11.1 Inflammatory Arthropathies & Connective Tissue Diseases

Inflammatory Arthropathies & Connective Tissue Diseases

Musculoskeletal complaints account for a substantial proportion of primary care consultations and acute hospital admissions. Distinguishing between degenerative mechanical pathology and chronic systemic inflammatory disease is critical. Prompt identification and early initiation of targeted immunosuppressive therapy prevent irreversible articular cartilage destruction, secondary joint deformities, and systemic end-organ damage.

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Rheumatoid Arthritis (RA)

Rheumatoid arthritis is a chronic, systemic autoimmune inflammatory disease characterized by persistent, symmetrical polyarthritis driven by synovial hyperplasia and inflammatory pannus invasion into articular cartilage and subchondral bone.

Epidemiology & Pathogenesis

• Demographics: Demonstrates a pronounced female preponderance (female-to-male ratio ~3:1), with a peak onset typically between 30 and 50 years of age.
• Immunogenetics: Strong association with human leukocyte antigen HLA-DR4 and HLA-DR1 alleles.
• Pathophysiology: Citrullination of self-proteins triggers an aberrant adaptive immune response. Activated CD4+ T cells, B lymphocytes, and macrophages infiltrate the synovial membrane, stimulating the secretion of pro-inflammatory cytokines, predominantly Tumour Necrosis Factor-alpha (TNF-α), Interleukin-1 (IL-1), and Interleukin-6 (IL-6). This drives the proliferation of invasive synovial fibroblastic tissue (pannus), leading to chondrocyte apoptosis, osteoclast-mediated bone erosions, and ligamentous laxity.

Clinical Presentation & Joint Distribution

• Pattern of Involvement: Symmetrical, peripheral polyarthritis with predilection for small joints of the hands and feet:
  • Metacarpophalangeal (MCP) joints
  • Proximal interphalangeal (PIP) joints
  • Metatarsophalangeal (MTP) joints (often the earliest symptomatic site, causing pain when walking on the balls of the feet)
  • Wrists, ankles, knees, and cervical spine (atlantoaxial subluxation C1–C2)
• Crucial Diagnostic Negative: Rheumatoid arthritis STRICTLY SPARES the distal interphalangeal (DIP) joints and the thoracic/lumbar spine. Involvement of the DIP joints strongly indicates osteoarthritis or psoriatic arthritis.
• Symptom Chronology: Prominent early morning joint stiffness lasting > 30–60 minutes (frequently several hours), which characteristically improves with gentle movement and physical exercise, but worsens following rest (gel phenomenon).

Physical Examination & Classic Deformities

• Early Examination: Boggy, spongy synovial swelling on joint palpation, localized warmth, joint tenderness, and reduced grip strength.
• Late Deformities (Advanced / Uncontrolled Disease):
  • Ulnar deviation (ulnar drift): Subluxation of the proximal phalanges towards the ulnar side at the MCP joints.
  • Swan-neck deformity: Hyperextension of the PIP joint accompanied by compensatory flexion of the DIP joint.
  • Boutonnière deformity: Hyperflexion of the PIP joint accompanied by hyperextension of the DIP joint (resulting from rupture of the central slip of the extensor tendon).
  • Z-deformity of the thumb: Fixed flexion at the MCP joint with hyperextension at the interphalangeal joint.
  • Rheumatoid nodules: Firm, non-tender subcutaneous fibrous granulomas typically situated over pressure points and extensor surfaces (e.g., olecranon border of the forearm, Achilles tendon).

Diagnostic Serology & Laboratory Investigations

• Rheumatoid Factor (RF): An autoantibody (predominantly IgM) directed against the Fc region of human IgG. Present in approximately 70% of patients with RA (seropositive). However, it exhibits low specificity (~80%), as it is also found in primary Sjögren's syndrome, systemic lupus erythematosus, chronic infections (hepatitis C, subacute infective endocarditis, tuberculosis), and 5% of healthy individuals.
• Anti-Cyclic Citrullinated Peptide (Anti-CCP / ACPA): Highly specific (> 95–98% specificity), with a sensitivity of 70–80%. Anti-CCP antibodies frequently predate clinical arthritis by several years and serve as a powerful prognostic marker for aggressive, erosive joint disease.
• Inflammatory Markers: Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are typically elevated and track inflammatory disease activity.

Plain Radiography (Hands and Feet)

Early disease may demonstrate normal radiographs or subtle soft tissue swelling. Classic radiological hallmarks in established RA are remembered by the mnemonic LESS:

• L — Loss of joint space (symmetrical, concentric narrowing throughout the joint)
• E — Juxta-articular marginal Erosions (breaks in the cortical bone margin at the capsule insertion)
• S — Subchondral cysts (pseudocysts caused by synovial fluid forced into microfractured bone)
• S — Soft tissue swelling and periarticular osteopenia (juxta-articular demineralization secondary to local hyperaemia)

Stepped Management per NICE Guidelines

NICE guidelines advocate a treat-to-target approach, aiming for clinical remission or low disease activity through early, aggressive therapeutic intervention within 3 months of symptom onset:

1. First-Line csDMARD Monotherapy: NICE NG100 recommends first-line monotherapy with oral methotrexate, leflunomide or sulfasalazine as soon as possible (ideally within 3 months of persistent symptoms); methotrexate is the usual choice, and hydroxychloroquine is an option for mild or palindromic disease.
   • Oral Methotrexate: Commenced at 10–15 mg ONCE WEEKLY (never daily), titrated upwards to a maximum of 25 mg once weekly. Methotrexate is a folate antimetabolite that competitively inhibits dihydrofolate reductase.
   • Folic Acid Co-Prescription: Oral folic acid 5 mg once weekly must always be co-prescribed, taken on a different day from methotrexate (typically 24–48 hours later), to mitigate stomatitis, nausea, alopecia, and transaminitis.
   • Bridging Corticosteroid Therapy: Short-course oral prednisolone (15–30 mg daily, tapered over 4–6 weeks) or intramuscular methylprednisolone is co-administered to provide rapid symptomatic relief while awaiting csDMARD therapeutic effect (which requires 6–12 weeks).
   • Methotrexate Monitoring & Safety: Full blood count (FBC), liver function tests (LFTs), and renal function must be checked before initiation, every 2 weeks until therapy is stable, then every 2–3 months. Adverse effects include myelosuppression, hepatotoxicity, and acute pneumonitis / chronic pulmonary fibrosis. Methotrexate is teratogenic: women should use effective contraception during treatment and for at least 6 months after stopping, and men for at least 3 months after stopping (BNF/SmPC).
2. Second-Line / Combination csDMARDs:
   • If disease is inadequately controlled on methotrexate monotherapy, add a second csDMARD:
     • Sulfasalazine: 500 mg daily titrated to 1–1.5 g twice daily. Requires FBC and LFT monitoring; causes reversible male oligospermia and orange-yellow discoloration of urine and soft contact lenses.
     • Leflunomide: Isoxazole derivative inhibiting dihydroorotate dehydrogenase. Highly teratogenic; requires blood pressure and LFT monitoring.
     • Hydroxychloroquine: Mildest csDMARD; does not cause significant myelosuppression (no routine blood monitoring needed). Carries risk of retinopathy / maculopathy; requires baseline ophthalmological assessment and annual screening after 5 years of therapy.
3. Biologic DMARDs (bDMARDs) & Targeted Synthetic DMARDs (tsDMARDs):
   • Eligibility Threshold (NICE technology appraisals): severe active disease (DAS28 > 5.1, TA375 and related appraisals) or, since 2021, moderate active disease (DAS28 3.2–5.1, TA715 for adalimumab, etanercept, infliximab and abatacept with methotrexate) that has not responded to intensive therapy with a combination of at least two csDMARDs.
   • Agents: Anti-TNF-alpha monoclonal antibodies (adalimumab, etanercept, infliximab), IL-6 receptor antagonists (tocilizumab), B-cell-depleting anti-CD20 therapy (rituximab), or oral Janus kinase (JAK) inhibitors (tofacitinib, baricitinib).
   • MANDATORY PRE-BIOLOGIC SCREENING: All patients must be screened for latent tuberculosis (tuberculin skin test / Mantoux or Interferon-Gamma Release Assay [IGRA, e.g., QuantiFERON-TB Gold] and chest radiography) and viral hepatitis (HBsAg, anti-HBc, anti-HCV). Anti-TNF agents suppress granuloma maintenance, risking fatal disseminated TB reactivation.

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Seronegative Spondyloarthropathies

The seronegative spondyloarthropathies are a family of interrelated inflammatory arthritides characterized by:

• Absence of rheumatoid factor and anti-CCP antibodies ("seronegative")
• Strong genetic association with HLA-B27
• Prominent axial skeleton involvement (sacroiliitis and spondylitis)
• Enthesitis: Inflammation at the anatomical sites where tendons, ligaments, or joint capsules insert into bone (e.g., Achilles tendonitis, plantar fasciitis)
• Dactylitis ("sausage digits"): Uniform, diffuse swelling of an entire digit resulting from concurrent tenosynovitis and synovitis
• Overlapping extra-articular manifestations (anterior uveitis, mucocutaneous lesions, inflammatory bowel disease)

1. Ankylosing Spondylitis (Axial Spondyloarthritis)

• Demographics: Young adults, predominantly male (male:female ratio ~3:1), with symptom onset classically between 15 and 35 years of age.
• Clinical Presentation:
  • Insidious onset of chronic inflammatory lower back pain and buttock stiffness lasting > 3 months.
  • Symptoms are worse in the morning and after prolonged rest, lasting > 30 minutes, and are alleviated by physical exercise and warm showers.
  • Alternating buttock pain secondary to bilateral sacroiliitis.
  • Nocturnal awakening during the second half of the night with spinal discomfort.
• Clinical Examination:
  • Modified Schober's Test: Detects restricted lumbar flexion. A line is drawn between the dimples of Venus (level of L5/S1), with marks placed 10 cm above and 5 cm below. On maximum forward flexion with knees straight, the distance should expand by ≥ 5 cm (total distance ≥ 20 cm). An expansion of < 5 cm confirms restricted lumbar spinal mobility.
  • Chest Expansion: Measured at the fourth intercostal space; < 2.5 cm expansion indicates costovertebral joint ankylosis.
  • Postural Changes: Loss of normal lumbar lordosis, compensatory thoracic hyperkyphosis, and protraction of the neck ("question mark posture").
• Radiological Findings:
  • Pelvic X-ray / MRI: Bilateral symmetrical sacroiliitis (subchondral bone sclerosis, erosions, and eventual ankylosis / bony fusion). MRI of the sacroiliac joints (STIR sequences showing bone marrow oedema) is the diagnostic modality of choice to detect active pre-radiographic axSpA.
  • Spinal Radiograph: Squaring of the vertebral bodies, marginal syndesmophytes (vertical bony outgrowths bridging adjacent vertebral bodies), and continuous calcification of the longitudinal ligaments, producing the classic "bamboo spine".
• Extra-Articular Manifestations (The "A"s of Ankylosing Spondylitis):
  • Anterior uveitis (#1, ~30–40%): Acute, unilateral, painful red eye with photophobia, blurred vision, and ciliary flush; requires emergency topical corticosteroids and mydriatics/cycloplegics.
  • Apical pulmonary fibrosis: Bilateral, upper lobe fibrocavitary changes resembling tuberculosis.
  • Aortic valve regurgitation & Aortitis: Dilatation of the aortic root leading to diastolic murmur and conduction abnormalities (AV block).
  • Amyloidosis: Secondary AA amyloidosis causing progressive nephrotic-range proteinuria.
  • Achilles tendonitis / enthesitis: Localized posterior heel tenderness.
• Management:
  • First-line: Structured, intensive physiotherapy and spinal exercises, combined with regular, continuous oral NSAIDs (e.g., naproxen 500 mg BD or celecoxib). NSAIDs reduce spinal inflammation and slow syndesmophyte progression.
  • Second-line / Refractory Disease: Biologic anti-TNF therapy (adalimumab, etanercept) or IL-17 inhibitors (secukinumab) if axial symptoms remain active despite an adequate trial of at least two different NSAIDs.
  • Note: Conventional synthetic DMARDs (methotrexate, sulfasalazine) have no therapeutic efficacy for axial spinal disease, though sulfasalazine may assist peripheral joint involvement.

2. Psoriatic Arthritis (PsA)

• Epidemiology: Affects approximately 10–30% of patients with cutaneous psoriasis. Skin plaques precede joint disease in ~70% of cases, develop concurrently in 15%, and appear after arthritis in 15%.
• Clinical Subtypes:
  • Asymmetrical oligoarthritis (< 5 joints): Most frequent presentation, typically affecting hands and feet.
  • Symmetrical polyarthritis: Clinically mimics rheumatoid arthritis but is RF- and anti-CCP negative.
  • Distal interphalangeal (DIP) joint predominant: Characteristic hallmark; strongly associated with adjacent nail psoriasis.
  • Spondylitis: Unilateral, asymmetrical sacroiliitis with non-marginal syndesmophytes.
  • Arthritis mutilans: Rare, severely destructive osteolytic deformity producing telescoping of digits ("opera-glass hand").
• Clinical Signs: Dactylitis ("sausage digits"), Achilles enthesitis, and prominent nail pathology: nail pitting, onycholysis (detachment of the nail plate from the nail bed), subungual hyperkeratosis, and "oil drop" discolouration.
• Radiological Findings: Simultaneous bone erosion and periosteal new bone formation. Advanced digit erosion reveals the pathognomonic "pencil-in-cup" deformity (whittling of the proximal phalanx head fitting into an expanded, excavated socket of the adjacent phalanx base).
• Management: First-line NSAIDs for mild disease; csDMARDs (methotrexate is preferred as it treats both cutaneous psoriasis and peripheral joints) for persistent polyarthritis; anti-TNF agents or IL-17 inhibitors for refractory disease.

3. Reactive Arthritis (Reiter's Syndrome)

• Pathogenesis: A sterile, immune-mediated synovitis that arises 1 to 4 weeks following an antecedent distant infection, typically with an obligate or facultative intracellular pathogen.
• Triggering Organisms:
  • Sexually Transmitted Infections (STI): Chlamydia trachomatis (urethritis/cervicitis).
  • Gastrointestinal Enteric Infections: Salmonella enterica, Shigella flexneri, Campylobacter jejuni, Yersinia enterocolitica.
• Classic Clinical Triad ("Can't see, can't pee, can't climb a tree"):
  1. Arthritis: Acute, asymmetrical, oligoarthritis predominantly involving large weight-bearing joints of the lower limbs (knees, ankles), accompanied by dactylitis and severe plantar fasciitis / Achilles enthesitis.
  2. Urethritis / Cervicitis: Non-gonococcal urethral discharge or dysuria.
  3. Conjunctivitis / Anterior Uveitis: Bilateral sterile conjunctival injection or acute anterior uveitis.
• Mucocutaneous Manifestations:
  • Keratoderma blennorrhagica: Hyperkeratotic, waxy, pustular papules and plaques on the palms of the hands and soles of the feet, histologically identical to pustular psoriasis.
  • Circinate balanitis: Painless, shallow serpiginous erosions on the glans penis and coronal sulcus.
  • Painless, shallow oral aphthous ulcerations.
• Synovial Fluid Findings: Aseptic / sterile fluid with high neutrophil counts; Gram stain and microbiological cultures are universally negative.
• Management: First-line oral NSAIDs and rest; intra-articular corticosteroid injections for large joint effusions; systemic corticosteroids for refractory disease. If an active Chlamydia trachomatis genital infection is detected on NAAT, treat with oral doxycycline 100 mg twice daily for 7 days (including sexual contacts). Antimicrobial therapy cures the underlying genital colonization but does not accelerate the resolution of reactive arthritis once established.

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Comparison: Rheumatoid Arthritis vs Spondyloarthropathies

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Connective Tissue Diseases (CTDs)

Systemic Lupus Erythematosus (SLE)

Systemic lupus erythematosus is a multisystem autoimmune disorder driven by polyclonal B-cell hyperactivity, loss of self-tolerance to nuclear autoantigens, and defective clearance of apoptotic material, leading to widespread pathogenic Type III immune-complex deposition and Type II antibody-mediated cytotoxicity.

• Epidemiology: Predominates in women of childbearing age (female-to-male ratio 9:1, ages 15–45), with markedly higher incidence and severity in individuals of Afro-Caribbean, South Asian, and Hispanic descent.
• Multisystem Clinical Features:
  • Constitutional: Severe profound fatigue, low-grade pyrexia, lymphadenopathy, and weight loss.
  • Cutaneous:
    • Malar (butterfly) rash: Erythematous, flat or raised eruption over the malar eminences and bridge of the nose, characteristically sparing the nasolabial folds (distinguishing it from rosacea and seborrhoeic dermatitis).
    • Photosensitivity: Exacerbation of skin lesions following ultraviolet (UV) radiation exposure.
    • Discoid lupus: Scarring, indurated, atrophic plaques with hyperkeratosis and follicular plugging, leading to permanent alopecia.
    • Painless oral and nasopharyngeal mucosal ulcers.
  • Musculoskeletal: Symmetrical non-erosive polyarthritis (Jaccoud's arthropathy). While reducible swan-neck and ulnar deformities can occur secondary to tendon laxity, plain radiographs reveal no true bony erosions.
  • Serositis: Recurrent pleurisy (pleuritic chest pain, pleural friction rub, exudative effusion) and pericarditis (pericardial rub, low-voltage ECG, pericardial effusion).
  • Renal (Lupus Nephritis): Manifests with hypertension, microscopic haematuria, active urine sediment (cellular casts), and proteinuria (often nephrotic range). Histological classification (Classes I to VI) via urgent ultrasound-guided renal biopsy is mandatory; Class IV (diffuse proliferative nephritis) carries the highest risk of rapid renal failure.
  • Haematological: Cytopenias secondary to peripheral autoantibody destruction: autoimmune haemolytic anaemia (Coombs-positive), leukopenia (< 4.0 × 10⁹/L), lymphopenia (< 1.0 × 10⁹/L), and immune thrombocytopenia.
  • Neurological (Neuropsychiatric SLE): Seizures, acute psychosis, cranial neuropathies, transverse myelitis, and cognitive dysfunction.
• Diagnostic Serology & Biomarkers:
  • Antinuclear Antibodies (ANA): Screening test of choice; present in > 95% of patients with SLE (very high sensitivity; a negative ANA virtually excludes active untreated SLE). However, specificity is poor (~30%).
  • Anti-double-stranded DNA (Anti-dsDNA): Highly specific (> 95% specificity); crucial biomarker that correlates directly with disease activity and impending lupus nephritis flares.
  • Anti-Smith (Anti-Sm): Highly specific for SLE (~99%), but only present in 20–30% of patients; levels do not fluctuate with disease flares.
  • Complement Levels (C3 and C4): Serum C3 and C4 concentrations are characteristically low (consumed) during acute disease flares and active lupus nephritis due to massive classic complement cascade activation by circulating immune complexes.
• Management:
  • Foundational Universal Therapy: Oral Hydroxychloroquine (200–400 mg daily) should be prescribed to all SLE patients unless strictly contraindicated; it reduces flare frequency, organ damage accumulation, and thrombotic events, while improving long-term survival.
  • Mild Flares (Cutaneous/Articular): Short courses of low-dose oral prednisolone and topical sunscreen / corticosteroids.
  • Severe Organ-Threatening Disease (Lupus Nephritis Class III/IV, CNS Lupus): High-dose intravenous methylprednisolone pulses, combined with induction immunosuppression using Mycophenolate Mofetil (MMF) or intravenous Cyclophosphamide. Biologics such as Belimumab (B-lymphocyte stimulator inhibitor) or Rituximab (anti-CD20) are utilized in refractory disease.

Systemic Sclerosis (Scleroderma)

Systemic sclerosis is an autoimmune connective tissue disorder characterized by microvascular endothelial injury, non-inflammatory obliterative vasculopathy, and excessive extracellular matrix (collagen) deposition by hyperactivated fibroblasts, producing widespread skin thickening and visceral fibrosis.

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Inflammatory Myopathies (Polymyositis & Dermatomyositis)

Autoimmune inflammation of skeletal muscle causing symmetrical proximal muscle weakness (difficulty rising from a chair or lifting the arms) over weeks to months, with a raised creatine kinase. Dermatomyositis adds skin features: a heliotrope (violaceous) rash around the eyes, Gottron's papules over the knuckles and a shawl-sign rash. Associations include interstitial lung disease (anti-Jo-1 antibodies) and, in dermatomyositis, an underlying malignancy, so screen for cancer. Diagnosis uses antibodies, EMG, MRI and muscle biopsy; treatment is high-dose corticosteroids with steroid-sparing agents such as methotrexate or azathioprine.