Rheumatoid Arthritis
Definition
Rheumatoid Arthritis (RA) is a chronic autoimmune disorder that specifically targets the synovial membrane of joints, leading to inflammation, pain, and potential joint damage. Manifesting as symmetrical polyarthritis, it typically affects small joints on both sides of the body. Aside from joints, this systemic autoimmune condition can also impact organs like the skin, heart, lungs, eyes, blood vessels, and the nervous system.
Risk Factors
While the exact cause of RA remains unknown, certain risk factors contribute to its development.
Genetics: Having a family history of RA increases the risk, but also specific genetic markers, like HLA-DRB, are linked to a higher susceptibility.
Sex: Ratio of women to men developing RA is 3:1 and according to some sources even 7:1
Smoking
Environmental Factors: Exposure to certain environmental factors, such as pollutants and occupational hazards, may contribute to RA risk.
Hormones: Hormonal factors, including changes related to pregnancy and menopause, may influence RA risk.
Obesity
Infections: Some infections, particularly those related to bacteria and viruses, may trigger or exacerbate RA in genetically predisposed individuals.
Periodontal Disease: Poor oral health and periodontal disease have been linked to an increased risk of RA.
Pathophysiology
The pathophysiology of rheumatoid arthritis involves a complex interplay of genetic, environmental, and immunologic factors. Central to the pathophysiological process of RA is the production of antibodies, with rheumatoid factor (RF) present in about 70% of RA patients and anti-citrullinated protein antibodies (ACPAs) detected in approximately 80%. Notably, ACPAs often precede the onset of RA, therefore serving as predictive markers.
These autoantibodies play a crucial role in fostering chronic inflammation and the formation of a hypertrophic synovium, known as pannus. The aggregation and deposition of immune complexes in the synovium, followed by the infiltration of immune cells, particularly T-cells and macrophages, contribute to the formation of the pannus. These infiltrating cells release inflammatory cytokines, particularly tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1) and interleukin-6 (IL-6). These inflammatory mediators, stimulate and activate fibroblasts, which results in the hypertrophy of the synovium.
The hypertrophic synovium or pannus releases enzymes, such as collagenase and stromelysin, that contribute to the destruction of cartilage. Additionally, the inflammatory mediators produced by the pannus, particularly IL-1 and TNF-α, also stimulate osteoclast-mediated bone absorption, exacerbating joint damage.
Signs and Symptoms
Rheumatoid arthritis typically exhibits a gradual onset over weeks to months. Initial symptoms are nonspecific, resembling flu-like symptoms such as subfebrile temperatures, myalgias, and fatigue. Subtle joint pain may also be present. As the disease progresses, more specific symptoms emerge, including morning stiffness lasting > 60 minutes, joint swelling, and polyarticular pain with a symmetric distribution pattern, meaning that the joints on both sides of the body are involved.
The most commonly affected joints in RA include the Proximal interphalangeal (PIP) joints, Metacarpophalangeal (MCP) joints, wrist, and Metatarsophalangeal joints (foot). Knees, shoulders and elbows can also be affected, but usually not as frequently and severely as the small joints of the hand and the feet. To differentiate from other illnesses, it's crucial to note that distal interphalangeal joints are almost never affected by RA. In such cases, consideration should be given to alternative diagnoses such as psoriatic arthritis, gout, or osteoarthritis.
In advanced disease or when proper medication hasn’t been administered, characteristic hand signs may appear, which collectively can result in the so-called "rheumatoid hand."
These signs include:
Swan neck deformity (hyperextended PIP and flexed DIP)
Boutonniere deformity (hyperextended DIP and flexed PIP)
90°-90° deformity of the thumb (hyperextended DIP and flexed thumb basal joint)
Ulnar deviation of the fingers at the MCP joints.
Extra-articular manifestations can involve organs such as the skin, eyes, lungs, and heart.
Rheumatoid Nodules: Firm subcutaneous lumps, often at pressure points or over joints
Rheumatoid Lung Disease: Inflammation in the lungs, leading to conditions such as interstitial lung disease (ILD) or pleuritis, which can impair lung function, due to scarring.
Cardiovascular Involvement: Increased risk of cardiovascular diseases, including atherosclerosis and heart attacks.
Ocular Manifestations: Conditions such as scleritis (inflammation of the sclera of the eye), dry eye syndrome (keratoconjunctivitis sicca) or secondary Sjögren's syndrome (autoimmune disease attacking the salivary glands and the lacrimal gland) may occur.
Rheumatoid Vasculitis: Inflammation affecting blood vessels, leading to vasculitis and potential organ damage.
Felty's Syndrome: A rare complication characterized by RA, splenomegaly, and neutropenia.
Neurological Involvement: Some individuals may experience peripheral neuropathy or compression neuropathies (e.g., carpal tunnel syndrome).
Diagnosis
Diagnosing rheumatoid arthritis early and accurately is essential for effective management. The diagnosis involves a combination of clinical evaluation, laboratory tests, and imaging studies.
Clinical evaluation
The clinical examination focuses on cardinal signs such as joint tenderness, swelling, joint stiffness and increased joint warmth. A critical aspect of the clinical examination consists in testing the passive and active range of motion in joints, which in RA is often impaired, particularly in advanced disease stages. Another essential feature of RA is the exacerbation of symptoms with rest and improvement with movement. This distinctive characteristic is specific to inflammatory arthritides, aiding in the differentiation from conditions like osteoarthritis, where symptoms improve with rest and worsen with activity. Additionally, Gaenslen's handshake, involving the exertion of pressure on the metacarpophalangeal joints, serves as a valuable diagnostic tool for RA. A positive result is determined by the manifestation of pain in response to moderate pressure on the MCP joints.
Laboratory Tests
Blood tests including c-reactive protein (CRP), erythrocyte sedimentation rate (ESR), Anti citrullinated peptide antibodies (ACPA), and rheumatoid factor (RF) are crucial in the diagnosis and monitoring of the disease. These markers allow also the differentiation between seropositive and seronegative RA. Seropositive meaning that ACPA and/or RF are elevated and seronegative meaning that they are below the established threshold. ESR and CRP, which are unspecific inflammatory parameters aren’t important for detecting the disease, but for monitoring its progression and severeness. Elevated values correlate with a more severe and destructive disease or with an inadequate therapy.
Imaging
Imaging, such as X-rays, MRI and joint ultrasonography can help assess joint damage. The typical findings in RA are:
Joint Erosions
Joint Space Narrowing
Soft Tissue Swelling
Subchondral Bone Changes: Changes in the subchondral bone, such as sclerosis (increased bone density) and cyst formation, may be evident on X-rays.
Atlantoaxial subluxation can also be detected with MRI or X-rays, it occurs in 1-5% of people with RA. The displacement of the atlantoaxial joint, results from synovitis in the atlantoaxial joint. This subluxation can lead to instability in the upper cervical spine, potentially causing compression of the spinal cord or the brainstem.
Diagnostic Criteria
In 2010 EULAR and ACR collaborated to create the diagnostic criteria for RA. A definitive diagnosis of RA requires a score of ≥ 6/10 with a concomitant joint inflammation not better explainable by another cause.
DIP joints, first CMC joints and first MTP joints are excluded from assessment.
Shoulders, elbows, hips, knees and ankles count as large joints.
MCP joints, PIP joints, second through fifth MTP joints, thumb IP joints and count as small joints
Negative means less than or equal to the upper limit of normal (ULN); low positive means > ULN; high positive means >3× ULN;
Therapy
Treatment strategies for RA aim to control inflammation, relieve symptoms, prevent joint damage, and improve overall quality of life. During the acute phase a medication with NSAIDs (e.g. Ibuprofen) and oral glucocorticoids is recommended, in severe cases an intraarticular glucocorticoid infiltration may also be considered.
Initiating long-term therapy promptly is vital for optimizing patient outcomes. Disease-modifying antirheumatic drugs (DMARDs), such as Methotrexate, are the preferred option in this regard. DMARDs distinguish themselves from NSAIDs by their ability to not only alleviate symptoms but also to actively slow down the progression of the disease and, in certain cases, even achieve remission. To bridge the period until DMARDs take full effect, a short-term use of NSAIDs and/or glucocorticoids is recommended.
Methotrexate (MTX) is often the first choice DMARD and is administered weekly. The effectiveness of the therapy should be assessed after 3 to 6 months, if there’s insufficient improvement, additional DMARDs like Leflunomide or Sulfasalazine can be combined with MTX. Hydroxychloroquine is another DMARD, which may be considered in mild cases of RA.
If multiple DMARDs show no effect after 3 months, Biologics become a consideration. Commonly used Biologics in RA include Anti-TNF-α antibodies (adalimumab, infliximab, etanercept, golimumab, and certolizumab), Interleukin-6 receptor blockers (tocilizumab), Interleukin-1 receptor blockers (anakinra), JAK inhibitors (Baricitinib, Tofacitinib, Upadacitinib), and Anti-CD20 antibodies (rituximab).
In addition to pharmaceutical therapy, physical therapy and lifestyle modifications, such as exercise and joint protection techniques, play pivotal roles in symptom management and maintaining joint functionality. Surgical interventions, like joint replacement surgeries, may be considered in severe cases to restore joint function and alleviate pain.
To consistently evaluate the effectiveness of therapy, it is recommended to utilize the Disease Activity Score (DAS28), which assesses tenderness and swelling in 28 joints, together with regular blood tests measuring ESR and CRP. These measures facilitate the timely adaptation of therapy in case of reduced effectiveness.
References
Wilson D. Rheumatoid factors in patients with rheumatoid arthritis. Can Fam Physician. 2006 Feb;52(2):180-1. PMID: 16529390; PMCID: PMC1479719.
van de Stadt LA, de Koning MH, van de Stadt RJ, Wolbink G, Dijkmans BA, Hamann D, van Schaardenburg D. Development of the anti-citrullinated protein antibody repertoire prior to the onset of rheumatoid arthritis. Arthritis Rheum. 2011 Nov;63(11):3226-33. doi: 10.1002/art.30537. PMID: 21792832.
Lam J, Takeshita S, Barker JE, Kanagawa O, Ross FP, Teitelbaum SL. TNF-alpha induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand. J Clin Invest. 2000 Dec;106(12):1481-8. doi: 10.1172/JCI11176. PMID: 11120755; PMCID: PMC387259.
Britsemmer K, Ursum J, Gerritsen M, van Tuyl LH, van Schaardenburg D. Validation of the 2010 ACR/EULAR classification criteria for rheumatoid arthritis: slight improvement over the 1987 ACR criteria. Ann Rheum Dis. 2011 Aug;70(8):1468-70. doi: 10.1136/ard.2010.148619. Epub 2011 May 17. Erratum in: Ann Rheum Dis. 2011 Nov;70(11):2060. van Tuyl, Lilian [corrected to van Tuyl, L H]. PMID: 21586440.
