18.3 Seronegative Spondyloarthropathies

6. Seronegative Spondyloarthropathies: Overview & Axial SpA

The seronegative spondyloarthropathies (SpA) are a clinically and genetically interrelated family of chronic inflammatory arthritides characterized by: (1) Absence of RF and anti-CCP; (2) Strong genetic association with HLA-B27; (3) Pathognomonic enthesitis (inflammation at sites of tendon, ligament, or joint capsule insertion into cortical bone); (4) Dactylitis ("sausage digits"); and (5) Axial spinal inflammation and/or asymmetrical peripheral oligoarthritis.

Ankylosing Spondylitis (Axial Spondyloarthritis)

Axial SpA is a chronic inflammatory disorder predominantly affecting the sacroiliac joints and axial skeleton, with a male predilection (2:1 to 3:1) and peak onset between 20 and 30 years.

                     Axial SpA Diagnostic & Radiographic Spectrum
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1. Early / Non-Radiographic Axial SpA                               2. Established Ankylosing Spondylitis
   - Normal plain pelvic radiographs                                  - Bilateral sacroiliitis on plain X-ray
   - MRI (STIR): Bone marrow oedema                                   - Vertebral squaring ('shiny corners')
     and active subchondral sacroiliitis                              - Thin, vertical syndesmophytes
   - HLA-B27 positive in > 90%                                        - Complete fusion ('bamboo spine')

• Clinical Presentation: Characterized by inflammatory back pain (IBP), which must be clearly differentiated from common mechanical low back pain:

• Clinical Examination Signs:
  • Modified Schober's Test: Assesses loss of lumbar spine flexion. With the patient standing erect, a mark is made at the lumbosacral junction (level of dimples of Venus / L5 spinous process); a second mark is placed 10 cm superiorly, and a third mark 5 cm inferiorly (total 15 cm distance). The patient bends forward maximally with straight knees. Normal expansion is >= 5 cm (total distance >= 20 cm). Expansion < 5 cm indicates restricted lumbar flexion diagnostic of lumbar spinal ankylosis.
  • Occiput-to-Wall Distance: In advanced disease, loss of lumbar lordosis, accentuation of thoracic kyphosis, and fixed cervical flexion prevent the occiput from touching a vertical wall while standing with heels and buttocks against it.
  • Reduced Chest Expansion: Costovertebral and costosternal joint ankylosis restricts rib cage excursion. Chest expansion measured at the 4th intercostal space < 2.5 cm is abnormal.
• Imaging Hallmarks:
  • MRI of Sacroiliac Joints (STIR sequence): The diagnostic gold standard for early, non-radiographic axial SpA before irreversible bony changes develop. Demonstrates subchondral bone marrow oedema (active sacroiliitis) reflecting intense osteitis.
  • Pelvic Radiographs: Demonstrates bilateral, symmetrical sacroiliitis: subchondral sclerosis, joint margin blurring, erosions, and eventual complete bony fusion.
  • Spine Radiographs: Sclerosis of anterior vertebral margins producing "shiny corners" (Romanus lesions), followed by vertebral body squaring. Calcification and ossification of the outer fibres of the annulus fibrosus form delicate, thin, vertically oriented bony bridges termed syndesmophytes. Symmetrical syndesmophytes bridging successive vertebrae alongside ossification of interspinous ligaments (the "dagger sign") produce the classical "bamboo spine". Prone to low-impact transverse spinal fractures (commonly lower cervical spine) that cause catastrophic spinal cord injury.
• Extra-Skeletal Manifestations:
  • Acute Anterior Uveitis (Iritis): The most common extra-skeletal feature (occurs in 25–30% of patients). Characteristically unilateral, presenting with acute eye pain, photophobia, ciliary injection, and blurred vision. Managed with topical corticosteroid and mydriatic drops.
  • Cardiovascular: Ascending aortitis causing fibrous thickening and dilation of the aortic root, producing aortic regurgitation. Fibrosis extending into the membranous interventricular septum causes atrioventricular nodal conduction blocks (PR prolongation, complete heart block).
  • Pulmonary: Upper lobe fibrocavitary disease (apical pulmonary fibrosis), often bilateral; cavitating fibrotic bullae can become colonized by Aspergillus fumigatus, forming aspergillomas (fungus balls).
  • Neurological: Cauda equina syndrome secondary to chronic lumbosacral dural ectasia.
• Therapeutic Strategy:
  • Non-Pharmacological (Cornerstone): Daily spinal extension exercises and specialized physiotherapy are mandatory to maintain posture and chest expansion.
  • First-Line Pharmacotherapy: Continuous, full-dose NSAIDs (e.g. naproxen, celecoxib) provide symptomatic relief and may retard syndesmophyte formation.
  • Second-Line Biologics: Patients with persistent active axial disease despite two different NSAIDs are escalated directly to anti-TNF therapy (e.g. adalimumab, etanercept) or anti-IL-17A inhibitors (secukinumab, ixekizumab).
  • CRUCIAL EXAM FACT: Conventional csDMARDs (methotrexate, sulfasalazine) are ineffective for axial spine disease and sacroiliitis; their utility is strictly limited to managing concurrent peripheral arthritis.

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7. Psoriatic, Reactive & Enteropathic Arthritis

Psoriatic Arthritis (PsA)

An inflammatory arthritis developing in 20–30% of patients with cutaneous psoriasis; skin lesions precede joint symptoms by years in 70%, but arthritis appears concurrently or preceding rash in 15–20%.

• Clinical Phenotypes (Moll & Wright Classification):
  1. Asymmetrical Oligoarthritis (< 5 joints): Historically most common; affects knees, ankles, and small digits.
  2. Symmetrical Polyarthritis: Symmetrical involvement of MCP and PIP joints, mimicking rheumatoid arthritis, but RF and anti-CCP negative.
  3. Distal Interphalangeal (DIP) Predominant: Classic form; DIP joint involvement tightly coupled with overlying psoriatic nail disease.
  4. Axial Spondylitis / Sacroiliitis: Unilateral or asymmetrical sacroiliitis with bulky, coarse, asymmetrical non-marginal syndesmophytes (paramarginal calcifications), distinct from the delicate syndesmophytes of AS.
  5. Arthritis Mutilans: Severe, destructive, osteolytic resorption of phalanges and metacarpals, resulting in telescoping of fingers ("telescoping digits" / opera-glass hand / main en lorgnette).
• Key Features: Dactylitis ("sausage digit" from simultaneous flexor tenosynovitis and joint synovitis) and psoriatic nail dystrophy (present in > 80% of PsA vs 30% of uncomplicated psoriasis: nail pitting [> 20 pits], onycholysis, subungual hyperkeratosis, and "oil drop" / salmon patch discoloration).
• Radiography: Pathognomonic "pencil-in-cup" deformity—marked periarticular bone erosion producing tapering/sharpening of the proximal phalanx head ("pencil") which projects into an expanded, excavated socket of the adjacent distal phalanx base ("cup"). Displays periostitis (fluffy new bone formation) and absence of periarticular osteopenia (unlike RA).

Reactive Arthritis (ReA)

An acute, sterile autoimmune synovitis that develops 1 to 4 weeks following an antecedent gastrointestinal or genitourinary mucosal infection.

• Triggering Pathogens:
  • Gastrointestinal / Enteric: Campylobacter jejuni, Salmonella enteritidis/typhimurium, Shigella flexneri, Yersinia enterocolitica, and Clostridioides difficile.
  • Genitourinary: Chlamydia trachomatis (predominant GU trigger) and Ureaplasma urealyticum.
• Clinical Presentation: Asymmetrical, acute, inflammatory oligoarthritis predominantly involving large weight-bearing lower limb joints (knee, ankle, subtalar). Strongly associated with Achilles enthesitis, plantar fasciitis, and dactylitis.
• The Classical Triad: Historically known as Reiter's syndrome: Arthritis, non-gonococcal urethritis / cervicitis, and conjunctivitis (sterile, bilateral).
• Distinctive Mucocutaneous Lesions:
  • Circinate Balanitis: Painless, superficial, serpiginous, erythematous erosions with raised white borders on the glans penis and coronal sulcus (occurs in up to 40% of men).
  • Keratoderma Blennorrhagica: Hyperkeratotic, waxy, brownish-red papules and plaques on the soles of the feet and palms of the hands; clinically and histologically indistinguishable from pustular psoriasis.
  • Painless Superficial Oral Ulcers: Palatal and buccal mucosal erosions.
• Management: Active Chlamydia infection must be treated with oral antibiotics (e.g. doxycycline) for both the patient and sexual partners to clear mucosal carriage, but antibiotics do not alter or accelerate resolution of the established reactive arthritis. Acute arthritis is treated with NSAIDs and intra-articular corticosteroid injections. Chronic, persistent cases (> 3 months) respond to sulfasalazine or methotrexate.

Enteropathic Arthritis

Inflammatory arthritis complicating Inflammatory Bowel Disease (IBD)—Crohn's disease and Ulcerative Colitis.

• Type 1 (Pauciarticular): Involves < 5 joints, predominantly large lower-limb joints (knees, ankles). Parallels bowel disease activity; flares coincide with intestinal relapses. Effectively treated by medically or surgically controlling the underlying bowel inflammation.
• Type 2 (Polyarticular): Involves >= 5 joints, predominantly small joints of the hands symmetrically. Independent of bowel disease activity; runs a persistent, chronic course uncoupled from luminal inflammation.
• Axial Spondylarthritis in IBD: Manifests as sacroiliitis and spondylitis. Associated with HLA-B27 in 50–70% of cases. Its progression is completely independent of bowel disease activity. NSAIDs must be used with extreme caution as they can trigger severe relapses of mucosal IBD; anti-TNF agents (infliximab, adalimumab) provide dual efficacy for both bowel and joint pathology.

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8. Comparative Synthesis: RA vs. Spondyloarthropathies vs. Gout