Rheumatoid Arthritis: Causes, Symptoms, and Prevalence

• Rheumatoid arthritis (RA) is an immune-mediated inflammatory arthritis.
• RA has a progressive, remitting/relapsing course.
• RA leads to synovial inflammation, bone and cartilage destruction, hyperplasia, and systemic changes.
• RA negatively impacts the health-related quality of life and increases mortality.
• RA is defined as a systemic inflammatory polyarthritic disease of autoimmune origin with an unknown cause.
• RA causes equal and varied levels of joint movement.
• RA affects 0.6% of adults in the United States and is declining due to better treatments.
• Women are affected 2 to 3 times more than men.
• The prevalence of RA increases with age, typically presenting between ages 20-60.
• The exact cause of RA is unknown.
• Predisposing factors include genes (HLA-DRB1 alleles), environment (smoking, air pollution), hormones, and reproduction.
• A possible genetic predisposition coupled with an environmental trigger may cause RA.
• An antigen-antibody reaction results in an inflammatory response.
• RA occurs in all races and ethnic groups.
• RA typically occurs between ages 40 and 60 years.
• In children, the mean age of onset is 1-3 years, with 30% experiencing severe long-term effects.
• Risk factors include family history, female sex, age 40 and older, obesity, celiac disease, cigarette smoking, diets high in processed foods/refined carbohydrates/trans fatty acids/arachidonic acid, and vitamin D deficiency.

Assessment Findings

• Onset may be acute (over 24 hours) or gradual and insidious.
• Constitutional symptoms include weakness, malaise, fatigue, anorexia, weight loss, and depression.
• Other constitutional symptoms include lymphadenopathy, aches, low-grade fever, eye inflammation, vasculitis, pericarditis, and pleurisy.
• Joint pain/stiffness occurs at rest and with movement, disturbs sleep, and lasts >1 hour in the morning upon arising.
• Polyarticular involvement includes proximal interphalangeal (PIP), metacarpophalangeal (MCP), wrist, elbow, knee, and ankle joints.
• Symptoms are typically symmetrical.
• Rheumatoid nodules may occur on extensor surfaces of elbows and fingers, indicating more severe disease.
• Symptoms are usually present for 9 months prior to diagnosis.

Differential Diagnoses

• Differential diagnoses include fibromyalgia, osteoarthritis, viral syndrome, systemic lupus erythematosus, soft tissue syndrome, scleroderma, dermatomyositis & polymyositis, polymyalgia vasculitis, Lyme disease, and spondyloarthropathies.

Pathophysiology

• Stage 1 (Early): Targets the synovial lining on diarthrodial (wrist, elbow, hip & knee) joints.
• Stage 1 (Early): Early changes occur in small blood vessels and capillaries.
• Stage 1 (Early): Increased synovial lining production and T-lymphocyte infiltration occurs.
• Stage 2 (Later disease progression): Diffuse infiltration with B & T lymphocytes, macrophages & plasma cells
• Stage 2 (Later disease progression): Hyperplastic thickening of lining with formation of new blood vessels (pannus) occurs.
• Pannus (granulation tissue) destroys cartilage & subchondral bone.

Clinical Presentation (I): Articular Manifestations

• Typical first symptom is stiffness in one or more joints with painful articulation and tenderness.
• A varied number of joints are involved initially, but it becomes polyarticular (5 or more joints).
• Palindromic presentation: Swelling in 1 or 2 joints lasts for days to weeks, then resolves but recurs in similar or other joints with worsening location pattern later.
• Joints involved typically include proximal interphalangeal (PIP) and metacarpophalangeal (MCP) of hands, wrists, and small joints of feet (metatarsophalangeal - MTP).
• Other affected joints are elbows, shoulders, knees, ankles, and the cervical spine.
• Symptoms develop slowly over weeks to months, but can have explosive onset over 24 to 48 hours of polyarticular flare in rare cases.
• The spine and distal interphalangeal (DIP) joints are typically not affected.

Clinical Presentation (II): Extra-Articular Manifestations

• Extra-articular manifestations are symptoms and conditions that affect organs and tissues outside of the joints.
• Subcutaneous nodules may appear on pressure areas like elbows and areas of trauma.
• Rheumatoid nodules can occur on cardiac valves, pericardium, pleura, lung parenchyma, & spleen.
• Vasculitis can cause mononeuritis, skin infarcts, & ulceration.
• Ocular signs include Sjogren syndrome (dryness), episcleritis (inflammation of the eyes sclera), & scleritis.
• Respiratory manifestations include Interstitial Lung Disease or pleurisy.
• Cardiac manifestations include pericarditis or valvular heart disease.
• Peripheral nerve entrapments can lead to carpal tunnel syndrome.

Physical Exam (I): Signs and Symptoms

• Palpation and visual examination detect warmth and tenderness over the joint.
• The synovial membrane feels thick and boggy.
• Skin over the joint may appear thin, shiny, or ruddy.
• Examine affected joints closely for pain, stiffness, warmth, erythema, and limited range of motion.
• Pain is worse in the morning (> 1-hour duration) and relieved by movement.
• Stiffness is present in the morning and after rest from ADLs.
• Early detection is important for referral and early treatment initiation to halt progression and attempt remission.
• The disease commonly starts in the MCP, PIP, and MTP joints, followed by the wrists, knees, elbows, ankles, hips, and shoulders in roughly that order.
• Less commonly, and usually only in more advanced cases, RA may involve the temporomandibular, cricoarytenoid, and sternoclavicular joints.
• RA may involve the upper part of the cervical spine, particularly the C1–C2 articulation, but rarely involves the rest of the spine.
• Late-stage disease can cause ulnar deviation of the fingers at the MCPs, swan neck deformities (hyperextension of the PIP joints and flexion at the DIP joints).
• Boutonnière deformities present with flexion of the PIP joints and hyperextension of the DIP joints.

RA vs. OA

• Patients with RA often report involvement of small joints first, classically the PIP, MCP, and MTP joints, with involvement of large joints occurring later.
• Symptoms include pain, swelling, and stiffness, with stiffness often dominating.
• Patients with early disease often complain that rings no longer fit and that they have pain on the balls of the feet when walking in the morning.

Dx. Initial work up

• Labs: CBC, CMP, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP)
• Autoimmune markers: RF, Anti–cyclic citrullinated peptide (Anti-CCP). ANA (not useful for RA, but can r/o SLE)
• Radiology: Baseline X-ray of hands and feet
• MS Ultrasonography: Synovial capsule
• MRI: Can show subclinical synovitis, early erosive changes, and response
• Join aspiration: fluid analysis (r/o gout, pseudogout, septic arthritis, if diagnosis uncertain)
• Other: Screening for latent TB, retinopathy, HBV, HCV, HIV, melanoma, and non-melanoma skin cancer

Diagnostic Studies

• X-ray studies show joint space narrowing, bony erosion in joints, reduced bone density surrounding joints (periarticular osteopenia), and joint subluxation.
• Autoantibodies are positive in 75-80% of patients with RA.
• RF is elevated (20% of patients are negative despite having other RA symptoms).
• ACPA is present.
• Antinuclear antibody (ANA) is usually negative, but can be positive in 20-30% of patients.
• Anti-cyclic citrullinated peptide (anti-CCP) antibodies can detect RA earlier.
• ESR and CRP indicate acute nonspecific inflammation if positive.
• Serum uric acid is tested to rule out gout.
• Hepatitis B and C serologies are performed.
• Joint aspiration rules out infectious arthritis and gout.
• MRI and musculoskeletal ultrasound may identify subclinical synovitis.
• ESR is a good measure of RA disease activity.

Prevention

• Reduce modifiable risk factors.

Management

• Prompt diagnosis and treatment will minimize harmful sequelae.
• The goal is to achieve inactive disease clinically and structurally.

Nonpharmacologic Management

• Physical therapy, occupational therapy, and psychological interventions aid in achieving the goal.
• Exercise program considerations: increase in pain or swelling indicates excessive exercise, should not involve joints that are acutely inflamed, walking and exercises that boost muscle strength are recommended.
• Orthotics can relieve pain and prevent deformities.
• Functional insoles and therapeutic footwear can be helpful.
• Cold therapy provides analgesic, anti-inflammatory effects.
• Heat therapy provides relaxation and circulatory stimulation.
• Correct nutritional deficits.
• Avoid dietary sugar.
• Follow principles of the Mediterranean diet.
• Achieve and maintain a healthy BMI.
• Avoid allergens that precipitate symptoms.
• Surgery options: arthroscopy with synovectomy, arthroplasty.
• Education about illness and therapies improves the patient’s ability to form appropriate goals and participate in the treatment plan.

Pharmacologic Management

• The American College of Rheumatology recommends treatment with disease-modifying antirheumatic drugs (DMARDs) as soon as RA is identified.
• Glucocorticoids may be combined with DMARDs, but they should be tapered as soon as clinically indicated.
• The goal of treatment for rheumatoid arthritis is disease remission or low disease activity.

Newly Diagnosed RA Activity Level & Recommended therapy.

• Low disease activity: DMARD monotherapy (methotrexate first line).
• Moderate disease activity: DMARD monotherapy + short-term intermediate/high/low steroids or DMARD combination therapy
• High disease activity: DMARD combination therapy

Pharmacological Management

• Methotrexate has the most predictable effect on RA.
• Folate should be taken concurrently with methotrexate to reduce the risk of side effects (nausea, vomiting, stomatitis, GI intolerance, bone marrow toxicity, and abnormal liver function tests).

Pharmacological agents

• Syntetic DMARDs: Methotrexate (10-25mg weekly: needs to be given with folate), Hydroxychloroquine, Sulfasalazine, Leflunomide, Minocycline.
• Biologic DMARDs: TNF (adalimumab, certolizumag pegol, etanercept, golimumab, infliximab), IL-6 receptor (tocilizumab), CD 80/CD86 (abatacept), CD 20 (rituximab).
• Glucocorticoids/ NSAID: Low dose prednisone, NSAID, Intra-articular injections.

Initial Plan

• Referral to rheumatology or an expert person as soon as possible after diagnosis.
• Start DMARD therapy soon after diagnosis, with Methotrexate is recommended as the first-line treatment.
• Disease activity should be monitored regularly (target-to-target).
• Biologic therapies should be used where there is persistently active disease.
• Remission or low disease activity is the preferred target.

Treatment plan success can be measured by:

• A minimum 20%-50% improvement
• Moderate: 50%-70% improvement
• Remission: characterized by minimal or absent swollen joints.

Rheumatoid arthritis (RA) is an immune-mediated inflammatory arthritis with a progressive, remitting/relapsing course. RA leads to synovial inflammation, bone and cartilage destruction, hyperplasia, and systemic changes, negatively impacting the health-related quality of life and increases mortality. The exact cause of RA is unknown.