What is the natural history of Rheumatoid Arthritis (RA)?

From the Guidelines

Rheumatoid arthritis (RA) typically follows a progressive course characterized by periods of flares and remissions, with the disease usually beginning insidiously with fatigue, malaise, and generalized musculoskeletal pain before progressing to the characteristic symmetric polyarthritis affecting small joints, particularly the hands and feet. The natural history of RA is complex and involves several stages, including synovitis, pannus formation, and joint destruction, ultimately leading to deformities and disability if left untreated 1. Without treatment, joint damage occurs early, with a significant proportion of patients developing radiographic erosions within the first few years of disease onset. The disease can also be associated with extra-articular manifestations, including rheumatoid nodules, vasculitis, interstitial lung disease, pericarditis, and ocular complications.

Key features of the natural history of RA include:

• Symmetric polyarthritis affecting small joints, particularly the hands and feet
• Morning stiffness lasting 1 hour or longer
• Subcutaneous nodules and other extra-articular disease manifestations
• Joint damage and deformities, such as ulnar deviation, boutonnière and swan-neck deformities, and joint subluxations
• Reduced life expectancy, with an increased risk of comorbid conditions and mortality

Modern treatment approaches emphasize early, aggressive intervention with disease-modifying antirheumatic drugs (DMARDs) like methotrexate, often combined with biologics such as TNF inhibitors when indicated 1. This "treat-to-target" strategy aims to achieve remission or low disease activity within 3-6 months of diagnosis, significantly improving long-term outcomes by preventing irreversible joint damage and disability that characterized the natural history of untreated RA in the past. According to recent studies, therapy can be tapered successfully in some patients, and even sustained drug-free remission can be achieved in a subset of patients 1.

From the Research

Definition and Characteristics of Rheumatoid Arthritis (RA)

• Rheumatoid Arthritis (RA) is an idiopathic disease characterized by systemic inflammation, persistent synovitis, and the presence of autoantibodies 2
• It is a chronic autoimmune disease causing progressive joint damage that can lead to lifelong disability 3
• RA is a chronic multisystemic inflammatory disease with autoimmune features, and of unknown cause, associated with characteristic joint deformities and increased mortality rate 4

Natural History and Prognosis of RA

• The natural history of RA is best defined by a combination of disease-specific measures such as radiographs and remission rates, and patient-specific measures such as functional and work disability, total joint replacement, adverse drug reactions, social disruption, and premature mortality 5
• Prognosis depends largely on how RA is defined, since clinical RA has a worse and epidemiologic RA a better prognosis 5
• RA is a progressive disease in the clinic, particularly in patients with long-term follow-up 5

Pathogenesis of RA

• The pathogenesis of RA involves a complex network of various cytokines and cells that trigger synovial cell proliferation and cause damage to both cartilage and bone 3
• Involvement of the cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-6 is central to the pathogenesis of RA, but recent research has revealed that other cytokines also play a role 3
• The pathogenesis of RA seems to be multifactorial, where several cytokines, particularly interleukin-1 and tumor necrosis factor-alpha, are strongly involved in the induction and perpetuation of the chronic inflammatory process of the joints in RA and in the systemic manifestations of the disease 4

Treatment and Management of RA

• Current treatments of RA are inadequate in that they only partially control established RA, and despite optimal use of current antirheumatic agents, the outcome of many patients with RA consists of pain, severe functional decline, and premature death 4
• Treatments with disease-modifying antirheumatic drugs (DMARDs) are effective to control inflammation and decrease bone destruction, but the overall remission rates of RA still stay at a low level 6
• Promising targeted therapies under clinical or preclinical trials, especially epigenetic and metabolic regulators, are being explored to improve treatment outcomes 6