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Rheumatoid Arthritis: Many Management Strategies, No Cure
Maureen McMahon, MD, MS
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William J. Cardarelli, PharmD
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Rheumatoid Arthritis: Many Management Strategies, No Cure

Maureen McMahon, MD, MS
Inflammation
Induction of immune complexes is followed by systemic inflammation and elevated levels of serum autoantibodies (ACPAs and RF) and acute phase proteins.3 Cytokines, specifically TNF-alpha, interleukin (IL)-6, IL-1 and IL-17 are key mediators of inflammation, with local and systemic effects.27 TNF-alpha is responsible for increased monocyte activation and cytokine release, and increased polymorphonuclear leukocyte priming, apoptosis, and oxidative burst. TNF-alpha also plays a critical role in decreasing the synthesis of collagen and increasing production of acute-phase proteins.27 The impact of ILs in RA is discussed in more detail in part 2 of this supplement. However, it is important to know that ILs play a critical role in the amplification of immune response and have synergistic activity with TNF-alpha and interferon-gamma.

Clinically, the inflammatory phase is characterized by synovitis, joint swelling, and pain that results from an aggressive tissue response to the infiltration of leukocytes within the synovial compartment.4 Bone and cartilage loss can also be promoted through ACPAs binding to membrane-bound citrullinated vimentin. Macrophage activation occurs, resulting in activation of osteoclasts, chondrocytes, and osteoblasts, which also produces clinical symptomology, as does B-cell activation and the formation of RF immune complexes. This inflammatory process is established in patients with RA long before clinical symptoms are evident.4,26
 
Bone Erosion and Destruction
The unchecked processes of induction and inflammation in RA ultimately result in tissue destruction and remodeling in the synovial tissue and bone, and in areas such as the lungs.4 While bone remodeling is a normal physiologic process, bone formation is disrupted in RA.28 Osteoclasts are multinucleated cells that regulate the process of mineral homeostasis under normal circumstances. In RA, they are the primary mediators of bone destruction.27 Through a process that is mediated by TNF-alpha, IL-6, and receptor activator of nuclear factor kappa-B ligand, continuous differentiation of osteoclasts in RA leads to an imbalance in the process of remodeling and results in bony erosions and chronic joint destruction.28
 
Diagnosing RA
The presence or absence of ACPAs and RF are key markers in the clinical diagnosis of RA.1 Both RF and ACPAs may be detected several years prior to symptomatic disease in the preclinical phase, confirming the general consensus that the spectrum of RA begins years before the onset of clinical symptoms.4,12,29

There are no definitive diagnostic criteria for RA; however, a clinical diagnosis may be established by a rheumatologist based on classification criteria developed by the American College of Rheumatology (ACR), in association with the European League Against Rheumatism.1 Diagnosis is a 2-part process that includes establishing a patient’s “eligibility” and classifying the patient.  To be eligible for an RA classification, the patient must have at least 1 joint with synovitis (joint swelling) that is not explained by another disease.1  While the previous 1987 ACR crtieria relied on chronic and end-stage manifestations such as erosions and extra-articular features of disease, the updated criteria focus on identifying patients at an early stage. Early identification and treatment are critical in achieving control of disease and preventing joint injury and disability.

Continuous monitoring of the patient to measure disease activity or remission after treatment initiation is recommended using any one of a variety of instruments including the Patient Activity Scale (PAS) or PAS-II, Routine Assessment of Patient Index Data 3, Clinical Disease Activity Index, Disease Activity Score (DAS), and Simplified Disease Activity Index.8
 
Treating Patients With RA
The goals of treating patients with RA are focused on controlling symptoms (relieving pain and reducing inflammation) and slowing down or stopping structural damage, to maximize long-term health-related quality of life and normalize function.8,30 To achieve these goals in the long run, the 2015 ACR guidelines suggest consideration be given to cost of treatment and routine assessment of functional status.8

Treatments for patients with RA consist of traditional disease-modifying antirheumatic drugs (DMARDs), biologic therapies (TNF inhibitors and non-TNF biologics), glucocorticosteroids (mainly prednisone), and tofacitinib (a Janus kinase [JAK] inhibitor).8



 
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