18.1 Rheumatoid Arthritis: Pathophysiology, Clinical Features & Diagnosis

Inflammatory arthropathies represent a core examination domain in the MRCP(UK) Part 1 examination. Candidates must demonstrate detailed mastery of disease immunopathogenesis, autoantibody profiles, joint distribution, extra-articular manifestations, and guideline-directed pharmacotherapy, alongside the distinct clinical and radiographic features of the seronegative spondyloarthropathies.

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1. Rheumatoid Arthritis: Pathophysiology & Immunogenetics

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease characterized by persistent, symmetrical, invasive synovitis of diarthrodial joints.

Cellular & Molecular Pathophysiology

1. Loss of Self-Tolerance & Citrullination: Environmental triggers (most notably cigarette smoking and mucosal dysbiosis, particularly periodontal infection with Porphyromonas gingivalis) activate peptidylarginine deiminase (PAD) enzymes. PAD converts positively charged arginine residues within self-proteins (vimentin, fibrinogen, alpha-enolase, type II collagen) into neutral citrulline.
2. Antigen Presentation & the Shared Epitope: Citrullinated peptides are avidly bound and presented by antigen-presenting cells expressing the HLA-DRB1 'shared epitope'—a conserved five-amino acid sequence (positions 70–74, such as QKRAA, QRRAA) within the peptide-binding groove of the HLA-DR4/DRB1*0401 and *0404 beta-chain. This elicits CD4+ T-cell activation (Th1 and Th17 phenotypes).
3. Humoral Immunity & Synovial Homing: Activated T cells stimulate autoreactive B lymphocytes to differentiate into plasma cells that produce anti-cyclic citrullinated peptide (anti-CCP / ACPA) antibodies and rheumatoid factor (RF). Circulating immune complexes home to the microvasculature of the synovium, activating the classical complement pathway and recruiting monocytes and neutrophils.
4. Synovial Pannus Formation: The normally delicate, single-to-double-layered synovial lining undergoes marked hyperplastic proliferation, transforming into an aggressive, locally invasive fibrovascular tissue termed the pannus. The pannus consists of proliferated fibroblast-like synoviocytes (FLS), tissue macrophages, and neoangiogenic vessels driven by vascular endothelial growth factor (VEGF).
5. Cartilage Breakdown & Bone Erosion: Synovial macrophages and FLS release pro-inflammatory cytokines, predominantly tumour necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6). These cytokines induce chondrocytes and FLS to secrete matrix metalloproteinases (MMP-1, MMP-3, MMP-13), which degrade type II collagen and aggrecan, digesting articular cartilage. Concurrently, TNF-α and IL-6 massively upregulate receptor activator of nuclear factor kappa-B ligand (RANKL) on osteoblasts and T cells, driving the differentiation and activation of subchondral osteoclasts. Osteoclasts directly resorb bone at the synovial-bone junction, producing the hallmark marginal juxta-articular bone erosions.

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2. Clinical Patterns & Characteristic Joint Deformities

Joint Distribution & Symptoms

• Pattern: Classically a chronic, insidious, symmetrical polyarthritis involving small and medium diarthrodial joints.
• Predilection: Metacarpophalangeal (MCP) joints, proximal interphalangeal (PIP) joints, metatarsophalangeal (MTP) joints, and wrists. Later involvement includes knees, elbows, shoulders, ankles, and cervical spine.
• Crucial Exclusions: Rheumatoid arthritis strictly spares the distal interphalangeal (DIP) joints and the thoracolumbar spine. Joint involvement at DIPs suggests osteoarthritis or psoriatic arthritis; thoracolumbar spinal involvement suggests spondyloarthropathy.
• Diurnal Variation: Marked early morning joint stiffness lasting > 1 hour (frequently several hours), which characteristically improves with physical movement and warm showers, reflecting the "gelling" phenomenon of inflammatory synovial exudate (in stark contrast to osteoarthritis, where stiffness lasts < 30 minutes and worsens with prolonged exertion).

Characteristic Anatomical Deformities

Untreated or aggressive synovitis weakens surrounding tendons, ligaments, and joint capsules, precipitating signature anatomical deformities:

• Boutonnière Deformity: Hyperflexion of the PIP joint accompanied by hyperextension of the DIP joint. Caused by rupture or avulsion of the central slip of the extensor digitorum tendon over the PIP joint, allowing the lateral extensor bands to slip volarly.
• Swan-Neck Deformity: Hyperextension of the PIP joint accompanied by compensatory flexion of the DIP joint. Caused by stretching and laxity of the fibrocartilaginous volar plate at the PIP joint with contracture of intrinsic hand muscles.
• Ulnar Deviation / Ulnar Drift: Subluxation and ulnar deviation of the fingers at the MCP joints, secondary to damage to MCP collateral ligaments and extensor tendon subluxation under the mechanical pull of flexor tendons.
• Z-Deformity of the Thumb: Persistent flexion at the MCP joint with reciprocal hyperextension at the interphalangeal (IP) joint.
• Piano-Key Sign: Ulnar styloid prominence and dorsal instability resulting from tenosynovitis of the extensor carpi ulnaris and destruction of the distal radioulnar joint (triangular fibrocartilage complex).
• Atlantoaxial Subluxation (C1–C2 Instability): The transverse ligament of the atlas holds the odontoid process (dens) of C2 firmly against the anterior arch of C1. Pannus formation and erosive synovitis of the atlantoaxial synovial bursa weaken the transverse ligament, permitting anterior subluxation of C1 on C2. Clinically, patients present with occipital headache, neck stiffness, electric-shock sensations down the spine upon neck flexion (Lhermitte's sign), or progressive spastic quadriparesis. Mandatory exam rule: Patients with RA undergoing elective surgery require pre-operative flexion and extension lateral cervical spine radiographs to exclude atlantoaxial subluxation before endotracheal intubation, as neck extension during direct laryngoscopy risks fatal cervicomedullary cord transection.

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3. Extra-Articular Manifestations & Felty's Syndrome

Extra-articular features reflect systemic immune-complex deposition and vasculitis, occurring almost exclusively in patients who are seropositive for RF and anti-CCP.

Systemic Organ Involvement

• Rheumatoid Subcutaneous Nodules: Occur in 25–30% of seropositive patients, typically located over pressure points and extensor surfaces (olecranon process, extensor forearm, Achilles tendon). Histopathology demonstrates pathognomonic central fibrinoid necrosis surrounded by a radial palisade of CD68+ histiocytes (macrophages) and an outer mantle of lymphocytes.
• Pulmonary Complications:
  • Interstitial Lung Disease (ILD): The most common pattern is usual interstitial pneumonia (UIP) (subpleural reticulation, basal traction bronchiectasis, and honeycombing on HRCT), carrying a poorer prognosis than the NSIP pattern seen in other connective tissue diseases.
  • Pleural Effusion: Typically asymptomatic, unilateral exudative effusion. Biochemical analysis reveals a pathognomonic profile: characteristically very low glucose (< 1.6 mmol/L or < 30 mg/dL) due to defective glucose transport across the inflamed pleura, marked elevation of lactate dehydrogenase (LDH > 1,000 IU/L), low pH (< 7.20), and low complement levels.
  • Rheumatoid Pulmonary Nodules: Discrete, well-circumscribed nodules in lung parenchyma; may cavitate. In coal miners with RA, the coexistence of multiple pulmonary rheumatoid nodules and pneumoconiosis is designated Caplan's syndrome.
• Ocular Manifestations:
  • Episcleritis: Acute, painless or mildly uncomfortable segmental redness of the eye; engorged episcleral vessels move over the underlying sclera and blanch with topical phenylephrine 2.5%; benign and self-limiting.
  • Scleritis: Severe, deep, boring nocturnal ocular pain that radiates to the temple and periorbita; deep violaceous/bluish hue; vessels do not blanch with phenylephrine. Can cause scleral thinning and necrosis (scleromalacia perforans), presenting as anterior globe perforation; represents a medical emergency requiring high-dose systemic corticosteroids or biologics.
  • Keratoconjunctivitis Sicca (Secondary Sjögren's Syndrome): Occurs in 15–20% of RA patients, manifesting with xerophthalmia and xerostomia.
• Rheumatoid Vasculitis: Severe, late-stage complication of high-titre seropositive disease. Manifests as digital gangrene, nailfold capillary infarcts, non-healing deep leg ulcers, palpable purpura, and mononeuritis multiplex (acute foot or wrist drop due to arteritis of the vasa nervorum).
• Felty's Syndrome: A rare, severe complication occurring in long-standing, seropositive, nodular, erosive RA. Defined by the classic clinical triad:
  1. Rheumatoid arthritis (deforming, erosive, seropositive);
  2. Splenomegaly; and
  3. Neutropenia (absolute neutrophil count < 1.5 × 10⁹/L). Patients have a dramatically increased susceptibility to recurrent, life-threatening pyogenic bacterial infections (skin, pulmonary sepsis) and develop hyperpigmentation and chronic lower extremity ulcers. Management prioritizes aggressive RA control with methotrexate or rituximab; G-CSF is reserved for severe neutropenic sepsis.
• Secondary Amyloidosis (AA Amyloid): Prolonged active systemic inflammation elevates serum amyloid A (SAA), which deposits as beta-pleated sheets in renal glomeruli, presenting as progressive non-selective proteinuria, nephrotic syndrome, and renal impairment (diagnosed via Congo red staining exhibiting apple-green birefringence under polarized light).

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4. RA Diagnostics & Radiographic Progression

Diagnostic Serology & Acute Phase Reactants

• Rheumatoid Factor (RF): An autoantibody (predominantly IgM) directed against the Fc portion of human IgG. Present in 70–80% of RA patients (sensitivity ~75%), but specificity is modest (~70%). RF is positive in numerous non-RA conditions: primary Sjögren's syndrome (70%), SLE (20–30%), mixed cryoglobulinaemia (>90%), subacute bacterial endocarditis (SBE), chronic hepatitis C, tuberculosis, and 5% of healthy elderly individuals.
• Anti-Cyclic Citrullinated Peptide (Anti-CCP / ACPA): Directed against citrullinated antigens. Sensitivity is comparable to RF (~75–80%), but specificity exceeds 95–98%. Anti-CCP appears years before clinical arthritis, correlates strongly with aggressive radiographic joint erosion, and serves as an independent prognostic marker for severe disease.
• Inflammatory Markers: ESR and CRP are elevated, correlating with disease activity and used in composite scoring systems such as the DAS28 (Disease Activity Score evaluating 28 joints).

Radiographic Sequence on Plain Radiographs

Joint damage progresses along a predictable radiographic trajectory:

1. Soft Tissue Swelling: Earliest radiographic sign; fusiform swelling surrounding the joint capsule.
2. Periarticular Osteopenia (Juxta-articular Demineralization): Local hyperemia and cytokine-driven bone turnover deplete calcium in subchondral bone adjacent to the inflamed synovium.
3. Uniform Loss of Joint Space: Symmetrical destruction and thinning of articular cartilage across the entire joint cleft (in contrast to osteoarthritis, which causes focal, non-uniform joint space narrowing in weight-bearing zones).
4. Marginal Juxta-articular Bone Erosions: Pathognomonic focal bone loss occurring at the "bare areas" of the joint—regions within the joint capsule where bone is not protected by overlying hyaline cartilage.
5. Subluxation & Fibrous/Bony Ankylosis: Complete loss of joint architecture, joint displacement, and late fusion.

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