Rheumatoid Arthritis

Rheumatoid arthritis is an autoimmune condition that causes chronic inflammation of the synovial lining of the joints, tendon sheaths and bursa. It is an inflammatory arthritis. Synovial inflammation is called synovitis. Rheumatoid arthritis tends to be symmetrical and affects multiple joints. Therefore it is a symmetrical polyarthritis. Inflammation of the tendons increases the risk of tendon rupture.

It is three times more common in women than men. It most often develops in middle age but can present at any age. Family history is relevant and increases the risk of rheumatoid arthritis.

 

Genetic Associations

  • HLA DR4 (a gene often present in RF positive patients)
  • HLA DR1 (a gene occasionally present in RA patients)

 

Antibodies

Rheumatoid Factor (RF) is an autoantibody presenting in around 70% of RA patients. It is an autoantibody that targets the Fc portion of the IgG antibody. All antibodies have an Fc portion on them that is used to bind to cells of the immune system. Rheumatoid factor targets this Fc portion on immunoglobin G (IgG). This causes activation of the immune system against the patients own IgG causing systemic inflammation. Rheumatoid factor is most often IgM however they can be any class of immunoglobulin.

Cyclic citrullinated peptide antibodies (anti-CCP antibodies) are autoantibodies that are more sensitive and specific to rheumatoid arthritis than rheumatoid factor. Anti-CCP antibodies often pre-date the development of rheumatoid arthritis and give an indication that a patient will go on to develop rheumatoid arthritis at some point.

 

Presentation

It typically presents with a symmetrical distal polyarthropathy. The key symptoms are joint:

  • Pain
  • Swelling
  • Stiffness

Patients usually attend complaining of pain and stiffness in the small joints of the hands and feet, typically the wrist, ankle, MCP and PIP joints in the hands. They can also present with larger joints affected such as the knees, shoulders and elbows. The onset can be very rapid (i.e. overnight) or over months to years.

There are also associated systemic symptoms:

  • Fatigue
  • Weight loss
  • Flu like illness
  • Muscles aches and weakness

TOM TIP: Pain from an inflammatory arthritis is worse after rest but improves with activity. Pain from a mechanical problem such as osteoarthritis is worse with activity and improves with rest.

 

Palindromic Rheumatism

This involves self limiting short episodes of inflammatory arthritis with joint pain, stiffness and swelling typically affecting only a few joints. The episodes only last 1-2 days and then completely resolve. Having positive antibodies (RF and anti-CCP) may indicate that it will progress to full rheumatoid arthritis.

 

Common Joints Affected

  • Proximal Interphalangeal Joints (PIP) joints
  • Metacarpophalangeal (MCP) joints
  • Wrist and ankle
  • Metatarsophalangeal joints
  • Cervical spine
  • Large joints can also be affected such as the knee, hips and shoulders

TOM TIP: The distal interphalangeal joints are almost never affected by rheumatoid arthritis. If you come across enlarged painful distal interphalangeal joints this is most likely to be Heberden’s nodes due to osteoarthritis.

 

Atlantoaxial Subluxation

Atlantoaxial subluxation occurs in the cervical spine. The axis (C2) and the odontoid peg shift within the atlas (C1). This is caused by local synovitis and damage to the ligaments and bursa around the odontoid peg of the axis and the atlas. Subluxation can cause spinal cord compression and is an emergency. This is particularly important if the patient is having a general anaesthetic and requiring intubation. MRI scans can visualise changes in these areas as part of pre-operative assessment.

 

Signs in the Hands

Palpation of the synovium in around joints when the disease is active will give a “boggy” feeling related to the inflammation and swelling.

Key changes to look for and mention when examining someone with rheumatoid arthritis are:

  • Z shaped deformity to the thumb
  • Swan neck deformity (hyperextended PIP with flexed DIP)
  • Boutonnieres deformity (hyperextended DIP with flexed PIP)
  • Ulnar deviation of the fingers at the knuckle (MCP joints)

Boutonnieres deformity

Boutonnieres deformity is due to a tear in the central slip of the extensor components of the fingers. This means that when the patient tries to straighten their finger, the lateral tendons that go around the PIP (called the flexor digitorum superficialis tendons) pull on the distal phalynx without any other supporting structure, causing the DIPs to extend and the PIP to flex.

 

Extra-articular Manifestations

  • Pulmonary fibrosis with pulmonary nodules (Caplan’s syndrome)
  • Bronchiolitis obliterans (inflammation causing small airway destruction)
  • Felty’s syndrome (RA, neutropenia and splenomegaly)
  • Secondary Sjogren’s Syndrome (AKA sicca syndrome)
  • Anaemia of chronic disease
  • Cardiovascular disease
  • Episcleritis and scleritis
  • Rheumatoid nodules
  • Lymphadenopathy
  • Carpel tunnel syndrome
  • Amyloidosis

 

Investigations

The diagnosis of rheumatoid arthritis is clinical in patients with features of rheumatoid arthritis (i.e. symmetrical polyarthropathy affecting small joints). A few extra investigations are required at diagnosis:

  • Check rheumatoid factor
  • If RF negative, check anti-CCP antibodies
  • Inflammatory markers such as CRP and ESR
  • X-ray of hands and feet

Ultrasound scan of the joints can be used to evaluate and confirm synovitis. It is particularly useful where the findings of the clinical examination are unclear.

 

Xray changes

  • Joint destruction and deformity
  • Soft tissue swelling
  • Periarticular osteopenia
  • Boney erosions

 

Referral

NICE recommend referral for any adult with persistent synovitis, even if they have negative rheumatoid factor, anti-CCP antibodies and inflammatory markers. The referral should be urgent if it involves the small joints of the hands or feet, multiple joints or symptoms have been present for more than 3 months.

 

Diagnosis

Diagnostic criteria come from the American College of Rheumatology (ACR) / European League Against Rheumatism (ELAR) from 2010:

Patients are scored based on:

  1. The joints that are involved (more and smaller joints score higher)
  2. Serology (rheumatoid factor and anti-CCP)
  3. Inflammatory markers (ESR and CRP)
  4. Duration of symptoms (more or less than 6 weeks)

Scores are added up and a score greater than or equal to 6 indicates a diagnosis of rheumatoid arthritis.

 

DAS28 Score

The DAS28 is the Disease Activity Score. It is based on the assessment for 28 joints and points are given for:

  • Swollen joints
  • Tender joints
  • ESR/CRP result

It is useful in monitoring disease activity and response to treatment.

 

Health Assessment Questionnaire (HAQ)

This questionnaire measures functional ability. NICE recommend using this at diagnosis to check the response to treatment.

 

Prognosis

Prognosis varies between patients from mild and remitting to severe and progressive. There is a worse prognosis with:

  • Younger onset
  • Male
  • More joints and organs affected
  • Presence of RF and anti-CCP
  • Erosions seen on xray

 

Management

Starting treatment early is associated with better outcomes. It is essential to have fully involvement of multidisciplinary team including specialist nurses, physiotherapy, occupational therapy, psychology and podiatry.

A short course of steroids can be used at first presentation and during flare ups to quickly settle the disease. NSAIDs/COX-2 inhibitors are often effective but risk GI bleeding so are often avoided or co-prescribed with proton pump inhibitors (PPIs).

The aim is to induce remission or get as close to remission as possible. CRP and DAS28 is used to monitor the success of treatment. Aim to reduce the dose to the “minimal effective dose” that controls the disease.

 

NICE guidelines for Disease Modifying Anti-Rheumatic Drugs (DMARDs):

  • First line is monotherapy with methotrexate, leflunomide or sulfasalazine. Hydroxychloroquine can be considered in mild disease and is considered the “mildest” anti rheumatic drug.
  • Second line is 2 of these used in combination.
  • Third line is methotrexate plus a biological therapy, usually a TNF inhibitor.
  • Fourth line is methotrexate plus rituximab

Pregnant women tend to have an improvement in symptoms during pregnancy, probably due to the higher natural production of steroid hormones. Sulfasalazine and hydroxychloroquine are considered as DMARDs in pregnancy.

 

Biological Therapies

  • Anti-TNF (adalimumab, infliximab, etanercept, golimumab and certolizumab pegol)
  • Anti-CD20 (rituximab)
  • Anti-IL6 (sarilumab)
  • Anti-IL6 receptor (tocilizumab)
  • JAK inhibitors (tofacitinib and baricitinib)

TOM TIP: The most important biologics to remember are the TNF inhibitors adalimumab, infliximab and etanercept and it is also worth remembering rituximab. The others are very unlikely to come up in your exams but are worth being aware of. Just remember they all lead to immunosuppression so patients are prone to serious infections. They can also lead to reactivation of dormant infections such as TB and hepatitis B.

 

Surgery

Orthopaedic surgery used to be an important part of management where joint deformities caused significant problems with function, however the DMARDS and biologics mean that now patients are less likely to progress to that stage.

 

Methotrexate

Methotrexate works by interfering with the metabolism of folate and suppressing certain components of the immune system. It is taken by injection or tablet once a week. Folic acid 5mg is also prescribed once a week to be taken on a different day to the methotrexate.

Notable Side Effects

  • Mouth ulcers and mucositis
  • Liver toxicity
  • Pulmonary fibrosis
  • Bone marrow suppression and leukopenia (low white blood cells)
  • It is teratogenic (harmful to pregnancy) and needs to be avoided prior to conception in mothers and fathers

 

Leflunomide

Leflunomide is an immunosuppressant medication that works by interfering with the production of pyrimidine. Pyrimidine is an important component of RNA and DNA.

Notable Side Effects

  • Mouth ulcers and mucositis
  • Increased blood pressure
  • Rashes
  • Peripheral neuropathy
  • Liver toxicity
  • Bone marrow suppression and leukopenia (low white blood cells)
  • It is teratogenic (harmful to pregnancy) and needs to be avoided prior to conception in mothers and fathers

 

Sulfasalzine

Sulfasalazine works as an immunosuppressive and anti-inflammatory medications. The mechanism is not clear but may be related to folate metabolism. It appears to be safe in pregnancy however women need adequate folic acid supplementation.

Notable Side Effects

  • Temporary male infertility (reduced sperm count)
  • Bone marrow suppression

 

Hydroxychloroquine

Hydroxychloroquine is traditionally an anti-malarial medication. It acts as an immunosuppressive medication by interfering with Toll-like receptors, disrupting antigen presentation and increasing the pH in the lysosomes of immune cells. It is thought to be safe in pregnancy.

Notable Side Effects

  • Nightmares
  • Reduced visual acuity (macular toxicity)
  • Liver toxicity
  • Skin pigmentation

 

Anti-TNF drugs

Tumour necrosis factor is a cytokine involved in stimulating inflammation. Blocking TNF reduces inflammation. Some examples of anti-TNF drugs are:

  • Adalimumab
  • Infliximab
  • Golimumab
  • Certolizumab pegol
  • Etanercept

Adalimumab, infliximab, golimumab and certolizumab pegol are monoclonal antibodies to tumour necrosis factor. Etanercept is a protein that binds TNF to the Fc portion of IgG and thereby reduces its activity.

Notable Side Effects

  • Vulnerability to severe infections and sepsis
  • Reactivation of TB and hepatitis B

 

Rituximab 

Rituximab is a monoclonal antibody that targets the CD20 protein on the surface of B cells. This causes destruction of B cells. It is used for immunosuppression for autoimmune conditions such as rheumatoid arthritis and cancers relating to B cells.

Notable Side Effects

  • Vulnerability to severe infections and sepsis
  • Night sweats
  • Thrombocytopenia (low platelets)
  • Peripheral neuropathy
  • Liver and lung toxicity

 

TOM TIP: There are a lot of side effects to remember for your exams. Many of them are shared between medications. Try to remember the unique ones as these are more likely to be tested:

  • Methotrexate: pulmonary fibrosis
  • Leflunomide: Hypertension and peripheral neuropathy
  • Sulfasalazine: Male infertility (reduces sperm count)
  • Hydroxychloroquine: Nightmares and reduced visual acuity
  • Anti-TNF medications: Reactivation of TB or hepatitis B
  • Rituximab: Night sweats and thrombocytopenia

 

Last updated March 2019
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