Rheumatoid Arthritis (RA)
Causes and Risk Factors
RA is generally thought to be caused by a combination of genetic factors and environmental triggers (the “two-hit” hypothesis):
| The genetic hit |
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| The environmental hit |
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Pathophysiology
Disclaimer:
The pathophysiology of RA presented here is intentionally simplified for a non-specialist level. The exact pathogenesis of RA is complex and involves numerous interacting genetic, environmental and immunological mechanisms.
The mechanism of RA can be broken down into a cascade of events that starts outside the joint and eventually leads to severe joint destruction. [Ref1][Ref2]
| Pathophysiology step | Description |
|---|---|
| 1. Abnormal protein modification (citrullination) | This process often begins extra-articularly, often in the lungs (from smoking) or the gums (from gingivitis)
The environmental stress causes the enzyme PAD to convert the amino acid arginine into citrulline (citrullination) |
| 2. Creation of autoantibodies | Due to the body’s genetic susceptibility (HLA-DRB1), the body’s immune system recognises these citrullinated proteins as foreign bodies and produces autoantibodies against them, including:
The antibodies can be present in the blood up to 10 years before joint symptoms begin |
| 3. Migration to the joint | The autoantibodies and immune cells migrate from the bloodstream into the synovium |
| 4. Joint inflammation | Once inside the joint, the immune cells trigger an inflammatory response that releases large amounts of pro-inflammatory cytokines, importantly:
Chronic inflammation results in:
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Immune cells involved in joint inflammation in RA: [Ref1][Ref2]
- Antigen-presenting cells (esp. dendritic cells) trigger the immune cascade (by presenting the citrullinated proteins to CD4+ T cells)
- Activated CD4+ T cells do 2 main actions
- Recruit neutrophils (by producing IL-17) → neutrophils mediate the direct joint damage by releasing pro-inflammatory cytokines, proteases, and ROS
- Activate B cells → autoantibody production → innate immune damage
Exam-important pathophysiology:
The core pathology of RA is defined by persistent synovial inflammation (synovitis) and hyperplasia → pannus formation → cartilage degradation and bone erosion (hallmark features of RA)
Clinical Features
Peak age of incidence: 70-80 y/o
| Category | Subcategory | Clinical features |
|---|---|---|
| Articular features | Symptoms | Gradual onset (over weeks to months) of chronic (>6 weeks):
Joint involvement in RA:
Characteristically, RA spares the following joints:
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| Signs |
Joint redness and warmth are typically absent |
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| Advanced deformities | The following deformities are classic of RA but only seen in advanced RA (and is rarely seen nowadays with the early initiation of DMARDs):
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| Extra-articular features | Constitutional |
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| Skin | Rheumatoid nodules – most common extra-articular findings
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| Eye |
NB anterior uveitis is NOT considered a typical ocular manifestation of RA |
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| Cardiovascular |
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| Lungs |
RA also increases the risk of pulmonary embolism |
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| Musculoskletal |
Due to the symmetrical nature of RA, carpal tunnel syndrome and tenosynovitis is more likely to present bilaterally |
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| Other |
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Important features that distinguish OA from inflammatory arthritis (e.g. )
| Feature | Osteoarthritis | Inflammatory arthritis |
|---|---|---|
| Pain pattern |
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| Morning stiffness |
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| Symmetry (of the affected joints) |
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Referral Criteria
Refer for specialist opinion in any adult with synovitis of undetermined cause
Refer urgently if ANY of the following (even if there are normal acute phase reactants and -ve serology):
- Small joints of the hands or feet are affected
- >1 joint affected
- Delay of ≥3 months between symptom onset and seeking medical advice
Investigation and Diagnosis
Do not delay specialist referral while arranging these investigations. In primary care, the priority is prompt referral to rheumatology.
NICE recommends the following tests:
- Rheumatoid factor, and
- X-ray of the hand and feet
If rheumatoid factor is -ve → consider measuring anti-CCP antibodies
Other Investigations and Interpretation in RA
| Investigation | Finding in RA |
|---|---|
| X-ray (hands and feet) | Early disease:
Moderate disease:
Advanced disease:
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| Other imaging |
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| Serology |
Other / emerging autoantibodies include anti-CarP, anti-acetylated protein antibodies, anti-MAA (specifically associated with RA-related ILD) |
| Acute phase reactants |
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| Synovial fluid analysis |
If WCC count 25,000/mm3, septic arthritis must be excluded |
Diagnostic Criteria
Important information about the 2010 ACR/EULAR Classification Criteria for RA:
- The criteria were developed primarily to support standardised patient classification for research and clinical trials
- NICE does not make any recommendations regarding the use of the classification criteria to diagnose or exclude RA
However, the criteria remain useful for understanding and recognising the typical pattern of early RA.
The 2010 ACR/EULAR Classification Criteria is a point-based system across 4 domains:
| Number and size of involved joints |
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| Serological testing |
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| Acute phase reactants |
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| Symptom duration |
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A total score of 6 or greater is considered diagnostic of RA.
Prognosis
The following factors are associated with a poor prognosis and worse outcomes [Ref1][Ref2]
| Patient factors |
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| Investigation findings |
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Management
The treatment goal in active RA is:
- Complete remission, or
- Low disease activity (treat-to-target), if remission not possible
Acute Flare Management
Acute flares should be managed with short-term glucocorticoid therapy
The choice of corticosteroid route depends on the extent of joint involvement:[Ref1][Ref 2]
- Localised (mono- or oligoarticular disease) → intra-articular steroid injection (e.g. triamcinolone hexacetonide)
- Non-localised (polyarticular disease) → IM corticosteroid injection (e.g. methylprednisolone) (typically a single injection) or oral corticosteroid (e.g. prednisolone) (typically a short course of 2-4 weeks with a reducing dose regimen)
Long-Term Management (DMARDs)
Disease-modifying antirheumatic drugs (DMARDs) are the mainstay of long-term treatment for rheumatoid arthritis
- DMARDs suppress disease activity, reduce flares and help prevent progressive joint damage and disability
- Following the diagnosis of RA, DMARDs should be started ASAP, ideally within 3 months of symptom onset
- In addition to DMARDs, also consider adding oral NSAIDs when control of pain or stiffness is inadequate
If the treatment target is not achieved despite dose optimisation, step up treatment accordingly:
| Treatment step | Description |
|---|---|
| Step 1 | Conventional DMARD monotherapy with ANY of the following:
Consider hydroxychloroquine in mild RA or palindromic rheumatism Upon starting a new conventional DMARD, consider a short-term bridging therapy with corticosteroids (oral / IM / IA) Purpose:
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| Step 2 | ADD a conventional DMARD to the existing monotherapy, ANY of the following
The patient would now be on dual therapy of conventional DMARDs |
| Step 3 | Offer methotrexate PLUS a biological DMARD
Choice of biological DMARD:
If there is severe RA (DAS28 >5.1) which inadequately responded to at least 1 TNF inhibitor → methotrexate PLUS rituximab Disclaimer: NICE did not make specific recommendations on what classes of biological DMARDs. Instead, it provides separate technology appraisals for individual biological DMARDs, which is confusing and complicated. For educational purposes, the above section is written in line with standard clinical practice and textbook approaches that are frequently tested in exams, while taking NICE guidelines into account. |
Monitoring Treatment
Measure / assess the following to monitor treatment:
- CRP
- DAS28
- Health Assessment Questionnaire (HAQ) to measure functional ability