Epidemiology and Risk Factors

Epidemiology

• Worldwide incidence: 3 per 10,000 people per year
• More prevalent in:
  • Native Americans
  • North America
  • Northern Europe
• 2–3 times more common in women
• Peak age of presentation is 30–50-years-old.

Risk factors

The cause of rheumatoid arthritis (RA) is unknown, but several risk factors play a role.

• Genetic predisposition:
  • 2–3 times more likely in those with a 1st-degree relative with RA
  • Associated with:
    • HLA-DR1
    • HLA-DR4
• Environmental factors:
  • Lifestyle:
    • Cigarette smoking 
    • Obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity 
  • Hormonal
  • Infectious:
    • Epstein-Barr virus Epstein-Barr Virus Epstein-Barr virus (EBV) is a linear, double-stranded DNA virus belonging to the Herpesviridae family. This highly prevalent virus is mostly transmitted through contact with oropharyngeal secretions from an infected individual. The virus can infect epithelial cells and B lymphocytes, where it can undergo lytic replication or latency. Epstein-Barr Virus (EBV)
    • Parvovirus B19 Parvovirus B19 Primate erythroparvovirus 1 (generally referred to as parvovirus B19, B19 virus, or sometimes erythrovirus B19) ranks among the smallest DNA viruses. Parvovirus B19 is of the family Parvoviridae and genus Erythrovirus. In immunocompetent humans, parvovirus B19 classically results in erythema infectiosum (5th disease) or "slapped cheek syndrome." Parvovirus B19
    • Hepatitis B Hepatitis B Hepatitis B virus (HBV) is a partially double-stranded DNA virus, which belongs to the Orthohepadnavirus genus and the Hepadnaviridae family. Most individuals with acute HBV infection are asymptomatic or have mild, self-limiting symptoms. Chronic infection can be asymptomatic or create hepatic inflammation, leading to liver cirrhosis and hepatocellular carcinoma (HCC). Hepatitis B Virus and C 
    • Rubella Rubella Rubella (also known as German measles or three-day measles) is caused by a single-stranded, positive-sense RNA virus of the Togaviridae family. Rubella only infects humans and spreads prenatally via vertical transmission or postnatally via droplet contact. Congenital rubella is associated with a classic triad of symptoms: cataracts, cardiac defects, and deafness. Infection in children and adults may be mild and present with constitutional symptoms along with a viral exanthem. Rubella Virus
    • Mycoplasma Mycoplasma Mycoplasma is a species of pleomorphic bacteria that lack a cell wall, which makes them difficult to target with conventional antibiotics and causes them to not gram stain well. Mycoplasma bacteria commonly target the respiratory and urogenital epithelium. Mycoplasma pneumoniae (M. pneumoniae), the causative agent of atypical or "walking" pneumonia. Mycoplasma
    • Recurrent dental infections

Pathophysiology

• Not completely understood
• An external trigger sets off the autoimmune response and ↑ expression of enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes that convert arginine to citrulline → creation of antigens
• B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells produce antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins to citrullinated proteins → bind to fibrinogen and collagen → complement activation
• Synovium is infiltrated by immune cells (e.g., macrophages, mast cells, B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells, CD4 T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells) → cytokine and chemokine production → synovial membrane thickening and villus formation
• Hyperplastic synovial tissue (pannus) releases: 
  • Collagenase
  • Stromelysin
  • Interleukins Interleukins Interleukins are a type of cytokines (signaling proteins) that communicate messages between different parts of the immune system. The majority of interleukins are synthesized by helper CD4 T lymphocytes along with other cells such as monocytes, macrophages, and endothelial cells. Interleukins (IL)
  • Tumor necrosis factor Tumor necrosis factor Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF) ( TNF TNF Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF))-alpha
• Leads to:
  • Continued synovial inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation
  • Cartilage Cartilage Cartilage is a type of connective tissue derived from embryonic mesenchyme that is responsible for structural support, resilience, and the smoothness of physical actions. Perichondrium (connective tissue membrane surrounding cartilage) compensates for the absence of vasculature in cartilage by providing nutrition and support. Cartilage destruction
  • Osteoclasts-mediated bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones destruction

Diagnosis

Rheumatoid arthritis (RA) diagnosis is based on high clinical suspicion and confirmed by serology and imaging.

Laboratory testing

• General:
  • Complete blood count (CBC):
    • ↓ Hemoglobin → anemia of chronic disease
    • ↑ Platelets Platelets Platelets are small cell fragments involved in hemostasis. Thrombopoiesis takes place primarily in the bone marrow through a series of cell differentiation and is influenced by several cytokines. Platelets are formed after fragmentation of the megakaryocyte cytoplasm. Platelets
    • Neutropenia Neutropenia Neutrophils are an important component of the immune system and play a significant role in the eradication of infections. Low numbers of circulating neutrophils, referred to as neutropenia, predispose the body to recurrent infections or sepsis, though patients can also be asymptomatic. Neutropenia → Felty syndrome
    • Mild leukocytosis may be present.
  • Inflammatory markers:
    • ↑ Erythrocyte sedimentation rate (ESR) 
    • ↑ C-reactive protein (CRP)
    • ↑ Ferritin
• Serology:
  • Rheumatoid factor (RF):
    • Present in 70%–80% of patients
    • RF is present in 15% of patients without RA.
  • Anti-cyclic citrullinated peptide (anti-CCP) antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: highly specific
  • Antinuclear antibody (ANA): 
    • Nonspecific
    • Positive in 30% of patients
• Synovial fluid analysis:
  • Leukocytosis (5,000–50,000 cells/microliter) with neutrophil predominance
  • ↓ Glucose
  • Gram stain and gram culture both negative
  • Negative for crystals

Imaging

• Radiographs:
  • May be normal in early disease
  • Soft tissue swelling
  • Periarticular osteopenia
  • Bony erosion
  • Joint-space narrowing
  • Joint subluxation
• Ultrasonography:
  • Erosion
  • Joint-space narrowing
  • Synovitis
• Magnetic resonance imaging (MRI): 
  • More sensitive than radiographs
  • Detects erosion earlier
  • Evaluates hypertrophic and inflamed synovial tissue

Management and Prognosis

Management

The goal is to prevent deformity and permanent damage. Patients should be referred to a rheumatologist.

Nonpharmacological therapies:

• Physical and occupational therapy
• Smoking cessation

Acute exacerbation management:

• Nonsteroidal antiinflammatory drugs (NSAIDs)
• Glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids:
  • Can be used as a bridge to disease-modifying antirheumatic drug ( DMARD DMARD Disease-modifying antirheumatic drugs are antiinflammatory medications used to manage rheumatoid arthritis. The medications slow, but do not cure, the progression of the disease. The medications are classified as either synthetic or biologic agents and each has unique mechanisms of action and side effects. Disease-modifying Antirheumatic Drugs) therapy or for acute flares
  • Options: systemic or intraarticular injection

Long-term pharmacological therapy:

• DMARDs:
  • Should be initiated in all patients upon diagnosis
  • Methotrexate is usually the 1st choice.
  • Additional options: sulfasalazine, hydroxychloroquine, azathioprine, leflunomide
• TNF TNF Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF)-alpha inhibitors:
  • May be added if DMARD DMARD Disease-modifying antirheumatic drugs are antiinflammatory medications used to manage rheumatoid arthritis. The medications slow, but do not cure, the progression of the disease. The medications are classified as either synthetic or biologic agents and each has unique mechanisms of action and side effects. Disease-modifying Antirheumatic Drugs therapy is not effective
  • Options: etanercept, adalimumab, infliximab, golimumab, certolizumab
• Other biologic therapy options:
  • IL-6 inhibitors (tocilizumab)
  • CD20 monoclonal antibody (rituximab)
  • Selective T cell costimulation blocker (abatacept)

Surgery:

• Indicated for severe damage and limited function
• Can be considered if pharmacologic therapy is unsuccessful
• Options:
  • Joint replacement
  • Joint fusion
  • Synovectomy

Additional considerations:

• While on glucocorticoid treatment, patients should be monitored for:
  • Osteoporosis Osteoporosis Osteoporosis refers to a decrease in bone mass and density leading to an increased number of fractures. There are 2 forms of osteoporosis: primary, which is commonly postmenopausal or senile; and secondary, which is a manifestation of immobilization, underlying medical disorders, or long-term use of certain medications. Osteoporosis
  • Diabetes
  • Hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension
• Appropriate vaccinations should be given to prevent infectious complications of immunosuppressive medications.
• All patients should be screened for tuberculosis Tuberculosis Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis and hepatitis.
• Patients require ongoing laboratory monitoring for drug toxicity:
  • CBC
  • Liver function
  • Creatinine
• Cervical spine imaging prior to surgical procedures:
  • Evaluate for cervical subluxation (most often at the atlantoaxial joint).
  • Intubation can be fatal in those with cervical instability.

Prognosis

• RA is a chronic, progressive disease:
  • The majority of patients relapse.
  • 10% will be severely disabled despite adequate management.
• Associated with an increased risk of:
  • Cardiovascular disease
  • Infection
  • Respiratory disease
  • Gastrointestinal bleeding Gastrointestinal bleeding Gastrointestinal bleeding (GIB) is a symptom of multiple diseases within the gastrointestinal (GI) tract. Gastrointestinal bleeding is designated as upper or lower based on the etiology's location to the ligament of Treitz. Depending on the location of the bleeding, the patient may present with hematemesis (vomiting blood), melena (black, tarry stool), or hematochezia (fresh blood in stools). Gastrointestinal Bleeding
  • Lymphoma (especially with Felty syndrome)
• 2–3 times higher risk of death than the general population
• Risk factors for a poor prognosis:
  • Extraarticular manifestations
  • Advanced age
  • Women
  • Caucasians
  • Early erosion on imaging
  • Cigarette smoking
  • High inflammatory markers and/or antibody titers
  • ≥ 20 affected joints

Differential Diagnosis

• Osteoarthritis (OA): a “wear and tear” form of arthritis due to cartilage destruction and changes of the subchondral bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones. Patients develop gradual joint pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, stiffness lasting < 30 minutes, and decreased range of motion. The PIP, DIP, and CMC joints are frequently affected. Diagnosis is clinical and supported with radiographic joint findings. Inflammatory markers, RF, and anti-CCP are negative. Management includes analgesics, intraarticular steroid injections, and surgery for advanced disease.
• Gout: a disease caused by hyperuricemia, which leads to arthritis from the precipitation of monosodium urate crystals in the joints. Gout is often monoarticular, and usually involves pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, tenderness, swelling, erythema, and warmth of the 1st MTP joint. Diagnosis is confirmed by the identification of negatively birefringent, needle-shaped crystals in the synovial fluid. Management includes NSAIDs, colchicine, corticosteroids, and uric acid reduction with allopurinol.
• Pseudogout: intraarticular calcium pyrophosphate deposition with unclear etiology. Patients present with acute flares of joint swelling, warmth, and pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain. Pseudogout usually affects larger joints, such as the knee. Diagnosis is confirmed by the identification of positively birefringent, rhomboid crystals in the synovial fluid. Management includes NSAIDs, corticosteroids, and colchicine.
• Psoriatic arthritis: a spondyloarthropathy occurring in patients with psoriasis Psoriasis Psoriasis is a common T-cell-mediated inflammatory skin condition. The etiology is unknown, but is thought to be due to genetic inheritance and environmental triggers. There are 4 major subtypes, with the most common form being chronic plaque psoriasis. Psoriasis. Psoriatic arthritis is inflammatory, frequently asymmetric, and involves both small and large joints, including DIP joints and the sacroiliac spine. Symptoms may also include enthesopathy and dactylitis. Diagnosis is clinical and should be suspected in patients with psoriasis Psoriasis Psoriasis is a common T-cell-mediated inflammatory skin condition. The etiology is unknown, but is thought to be due to genetic inheritance and environmental triggers. There are 4 major subtypes, with the most common form being chronic plaque psoriasis. Psoriasis. Management includes DMARDs and biologic agents.
• Reactive arthritis Reactive arthritis Reactive arthritis is a seronegative autoimmune spondyloarthropathy that occurs in response to a previous gastrointestinal (GI) or genitourinary (GU) infection. The disease manifests as asymmetric oligoarthritis (particularly of large joints in the lower extremities), enthesopathy, dactylitis, and/or sacroiliitis. Reactive Arthritis: a spondyloarthropathy often precipitated by a gastrointestinal or genitourinary infection. Patients may present with asymmetric arthritis, typically of the lower extremities. Reactive arthritis Reactive arthritis Reactive arthritis is a seronegative autoimmune spondyloarthropathy that occurs in response to a previous gastrointestinal (GI) or genitourinary (GU) infection. The disease manifests as asymmetric oligoarthritis (particularly of large joints in the lower extremities), enthesopathy, dactylitis, and/or sacroiliitis. Reactive Arthritis can be associated with fever, tendinitis, enthesitis, mucocutaneous ulcers, and conjunctivitis Conjunctivitis Conjunctivitis is a common inflammation of the bulbar and/or palpebral conjunctiva. It can be classified into infectious (mostly viral) and noninfectious conjunctivitis, which includes allergic causes. Patients commonly present with red eyes, increased tearing, burning, foreign body sensation, and photophobia. Conjunctivitis. Diagnosis is clinical and management includes NSAIDs, DMARDs, and treatment of the infection.