Polyenthesitis: A Comprehensive Clinical Review for the Internist

Dr Neeraj Manikath , claude.ai

Abstract

Polyenthesitis, characterized by inflammation at multiple tendon and ligament insertion sites, represents a cardinal feature of spondyloarthropathies and several other rheumatologic conditions. This review synthesizes current understanding of polyenthesitis pathophysiology, clinical manifestations, diagnostic approaches, and management strategies, with emphasis on practical clinical pearls for the practicing internist.

Introduction

Enthesitis—inflammation at the insertion of tendons, ligaments, or joint capsules into bone—occurs as an isolated phenomenon or as part of systemic inflammatory conditions. When multiple entheses are affected simultaneously or sequentially, the term polyenthesitis applies. Recognition of this condition proves critical, as it frequently heralds spondyloarthropathy (SpA) and guides therapeutic decisions. Despite its prevalence in rheumatologic practice, polyenthesitis remains underrecognized in general internal medicine settings, often mistaken for mechanical pain or fibromyalgia.

Pathophysiology: Beyond Simple Inflammation

The enthesis represents a unique anatomical structure where mechanical stress concentrates. Modern understanding reveals enthesitis results from an interplay between mechanical stress, immune dysregulation, and tissue-specific factors. The "synovio-entheseal complex" concept suggests that inflammation spreads from entheses to adjacent synovium, explaining the characteristic clinical pattern seen in spondyloarthropathies.

HLA-B27, present in 80-90% of ankylosing spondylitis patients, contributes through multiple mechanisms: misfolding leading to endoplasmic reticulum stress, altered peptide presentation, and formation of disease-promoting homodimers. However, HLA-B27 presence alone proves insufficient—only 5-6% of HLA-B27-positive individuals develop spondyloarthropathy, indicating additional genetic and environmental factors participate.

Recent research implicates the IL-23/IL-17 axis as central to enthesitis pathogenesis. Mechanical stress triggers IL-23 production by entheseal resident cells, subsequently activating IL-17-producing cells including γδ T cells, type 3 innate lymphoid cells, and mucosal-associated invariant T cells. This pathway explains the efficacy of IL-17 and IL-23 inhibitors in treating spondyloarthropathies.

Clinical Pearl #1: The enthesis organ concept recognizes that inflammation doesn't remain confined to the insertion point but involves adjacent bone marrow, periosteum, and soft tissues. This explains why MRI proves more sensitive than clinical examination for detecting enthesitis.

Clinical Manifestations: The Art of Recognition

Common Entheseal Sites

Polyenthesitis demonstrates predilection for specific anatomical locations:

Lower extremities (most common):

Achilles tendon insertion (posterior heel)
Plantar fascia insertion (inferior heel)
Patellar tendon insertions (superior and inferior pole of patella)
Iliac crests
Greater trochanters
Ischial tuberosities

Upper extremities:

Lateral and medial epicondyles
Rotator cuff insertions
Costochondral junctions

Axial skeleton:

Spinous processes
Sacroiliac joints (technically entheseal in nature)

Clinical Characteristics

Enthesitis pain exhibits distinctive features that differentiate it from mechanical causes:

Inflammatory pattern: Pain worse with rest, improves with activity (contrast with mechanical pain)
Morning stiffness: Typically exceeding 30 minutes
Nocturnal pain: Often disrupts sleep, particularly in second half of night
Loading sensitivity: Tender to direct palpation and stress maneuvers
Asymmetric distribution: Unlike rheumatoid arthritis, often affects sites asymmetrically

Clinical Pearl #2: The "9 AM rule"—if a patient with suspected enthesitis feels worst at 9 AM (after nocturnal rest and morning stiffness) rather than 9 PM (after day's activities), think inflammatory rather than mechanical etiology.

Associated Features

Polyenthesitis rarely occurs in isolation. Vigilant clinicians search for:

Inflammatory back pain: Particularly sacroiliitis
Peripheral arthritis: Often asymmetric, lower-extremity predominant
Dactylitis: "Sausage digits" from combined tenosynovitis and soft tissue inflammation
Extra-articular manifestations: Uveitis (anterior, acute, unilateral), psoriasis, inflammatory bowel disease
Family history: First-degree relatives with spondyloarthropathy, psoriasis, or inflammatory bowel disease

Differential Diagnosis: A Systematic Approach

Primary Spondyloarthropathies

Ankylosing Spondylitis: Axial involvement predominates, with polyenthesitis affecting 30-50% of patients. Males affected more commonly, typically presenting in third decade.

Psoriatic Arthritis: Enthesitis occurs in 35-50% of cases, often preceding or accompanying skin disease. Nail changes (pitting, onycholysis) provide diagnostic clues.

Reactive Arthritis: Post-infectious syndrome classically following genitourinary or gastrointestinal infections. Enthesitis, particularly of lower extremities, represents a cardinal feature of the classic triad.

Enteropathic Arthritis: Associated with inflammatory bowel disease (both Crohn's and ulcerative colitis). Arthritis may precede bowel symptoms in 20% of cases.

Other Rheumatologic Conditions

SAPHO Syndrome (Synovitis, Acne, Pustulosis, Hyperostosis, Osteitis): Rare condition combining skin and bone manifestations with enthesitis.

Adult-onset Still's Disease: Occasionally presents with enthesitis alongside characteristic fever, rash, and arthritis.

Familial Mediterranean Fever: Enthesitis occurs during acute attacks in some patients.

Mechanical and Degenerative Causes

Overuse injuries and degenerative changes affect similar sites but lack inflammatory characteristics. Age, activity patterns, and pain characteristics help differentiate these conditions.

Clinical Pearl #3: The "squeeze test"—gentle compression of the metatarsophalangeal joints reproduces pain in inflammatory arthritis but typically spares entheseal insertions. Conversely, direct pressure over the Achilles insertion or plantar fascia origin elicits exquisite tenderness in enthesitis.

Diagnostic Evaluation: From Bedside to Imaging

Clinical Assessment

Several validated indices assess enthesitis severity:

Leeds Enthesitis Index (LEI): Examines six sites bilaterally—lateral epicondyles, medial femoral condyles, Achilles insertions. Simple, quick, useful for monitoring.

Maastricht Ankylosing Spondylitis Enthesitis Score (MASES): Evaluates 13 sites, includes axial and appendicular locations. More comprehensive but time-consuming.

Spondyloarthritis Research Consortium of Canada (SPARCC) Enthesitis Index: Assesses 16 entheseal sites, correlates well with imaging findings.

Clinical Pearl #4: Don't forget to examine the plantar fascia insertion—patients often neglect mentioning heel pain, assuming it represents a minor issue. Ask specifically: "Does the bottom of your heel hurt when you take your first steps in the morning?"

Laboratory Studies

No specific laboratory test diagnoses enthesitis, but several markers aid assessment:

HLA-B27: Positive in majority of axial spondyloarthropathy patients but lacks specificity. More useful for risk stratification than diagnosis.

Inflammatory markers: ESR and CRP elevate in only 40-50% of active spondyloarthropathy patients—normal values don't exclude disease.

RF and anti-CCP antibodies: Should be negative; positivity suggests alternative diagnosis (rheumatoid arthritis).

Imaging Modalities

Ultrasound: Emerging as first-line imaging for peripheral enthesitis. Findings include:

Tendon thickening
Hypoechoic changes
Enthesophyte formation
Power Doppler signal (active inflammation)
Bony erosions

Advantages include accessibility, cost-effectiveness, dynamic assessment capability, and absence of radiation. Operator dependence represents the primary limitation.

MRI: Gold standard for detecting both peripheral and axial enthesitis. Demonstrates:

Bone marrow edema (active inflammation)
Soft tissue edema
Erosions and new bone formation
Fatty infiltration (chronic changes)

STIR (Short Tau Inversion Recovery) sequences prove particularly sensitive for detecting active inflammation.

Plain Radiography: Insensitive for early disease but demonstrates chronic changes including enthesophytes, erosions, and new bone formation. Remains valuable for assessing disease progression and structural damage.

Clinical Pearl #5: The "double anterior talofibular sign"—when MRI shows edema at both the superior and inferior aspects of the posterior calcaneus (Achilles and plantar fascia insertions), suspect spondyloarthropathy rather than isolated mechanical overuse.

Management: A Multimodal Approach

Non-Pharmacological Interventions

Physical therapy: Supervised exercise programs improve function and reduce pain. Emphasis should be placed on:

Stretching tight entheseal structures
Strengthening surrounding musculature
Proprioceptive training
Avoidance of excessive impact loading

Orthotic devices: Heel cups, arch supports, or custom orthotics may benefit those with lower extremity involvement.

Education: Patient understanding of disease chronicity, flare patterns, and treatment expectations improves adherence and outcomes.

Pharmacological Management

NSAIDs: First-line therapy for mild to moderate symptoms. Continuous dosing (rather than as-needed) proves more effective for inflammatory conditions. COX-2 selective agents offer gastrointestinal protection for at-risk patients.

Local Corticosteroid Injections: Provide temporary relief for particularly troublesome sites. Limit frequency to avoid tendon weakening—no more than 3-4 injections per site per year. Use ultrasound guidance when available to ensure accurate placement and avoid direct intratendinous injection.

Conventional DMARDs:

Sulfasalazine: Modest efficacy for peripheral manifestations; ineffective for axial disease
Methotrexate: Limited evidence for enthesitis specifically, though commonly used for associated peripheral arthritis and psoriasis

Biologic DMARDs: Represent major therapeutic advance for moderate to severe disease.

TNF inhibitors (infliximab, etanercept, adalimumab, certolizumab, golimumab): Effective for both axial and peripheral manifestations. Response rates approach 60-70% for enthesitis.
IL-17 inhibitors (secukinumab, ixekizumab): Highly effective, particularly in psoriatic arthritis. May offer advantages over TNF inhibitors in some studies.
IL-23 inhibitors (risankizumab, guselkumab): Newer agents showing promise, particularly for psoriatic arthritis with enthesitis.

JAK inhibitors (tofacitinib, upadacitinib): Oral alternatives demonstrating efficacy in psoriatic arthritis and ankylosing spondylitis.

Clinical Pearl #6: When injecting entheseal sites, use a "peppering" technique—inject around rather than into the tendon insertion, creating multiple small deposits in the peritendinous area. This reduces tendon rupture risk while providing anti-inflammatory benefit.

Treatment Algorithm

Mild disease (1-2 entheseal sites, minimal functional impairment):

NSAIDs continuous therapy
Physical therapy
Local corticosteroid injection if needed

Moderate disease (3+ sites or significant functional impairment):

NSAIDs
Physical therapy
Consider sulfasalazine if peripheral arthritis present
TNF or IL-17 inhibitor if inadequate response after 3 months

Severe disease (extensive involvement, poor quality of life):

Early introduction of biologic therapy
Combination with NSAIDs as needed
Intensive physical therapy

Hack for Clinical Practice: Create a simple smartphone reminder system for patients to rate morning stiffness duration and pain levels weekly. This longitudinal data proves invaluable for assessing treatment response and often reveals patterns patients don't recall during visits.

Special Populations

Pediatric Patients

Enthesitis-related arthritis represents a distinct juvenile idiopathic arthritis subtype. These children often present with lower extremity enthesitis preceding inflammatory back pain by years. HLA-B27 positivity approaches 70-90%. Long-term monitoring proves essential as many develop ankylosing spondylitis in adulthood.

Pregnancy

Most spondyloarthropathy patients experience disease improvement during pregnancy, though some face challenges. Sulfasalazine and certain biologics (certolizumab, infliximab until third trimester) may be continued. NSAIDs should be avoided after 20 weeks gestation.

Elderly Patients

Late-onset spondyloarthropathy does occur, though less commonly. Consider alternative diagnoses including polymyalgia rheumatica, calcium pyrophosphate deposition disease, and osteoarthritis. NSAID use requires caution given cardiovascular and renal risks.

Prognosis and Monitoring

Polyenthesitis severity varies considerably. Some patients experience mild, intermittent symptoms while others develop chronic, disabling pain and functional impairment. Poor prognostic factors include:

Extensive entheseal involvement
Axial disease
Elevated inflammatory markers
Younger age at onset
HLA-B27 positivity

Regular monitoring should assess:

Symptom control and functional status
Disease activity indices
Structural damage progression (radiographs every 2-3 years)
Medication adverse effects
Cardiovascular risk factors (increased in inflammatory arthritis)
Osteoporosis screening

Oyster for Academic Discussion: The "mechanical stress paradox"—why do some high-stress entheseal sites (wrist extensors in manual laborers) rarely develop inflammatory enthesitis while others do? This observation suggests tissue-specific immune regulation at entheses, an area of active investigation that may yield future therapeutic targets.

Future Directions

Emerging research explores:

Biomarkers predicting treatment response
Precision medicine approaches based on genetic and immune profiles
Novel therapeutic targets including the JAK-STAT pathway
Microbiome's role in spondyloarthropathy pathogenesis
Advanced imaging techniques for subclinical disease detection

Conclusion

Polyenthesitis represents a common yet often underappreciated manifestation of spondyloarthropathies and related conditions. Internists armed with knowledge of characteristic clinical features, appropriate diagnostic evaluation, and evidence-based management strategies can significantly impact patient outcomes. High clinical suspicion, systematic evaluation, and early appropriate treatment prevent progression to chronic disability. As our understanding of enthesitis pathophysiology advances and therapeutic options expand, the prognosis for affected patients continues to improve.

Final Pearl for Practice: When examining any patient with chronic musculoskeletal pain, always palpate the Achilles insertions and plantar fascia origins—these high-yield sites frequently reveal undiagnosed enthesitis and open the door to correct diagnosis and treatment.

Key References

Baraliakos X, et al. Enthesitis in spondyloarthritis. RMD Open. 2022;8(1):e001922.
Schett G, Lories RJ, D'Agostino MA, et al. Enthesitis: from pathophysiology to treatment. Nat Rev Rheumatol. 2017;13(12):731-741.
Kaeley GS, Eder L, Aydin SZ, et al. Enthesitis: A hallmark of psoriatic arthritis. Semin Arthritis Rheum. 2018;48(1):35-43.
Mease PJ, Gladman DD, Collier DH, et al. Etanercept and methotrexate as monotherapy or in combination for psoriatic arthritis: primary results from a randomized, controlled phase III trial. Arthritis Rheumatol. 2019;71(7):1112-1124.
Benjamin M, McGonagle D. The anatomical basis for disease localization in seronegative spondyloarthropathy at entheses and related sites. J Anat. 2001;199(Pt 5):503-526.
Sieper J, Poddubnyy D. Axial spondyloarthritis. Lancet. 2017;390(10089):73-84.
Ritchlin CT, Colbert RA, Gladman DD. Psoriatic Arthritis. N Engl J Med. 2017;376(10):957-970.
D'Agostino MA, Aegerter P, Bechara K, et al. How to diagnose spondyloarthritis early? Accuracy of peripheral enthesitis detection by power Doppler ultrasonography. Ann Rheum Dis. 2011;70(8):1433-1440.

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