Topic: effects of the biological drug treatment on status of joint tissues and healing process in the postoperative wound of the patients with rheumatoid arthritis [RA]




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НазваниеTopic: effects of the biological drug treatment on status of joint tissues and healing process in the postoperative wound of the patients with rheumatoid arthritis [RA]
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Topic: EFFECTS OF THE BIOLOGICAL DRUG TREATMENT ON STATUS OF JOINT TISSUES AND HEALING PROCESS IN THE POSTOPERATIVE WOUND OF THE PATIENTS WITH RHEUMATOID ARTHRITIS [RA].


Institute of Rheumatology in Warsaw, Poland

BACKGROUND. Rheumatoid arthritis (RA) is a chronic, progressive, autoimmune inflammatory disease of unknown aetiology that attacks the synovial tissue and leads to irreversible joint damage, chronic pain, stiffness, and functional impairment. Without treatment, most RA patients develop permanent bone erosions and joint space narrowing, in the chronic stage many disabled patients [pts] require joint replacement surgery.

RA affects approximately 1% of the world's adult population; over 2 million people in the US alone. They are mostly adults between the ages of 30 and 60 years, with a 2.5-fold higher prevalence in women than in men.

Inflammation is the major factor driving the progression of structural damage in RA. The severity of inflammation and progression of joint damage varies from patient to patient. When inflammation is more severe, extensive joint damage can occur within only a few years of disease onset.

The goal of RA management is to suppress inflammation and prevent structural damage and decrease the clinical signs and symptoms. The American College of Rheumatology Guidelines for the management of RA, recommend combination therapy with currently approved agents for patients with active disease despite adequate doses of methotrexate [MTX] treatment of 3-6 months' duration (1). All patients not responding satisfactorily to conventional disease-modifying anti-rheumatic drugs (DMARDs), particularly those who are progressing rapidly despite this therapy, should be considered for more aggressive treatment, e.g. with a biologic plus MTX. In many cases, this will require a more aggressive treatment strategy and close monitoring of structural damage.

Clinical diagnosis of RA bases on the recommended ACR criteria (1987) modified by ACR/EULAR (2009).

Monitoring of RA course and response to therapy: a/ measurement of disease activity based on the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) response criteria as the Disease Activity Score (DAS 28). b/evaluation of functional ability (by functional tests e.g. the health assessment questionnaire or a combined predictor of progression scoring system.

Several types of biological markers have been used to assess disease activity/progression and treatment response in RA pts: genetic markers, auto-antibodies, inflammation markers, cartilage markers and bone markers. The most common are markers of inflammation (the acute-phase reactants C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). RA affects the different tissues of the joint including bone, cartilage and the synovial membrane. Serum biomarkers of cartilage/collagen damage and proteoglycan turnover are useful in evaluation of joint damage. Estimation of these markers in relation to radiographic joint destruction enable clinicians to identify rapidly progressing patients.


Inflammation in RA involves synovium and is strongly associated with destruction of the bone marrow, cartilage and bone tissue. The inflammatory immune response is regulated by pro- and anti-inflammatory cytokines. Pro-inflammatory cytokines: IL-1, IL-6, IL-15, IL-18 and TNF-α, initiate an inflammatory response. Other cytokines: IL-4 and IL-10 control these responses. In RA, the balance unbalance between pro- and anti-inflammatory cytokines is responsible for continued inflammation; chronically increased levels of pro-inflammatory cytokines cause prolonged inflammation and progressing structural damages. TNF-α is one of the most important pro-inflammatory cytokine responsible for inflammation and joint destruction in RA. TNF-α stimulates the release of metalloproteinases by fibroblasts that destroy joint tissue. Anti-TNF-α-targeted biologic agents have been shown to reduce joint inflammation and significantly slow radiographic progression of joint damage.

Therapy. During past decades have been seen rapid advances in the understanding of the pathogenesis RA and in therapeutic options for many pts. Great advances have been made in the treatment of RA since the introduction of biologic therapy. The tumor necrosis factor [TNF]-α-antagonists infliximab, etanercept, adalimumab s. (HUMIRA), and the interleukin (IL)-1 receptor antagonist anakinra, were the first generation of biologics to be approved in the treatment of RA. However, approximately 30-40% of patients with established disease fail to respond to TNF-α antagonists and the majority of those that respond initially, do not achieve complete remission.

TNF inhibitors. A number of clinical trials have evaluated the new biologics, the TNF inhibitors as well as IL-1 inhibitor in RA. Most of the initial studies included pts who had active disease despite receiving MTX therapy. Results showed that addition of a biologic to MTX significantly improved patient outcomes; the biologics were superior in preventing x-ray progression and structural damage in comparison to MTX. Three separated showed that the combination of a disease-modifying antirheumatic drug (DMARD): MTX plus a biologic (etanercept, or adalimumab, or infliximab), is superior to either monotherapy with a biologic or MTX (2, 3, 4). There is still a large number of patients that have an incomplete response, or no response to TNF inhibitors (probably 5%-10%).

Available TNF-α antagonists (infliximab, adalimumab and etanercept) are generally well tolerated, however in series of clinical observations TNF-α antagonists increased susceptibility to infections and tumor development. TNF-α inhibition causes a significant clinical improvements but this cytokine also plays a pivotal role in defense against infections, especially intracellular organisms. At the infection site, TNF-α enhances endothelial cell activation, inflammatory cell recruitment also increases the ability of activated macrophages to phagocytose and kill mycobacteria.

The data on anti-TNF drugs have produced conflicting messages, with some studies suggesting increased infection rates, and others no difference from controls. Possible explanation for this discordant data might be that anti-TNF agents are often given concomitantly with MTX and prednisolone, or other DMARDs, which may increase infection risk.


Healing of wounds. The injuries during orthopedic surgery initiate a complex of biological processes that result in wound healing. Wound healing is a complicated process composed of several stages such as the inflammatory, proliferative, and remodeling. This process is performed and regulated by numerous growth factors, cytokines and chemokines. Of particular importance is the epidermal growth factor (EGF) family, transforming growth factor beta (TGF-beta) family, fibroblast growth factor (FGF) family, vascular endothelial growth factor (VEGF), granulocyte macrophage colony stimulating factor (GM-CSF), platelet-derived growth factor (PDGF), connective tissue growth factor (CTGF) [1].

Growth factors play a crucial role in the initial phases of wound healing like the cells division, migration, differentiation. The major families of growth factors contain: epidermal growth factor (EGF), transforming growth factor-beta (TGF-β), insulin-like growth factor (IGF), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), interleukins (ILs), and colony-stimulating factor (CSF) [2].

Dynamic interactions between growth factors and extracellular matrix (ECM) are integral to wound healing. The interactions between cells and ECM via integrins, which enables cells to respond to growth factors expression. Growth factors such as TGF-β also regulate the production of ECM components [3, 4].

The observations suggest that TGF-α may be released into the site of injury by macrophages or other cell types, and may play a crucial role during tissue inflammatory responses. Furthermore, TGF-α may play an important role after injury and inflammation during wound healing and repair [5].

The inflammatory phase in wound healing is considered to be a preparatory process for the formation of new tissue. A few experimental studies about influence of TNF-α on wound healing showed that TNF- α may play either a beneficial or detrimental role in wound healing. The impaired wound healing was related to high level of TNF-α in local tissue.

Animal studies have suggested that anti-TNF agents may have the potential to affect the healing response, but it is not clear whether their effects are deleterious or beneficial. The study on rats suggested that excessive TNF- α production may inhibit skin wound healing; and the blocking of TNF- α might restore fibroblast growth activity and normalize a healing response [1,2]. There are not many the large-scale prospective studies in humans about the TNF antagonists and surgical wound healing.


Patients with RA commonly used drugs decreasing the inflammatory or autoimmune response, among them are nonsteroidal antiinflammatory drugs, corticosteroids, DMARDs and biologic agents. These drugs affect inflammation and local immune responses, necessary for proper healing of operative wound, which results in potentially undesirable postoperative complications (wound dehiscence, infection, and impaired collagen synthesis) and delay in wound healing of soft tissue and bone. No clear consensus exists on the optimum time for withholding therapy before surgery. Some retrospective and prospective clinical studies were carried out on the effect anty-RA on recovery after orthopedic surgery and risk of postoperative complications. One group investigated the effects of TNF-α inhibition with etanercept or infliximab on infectious or healing complications after orthopedic foot and anklesurgery (115). Thirty-one patients with rheumatoid arthritis were enrolled in this prospective study. No differences were noted between the two groups with respect to usage of NSAIDs, methotrexate, leflunomide, or corticosteroids (doses were not specified). Investigators concluded that TNF-α inhibitors could be safely administered in the perioperative period without increasing the risk of infectious or healing complications. No clear-cut answer appeared in relation to perioperative management of antiinflammatory TNF-a blocking agents and their influence on the wound healing of patients undergoing orthopedic and other surgical procedures.


Pathology. In patients with RA, the affected joints develop chronic synovitis that is characterized by hyperplasia of lining cells, infiltration of inflammatory cells and abundant neovascularization. Various factors such as proteinases, growth factors and cytokines produced in synovium implicate in the destruction of articular cartilage and subchondral bones. Among the proteinases, matrix metalloproteinases (MMPs), a gene family of zinc metalloproteinases, play a major role in the proteolytic degradation of extracellular matrix (ECM) macromolecules of cartilage and bone.

Angiogenesis in the synovium during RA begins at the early stage of the disease and is crucial for progression of the synovitis. Synovial angiogenesis is a central mechanism to synovial proliferation and pannus formation, is largely dependent on vascular endothelial growth factor (VEGF).Binding of VEGF to its receptors on endothelial cells enhances not only their proliferation and migration but also production of MMPs. In addition, VEGF stimulates other cells such as chondrocytes to induce expression of MMPs.

Histopathological examination of synovial specimens can contribute to the diagnosis of chronic joint diseases. For scoring of synovitis can be introduced grading system, based on the semiquantitative or computer-assisted evaluation of the three determining features of chronic synovitis: enlargement of synovial lining, density of synovial stroma and inflammatory infiltrate. The intensity of the cellular infiltrate, the levels of activation and the amount of secreted products vary greatly between individual patients with RA. Many studies of synovial tissue have been reported that indicate associations between immunohistological features of inflammation and clinical measures of disease activity. Evidence for heterogeneity of the synovial component of RA comes from studies describing three distinct patterns of lymphoid organization in the synovium. Based upon the topography of tissue-infiltrating mononuclear cells, diffuse, follicular, and granulomatous variants of rheumatoid synovitis can be distinguished. Each pattern of lymphoid organization correlates with a unique profile of tissue cytokines, demonstrating that several pathways of immune deviation modulate disease expression in RA.

Serial synovial biopsies in open therapeutic studies and in randomised clinical trials showed that the immunohistological features of RA changed after treatment with DMARD, oral corticosteroids and targeted biological agents. The mediators of inflammation that changed in therapeutic studies include mononuclear cell populations, adhesion molecule expression, levels of cytokine production and MMPs. The effect of blockade of TNF-α on TNF-α production in synovial tissue was evaluated in patients treated with infliximab. The authors found that synovial TNF-α synthesis was reduced 2 weeks after infliximab treatment.


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PROGRAM OF THE STUDY

Amis: Tracking the immunological and pathomorphological responses of a healing wound and the joint tissues in the RA patients during TNF-α inhibitors therapy modified in perioperative setting.

Material and methods: The prospective study on 150 – 200 patients [pts] with RA .

The patients selection: clinical evaluation the RA degree: questionnaires, DAS 28, radiological and immunological data. General conditions of the pts. From the study will be excluded the pts presenting other diseases like: diabetes mellitus, other autoimmunological diseases, obesity and advanced stage of chronic diseases. Operation: type, postoperative course, anaesthesia, duration of the operation. The pts will be divided in 3 groups: A, B and C according to the treatment protocol; each group of 50 - 65 pts.

Group A: RA pts treated with TNF-α inhibitors (and other anti-inflammatory drugs such as: steroids and/or non-steroid anti-inflammatory drugs but without methotrexate). HUMIRA treatment for 4-6 months before operation; suspended for 2 weeks before and 2 weeks after operation.

Group B: RA pts treated with TNF-α inhibitors continuously (and other anti-inflammatory drugs such as: steroids and/or non-steroid anti-inflammatory drugs but without methotrexate). HUMIRA treatment for 4-6 months before operation and continuing during and after operation. Group C: RA pts without TNF-α inhibitors treated by various anti-inflammatory drugs such as: steroids and/or non-steroid anti-inflammatory drugs but without methotrexate and without HUMIRA.


HUMIRA: Treatment by TNF-α inhibitors will be reconsidered according to its characteristics, concentration, indications, period of therapy.

The therapeutic effect of TNF-α inhibitors will be explored as: a/ local effect: in soft tissues, bone ; and b/ systemic effect - concentration of the immunological parameters measured in the blood before operations, evaluation of the RA regression, clinical and laboratory analyses. The list of parameters used for the therapeutic effectiveness of the biological treatment: DAS28, RTG and serological: RF, anti-CCP, CRP, TNFα, IL-1, IL-6.


Material: I/ blood (24 hrs before operation) and postoperative fresh joint tissues for: *drug concentration (TNF-α inhibitors); * the histopathological study; *tissue concentration of TGF-β, TNFα, VEGF, IL-1, IL-6, MMP-1, MMP-9, TIMP-1.

II/ blood (systemic effect) and drainage fluid (local effect) for serological study – 12 hrs, 36 hrs , 7th and 14th day after operation. Drainage fluid analysis for: PDGF, TGF- β, białka BMP, IGF, TNF, VEGF, IL-1, IL-6, MMP-1, MMP-9, TIMP-1, leptin, GM-CSF.

Serum analysis for: PDGF, TGF-β, białka BMP, IGF, TNF, VEGF, IL-1, IL-6, MMP-1, MMP-9, TIMP-1, leptin, GM-CSF, procalcitonine .

III/ Synovial tissue samples obtained from patients at the time of joint replacement surgery (knees or hips). Synovial tissue samples for histopathology:H&E staining (synovitis scoring by automated analysis, cell inflammatory response – macrophages, limfocytes T and B) and immunohistochemistry: VEGF receptors, CD31, CD34, TGF-β.

Follow up; clinical assessment of the pts in 7th and 14th day. After 3, 6 months on the base of the questionnaires.

Final evaluation of the data


Dissemination: seminars/trainings for postgraduated doctors in perioperative management of the RA patients with the biological therapy.

Publications, conferences presentations, Ph.D. theses.


.

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