ARTHRITIS & RHEUMATISM Vol. 56, No. 11, November 2007, pp 3601–3609 DOI 10.1002/art.23078 © 2007, American College of Rheumatology Histopathologic Changes at “Synovio–Entheseal Complexes” Suggesting a Novel Mechanism for Synovitis in Osteoarthritis and Spondylarthritis Michael Benjamin1 and Dennis McGonagle2 Objective. To determine the extent to which dif- mechanism by which synovitis could develop in both ferent entheses form part of a “synovio–entheseal com- degenerative joint disease and spondylarthritis. plex” (SEC) and whether such SECs are commonly associated with the presence of inflammatory cells and The central importance of the enthesis in under- evidence of enthesis microdamage. standing the pathophysiology of inflammation in the Methods. Specimens from 49 cadaveric entheses spondylarthritides (SpA) has reemerged during the last were processed for histologic study, and all soft tissue decade (1). It has been aided by the development of the components of the entheses or enthesis organs were “enthesis organ concept” (2), which explains why tissues examined. To exclude articular cartilage degeneration adjacent to the enthesis itself are also subject to patho- as a triggering factor for synovitis, the selected entheses logic change. While the link between enthesitis and included 17 that were not immediately adjacent to such osteitis in SpA has been clarified in recent studies that cartilage. demonstrate a close functional integration of the enthe- Results. An SEC was present at 82% of entheses. sis with neighboring bone (3), the connection between These included 47% of the attachments not adjacent to enthesitis and synovitis (the other cardinal manifestation articular cartilage, where the synovium was that of of SpA) remains a subject of debate, and synovial bursae or tendon sheaths. One or more of a wide variety inflammation has consistently been viewed as being of degenerative changes were noted on the soft tissue independent of the inflammation occurring at entheses side of every enthesis; the most common changes were (4). cell clustering and/or fissuring (in 76% of entheses). In addition to the obvious relationship between Synovial villus formation or inflammatory cell infiltra- the enthesis and SpA, there may be a link between the tion was seen in 85% of entheses, and in 73% of enthesis organ and the development of generalized attachments there were also inflammatory cells in the nodal osteoarthritis (OA), since enthesis and ligament enthesis organ itself. The changes included synovial abnormalities as determined by magnetic resonance invasion (pannus formation) of the enthesis. imaging (MRI) are common in early disease (5,6). This Conclusion. Entheses are frequently juxtaposed observation is further supported by MRI studies showing to synovium, thus forming SECs. They are also often similar patterns of involvement of entheses in early associated with both degenerative and inflammatory psoriatic arthritis and generalized nodal OA of the distal changes, and the latter may involve the immediately interphalangeal joints, although inflammation was much adjacent synovium. These findings suggest a novel more severe in the former (7). Preliminary histologic studies of involved structures suggest that these enthe- seal regions are common sites of microdamage (6). 1Michael Benjamin, PhD, Cardiff University, Cardiff, UK; Furthermore, MRI studies have occasionally shown that 2Dennis McGonagle, FRCPI, PhD, University of Leeds, Leeds, UK, prominent synovitis can occur in early generalized nodal and Calderdale Royal Hospital, Halifax, UK. Address correspondence and reprint requests to Michael OA, at a stage when the articular cartilage appears Benjamin, PhD, Professor of Musculoskeletal Biology and Sports relatively normal (5). This suggests that some other joint Medicine Research, Cardiff University, Museum Avenue, Cardiff structure(s) could be contributing to synovitis. The fact CF10 3US, UK. E-mail: [email protected]. Submitted for publication March 29, 2007; accepted in revised that synovitis may occur in retrocalcaneal bursae and at form August 13, 2007. other entheseal sites devoid of articular cartilage (8) 3601 3602 BENJAMIN AND McGONAGLE raises the possibility that pathologic changes at the we have proposed that entheses form a functional unit enthesis could be a contributing factor in joint synovitis. with adjacent synovium, termed the “synovio–entheseal Collectively, these findings suggest that tissue complex” (SEC) (9). While SECs could be important in microdamage or aberrant repair responses at entheses fibrocartilage homeostasis under normal conditions, it is may contribute to synovitis adjacent to attachment sites possible that they are detrimental in the setting of in a variety of diseases or types of injury. Consequently, enthesis microdamage and contribute to the propensity Table 1. Anatomic sites of the entheses examined Presence or absence of a synovial– Adjacent to entheseal articular Enthesis complex cartilage 1. Abductor pollicis brevis insertion ϩ Yes 2. Abductor pollicis longus insertion ϩ Yes 3. Achilles tendon insertion ϩ No 4. Adductor longus origin Ϫ No 5. Adductor magnus insertion (hamstring part) Ϫ No 6. Annulus fibrosus (L4–L5) Ϫ No 7. Anterior cruciate ligament (tibial attachment) ϩ Yes 8. Anterior cruciate ligament (femoral attachment) ϩ Yes 9. Common tendon of biceps brachii and coracobrachialis ϩ No 10. Biceps brachii insertion ϩ No 11. Biceps femoris insertion ϩ Yes 12. Collateral ligaments of the interphalangeal joints of fingers ϩ Yes 13. Common extensor muscle origin ϩ Yes 14. Common flexor muscle origin ϩ Yes 15. Extensor carpi radialis brevis insertion ϩ Yes 16. Extensor carpi radialis longus insertion ϩ Yes 17. Extensor carpi ulnaris insertion ϩ Yes 18. Extensor digitorum ϩ Yes 19. Extensor hallucis longus insertion ϩ Yes 20. Extensor pollicis longus insertion ϩ Yes 21. Facet joint capsule ϩ Yes 22. Flexor carpi ulnaris insertion plus origin of hypothenar muscles ϩ Yes 23. Flexor digitorum profundus insertion ϩ Yes 24. Flexor hallucis longus insertion ϩ Yes 25. Flexor pollicis longus insertion ϩ Yes 26. Gastrocnemius insertion (lateral head) ϩ Yes 27. Gluteus medius insertion ϩ No 28. Gluteus minimus insertion ϩ No 29. Gracilis insertion Ϫ No 30. Iliopsoas insertion Ϫ No 31. Interspinous ligament (L5–S1) Ϫ No 32. Medial collateral ligament of the 1st metatarsophalangeal joint ϩ Yes 33. Medial collateral ligament of the knee (femoral attachment) ϩ Yes 34. Obturator internus insertion ϩ No 35. Patellar tendon insertion ϩ No 36. Patellar tendon origin ϩ Yes 37. Peroneus brevis insertion/capsule of tarsometatarsal joint ϩ Yes 38. Peroneus longus insertion ϩ Yes 39. Pes anserinus insertion ϩ No 40. Popliteus tendon origin/lateral collateral ligament ϩ Yes 41. Posterior cruciate ligament (tibial attachment) ϩ Yes 42. Pronator teres insertion Ϫ No 43. Quadriceps tendon insertion ϩ Yes 44. Sacroiliac joint (interosseous ligament) Ϫ Yes 45. Sartorius (origin) Ϫ No 46. Subscapularis insertion ϩ No 47. Supraspinatus insertion ϩ Yes 48. Tibialis anterior insertion ϩ Yes 49. Triceps brachii insertion ϩ Yes “SYNOVIO–ENTHESEAL COMPLEXES” IN OA AND SpA 3603 for synovial inflammation in a wide range of joint 17 sites not immediately adjacent to such cartilage diseases and injuries. To explore this issue further, we (47%). In these instances, this was synovium lining investigated 1) the extent to which different entheses can either a bursa or a tendon sheath (Figures 1a and b). form part of an SEC, 2) whether inflammatory cells can Thus, at the trochanteric insertion of the gluteus mini- be found at “normal” SECs, and 3) whether SECs are mus (which is a considerable distance from the hip joint frequently associated with evidence of soft tissue micro- cartilage), for example, the synovium contributing to the damage. We addressed these issues by examining enthe- SEC lined bursae that were both deep and superficial to ses from 49 different anatomic sites in the limbs and the tendon near its attachment site (Figure 1a). The spine of elderly, dissecting-room cadavers. Achilles tendon enthesis was a further clear example in which the synovium of the SEC was remote from any articular cartilage. The synovium covered the tip of MATERIALS AND METHODS Kager’s fat-pad as the latter protruded into the bursa, Specimens were collected from 60 cadavers (35 male, thus bringing it very close to the enthesis itself. 25 female; mean age 84 years [range 49–101]) donated to It is important to recognize that although SECs Cardiff University for anatomic investigation under the provi- could indeed be distant from articular cartilage, they sion of the 1984 Anatomy Act and the 1961 Human Tissue Act. could nevertheless still be associated with synovium that The cadavers had been perfused with an embalming fluid containing 4% formaldehyde and 25% alcohol. They were was continuous with that of the joint. This is because selected according to the quality of preservation and the some bursae are extensions of the joint cavity that absence of grossly visible abnormalities in the region of protrude a considerable distance from the joint. Thus, at interest, although access to medical histories was not possible. the insertion of the subscapularis on the lesser tuberosity The 49 anatomic sites examined histologically are listed in of the humerus, the synovium of the SEC originated Table 1 and included 19 entheses from the upper limb, 26 from from a neighboring bursa and from the biceps tendon the lower limb, and 4 from the spine.