Rheumatoid arthritis

• RA characteristics on XR (LESS)

  • L - loss of joint space
  • E - erosions MCP joints (knuckle)
  • S - Soft tissue swelling
  • S - soft bones (osteopenia) around joints
• Rheumatoid arthritis is an autoimmune condition that causes chronic inflammation in the synovial lining of the joints, tendon sheaths and bursa.
• RA is a type of inflammatory arthritis
• RA tends to present as symmetrical distal polyarthritis
• Most common joints affected:

  • Metacarpophalangeal (MCP) joints - knuckle
  • Proximal interphalangeal (PIP) joints
  • Wrist
  • MTP joint in the feet
  • DOES NOT TYPICALLY AFFECT THE DISTAL INTERPHALANGEAL JOINTS (DIP) UNLIKE IN OA
• Risk factors:

  • Female sex (2-3x more common) - north American and western European ethnicity most at risk
  • Smoking
  • Obesity
  • Family history - HLA-DR4
  • Infectious trigger hypothesis - acute infection may trigger RA due to molecular mimicry
  • Occupational exposures - airborne inhalant exposures like silica and chemical fertilisers
• Antibodies:

  • Rheumatoid factor autoantibody present in around 70%
  • Anti-cyclic citrullinated peptide antibodies (anti-CCP)are more sensitive and specific - present in around 80%
• The speed of onset can vary from rapid (e.g., overnight) to gradual (e.g., over months). The three joint symptoms are: 

  • Pain
  • Stiffness
  • Swelling 
• Examination:

  • Tenderness
  • Synovial thickening
  • Boggy feeling - pannus (abnormal layer of granulation tissue) - difficult to palpate joint line
  • Reduced range of movement
  • All of above can result in difficulty with fine motor tasks e.g. buttoning a shirt
• Rheumatoid arthritis very rarely affects the distal interphalangeal joints. Enlarged and painful distal interphalangeal joints are more likely to represent Heberden’s nodes due to osteoarthritis.
• Large joints such as the ankle, knee, hips, and shoulders can also be affected. It can affect the cervical spine (but not the lumbar spine).
• Associated systemic symptoms include:

  • Fatigue
  • Weight loss
  • Flu-like illness
  • Muscles aches and weakness
• Inflammatory arthritis symptoms are worse with rest and improve with activity. They are worst in the morning. Symptoms of mechanical problems (e.g., osteoarthritis) are worse with activity and improve with rest.
• Palindromic rheumatism:

  • Self-limiting episodes of inflammatory arthritis with pain, stiffness and swelling typically affecting only a few joints
  • The symptoms last days, then completely resolve
  • Joints appear normal between episodes
  • RF and anti-CCP antibodies may indicate that it will progress to RA
• Hand signs in advanced disease:

  • Z shaped deformity to the thumb - flexion of MCP and hyperextension of the IP joint
  • Z deformity at wrist - radial deviation at the wrist, ulnar deviation of the digits at MCP joints
  • Swan neck deformity (hyperextended PIP and flexed DIP)
  • Boutonniere deformity (hyperextended DIP and flexed PIP)
  • Effective treatments means it is unusual for RA to get to this stage
• Atlantoaxial subluxation:

  • Occurs in the cervical spine
  • Synovitis and damage to the ligaments around the axis (C2) allow it to shift within the atlas (C1)
  • Subluxation can lead to spinal cord compression
• Eye manifestations:

  • Dry eye syndrome (keratoconjunctivitis)
  • Episcleritis (inflammation between the conjunctiva and sclera)
  • Scleritis
  • Uveitis
  • Keratitis
  • Cataracts (secondary to steroids)
  • Retinopathy (secondary to hydroxychloroquine)
• NICE referral guidelines:

  • Urgent rheumatology for patients with persistent synovitis (to be seen with three weeks)
  • Suggest considering NSAID and arranging baseline bloods whilst awaiting assessment
• Initial investigations:

  • Baseline FBC, U+Es, LFTs
  • Bone profile - vit D deficiency common in RA
  • Inflammatory markers - CRP and ESR (normal in 40%)
  • autoantibodies - rheumatoid factor (less sensitive and specific) and anti-CCP (predictor of worse outcome)
  • X-rays of hands and feet for bone changes (first line)
  • USS - effusions, visualise tendons, synovitis
  • MRI - active joint and soft tissue disease
  • US and MRI good to detect early inflammatory arthritis
• The diagnosis is based on clinical findings and blood results. The American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria from 2010 can be used to make the diagnosis. 
• Scoring systems:

  • Health Assessment Questionnaire (HAQ) measures functional ability. Baseline HAQ score at diagnosis to assess the response to treatment
  • Disease activity score 28 joints (DAS28) - assesses 28 joints and assigns points for swollen joints, tender joints and ESR/CRP result
• Short term steroids may be used at initial presentation, when initiating a new treatment and during flares to induce remission
• Treatment is with conventional disease-modifying anti-rheumatic drugs (cDMARDs) and biologic DMARDs:

  1. Monotherapy with methotrexate, leflunomide or sulfasalazine. Consider hydroxychloroquine for mild or palindromic disease. Usually with bridging steroid therapy for 2-3 months to allow DMARDs to take effect
  2. Combination treatment with multiple  cDMARDs
  3. Biologic therapies (usually alongside methotrexate) - sometimes might be first line in severely active progressive disease
• Hydroxychloroquine may be used in mild disease and palindromic rheumatism. It is the “mildest” DMARD.
• Pregnancy can improve symptoms

  • Hydroxychloroquine and sulfasalazine are considered safe in pregnancy
  • Methotrexate and leflunomide are teratogenic
• Adalimumab, infliximab and etanercept are TNF inhibitor biologics

  Side effects = reactivation of TB
• Rituximab is a monoclonal antibody that targets the CD20 protein on the surface of B cells

  Side effects = night sweats and thrombocytopenia
• Biologics side effects:

  • immunosuppression
  • Increased risk of infection
  • Increased risk of certain cancers e.g. skin
  • Reactivation of latent TB (Anti-TNF meds)
• Methotrexate interferes with folate metabolism and suppresses the immune system. It is given once a week. Folic acid 5mg is taken once a week (on a different day to the methotrexate). Side effects include:

  • Mouth ulcers and mucositis
  • Liver toxicity
  • Bone marrow suppression and leukopenia (low white blood cells)
  • Teratogenic (harmful to pregnancy) and needs to be avoided before conception in both women and men
  • Need to monitor FBC, renal and liver function tests every 1-2 weeks when establishing and then every 2-3 months
• Leflunomide is an immunosuppressant medication that interferes with the production of pyrimidine. Pyrimidine is an important component of RNA and DNA. Side effects include:

  • Mouth ulcers and mucositis
  • Increased blood pressure
  • Liver toxicity
  • Bone marrow suppression and leukopenia (low white blood cells)
  • Teratogenic (harmful to pregnancy) and needs to be avoided before conception in both women and men
  • Peripheral neuropathy
• Sulfasalazine is an immunosuppressive and anti-inflammatory medication. The exact mechanism is not clear. Side effects include:

  • Orange urine
  • Reversible male infertility (reduced sperm count and quality)
  • Bone marrow suppression
  • Risk of neonatal haemolysis in 3rd trimester
• Hydroxychloroquine is traditionally an antimalarial medication. It suppresses the immune system by interfering with Toll-like receptors, disrupting antigen presentation and increasing the pH in the lysosomes of immune cells. Side effects include:

  • Retinal toxicity (reduced visual acuity (macular toxicity)
  • Blue-grey skin pigmentation
  • Hair lightening (bleaching)
  • Can precipitate a haemolytic crisis in G6PD deficiency
  • Avoid in pregnancy but do not withdraw if well controlled disease
• Methotrexate can cause pneumonitis
• Antinuclear antibody (ANA) raised in up to 30% - only check if other sign or symptoms that suggest lupus or another connective tissue disease
• Stages of joint damage:

  • Following suspected triggering event patients develop anti-CCP antibodies

  1. Infiltration of synovial joints with immune cells and a subsequent pro-inflammatory response
  2. Causes synovitis - typically symmetrical polyarthropathy of small joints
  3. Continued inflammatory response causes thickening of synovial membrane and cartilage damage - pannus forms over ends of joints
  4. Damage to the bone - bony loss and periarticular erosions
  5. Destruction of surrounding tendons, ligaments and blood vessels
• Presentation:

  • Joint pain that is worse at rest
  • Joint swelling
  • Joint stiffness - typically early morning stiffness lasting >1 hr
  • Constitutional symptoms - myalgia, fatigue, low-grade fever, low mood
• Foot signs:

  • Hammer toe
  • Compensatory flexion of toes due to weakening and subluxation of surrounding tendons
• Extra articular manifestations:

  • Occur in around 40% of RA patients
  • Generally reflect longstanding inflammation and more active/severe disease
  • Often caused by active vasculitis
  • More likely to occur in patients who are seropositive, especially with high titres of autoantibodies
• Ocular extra articular manifestations:

  • Keratoconjunctivitis sicca - dry eyes, if accompanied with xerostomia (dry mouth) suggests secondary Sjogren's syndrome
  • Episcleritis - inflammation of superficial layer of sclera
  • Scleritis - inflammation of whole sclera
• Cardiac extra articular manifestations:

  • Pericarditis - part of serositis (inflammation of serous membrane)
  • Myocarditis
  • Non infective endocarditis
  • Increased risk of ischaemic heart disease (damage from inflammatory cytokines)