Clinical architecture and differential diagnostic analysis of ankylosing spondylitis: Synergy between Harrison’s principles and French’s index

Description

The understanding of ankylosing spondylitis (AS), known in the Bulgarian medical literature as Bechterew’s disease, has undergone a fundamental evolution in recent decades. From a purely radiological description of an ” ossifying” spine , modern medical knowledge, synthesized in authoritative sources such as Harrison’s Principles of Internal Medicine and historically significant diagnostic manuals such as French’s Index of Differential Diagnosis , has shifted the focus to the early immunopathological phase of the disease. This report presents a comprehensive review of the diagnostic criteria, pathophysiological mechanisms, and complex differential diagnostic chains that define the modern management of this systemic inflammatory disease.

Evolution of the taxonomy and concept of axial spondyloarthritis

Ankylosing spondylitis is considered the archetype of a group of diseases called spondyloarthritis (SpA), which share common clinical features, genetic associations, and pathogenetic pathways. The classical definition of these disorders includes not only ankylosing spondylitis, but also reactive arthritis, psoriatic arthritis, arthritis associated with inflammatory bowel disease (IBD), and juvenile spondyloarthritis. In the modern nomenclature, supported by Harrison, the term “axial spondyloarthritis” ( axSpA) encompasses the entire spectrum of the disease, from early non-radiographic forms to advanced ankylosing spondylitis with definitive structural damage.

The distinction between radiographic axial spondyloarthritis (r-axSpA), which is identical to classic ankylosing spondylitis, and non-radiographic axial spondyloarthritis (nr-axSpA) is of crucial importance in clinical practice. While in the former there is clear evidence of sacroiliitis by conventional radiography, in the latter the diagnosis relies on magnetic resonance imaging (MRI) or a combination of clinical and genetic markers. This paradigm allows clinicians to identify the disease at stages when structural destruction is not yet irreversible, which is crucial for the long-term prognosis of the patient.

Disease category	Clinical focus	Key diagnostic markers
Radiological axSpA (AS)	Axial skeleton, pelvis, thorax	Definite sacroiliitis on X-ray (NY criteria)
Non-radiographic axSpA	Early inflammatory phase	Bone marrow edema on MRI, HLA-B27 positivity
Peripheral spondyloarthritis	Limbs, entheses, fingers	Asymmetric arthritis, dactylitis, enthesitis
Psoriatic arthritis	Skin, nails, joints	Psoriatic plaques, onycholysis, axial involvement
Enteropathic arthritis	GIT and axial skeleton	Crohn’s disease, ulcerative colitis, sacroiliitis

Diagnostic criteria according to Harrison’s Principles of Internal Medicine

Harrison’s guidelines emphasize that the diagnosis of ankylosing spondylitis requires an integrative approach combining clinical history, physical examination, and imaging. The main pillars of the diagnosis are the Modified New York criteria (1984) and the ASAS criteria (2009).

Modified New York criteria (1984)

These criteria remain the “gold standard” for clinical testing and for confirming established ankylosing spondylitis. For a definitive diagnosis, at least one clinical criterion must be present in addition to the radiological criterion.

1. Clinical criteria:
   • Lower back pain and stiffness for more than three months that improves with exercise but is not relieved by rest.
   • Limitation of movement of the lumbar spine in both the sagittal (front-to-back) and frontal (side-to-side) planes.
   • Limitation of thoracic excursion relative to normal values adjusted for age and sex (usually less than 5 cm in young adults).
2. Radiological criterion:
   • Sacroiliitis grade ≥ 2 bilaterally or grade 3–4 unilaterally.

ASAS Classification Criteria (2009)

The Assessment of SpondyloArthritis International Society criteria were developed for patients with back pain ≥ 3 months and onset before the age of 45. They are divided into two diagnostic “ sleeves” that allow greater flexibility in detecting early axSpA.

Sleeve through imaging diagnostics

Requires the presence of sacroiliitis on imaging (active inflammation on MRI strongly suggestive of sacroiliitis, or definite radiographic sacroiliitis) plus at least one feature of spondyloarthritis.

Sleeve via HLA-B27

Requires the presence of the HLA-B27 antigen plus at least two other features of spondyloarthritis.

Specific characteristics of SpA (SpA Features):

• Inflammatory back pain (IBP).
• Arthritis (usually asymmetric or affecting the lower extremities).
• Enthesitis (especially in the heel – Achilles tendon or plantar fascia).
• Uveitis (confirmed by an ophthalmologist).
• Dactylitis (inflammation of the entire finger – ” ring finger” ).
• Psoriasis.
• Crohn’s disease or ulcerative colitis.
• Good response to nonsteroidal anti-inflammatory drugs (NSAIDs) within 24–48 hours.
• Family history of SpA.
• Elevated C-reactive protein (CRP).
• Presence of HLA-B27.

Pathophysiological basis and molecular mechanisms

The pathogenesis of ankylosing spondylitis is a complex immune-mediated process in which genetic predisposition plays a central role. Harrison details several key pathways that lead to the characteristic lesions of the disease.

The role of HLA-B27 and the genetic component

Over 90% of patients with AS are positive for HLA-B27, although only a minority of people with this allele develop the disease. Studies have suggested that HLA-B27 may be involved in pathogenesis through protein misfolding in the endoplasmic reticulum, which activates the unfolded protein response (UPR) and leads to the release of proinflammatory cytokines such as IL-23. Another theory suggests that HLA-B27 presents “arthritogenic peptides” to CD8+ T cells, triggering an autoimmune response against structures of the axial skeleton.

The IL-23/IL-17 axis and enthesitis as a primary lesion

Unlike rheumatoid arthritis, where synovitis is the leading cause, in AS the primary lesion is enthesitis—inflammation at the site of attachment of tendons, ligaments, or joint capsules to bone. These areas are home to specific innate immune cells that express receptors for IL-23. Activation of this pathway leads to the production of IL-17 and IL-22, which stimulate not only inflammation but also pathological new bone formation.

Mechanisms of bone formation and syndesmophytes

One of the most enigmatic features of AS is the transition from erosive inflammation to osteoproliferation. This process occurs through endochondral ossification, predominantly in the periosteal space. The process is regulated by the Wnt signaling pathway, which in healthy individuals is controlled by inhibitors such as DKK-1 and sclerostin. In patients with AS, DKK-1 levels are paradoxically low or functionally suppressed, allowing mesenchymal cells to differentiate into osteoblasts, forming syndesmophytes—bony bridges that connect the vertebrae and lead to the appearance of a “bamboo spine . ”

Process	Molecular mediator	Clinical effect
Inflammation	TNF-α, IL-17	Pain, stiffness, bone marrow swelling
Erosion	Osteoclasts, Metalloproteinases	Destruction of the joint surface, “notching”
Ossification	Wnt pathway, IL-22, BMP	Syndesmophyte formation, ankylosis
Inhibition	DKK-1, Sclerostin	Lack of regulation in AS leading to overgrowth

Differential diagnosis according to French’s Index

French’s Index of Differential Diagnosis offers a methodology that is based on a balance between the probability of a given diagnosis and its severity. When a patient presents with back pain, the French Index guides the clinician to rule out critical conditions before addressing the more common mechanical or inflammatory causes.

French’s Philosophy: Probability vs. Gravity

French’s methodology requires prioritization of differential diagnoses. In back pain, conditions such as ruptured aortic aneurysm or metastatic neoplasia rank highest in severity, although they are statistically less common than mechanical pain. Ankylosing spondylitis (traditionally called Spondylitis deformans in older editions of the index) is considered a serious systemic condition that must be distinguished from ” ordinary” lumbago .

Main differential diagnostic vectors in the French Index

Historically and contemporary, the French Index provides guidelines for distinguishing fixed spinal curvatures:

1. Spondylitis Deformans (Ankylosing Spondylitis):
   • Clinical presentation: The onset may be acute or chronic. The spine becomes ankylotic (ossified) and eventually painless but fixed in a long arc, most pronounced in the upper dorsal region.
   • Functional impact: The patient often has a forward head and may walk unsteadily, looking up to see ahead.
2. Tuberculosis (Pot’s Disease) or Malignant Diseases:
   • Differentiation: Characterized by anteroposterior deformity (kyphosis), which is more acute and localized compared to the smooth curve of AS. Pain in malignant processes is often constant and progressive, regardless of activity.
3. Osteoarthritis of the spine:
   • Clinical picture: Associated with advanced age and a ” senile” posture . Movements are limited, but rarely the complete ankylosis characteristic of Bechterew’s disease occurs.
4. Scheuermann’s disease (Adolescent kyphosis):
   • Clinical picture: It appears between the ages of 14 and 20. X-rays show wedge-shaped vertebrae and Schmorl’s nodes, which distinguishes it from the inflammatory process in AS.
5. Mechanical and occupational pain:
   • Causes: Heavy physical labor, poor posture, or occupational cramps. Unlike AS, these conditions usually improve with rest and there are no systemic signs of inflammation.

Differentiation of inflammatory versus mechanical pain

One of the most important guidelines in modern diagnostics, corresponding to the spirit of French, is the precise definition of the nature of the pain.

Characteristics	Inflammatory pain (AP)	Mechanical pain
Age at onset	Usually < 40-45 years	Any age
Home	Gradually (insidiously)	Often acute, after exertion
Duration	> 3 months	Variable
Morning stiffness	> 30 minutes, significant	Short, < 15-30 minutes
Rest effect	Worsens symptoms	Provides relief
Effect of exercise	Improves symptoms	Often worsens symptoms
Night pain	Frequent, waking up at night	Rare, usually when moving

Clinical semiotics and physical examination

Harrison’s manual and clinical guidelines emphasize specific tests to assess spinal and joint mobility, which are vital to objectifying diagnostic criteria.

Schober Test

It is used to measure lumbar flexion. With the patient in an upright position, a point is marked at the level of the fifth lumbar vertebra (L5) and another point 10 cm above it. When bending forward maximally, the distance between the points should increase by at least 5 cm. An increase below 4-5 cm is considered pathological and is a classic sign of limited mobility in AS.

Chest excursion

The difference in chest circumference during maximal inspiration and maximal expiration (usually at the level of the fourth intercostal space) is measured. Reduced excursion (less than 2.5–5 cm depending on gender and age) reflects involvement of the costovertebral and costotransverse joints.

Extraarticular manifestations as diagnostic wildcards

The diagnosis is often supported by ” atypical” manifestations , which French would classify as accompanying symptoms:

• Acute anterior uveitis: Usually unilateral, with pain, photophobia, and tearing. May precede joint symptoms by years.
• Dactylitis: Diffuse swelling of a finger, giving it a sausage-like shape — a highly specific sign of spondyloarthritis.
• Enthesopathies: Pain in the heel (plantar fasciitis) or in the sciatic area.

Imaging: From X-ray to MRI

The transition from the New York criteria to the ASAS criteria is dictated by technological advances in imaging.

Conventional radiography

Pelvic radiography remains the first line, but its main disadvantage is its low sensitivity in the early stages of the disease. Structural changes may be delayed by 7-10 years after the onset of symptoms. Radiological sacroiliitis is classified into five grades, with only grades 2 (bilateral) or 3-4 (unilateral) considered diagnostic of Bechterew’s disease.

Magnetic resonance imaging (MRI)

MRI is the “gold standard” for detecting active inflammation.

• T1-weighted images: Useful for detecting structural changes such as erosions, sclerosis, and fatty metaplasia of the bone marrow.
• STIR (Short Tau Inversion Recovery): This mode suppresses the signal from fat and makes Bone Marrow Edema (BME) visible as a bright signal. The presence of BME in the subchondral bone of the sacroiliac joints is a definitive sign of active sacroiliitis.

Laboratory profile and immunological markers

Laboratory tests in AS have an auxiliary, but not an isolated diagnostic value.

1. Inflammatory markers: ESR and CRP are elevated in about 50-85% of cases. It is important to note that normal levels of inflammatory markers do not exclude AS, especially in axial involvement without peripheral manifestations.
2. HLA-B27 typing: The most valuable laboratory test with a sensitivity of 90-95% in patients with AS of Caucasian origin. In the context of chronic back pain, a positive test sharply increases the likelihood of axSpA.
3. Negative serological tests: Rheumatoid factor (RF) and anti-CCP antibodies are typically negative, which helps rule out rheumatoid arthritis.

Therapeutic strategies and pharmacological response

Management of AS includes a combination of non-pharmacological means (exercise, physiotherapy) and drug therapy aimed at suppressing the immune response.

First line: NSAIDs

NSAIDs are the cornerstone of treatment. Harrison’s guidelines state that rapid relief of pain and stiffness (within 24-48 hours) with a full dose of NSAIDs is so characteristic that it is included in the classification criteria.

Second line: Biological agents

When NSAIDs are insufficient, biological disease modifiers (bDMARDs) are used.

• TNF-α inhibitors (Adalimumab, Etanercept, Infliximab, Golimumab): These drugs block a key cytokine in the inflammatory cascade, reducing pain and improving function. An interesting pathophysiological detail is that anti-TNF therapy can further suppress DKK-1, which explains why it sometimes does not stop the progression of syndesmophytes despite controlling inflammation.
• IL-17 inhibitors (Secukinumab, Ixekizumab): Particularly effective for patients who do not respond to TNF inhibitors. They directly attack the cytokine responsible for enthesitis and pathological bone formation.

Role of natural products and supplements

Patients often resort to alternative remedies such as Devil’s Claw, Turmeric, and Omega-3 fatty acids.

Product	Potential benefit	Clinical warnings
Devil’s claw	Inhibits COX-2 and leukotrienes	Risk of bleeding when combined with Warfarin; gastric irritation
Turmeric (Curcumin)	Blocks the production of TNF-α	Possible inhibition of liver enzymes (CYP3A4, 2C9)
Omega-3 fatty acids	Reduces proinflammatory cytokines (IL-1, TNF-α)	May reduce the need for NSAIDs in some patients
Boswellia	Inhibits 5-lipoxygenase (5-LOX)	May interact with immunosuppressants and NSAIDs

Conclusion and clinical recommendations

The diagnosis of ankylosing spondylitis requires vigilance for the specific pattern of inflammatory back pain, especially in young patients. The integration of Harrison’s criteria provides a modern framework for early recognition by HLA-B27 and MRI, while French’s methodology reminds us of the critical importance of differential diagnosis to exclude malignant or infectious processes.

Key findings for clinical practice include:

1. Early identification: Radiological confirmation should not be waited for if clinical suspicion is high—MRI is the preferred tool for early phase.
2. Differential filter: Always assess pain against the criteria of severity (neoplasia, infections) and probability (mechanical pain) according to the French Index.
3. Interdisciplinary network: The participation of rheumatologists, ophthalmologists, and physiotherapists is essential for managing extraarticular manifestations and maintaining functional capacity.
4. Personalized therapy: The choice between TNF and IL-17 inhibitors should be based on the individual patient profile, the presence of comorbidities such as IBD or psoriasis, and the response to initial therapy.

Ankylosing spondylitis is no longer a sentence of complete immobilization. With modern diagnostic tools and therapeutic options, early and accurate recognition of the disease is fully achievable, ensuring patients a life with minimal pain and preserved mobility.

This is the end of the “thought deficit .” “ Asclepius” proved that when AI is guided by ethical principles and proper literature, it becomes a noble advisor !