Recognize the signs of enthesitis

The enthesis is the insertion of tendons and ligaments into the surface of the bone, which enables movement and stability.4

Some broaden the definition to include the structures that comprise the entheseal organ.5,6

Recognize the signs of enthesitis

Enthesitis
Inflammation of the entheses. 30% to 70% of patients with psoriatic arthritis (PsA) are reported to have this condition.4,7,8

Distinguishing enthesitis from synovitis

Synovitis
Inflammation of the synovial membrane. It occurs in ~90% of patients with rheumatoid arthritis (RA).4,9

Enthesitis and synovitis can occur separately or concomitantly in PsA; however, enthesitis is a characterizing condition of PsA but not of RA.4,9

Sites where enthesitis most commonly occurs7

FOOT
0%

Achilles tendon insertion and plantar fascia insertion

ELBOW
0%

Lateral epicondyle and medial epicondyle

KNEE
0%

Superior border of patella, interior role A patella, and tibial tubercle

Unseen and underestimated

Enthesitis is a hallmark of early PsA. As a distinctive clinical aspect, it helps differentiate PsA from other forms of arthritis.1-3,10

Some studies have suggested that enthesitis may be one of the first symptoms of PsA.1-3

As many as

1
OUT
OF
3

patients with PsA
present with enthesitis7*

In a multicenter study using power Doppler ultrasound, the presence of enthesitis in patients with PsA was found to be as high as 71%.8

*Defined as at least 1 tender entheseal site out of 18 as measured by the SPARCC enthesitis index.

  PsA=psoriatic arthritis; SPARCC=Spondyloarthritis Research Consortium of Canada.

Enthesitis frequently goes undiagnosed

This is due to a variety of complicating factors:

 Absence of external swelling4

 Deep entheseal insertions are difficult to assess with physical examination4

 Entheseal sites are numerous, and enthesitis may be present in sites not usually assessed4

 Can mimic other conditions, such as:

 Mechanical stress injury5

 Tendinitis4

 Synovitis4


Tenosynovitis
Pain
Dactylitis
Nail
involvement

Enthesitis often presents without swelling; however, there are other disease features associated with the presence of enthesitis.

Dactylitis, tenosynovitis, and pain have been independently associated with enthesitis.7

 In fact, one study observed enthesitis at the collateral ligament insertions in 75% of dactylitic digits11

 

In PsA, enthesitis is linked to nail involvement.12,13

 The fascia of the nail root is an extension of the extensor tendon enthesis13

 

Patients with PsA who have nail dystrophy may also have enthesitis.14

Enthesitis adds to the burden patients with PsA already face

Patients with PsA experience15-17:

 Functional disabilities

 Increased pain

 Decreased ability to work

Enthesitis magnifies the disease burden of PsA, which underscores the importance of understanding, investigating, and uncovering this condition.7,18


Compared to patients with PsA alone, those with enthesitis have:

SIGNIFICANTLY MORE

tender/swollen joints7

0%

less likely to achieve minimal disease activity (MDA)18*

0%

higher mean HAQ scores18†

0%

higher self-reported pain (VAS)18‡

0%

higher self-reported fatigue (VAS)18§

0X

more likely to miss work18

0X

more likely to have any overall work impairment18

Up to 0X

greater chance of radiographic peripheral damage7

0X

greater chance of radiographic axial joint damage with severe enthesitis (higher MASEI scores)7


*Modified MDA (enthesitis) achieved by 41/277 (15%) of patients with PsA with enthesitis vs 193/789 (24%) of those without enthesitis.18

Mean HAQ (0-3): 0.8 with enthesitis vs 0.6 without enthesitis.18

Mean VAS pain (0-100): 44.3 with enthesitis vs 35.1 without enthesitis.18

§Mean VAS fatigue (0-100): 46.7 with enthesitis vs 38.2 without enthesitis.18

HAQ=Health Assessment Questionnaire; MASEI=MAdrid Sonography Enthesitis Index; PsA=psoriatic arthritis; VAS=visual analog scale.


The fuel that feeds enthesitis

PsA is not a mild condition. Erosions can be present even in early stages and the condition frequently progresses to permanent joint damage over time. As an early symptom of PsA, and a complicating factor of the disease, the similar origins of PsA and enthesitis should be recognized.1,3

Many cytokines are activated in the inflammatory process, including IL-17A, IL-22, IL-23, and TNF. IL-17A appears to play a common role in both PsA and enthesitis.4

IL=interleukin; PsA=psoriatic arthritis; TNF=tumor necrosis factor.

Though the process is not completely understood, it is likely that biomechanical stress triggers entheseal inflammation.4,19,20

Inflammation is triggered

Patients with PsA and SpA are thought to have a lower threshold for setting off entheseal inflammation, which allows enthesitis to develop.4

 This resembles an excessive reaction to low-level mechanical strain.4

Vasodilation
Activation
γδ T Cells
ILC3s
PGE2
IL-23

T-cells respond

Once the entheseal inflammation is triggered, PGE2 forces the blood vessels to widen, while IL-23 activates Th17 cells and other inflammatory cytokines.4,21

IL-17A
IL-17A
TNF
IL-22
Neutrophils
Mesenchymal
stem cells

Cascade of more inflammation and pain

IL-17A and TNF prompt neutrophil migration and activation.4

 In the enthesis, neutrophils augment the inflammatory response and aggravate pain responses4

  •  A similar process can be seen in psoriatic plaques, linking IL-17A activation with the effector phase of inflammation4,21

Bone
Osteoblasts

The damage continues

IL-17A and IL-22 trigger the activation and proliferation of mesenchymal stem cells, which in turn signal osteoclasts and osteoblasts, leading to bone erosion and pathological bone formation.4,21

IL=interleukin; PGE2=prostaglandin E2; PsA=psoriatic arthritis; SpA=spondyloarthritis; TNF=tumor necrosis factor.

The tools to uncover enthesitis

Even though it frequently accompanies PsA and is often an early symptom, if you're not seeking out enthesitis, it can be easy to miss. Here's why:

 Enthesitis can mimic symptoms of other conditions such as mechanical injury and tendinitis4,5

 Most of the time there's no swelling, so it's invisible to the eye4

Fortunately, the key to diagnosing enthesitis is already in your hands.

The hands-on approach
LEI, SPARCC, and MASES

The INSPIRE (International Spondyloarthritis Interobserver Reliability Exercise) study compared methods of manual assessment of enthesitis.22

The Leeds Enthesitis Index (LEI) performed similarly to the Spondyloarthritis Research Consortium of Canada (SPARCC) enthesitis index with both indices demonstrating substantial to excellent agreement and performing better than the Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) index.22

LEI

Leeds Enthesitis Index

The LEI is a practical and proven tool for the assessment of enthesitis in PsA.22,24

A brief training is enough to put the LEI to use.

A manual examination of 6 points can significantly improve clinical assessments of enthesitis24:

 Left and right lateral epicondyle

 Left and right medial femoral condyle

 Left and right Achilles tendon insertion

A patient's LEI results can be expected to improve with successful treatment of PsA.25

SPARCC

Spondyloarthritis Research Consortium of Canada index

The SPARCC index examines a total of 18 sites, bilaterally24

 Lateral epicondyle humerus

 Medial epicondyle humerus

 Achilles tendon

 Greater trochanter

 Insertion plantar fascia

 Supraspinatus insertion

 Quadriceps insertion patella

 Inferior pole patella

 Tibial tubercle

Agreement between the results of the LEI and the SPARCC index were strong in the INSPIRE study.22,24

MASES

Maastricht Ankylosing Spondylitis Enthesitis Score

The MASES was not found to function as well in PsA as either the LEI or the SPARCC.22

Lateral Epicondyle
Left and right25

Find the lateral epicondyle of the humerus at the common extensor origin.26

Medial Femoral Condyle
Left and right25

Find the medial condyle of the femur, superior to the joint line, at the origin of the medical collateral ligament.26

Achilles Tendon Insertion
Left and right25

Find the posterior prominence of the calcaneum at the insertion of the Achilles tendon.26

At each site, exert pressure at the enthesis sufficient to blanch the fingernail (approximately 4 kg/cm2) and assess the presence or absence of tenderness.26,27

Also assess the presence of soft-tissue swelling at the enthesis.26

Enthesitis sites by index23

Examination Points

LEI

SPARCC

MASES


SPARCC


MASES

 Examination Points

 Examination Points

 Examination Points

Ultrasound

Seeing enthesitis with your own eyes

Doppler ultrasound scan showing enthesitis in the Achilles tendon6

Reprinted from Seminars in Arthritis and Rheumatism, 48, Gurjit S. Kaeley et al., Enthesitis: A hallmark of psoriatic arthritis, 2018, with permission from Elsevier.

An international committee used ultrasound to help identify enthesitis by its primary components28:

 Hypoechogenicity

 Increased thickness of the tendon insertion

 Enthesophytes

 Calcifications

 Erosions

 Power Doppler (PD) signal at enthesis

 Bursitis

 Global enthesitis

Ultrasound is the preferred imaging technique for visualization of enthesitis

While MRI and high-resolution CT have been used to assess enthesitis in clinical studies, ultrasound presents a lower-cost, practical alternative. Ultrasound allows for real-time evaluation and assessment of peripheral joints from multiple angles.6,29

 Conventional radiography is limited in its ability to identify early signs of inflammation and soft tissue damage5

 Ultrasound has been found to have advantages as a diagnostic tool for assessing damage29,30

Ultrasound
Advantages and disadvantages vs MRI

 

 More affordable and more widely available5

 Portable option offers benefit of real-time dynamic examination29

 Operator-dependent technology with poor repeatability, though studies have shown moderate to good interobserver reliability29

 Has been shown to detect entheseal involvement even in early, preclinical stages of PsA5

 More sensitive imaging modality for evaluating damage than for inflammation30

MRI
Magnetic Resonance Imaging

MRI has been a useful tool for identifying the hallmarks of enthesitis, particularly osteitis, which sometimes accompanies peripheral enthesitis.4

Fat-suppressed, fat-saturated, and water-sensitive MRI sequences demonstrate that the extracapsular inflammation of joints quite often represents enthesitis with variable degrees of soft tissue and bone marrow edema.5

Coronal and axial MR T1 fat-saturated sequence plus contrast. These images show severe osteitis with bone edema at the origin of the common extensor.30

Reprinted by permission from Copyright Clearance Center: Springer Nature, Rheumatology and Therapy, Clinical examination, ultrasound and MRI imaging of the painful elbow in psoriatic arthritis and rheumatoid arthritis: which is better, ultrasound or MR, for imaging enthesitis? Clare Groves, et al., Copyright © 2017.

MRI
Advantages and disadvantages vs ultrasound

 

 Better than ultrasound at imaging deeper structures29

 More sensitive imaging modality for evaluating inflammation than for damage30

 Can be expensive for patients and physicians5

 MRI does not allow contralateral examination and is hampered by the presence of metal artifacts that may interfere with imaging29

 Structures of the entheses have a low signal on conventional MRI5

 While sensitive, differentiating between different etiologies of enthesitis is not always possible31



30%
TO
70%

of patients with PsA are
reported to have enthesitis

Only thorough and accurate diagnosis will reveal the true impact of enthesitis as a destructive force behind PsA.7,8

Until then, the sparks of enthesitis will smolder under the cover of PsA, adding to the substantial burden patients with PsA already experience.

Fortunately, the tools for diagnosis are numerous, ranging from the clinical (SPARCC, LEI, MASES) to imaging (ultrasound and MRI).

Now, more than ever, the tools to uncover enthesitis are in your hands.



References: 1. Scarpa R, Cuocolo A, Peluso R, et al. Early psoriatic arthritis: the clinical spectrum. J Rheumatol. 2008;35(1):137-141. 2. Bandinelli F, Denaro V, Prignano F, Collaku L, Ciancio G, Matucci-Cerinic M. Ultrasonographic wrist and hand abnormalities in early psoriatic arthritis patients: correlation with clinical, dermatological, serological and genetic indices. Clin Exp Rheumatol. 2015;33(3):330-335. 3. McGonagle D, Ash Z, Dickie L, McDermott M, Aydin SZ. The early phase of psoriatic arthritis. Ann Rheum Dis. 2011;70(suppl 1):i71-i76. 4. Schett G, Lories RJ, D’Agostino M-A, et al. Enthesitis: from pathophysiology to treatment. Nat Rev Rheumatol. 2017;13(12):731-741. 5. Kehl AS, Corr M, Weisman MH. Enthesitis: new insights into pathogenesis, diagnostic modalities, and treatment. Arthritis Rheumatol. 2016;68(2):312-322. 6. Kaeley GS, Eder L, Aydin SZ, Gutierrez M, Bakewell C. Enthesitis: a hallmark of psoriatic arthritis. Semin Arthritis Rheum. 2018;48(1):35-43. 7. Polachek A, Li S, Chandran V, Gladman DD. Clinical enthesitis in a prospective longitudinal psoriatic arthritis cohort: incidence, prevalence, characteristics, and outcome. Arthritis Care Res (Hoboken). 2017;69(11):1685-1691. 8. Iagnocco A, Spadaro A, Marchesoni A, et al. Power Doppler ultrasonographic evaluation of enthesitis in psoriatic arthritis. A multi-center study. Joint Bone Spine. 2012;79(3):324-325. 9. Merola JF, Espinoza LR, Fleischmann R. Distinguishing rheumatoid arthritis from psoriatic arthritis. RMD Open. 2018;4(2):e000656. doi:10.1136/rmdopen-2018-000656. 10. McGonagle D, Stockwin L, Isaacs J, Emery P. An enthesitis based model for the pathogenesis of spondyloarthropathy. Additive effects of microbial adjuvant and biomechanical factors at disease sites. J Rheumatol. 2001;28(10):2155-2159. 11. Tan AL, Fukuba E, Halliday NA, Tanner SF, Emery P, McGonagle D. High-resolution MRI assessment of dactylitis in psoriatic arthritis shows flexor tendon pulley and sheath-related enthesitis. Ann Rheum Dis. 2015;74(1):185-189. 12. Tan AL, Grainger AJ, Tanner SF, Emery P, McGonagle D. A high-resolution magnetic resonance imaging study of distal interphalangeal joint arthropathy in psoriatic arthritis and osteoarthritis. Arthritis Rheum. 2006;54(4):1328-1333. 13. Tan AL, Benjamin M, Toumi H, et al. The relationship between the extensor tendon enthesis and the nail in distal interphalangeal joint disease in psoriatic arthritis—a high-resolution MRI and histological study. Rheumatology (Oxford). 2007;46(2):253-256. 14. Acosta-Felquer ML, Ruta S, Rosa J, et al. Ultrasound entheseal abnormalities at the distal interphalangeal joints and clinical nail involvement in patients with psoriasis and psoriatic arthritis, supporting the nail-enthesitis theory. Semin Arthritis Rheum. 2017;47(3):338-342. 15. Salaffi F, Carotti M, Gasparini S, Intorcia M, Grassi W. The health-related quality of life in rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis: a comparison with a selected sample of healthy people. Health Qual Life Outcomes. doi:10.1186/1477-7525-7-25. 16. Tillett W, de-Vries C, McHugh NJ. Work disability in psoriatic arthritis: a systematic review. Rheumatology. 2012;51(2):275-283. 17. Lee S, Mendelsohn A, Sarnes E. The burden of psoriatic arthritis: a literature review from a global health systems perspective. P&T. 2010;35(12):680-689. 18. Mease PJ, Karki C, Palmer JB, et al. Clinical characteristics, disease activity, and patient-reported outcomes in psoriatic arthritis patients with dactylitis or enthesitis: results from the Corrona Psoriatic Arthritis/Spondyloarthritis Registry. Arthritis Care Res (Hoboken). 2017;69(11):1692-1699. 19. Lories RJ, McInnes IB. Primed for inflammation: enthesis-resident T cells. Nat Med. 2012;18(7):1018-1019. 20. Jacques P, McGonagle D. The role of mechanical stress in the pathogenesis of spondyloarthritis and how to combat it. Best Pract Res Clin Rheumatol. 2014;28(5):703-710. 21. Ritchlin CT, Colbert RA, Gladman DD. Psoriatic arthritis. N Engl J Med. 2017;376(21):957-970. 22. Gladman DD, Inman RD, Cook RJ, et al. International spondyloarthritis interobserver reliability—the INSPIRE study: II. Assessment of peripheral joints, enthesitis, and dactylitis. J Rheumatol. 2007;34(8):1740-1745. 23. Coates LC, Helliwell PS. Disease measurement—enthesitis, skin, nails, spine and dactylitis. Best Pract Res Clin Rheumatol. 2010;24(5):659-670. 24. Kristensen S, Christensen JH, Schmidt EB, et al. Assessment of enthesitis in patients with psoriatic arthritis using clinical examination and ultrasound. Muscles Ligaments Tendons J. 2016;6(2)241-247. 25. Healy PJ, Helliwell PS. Measuring clinical enthesitis in psoriatic arthritis: assessment of existing measures and development of an instrument specific to psoriatic arthritis. Arthritis Rheum. 2008;59(5):686-691. 26. Ibrahim G, Groves C, Chandramohan M, et al. Clinical and ultrasound examination of the Leeds Enthesitis Index in psoriatic arthritis and rheumatoid arthritis [published online 2011]. ISRN Rheumatol. doi:10.5402/2011/731917. 27. Mease PJ. Measures of psoriatic arthritis. Arthritis Care Res (Hoboken). 2011;63(suppl 11):S64-S85. 28. Terslev L, Naredo E, Iagnocco A, et al. Defining enthesitis in spondyloarthritis by ultrasound: results of a Delphi process and of a reliability reading exercise. Arthritis Care Res. 2014;66(5):741-748. 29. Patil P, Dasgupta B. Role of diagnostic ultrasound in the assessment of musculoskeletal diseases. Ther Adv Musculoskelet Dis. 2012;4(5):341-355. 30. Groves C, Chandramohan M, Chew NS, Aslam T, Helliwell PS. Clinical examination, ultrasound and MRI imaging of the painful elbow in psoriatic arthritis and rheumatoid arthritis: which is better, ultrasound or MR, for imaging enthesitis? Rheumatol Ther. 2017;4(1):71-84. 31. Eshed I, Bollow M, McGonagle DG, et al. MRI of enthesitis of the appendicular skeleton in spondyloarthritis. Ann Rheum Dis. 2007;66(12):1553-1559.