality rates in patients with RA treated with tofacitinib are similar to those observed in patients with RA treated with biologic agents [17].

infeksiyonlara dikkat
Geliştirilen yeni Jak inhibitörleri Hiperkolesteolemi ve infeksiyonlara dikkat Ruxolitinib & baricitinib TYK2* JAK1 JAK1 JAK2 TYK2 JAK1 JAK2* JAK2 TYK2 JAK1 JAK3 JAK2 JAK2 Following binding of a cytokine to its transmembrane receptor, two members of the JAK family trans-phosphorylate each other and subsequently activate STATs, which dimerize and translocate to the nucleus, where they modulate the expression of target genes that mediate cell proliferation and differentiation. Given that JAKs have pleiotropic effects in many regulatory and immune pro-cesses, nonselective inhibition increases the risk of toxicity and adverse events, such as hypercholesterolemia and increased incidence of infections [10]. JAK inhibitors in development Ruxolitinib and baricitinib are two other nonselective JAK inhibitors that mainly target JAK1 and JAK2, and have been tested for the treatment of myelofibrosis (Phase III [18]) and RA (Phase IIb [19,20]). More selective inhibition of the JAK pathway might reduce the risk for adverse events, and several selective JAK inhibitors are currently investigated in clinical trials. Filgotinib, which selectively targets JAK1, showed promising 4-week results in a Phase IIa trial with patients with active RA taking MTX [21], and is currently being tested in an ongoing phase IIb trial. INCB also selectively targets JAK1 and demon-strated clinical efficacy in a recently reported 12-week phase IIa trial [22]. Decernotinib is a selective JAK3 inhibitor, and treatment of patients with active RA failing at least one DMARD resulted in improved clinical signs and symptoms of RA at week 12, although infections and increases in liver enzymes and cholesterol levels were reported as potential safety issues [23]. An increasing number of pharmaceutical companies are exploring this interesting therapeutic area of intracellular targeting, each with their own specific JAK inhibitor. Therefore, improving the balance between clinical efficacy in RA and the risk for serious adverse events with new kinase inhibitors might be a matter of time, but for the moment, close monitoring for adverse effects is essential. Growth/ maturation lymphoid cells Differentiation/ homeostasis T cells, NK cells B cell class switching Inflammation Antiviral Inflammation† Antitumor Naive T cell differentiation T cell homeostasis Inflammation Granulopoiesis Antiviral Inflammation Innate immunity Differentiation/ proliferation of Th17 cells Inflammation Erythropoiesis Myelopoiesis Megakaryocyte/ platelet production Growth Mammary development FUNCTION3 Filgotinib: Selektif Jak 1inh, Decernotinib: selektif JAK3 inh.

Yeni Hedef: T17 yolağı Targeting the Th17 pathway in RA Another ‘hot topic’ in the field of RA is the IL-17/Th17 pathway. IL-17 is a proinflammatory cytokine that is mainly, but not exclusively, produced by Th17 cells.

Bu yolak otoimmun hastalıklara yol açtığı gibi (RA, Psoriazis),
IL 17/ T17 yolağı’nı hedeflemek Following the discovery of the Th17 cell, research over the past decade has focused on both the differentiation process and the effector cytokines of this cell. Th17 differentiation from naıve CD4+ T cells is mediated by a combination of mediators, including IL-6, transforming growth factor (TGF)-b, and IL-23 , and is characterized by the transcription factor RORgT. IL-17, or IL-17A to be more accurate, is its hallmark cytokine, but Th17 cells can also produce other cytokines, such as IL- 17F, IL-21, IL-22, and GM-CSF. IL-17 and IL-17F, either as homodimers or heterodimers, bind to their ubiquitously expressed IL-17 receptor to induce proinflammatory responses. The IL- 17/Th17 pathway not only promotes host defense against extracellular bacteria and fungi, but is also associated with autoimmune diseases, such as RA and psoriasis. IL-17 and CD4+ IL-17-producing Th17 cells are enhanced in patients with RA compared with healthy controls [29] and, inter-estingly, an inadequate response to TNF inhibitors has been associated with increased levels of IL-17 and Th17 cells in patients with RA. Given its pathogenic role in arthritis, this IL-17/Th17 pathway has attracted wide interest for the development of immunosuppressive biologicals (Figures 3 and 4). OKUMA Indirectly targeting Th17 cells: Although this effect was not foreseen when the anti-IL-6R therapy tocilizumab was marketed, blocking IL-6 also inhibits the differentiation of Th17 cells [67], thereby changing the balance towards more regulatory T cells [68]. JAK inhibition by tofacitinib also has many effects, including the inhibition of IL-17 and IFNg by CD4+ cells [69]. Surprisingly, B cell targeting using rituximab has also been demonstrated to deplete CD4+ T cells [70] and reduce Th17 levels [71], but the mechanism still requires further investigation. …………………………………. Concluding remarks RA is very heterogeneous disease, and treating a patient with RA with the right drugs at the right time is a major challenge. With JAK and Th17 inhibitors, rheumatologists have interesting new tools to treat patients with RA who do not (or no longer) respond well to the already existing biologicals. These new tools might seem diverse in many aspects (e.g., oral, once-daily synthetic DMARDs targeting intracellular pathways, versus biological DMARDs admin-istered less frequent via injections targeting extracellular pathways), but they have one major commonality: they demonstrated their efficacy in reducing inflammation. Therefore, by using these drugs, new attempts can be made to put patients with active RA in remission. The major drawback of all new therapies is that it will become an even greater challenge to choose the right medication for the right patient. To identify subgroups of patients who might benefit from certain biological treat-ments, the clinical and molecular properties of patients need to be well characterized. Personalized medicine is required to improve clinical responsiveness in RA, and screening patients using biomarkers in serum or profiling of synovial tissue is essential to determine to a rapid and effective treatment strategy. In fact, rheumatologists and researchers should become more ambitious, not only find-ing new treatments for currently nonresponding patients, but also aiming to achieve ACR50 and ACR70 responses in most patients with RA by using carefully planned tailor-made combination treatments. A completely different level of modulating RA is the microbiome, which is currently gaining market traction [79]. A recent study showed the presence of Prevotella copri to be strongly correlated with disease in patients with new-onset untreated RA [80], and modulation of the microbiome has been shown to affect the onset and severity of experi-mental disease. Germ-free mice that were protected from spontaneous arthritis development had disrupted IL-17 production, whereas enhanced experimental arthritis after repeated oral inoculations with the periodontal pathogen Porphyromonas gingivalis was associated with increased levels of Th17 cells [81,82]. Changing environmental factors might increase the efficacy of current treatment strategies, and further understanding of the activation pathways in various organs and tissues might lead us to the final solution for RA; inducing tolerance for full and long-standing remission. For the moment, we will have to await further efficacy and safety data from trials targeting the JAK and IL-17/Th17 pathway, to see whether promise meets expectation. Bu yolak otoimmun hastalıklara yol açtığı gibi (RA, Psoriazis), bakterilere ve mantarlara karşı olan savunmada da önemli görev yaparlar

RA & PERİODONTİT

RA ve periodontit ilişkisi
Medicine Volume 93, Number 27, December 2014 Periodontitis and rheumatoid arthritis (RA) are two common chronic inflammatory diseases sharing a similar host mediated pathogenesis. Periodontitis is characterized by soft and hard tissue destruction around teeth, ultimately leading to tooth loss, while RA is characterized by destruction of cartilage and bone in the joints, mediated by similar bone resorptive cytokines and proteinases. Both diseases lead to significant morbidity, with periodontitis ultimately leading to tooth loss and loss of masticatory function, and RA leading to loss of joint function and loss of mobility. Over the past 15 years, a number of case–control studies have suggested an association between the two diseases….

A modified “two-hit” model of induction of severe chronic periodontitis by local and systemic factors, its relationship to RA, and their mitigation by periodontal host modulation therapy. The first “Hit” involves the periodontopathic microbial biofilm and its metabolic products, such as lipopolysaccharide/endotoxin, inducing a local inflammatory response characterized by increased production in the periodontium of, particularly, bone-resorptive cytokines (IL-1, IL-6, TNF-α) and tissue-destructive proteinases (MMP-8, MMP-9, MMP-13, and neutrophil elastase). The second “Hit” involves a medical disease associated with destructive periodontitis (e.g., RA) which, like chronic periodontitis, can induce systemic inflammation characterized by elevated levels of acute-phase proteins such as C-reactive protein and other biomarkers/mediators in the circulation (e.g., IL-1, IL-6, TNF-α, MMP-8, and MMP-9). “Therapeutic reduction” represents the clinical/biological response to SDD host modulation therapy, adjunctive to SRP. “Synergistic therapeutic reduction” represents the response to the combination of SDD plus an anti-inflammatory drug (e.g., flurbiprofen), adjunctive to SRP. This figure is a modification of one published by us previously. ……………………………… The high periodontitis prevalence in RA is confirmed by molecular detection of anaerobes and high antibody titers against periodontal bacteria in serum and synovial fluid of RA patients. A growing interest has been addressed to the correlation between RA and P gingivalis-associated periodontitis that represents one of the most investigated pathogens in periodontitis etiology. P gingivalis is actually the only known bacterium expressing a PAD enzyme, responsible for posttranscriptional protein modifications similar to those obtained from human PAD. OKUMA: Conclusions and Future Directions Numerous case–control studies have demonstrated an association between RA and periodontitis. Short-term clinical trials have shown that nonsurgical periodontal treatment can reduce RA disease activity and systemic inflammation, although these studies have had small sample sizes, and studies with larger sample sizes and longer-term follow-up are needed. Since SDD as an adjunct to SRP has been shown to effectively treat periodontitis [42], and to successfully improve the parameters of early RA [46], we propose inclusion of nonantimicrobial, systemically administered SDD alone or in combination with an anti-inflammatory agent and locally delivered doxycycline (for probing depths 5 mm and greater) in future clinical trials examining the effect of periodontal therapy on RA disease activity. All of these pharmaceutical approaches are adjunctive to SRP. Customizing treatment of periodontitis in RA patients based on their systemic inflammatory status (i.e., personalized medicine approach) should also be considered [72]. We hypothesize that the impact of periodontal treatment on RA may be greater in patients with more systemic inflammation and when SRP is used in combination with adjunctive periodontal host modulation therapy. Further longitudinal studies are also needed to address the temporal relationship between these two diseases. Questions to address via longitudinal studies and clinical trials include: Does a diagnosis of periodontitis precede the presence of serum ACPA and clinical presentation of RA? Is periodontitis merely another manifestation of RA (i.e., another “joint”)? Can treatment of periodontitis prevent the onset of clinical RA in patients at risk for RA or in patients who are already positive for ACPA? Can periodontal treatment meaningfully ameliorate the symptoms of RA and reduce RA disease activity? Lastly, mechanistic studies need to be conducted to better understand the connection between these two diseases. Ayrıca periodontit etkeni olan anaerob bakteri ‘porphyromonas gingivalis’ hücre sitrülasyonunda etkin olan PAD enzimi exprese eder.

Başarılı periodontit tedavisi ile RA’da dramatik iyileşme
Olgu sunumu FIGURE 2. (A) Second upper molar x-ray showed a chronic apical periodontitis on the mesiobuccal root. (B) Bone reconstitution appeared complete in the last second upper molar x-ray. A complete and long-lasting RA recovery after periodontal treatment in a male patient with RA and periodontitis is reported here. Considering the arthritis migrant trend, the large joint involvement and the apical periodontitis, a reactive arthritis was initially hypothesized. However, the involvement of 4 small joints, confirmed by the presence of synovitis and erosions in MRI and US of the second and third left MCP joints, the ACPAs high positivity, the length of disease >6 weeks, and the increase of inflammatory indices allowed to fully meet the 2010 EULAR/ACR RA Classification Criteria, with a total score of 8/10. Although RA with high ACPAs titer has been reported to be characterized by a worse prognosis, a rapid reversibility of clinical manifestations has instead been observed in this case after periodontitis treatment. OKUMA Several factors, including infections, have been considered in autoimmunity onset, leading to RA. In the last few years, an epidemiological association between RA and periodontitis has been observed; although the mechanism underlying this association is not clear, periodontitis has been suggested having a role in RA development and progression. Periodontitis is a highly prevalent chronic inflammatory oral disease, although the most severe forms are restricted to a limited percentage of population. It is an opportunistic infection, induced by a limited number of putative periodontopathic microorganisms, occurring in presence of individual predisposition and environmental risk factors, eventually leading to periodontal tissue destruction and tooth loss, if left untreated. The tissue-destroying process is often caused by Gram-negative anaerobic bacteria, such as Porphyromonas gingivalis, Prevotella intermedia, Tannerella forsythia, and Aggregatica bacter-actinomycetem comitans. The high periodontitis prevalence in RA is confirmed by molecular detection of anaerobes and high antibody titers against periodontal bacteria in serum and synovial fluid of RA patients. A growing interest has been addressed to the correlation between RA and P gingivalis-associated periodontitis that represents one of the most investigated pathogens in periodontitis etiology. P gingivalis is actually the only known bacterium expressing a PAD enzyme, responsible for posttranscriptional protein modifications similar to those obtained from human PAD. Although the PAD expressed in P gingivalis is quite different from the human variant, it has been demonstrated that it can produce irreversible citrullinated peptides from at least 2 known RA antigens, fibrinogen, and a-enolase. P gingivalis infection has also been suggested to be associated with increased risk for RA development. Periodontitis and RA share common risk factors, mainly including HLA-DRB1 alleles and smoking; in the patient’s medical history, in fact, a previous smoking status was reported. Moreover, both pathological conditions are characterized by an inappropriate inflammatory reaction mediated by immune cells, enzymes, and cytokines, which results in tissue damage. Giving these similarities, it could be postulated that the 2 illnesses may occur simultaneously in individuals with an intrinsic dysregulation of the inflammatory response. In the case reported here, the successful treatment of periodontal infection has been associated with a progressive improvement of RA clinical manifestations, a gradual resolution of arthritic symptoms, and a gain of US and MRI features. Laboratory tests also returned to normal values and disease activity dramatically improved from high disease activity to remission; only ACPAs remained positive. Fig 2 için açıklama: Nearly 6 weeks later, on the basis of a suspect dental lesion on x-ray, the patient was referred to a dental examination. He reported pain after pressure on tooth 46 as a chief complaint. The second upper molar x-ray showed a chronic apical periodontitis on the mesiobuccal root (see the radiolucency in Figure 2). The tooth had received an inadequate endodontic treatment. An endodontic retreatment was planned in order to remove the root canal system infection, particularly in the mesiobuccal root. The endodontic retreatment was performed in a single visit14,15; the root canal preparation was performed with M2 endodontic Ni-Ti instruments (Sweden and Martina, Carrare (Pd), Italy) and the irrigation was carried out with 5.25% sodium hypochlorite; the canals were filled with the Microseal system (Sybronendo, West Collins, Orange, CA).16 Simultaneously, the clinical periodontal examination evidenced diffuse signs of gingivitis (60% of gingival sites exhibiting bleeding after probing) and various 5-mm-deep periodontal pockets in the upper arch. Periodontal treatment consisted of full-mouth scaling and root planing with accurate oral hygiene instructions. Subsequently, in the right upper quadrant, an open flap debridement was done in periodontal pockets exceeding 5 mm. The patient was then requested to rinse the mouth with chlorhexidine for 2 weeks and he was recalled at 3 and 6 months for clinical control and hygienic prophylaxis. After 6 months, in conjunction with the healing of the endodontic lesion (Figure 2), the periodontal charting showed no probing values >3 mm nor the presence of signs of periodontal infection in the whole mouth. Cerrahi tedaviye ek submikrobiyal dozda verilen doksisiklin ve NSAID, erken RA semptomlarına iyi gelebilir

DENEYSEL TEDAVİLER

Yeni tedavi hedefi: Leptin
peptide hormone secreted by adipocytes, and has drawn much attention since its identification in Leptin belongs to one of the type I cytokine superfamily members and has a long-helix structure similar to interleukin (IL)-2, IL-6 and granulocyte colony-stimulating factor (G-CSF) Leptin, the ob gene product, is a 16-kDa non-glycosylated peptide hormone secreted by adipocytes, and has drawn much attention since its identification in 1995 [1]. Leptin belongs to one of the type I cytokine superfamily members, and has a long-helix structure similar to interleukin (IL)-2, IL-6 and granulocyte colony-stimulating factor (G-CSF) Numerous studies have suggested the importance of leptin against autoimmune diseases such as systemic lupus erythematosus (SLE), multiple sclerosis (MS) and psoriasis. To summarize our current understanding of the role of leptin in inflammatory responses and rheumatoid arthritis (RA), a systematic review was conducted to assess the discrepancy of leptin in RA and its effect on immunity according to different studies. Recently, emerging data have indicated that leptin is involved in the pathological function of RA, which is common in autoimmune disorders. This review discusses the possible consequences of leptin levels in RA. Blocking the key signal pathways of leptin and inhibiting the leptin activity-like leptin antagonist may be a promising way for potential therapeutic treatment of RA at risk of detrimental effects. However, leptin was increased in patients with RA and may also regulate joint damage. Thus, more understanding of the mechanism of leptin in RA would be advantageous in the future.

Leptin’in proiflamatuvar etkileri
Fig. 1. Effects of leptin on innate and adaptive immune system cells. Leptin regulates levels in some ways such as development, proliferation, apoptotic, maturation and activation both in innate immunity and adaptive immunity. Slaytta ne yaptığı görülüyor. In innate immunity, leptin increases phagocytosis and chemotaxis of monocytes and macrophages, regulates maturation and production of cytokines both between natural killer (NK) and dendritic cells (DC), as well as paracrine and autocrine immunomodulation in mast cells. In adaptive immunity, it promotes proliferation of naive T cells but not memory and regulatory T cells (Treg) cells. Leptin increases T helper type 1 (Th1) cell activation and immunoglobulin (Ig)G2α switching while it down-regulates IgG1 switching in Th2 cells. Meanwhile, it stimulates the release of cytokines in T and B cells. Doğal ve kazanılmış immuniteye de doğrudan etkisi var.

Potansiyel RA tedavi aracı leptin antagonizması
Conclusion Prevailing studies suggest that leptin is of great importance in the pathogenesis and treatment of RA through in-vitro and in-vivo models. More studies are needed to elucidate the mechanism of leptin in RA, although numerous data from a variety of models support the key role of leptin in immunity and autoimmune diseases. Leptin also has direct effects on both innate and adaptive immunity. Sparse clinical findings have been reported for therapeutic RA by induction of possible leptin signalling on molecule and gene levels. Blocking the key signal pathways of leptin and inhibiting leptin activity, such as with leptin antagonists, may be a promising way for the therapeutic potential of RA at risk of detrimental effects. In particular, it has a dual role with respect to its antiinflammatory and proinflammatory response. However, leptin is increased in patients with RA and may also regulate joint damage [30]. Hence, further understanding of the mechanism of leptin would be advantageous in the future in RA treatment. Leptin antagonism as a therapeutic target for RA As a key mediator against infection, immune responses, and even the induction of autoimmune diseases, leptin needs more research to identify whether leptin can become the pathogenesis of targeting autoimmune diseases in humans. Reduction of leptin levels in RA patients by fasting improves the clinical symptoms of autoimmune disease [131],, thus leptin antagonism has been proposed for the prevention of developing RA in people genetically susceptible to RA and other autoimmune diseases. A number of diverse approaches can be designed for antagonists. However, blocking the key signal pathways such as JAK/STAT may cause harmful effects. Recently, the progression of leptin mutants with antagonism and proteins inhibiting leptin activity offers new hope for possible treatment [132]. Many leptin mutants may be regarded as potent leptin antagonists both in vitro and in vivo [133]. A S120A/T121A binding site III leptin mutant may become a competitive inhibitor of leptin receptor signalling due to its linkage to the receptor but not its stimulation [133]. Nevertheless, PEGylation (polyethylene glycol) of this mutant is implied, which could promote the circulation lifetime of the S120A/T121A leptin antagonist, because leptin has a short half-life in circulation [134]. Additionally, the monoclonal antibody (mAb) against the human leptin receptor could provide a useful strategy, because of being a tissue-specific leptin antagonist. The antibody-blocking peripheral immune actions of leptin and leptin-induced production of TNF-α by human monocytes and T cell production suppresses leptin proinflammatory activity [135]. Leptin may be partly responsible for low-level systemic inflammation. Targeting leptin may be regarded as a therapeutic method in some clinical conditions, such as proinflammatory status or autoimmune diseases, which can control an excess of immune response. In vitro, neutralization using leptin mAb, when stimulating anti-CD3 and anti-CD28, leads to Treg cell proliferation [136]. In leptin- and ObR-deficient mice, Matarese et al. [137] showed an enhanced proliferation of Treg cells, indicating the possibility for treatment of immune and autoimmune diseases. Leptin receptors were also identified on mast cells, which could provide new insights in several therapeutic diseases. Recently, some molecules such as mAb have been reported to run as leptin antagonists and block leptin signalling [135]. Perhaps leptin antagonists could be a tool to control many inflammatory processes in which mast cells are present. In addition, a surprising role of leptin has been detailed in the regulation of bone formation [138,139]. The primary osteoblasts themselves can secrete leptin. In vitro, leptin can induce mineralization [139] and mediate stromal cells to differentiate into osteoblasts [140]. Glucocorticoids are effectively anti-inflammatory molecules useful for the treatment of RA, bowel disease and other inflammatory diseases. Glucocorticoids exert regulation of rat leptin production in vitro [141], and McLaughlin et al. [142] has found an evident rise in serum leptin by dexamethasone therapy, which may provide an idea for RA treatment. However, leptin antagonism could make individuals obese; glucocorticoid therapy has been applied for many years in the treatment of arthritis, but is limited due to side effects, including osteoporosis, diabetes and weight gain. Furthermore, as obese individuals have very high levels of leptin, if leptin had the effects proposed, autoimmune disease should be more common in severe obesity, but no evidence has accounted for this phenomenon.

Başka Hedef:Konnektif doku büyüme fakt.

CTGF yı bloke etmek niçin anlamlı?
CONCLUSION We confirmed that CTGF is a novel effecter molecule in the pathogenesis of RA. A schematic hypothesis of its role is presented in Figure 6. CTGF is a multiple functional cytokines and possess a several biological functions depend on the target cells. Although many candidate molecules on the cell surface have been suggested as specific CTGF receptors such as integrins, they have not been completely identified to date. Biological functions of CTGF may differ depend on its receptor as well as cell types. Although the mechanism of action and the importance of CTGF in contribution to the RA development are unclear, we showed that blocking the CTGF pathway could ameliorate CIA especially through the reduction of aberrant osteoclastogenesis. These data imply the possible mechanism underlying the efficacy of anti-CTGF antibody in the treatment with RA. Our study CTGF is important factor in the development of RA. These results may shed light on the new therapeutic strategies for RA. Further precise studies that will provide clues to assist in the development of new treatment for RA as well as a deeper understanding of its etiology are required. OKUMA CTGF was originally identified in human umbilical endothelial cell supernatants that exhibit platelet derived growth factor (PDGF)-like chemotactic and mitogenic activities toward mesenchymal cells; the cDNA was isolated from a human vein endothelial cells (HUVECs) cDNA expression library using anti-PDGF and it encoded a 349-amino acid protein[11]. CTGF belongs to the CCN protein family and is believed to be a downstream molecule of transforming growth factor (TGF)-β pathway[12]. Although several candidate specific CTGF receptors have been currently proposed, they have not yet been completely identified to date. CTGF is associated with several biological functions such as fibrosis, tumorigenesis, angiogenesis, and endochondral ossification[13]. in articular tissue, consisting different types of cells, is produced by chondrocytes and maintains cartilage tissue homeostasis via the autocrine process. Furthermore, incomplete knock-down of the CTGF gene dramatically inhibits osteoclast-like cell formation in mice, even though the complete knock-down mice exhibit embryonic lethality[14].

Hücre göçünü hedeflemek, Kemokinler
CHEMOKINES: CRITICAL REGULATORS OF LEUKOCYTE MIGRATION Chemokines are small, secreted proteins that play particularly prominent roles in directing leukocyte migration. There are over 40 chemokines in humans, readily identifiable from their amino acid sequence and subdivided into four subfamilies (CC, CXC, XC, CX3C) based on variations in a cysteine motif in the mature protein. These chemo attractants rapidly activate integrin mediated firm adhesion to arrest leukocytes on the endothelial surface, and these leukocytes then squeeze between endothelial cells into the tissue. Additional chemoattractant cues within the tissue directly extravasate leukocytes to specific tissue locales, or coordinate their departure via lymphatic vessels. Modulating leukocyte migration has obvious therapeutic potential, and over the years various molecules involved in this process have been investigated as novel therapeutic targets in rheumatoid arthritis and other autoimmune diseases OKUMA Leukocyte localization is a critical component of all immune and inflammatory responses. For effective recruitment into a target tissue, and subsequent migration into an appropriate microanatomical niche, leukocytes need to sense and integrate extracellular signals, and modify their adhesiveness and migratory properties accordingly. This is elegantly typified by the multistep paradigm of leukocyte recruitment from blood, a process referred to as extravasation (Fig. 1). Selectins mediate weak interactions between endothelial cells and leukocytes, allowing leukocytes to scan endothelial surfaces for chemoattractant cues, particularly chemokines. [1,2]. Foremost among these are the chemokines and their receptors, and this review focuses on ongoing efforts to identify suitable drug targets among this large family of proteins for the treatment of rheumatoid arthritis. CONCLUSION Chemokines and their receptors remain attractive therapeutic targets and the results of the ongoing clinical trials are eagerly awaited. However, it is becoming increasingly clear that there are substantial gaps in our understanding of the roles played by chemokines and their receptors in arthritis, particularly in human disease, and more indepth studies are required to more rigorously elucidate chemokine-dependent contributions to disease. By developing a deeper understanding of the complexity of chemokine/receptor interactions, and the precise pathological consequences of these interactions, we will increase our chances of identifying the best therapeutic targets in chemokine networks in rheumatoid arthritis and other autoimmune diseases.

Nanomedicine Autoimmune diseases are chronic, destructive diseases that can cause functional disability and multiple organ failure. Despite significant advances in the range of therapeutic agents, especially biologicals, limitations of the routes of administration, requirement for frequent long- term dosing and inadequate targeting options often lead to suboptimal effects, systemic adverse reactions and patient non-compliance.

İlacı hedefine ulaştırmak
Autoimmune and auto-inflammatory processes present a steadily growing clinical problem in human population. Treatment of these conditions is also an important pharmaco-economic challenge. The available treatment strategies for these disorders, including biologicals, are not completely specific and usually are focused only on selected targets involved in their immunopathogenesis. Another problem of current anti-inflammatory and immunosuppressive therapies is related to considerable systemic toxicity. Nanotechnology provides a unique opportunity for development of more efficacious and less toxic treatment modalities. Interestingly, it has a potential for intervention with both innate-dependent and acquired immune-dependent processes. Of special importance and perspective are interventions aimed at induction of specific immunologic tolerance in autoimmune conditions, in which pathogenic auto-antibodies or specific T cells react with specific and well characterized autoantigens (ie, multiple sclerosis, diabetes and some autoimmune bullous skin diseases). However, also in other autoimmune and auto-inflammatory conditions without known specific autoantigens and without generation of pathogenic autoantibodies and/or autoreac-tive T cells, nanotechnology will provide a powerful mode of therapeutic intervention, especially when particular steps of disease pathogenesis are well known (eg, systemic lupus erythematosus, psoriasis, systemic scleroderma, etc). Development of nanotechnology-based therapeutic strategies will make treatment of autoimmune disorders more targeted or personalized, and will substantially improve the therapeutic index (benefit to risk) in these quite different but frequent disorders. Novel therapeutics approaches in the form of proteins and nucleic acids are rapidly progressing toward the clinic (Table 4). However, the clinical application of nanocarriers in the treatment of autoimmune diseases is still in its infancy compared to a number of targeted nanoparticle delivery methods in autoimmune animal models (Table 3). With improved understanding of characteristics of autoimmune diseases, strategies can be developed to design novel biological drugs with high therapeutic impacts, which suppress autoantigen-specific immune responses, while the normal immune response remains virtually unaffected.

KULLANIMINDA TBC RİSKİ
RA’da BİYOLOJİK KULLANIMINDA TBC RİSKİ

TBC riskinE göre biyolojik ajan seçimi
Since the introduction of biologics for the treatment of rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), and psoriasis (Pso) an increased risk of tuberculosis (TB) reactivation in patients with latent tuberculosis infection (LTBI) has been recorded for anti-TNF agents, while a low or absent risk is associated with the non-anti-TNF targeted biologics. To reduce this risk several recommendation sets have been published over time, but in most of them the host-related risk, and the predisposing role to TB reactivation exerted by corticosteroids and by the traditional disease-modifying anti-rheumatic drugs has not been adequately addressed. Moreover, the management of the underlying disease, and the timing of biologic restarting in patients with TB occurrence have been rarely indicated. A multidisciplinary expert panel, the Italian multidisciplinary task force for screening of tuberculosis before and during biologic therapy (SAFEBIO), was constituted, and through a review of the literature, an evidence-based guidance for LTBI detection, identification of the individualized level of risk of TB reactivation, and practical management of patients with TB occurrence was formulated. The literature review confirmed a higher TB risk associated with monoclonal anti-TNF agents, a low risk for soluble receptor etanercept, and a low or absent risk for non-anti-TNF targeted biologics. Considering the TB reactivation risk associated with host demographic and clinical features, and previous or current non-biologic therapies, a low, intermediate, or high TB reactivation risk in the single patient was identified, thus driving the safest biologic choice. Moreover, based on the underlying disease activity measurement and the different TB risk associated with non-biologic and biologic therapies, practical indications for the treatment of RA, PsA, AS, and Pso in patients with TB occurrence, as well as the safest timing of biologic restarting, were provided. Tbc riski ile ilgili önceki çalışmalarda: konakçıya özel risk, DMARDve GK’un yüklediği risk araştırılamamış Bu İtalyan panelinin yaptığı da bu….

TBC reaktivasyon riskini arttıran faktörler
10 ve üstü major risk faktörü

Aktif TBC’de ne yapmalı/hangi ajanı tercih etmeli?

KARDİOVASKÜLER SİSTEM
RA & KARDİOVASKÜLER SİSTEM RA’da CV Morbidite % 48; CV mortalite % 60 artmıştır Etkin anti inflam tedaviye rağmen One of the most common and, indeed, serious complications is cardiovascular disease (CVD). A 48% and 60% excess risk of CV morbidity and mortality respectively, have been reported in RA patients. The association between RA and CVD has been linked to a pro-inflammatory state. However, this does not seem to be the only mechanism involved as an increased CV risk is still present despite the availability of well-established anti-inflammatory medications in this patient group

1.84 kat 1.89 kat RA’da MI riski artışı Hipertansiyonlu
RA’lıda Tip 2 Diyabetli RA’lıda 1.84 kat 1.89 kat Bazı hastalıklarda CVS hst risk faktörleri hastalığın karıştırıcı faktörleri nedeni ile genel populasyondaki risk faktörlerinden farklılık gösterir. Bu çalışma bunu araştırmak için yapılmış ve sonuçlar:…… (slayt)

RA’da kardiyovasküler morbidite artışı
Hipertansiyonlu RA’da: kat Tip 2 DM’li RA’lıda: kat Sigara içen RA’lıda: kat Hipekolesterolemi: kat Obez RA’lıda: kat Fiziksel inaktivite: İlişki yok CV morbidity (incidence of combined CV morbidity including MI, angina pectoris, heart failure, stroke, and peripheral arterial disease), In conclusion, our meta-analysis indicates that despite the increased CV risk associated with RA in general, traditional CV risk factors such as hypertension, T2D, smoking, hypercholesterolaemia and obesity, independently increase the risk of CV morbidity in this patient population, and the magnitude of this increase appears similar to that observed in the general population. This suggests that a careful diagnosis and management of CV risk factors should be considered as important as the management of the symptoms of RA in mitigating the risk of CV morbidity and mortality amongst these patients. RA’lı hastada bunları yok saymak, önem vermemek, sorgulamamak olmaz

MTX’in kardiyovasküler koruyuculuğu
Figure 3. Forest plot of odds ratios for cardiovascular disease events among patients with rheumatoid arthritis (RA) who received methotrexate (MTX) compared with those who did not, within studies that adjusted for RA clinical severity. MTX use was found associated with significantly reduced cardiovascular risk (overall pooled odds ratio =0.80;) Figure 4. Forest plot of odds ratios for cardiovascular disease events among patients with rheumatoid arthritis (RA) who received methotrexate (MTX) compared with those who did not, within studies that adjusted for use of the other RA- specific drugs. MTX use was demonstrated to predict significant decrease in cardiovascular disease events [overall pooled odds ratio =0.71;) Methotrexate use is associated with a lower risk of CVD among patients with chronic inflammation, such as those suffering from rheumatoid arthritis. These findings suggest that a direct treatment of inflammation using suitable drugs may reduce CVD risk. Methotrexate at low doses, such those used for maintenance therapy of RA, predicted a decreased risk of CVE. Since methotrexate doesn’t interfere with blood lipids, platelet aggregation or insulin resistance, the protective association may originate from mechanisms other than those exerted by antiplatelet drugs or statins. The choice of planning a randomized controlled trial to establish whether any causality relationship exists between methotrexate use and reduction in cardiovascular events even among patients free from rheumatoid arthritis and/or concurrent steroid or COXIB therapy appears warranted as a new desirable research direction in the cardiovascular field. MTX ile belirgin CVS risk düşüşü. Neden? Kan bileşenleri ile alakası yok. Etkili infl tedavisi? NSAID sparing etki?

Romatizmal hastalıklarda egzersiz

RA specifik egzersiz 2010 yılında European League Against Rheumatism (EULAR), RA’nın temelinde inflamatuvar artritlerde kardiyovasküler risk düzenlenmesini önermiştir . Peters MJ, Symmons DP, McCarey D, Dijkmans BA, Nicola P, Kvien TK, et al. EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis. Ann Rheum Dis 2010;69: Eski yıllarda istirahat etmek, ılımlı, pasif ve ağırlık bindirmeyen egzersizler RA’da temel yöntemdi. Hastalığın aktif dönemi için uygun olan bu yaklaşım, aktivite baskılandığında yetersiz kalıyordu. Son yıllarda dinamik egzersiz tedavisi gündeme girmiştir. Aerobik kapasite ve kas kuvvetini arttırmasına karşın, bu egzersizlerin hiçbir çalışmada hastalık aktivitesini arttırmadığı gösterilmiştir (45). Gaudin P, Leguen-Guegan S, Allenet B, Baillet A, Grange L, Juvin R. Is dynamic exercise beneficial in patients with rheumatoid arthritis? Joint Bone Spine 2008;75:11-7. RA için Egzersizler Kas kuvvetlendirme, majör gruplara yapılır. Üst ekstremite; pektoralis majör, omuz horizontal fleksiyon, trapezius, latissimus dorsi, biseps curl, triseps ekstansiyon, abdominal kaslar sit-up, alt ekstremite leg press (kuadriseps). Kas kuvvetlendirme, EHA izin verdiği ölçüde kişiye özel olarak yapılır. Kuvvetlendirme egzersizleri programı başlangıcında 10 dk. ısınma germe yapılır. İlk 2 hafta ağırlık minimal hastanın egzersiz öğrenme periyoduna, eklem ağrısı ve kas yaralanmasından korunmaya dikkat edilir. Üçüncü haftada hipertrofi hedeflenmeli, her kas grubuna 2 set/hafta egzersiz önerilmelidir. Bir set tekrar ara vermeden, yorgunluk tekrarı engelleyene kadar yapılır. Çoğu egzersiz için tekrar ağırlığı 1 RM’nin %70’idir. Egzersiz kişiye özeldir tekrar korunmalıdır. On beş tekrarın üstüne çıkıldığında, ağırlık 10 tekrarı yapabilecek kadar arttırılır. Her 6 haftada her kas grubu için set sayısı arttırılır. İki set/hafta başlanıp, 3 veya 4 set/hafta ile bitirilir. Aerobik egzersizler maksimum kalp hızının %50-70’i ile en az haftada 2 kez ve 6 hafta boyunca yapılır. Bisiklet ergometresi ile yapılabilir. Egzersiz bitiminde tekrar germelerle soğuma yapılır. İlk 4 hafta 15 dk./seans, 2 kez/hafta uygulanır. 5. haftada 5 dk. artırılır. Tüm egzersiz seansı 6 ay sonunda dk. olabilir. Koşu bandında yürüme maks. KH %60’ıyla 20 dk/gün, haftada 5 gün en az 2 hafta önerilir. Strasser B, Leeb G, Strehblow C, Schobersberger W, Haber P, Cauza E. The effects of strength and endurance training in patients with rheumatoid arthritis. Clin Rheum 2011;30:

ACR 2015 RA ÖNERİLERİ BOSTON — An American College of Rheumatology (ACR) panel is working on new rheumatoid arthritis guidelines that will include first-time information on glucocorticoids and the oral Janus kinase inhibitor tofacitinib. Amy Miller, senior director of quality for the ACR told Medscape Medical News to expect the new guidelines in the spring of 2015. Key recommendations from the current draft, which has not yet been peer-reviewed, were presented at the ACR 2014 Annual Meeting by Jasvinder Singh, MD, from the University of Alabama at Birmingham. "The panel strongly recommended a treat-to-target strategy, as opposed to a nontargeted approach, in both early and established rheumatoid arthritis," Dr Singh reported. For many patients the target will be low disease activity. "In some cases, however, another target may be chosen based on patient comorbidity and risk tolerance," Dr Singh explained.

Kılavuza göre tedaninin temel ilkeleri
In early rheumatoid arthritis — defined as a disease duration of less than 6 months — the panel strongly recommended disease-modifying antirheumatic drug (DMARD) monotherapy for DMARD-naive patients with low, moderate, or high disease activity.

Erken Romatoid Artrit (1)
Daha önce DMARD kullanmamış, Düşük, orta, ileri hst aktivitesi (her tür) In early rheumatoid arthritis — defined as a disease duration of less than 6 months — the panel strongly recommended disease-modifying antirheumatic drug (DMARD) monotherapy for DMARD-naive patients with low, moderate, or high disease activity. DMARD MONOTERAPİSİ

Mümkün olan en düşük doz ve kısa süreli GLUKOKORTİKOİD TEDAVİ
Erken Romatoid Artrit (2) Orta , yüksek hastalık aktivitesi olanlarda For patients with moderate or high disease activity who have a flare, the panel recommended glucocorticoid use at the lowest possible dose for the shortest period of time to provide the best benefit–risk ratio for the patient. Mümkün olan en düşük doz ve kısa süreli GLUKOKORTİKOİD TEDAVİ

NON TNF İNH BİYOLOJİK ± MTX
Erken Romatoid Artrit (3) DMARD monoterapisine rağmen orta, yüksek hastalık aktivitesi Patients who fail DMARD monotherapy and still have moderate to high disease activity should receive a combination of traditional DMARDs, a tumor necrosis factor (TNF) inhibitor with or without methotrexate, or a non-TNF-inhibitor biologic with or without methotrexate. KOMBİNE DMARD veya a TNF ± MTX veya NON TNF İNH BİYOLOJİK ± MTX

Erken Romatoid Artrit (4)
Bu hastalar atak yaşarlarsa veya hastalık orta yüksek düzeyde kalırsa If these patients experience a rheumatoid arthritis flare, short-term glucocorticoids are again recommended. The panel conditionally recommended adding low-dose glucocorticoids to the treatment regimen if these combination options are not effective and disease activity remains moderate to high. Ataklarda: Kısa dönem GK TEDAVİSİ Hala orta yüksek aktivite: Rejime ek düşük doz GK

Oturmuş Romatoid Artrit (1)
Daha önce DMARD kullanmamış, Düşük, orta, ileri hst aktivitesi (her tür) The draft treatment algorithm for established rheumatoid arthritis is similar to that recommended for early disease, Dr Singh reported. For DMARD-naive patients with established disease, DMARD monotherapy, usually methotrexate, is recommended as first-line treatment for those with low, moderate, or high disease activity. DMARD MONOTERAPİSİ (Genellikle MTX)

NON TNF İNH BİYOLOJİK ± MTX veya
Oturmuş Romatoid Artrit (2) DMARD monoterapisine rağmen orta, yüksek hastalık aktivitesi KOMBİNE DMARD veya a TNF ± MTX veya NON TNF İNH BİYOLOJİK ± MTX veya TOFACİTİNİB + MTX After DMARD failure, the panel strongly recommends the combination of traditional DMARDs, TNF inhibitor with or without methotrexate, non-TNF-inhibitor biologic with or without methotrexate, or tofacitinib plus methotrexate.

Oturmuş Romatoid Artrit (3)
Bu hastalar atak yaşarlarsa veya hastalık orta yüksek düzeyde kalırsa If disease activity remains moderate to high in these patients, physicians can consider adding low-dose glucocorticoids. Short-term glucocorticoids can also be used for rheumatoid arthritis flares. Ataklarda: Kısa dönem GK TEDAVİSİ Hala orta yüksek aktivite: Rejime ek düşük doz GK

Oturmuş Romatoid Artrit (4) Bir aTNF ajan başarısızsa NON TNF İNH BİYOLOJİK ± MTX veya BAŞKA bir a TNF ± MTX Patients who fail a single TNF inhibitor should next receive a non-TNF-inhibitor biologic with or without methotrexate, or another TNF inhibitor with or without methotrexate.

Oturmuş Romatoid Artrit (5) Çoğul aTNF ajan başarısızsa Next in line for those who fail multiple TNF inhibitors is a non-TNF-inhibitor biologic with or without methotrexate or tofacitinib with or without methotrexate. NON TNF İNH BİYOLOJİK ± MTX veya TOFACITINIB ± MTX

Non TNF Biyolojik başarısızlığında
Oturmuş Romatoid Artrit (6) Non TNF Biyolojik başarısızlığında Those who fail on a non-TNF inhibitor biologic should receive another non-TNF-inhibitor biologic with or without methotrexate. Başka bir NON TNF İNH BİYOLOJİK ± MTX

Başka bir NON TNF İNH BİYOLOJİK ± MTX veya
Oturmuş Romatoid Artrit (7) Bir aTNF ve non TNF biyolojik başarısızlığında Patients who fail a TNF inhibitor and non-TNF-inhibitor biologic should receive another non-TNF-inhibitor biologic with or without methotrexate or tofacitinib with or without methotrexate. Başka bir NON TNF İNH BİYOLOJİK ± MTX veya TOFACİTİNİB ± MTX

Bir aTNF ± MTX (daha önce kullanmamışsa)
Oturmuş Romatoid Artrit (8) Bir çok non-TNF biyolojik başarısızlığında Those who fail treatment with several non-TNF-inhibitor biologics should receive tofacitinib with or without methotrexate or a TNF inhibitor with or without methotrexate, provided they have not previously received a TNF inhibitor. TOFACİTİNİB ± MTX veya Bir aTNF ± MTX (daha önce kullanmamışsa)

NON TNF BİYOLOJİK , a TNF’ye tercih edilmeli
Yüksek riskli ve komplike hastalarda (1) Tedavi edilmiş ya da edilmemiş non melanom cild kanseri varsa The panel addressed a number of clinical scenarios in which patients with rheumatoid arthritis have current or previously treated comorbidities, the presence of which can alter treatment decisions. High-Risk Patients, Complicated Cases For patients with previously treated or untreated nonmelanoma skin cancer, a combination of DMARDs or a non-TNF-inhibitor biologic is favored over a TNF inhibitor. In contrast, treatment recommendations are the same for patients with or without a previously treated solid organ malignancy. NON TNF BİYOLOJİK , a TNF’ye tercih edilmeli

a TNF, TOFACİTİNİB’e tercih edilmeli
Yüksek riskli ve komplike hastalarda (2) Tedavi edilmiş ya da edilmemiş melanoma varsa For those with a previously treated or untreated melanoma, a TNF inhibitor is favored over tofacitinib. a TNF, TOFACİTİNİB’e tercih edilmeli

lenfoproliferatif hastalık varsa
Yüksek riskli ve komplike hastalarda (3) Tedavi edilmiş lenfoproliferatif hastalık varsa Recommendations become more specific for rheumatoid arthritis patients with a previously treated lymphoproliferative disorder, Dr Singh pointed out. For these patients, the panel recommended combination DMARD treatment over a TNF inhibitor, but they also recommended a non-TNF-inhibitor biologic — specifically abatacept, tocilizumab, and most strongly, rituximab — over a TNF inhibitor. Kombine DMARD a TNF’ye, bir NON TNF BİYOLOJİK (ABA, TOC , en fazla da RTX) a TNF’ye tercih edilmeli

Yüksek riskli ve komplike hastalarda (4)
Antiviral tedavi alan aktif hepatit B ve C infeksiyonu olanlar Patients with active hepatitis B or C infection receiving effective antiviral therapy can receive a DMARD, TNF inhibitor, non-TNF-inhibitor biologic, or tofacitinib, Dr Singh reported. Tüm seçenekleri kullanabilir

NON TNF İNH BİYOLOJİK veya TOFACİTİNİB kullanmalılar
Yüksek riskli ve komplike hastalarda (5) NYHA grade 3 veya 4 kalp yetmezliği olanlar veya aTNF tedavi altında bu açıdan kötüleşenler KOMBİNE DMARD veya NON TNF İNH BİYOLOJİK veya TOFACİTİNİB kullanmalılar Patients in New York Heart Association class III or IV heart failure should preferentially receive a combination of DMARDs, non-TNF-inhibitor biologic, or tofacitinib over a TNF inhibitor. The same holds true for those with worsening heart failure already receiving a TNF inhibitor.

KOMBİNE DMARD > a TNF;
Yüksek riskli ve komplike hastalarda (6) Ciddi enfeksiyon öyküsü olanlar For patients with a history of serious infection, a consensus was reached on the recommendation of combination DMARD therapy over a TNF inhibitor and abatacept over a TNF inhibitor. In contrast, for the same patient group, no consensus was reached on recommendations for the use of rituximab or tocilizumab over a TNF inhibitor. KOMBİNE DMARD > a TNF; ABA > a TNF

Yüksek riskli ve komplike hastalarda (7)
Herpes zoster aşısı -Ideally, patients 50 years and older should receive the herpes zoster vaccine before biologic therapy," Dr Singh noted. However, live attenuated vaccines, such as the herpes zoster vaccine, should not be given to patients with early or established rheumatoid arthritis if they are on any biologic therapy. 50 yaş üstünde hastalarda tedaviye başlamadan. Ama tedavi sırasında değil….

Oturmuş RA’lı çok az hasta tedavisiz iyilik halini sürdürebilir
Yüksek riskli ve komplike hastalarda (8) Oturmuş RA’lı çok az hasta tedavisiz iyilik halini sürdürebilir The panel also strongly recommended continuing therapy with traditional DMARDs, TNF inhibitor, non-TNF-inhibitor biologics, or tofacitinib in patients with established rheumatoid arthritis and low disease activity who are continuing on methotrexate. For those in remission and continuing on methotrexate, the panel recommended that physicians taper treatment, regardless of the regimen. "At the same time, the panel strongly recommended that not all therapies be discontinued," Dr Singh emphasized, because "clinical experience suggests that only a very small minority of patients with established rheumatoid arthritis are able to discontinue all treatment.« "I think the guidelines improve the overall care of people with rheumatoid arthritis and help form the basis for demonstrating the value of the care we provide," said Dr Flood. "And they help to tell us what the expected standard of quality of care is. If the ACR does not set the evidence-based standard for quality of care for patients with rheumatoid arthritis, then who could?"

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