Distinct synovial immunopathology in Behçet disease and psoriatic arthritis

Behçet disease (BD) is a systemic inflammatory disorder with oral and/or genital ulcerations, uveitis, and skin lesions as prototypic clinical symptoms [1]. The systemic nature of the disease is emphasized by the potential involvement of the central nervous system, the vascular system, the gut, and the kidney. Up to half of the patients with BD also display rheumatic features. The arthritis is usually monoarticular, intermittent, and not deforming and affects mainly knees or ankles. Less common rheumatic features are enthesitis, spondylitis, and sacroiliitis. This pattern of rheumatic inflammation as well as the association with eye, gut, and skin involvement display clinical similarities with spondyloarthritis (SpA) in general and psoriatic arthritis (PsA) in particular. Although the pathogenesis of BD is still poorly understood, the association with class I major histocompatibility complex molecules (HLA-B51 in BD and HLA-B27 in SpA) and the response to tumor necrosis factor (TNF) blockers in both diseases further support the possibility of common pathophysiological pathways.

Previous studies in psoriatic and non-psoriatic SpA and rheumatoid arthritis (RA) have indicated that detailed synovial histopathology can help to reveal differences in cellular and molecular immunopathology which are of interest for differential diagnosis, classification, and pathogenesis of the different types of arthritis [2–4]. Although joint involvement is clinically well recognized, few histologic studies have focused on the synovial features in BD [5–7]. Here, to explore the immunopathology of BD, we performed a detailed comparative study of early untreated synovitis in BD versus PsA.

Although BD is a relatively common and potentially severe systemic disease, the pathophysiology of the disease remains poorly understood. Microbial infections, sterile neutrophil-mediated inflammation, and autoimmune lymphocytes have all been implicated in the recurrent attacks of inflammation characteristic of this disease [1], leading to an ongoing debate on the autoimmune versus autoinflammatory origin of BD [17]. As we and others demonstrated previously that detailed analysis of the histopathology of the target lesions can yield important pathophysiological information in rheumatic conditions [2–4, 10], we took advantage here of the predilection of the disease for knee joints and the availability of biopsy sampling by needle arthroscopy to revisit in detail the synovial immunopathology of BD. None of the arthroscopies, performed primarily for diagnostic and/or therapeutical reasons, leads to cutaneous or joint complications, including pathergy-like reactions [18]. This observation indicates that it is medically and ethically acceptable to perform histology studies in BD.

Almost 30 years ago, a study a study assessed for the first time the histology of synovitis in six BD patients [5]. That study found no evidence of infection but a dense mixed inflammatory infiltrate with the prominent presence of neutrophils and scarcity of plasma cells in most samples. Similarly, a second study found a paucity of plasma cells in 12 BD synovial tissues but did not describe the presence of neutrophils [7]. Strikingly, they found ectopic lymphoid neogenesis, defined as the development of large lymphoid aggregates resembling secondary lymphoid organs [12–15], in 5 out of 12 samples. Unfortunately, the interpretation of both data sets is hampered by the inclusion of patients with long disease duration and the lack of a control group with non-BD synovitis. Including RA synovial tissue as control, a third study could not confirm the prominent infiltration with neutrophils or any other distinctive feature in seven BD cases but indicated that the findings may be influenced by the longer disease duration [6]. The present study was designed to overcome the limitations of these previous analyses by systematic comparison with a clinically related inflammatory arthritis, PsA, and by stringent selection of active, early, and untreated disease for both groups. As local disease activity is an important determinant of synovial histopathology [10], this design additionally allowed us to match BD and PsA for local disease activity as measured by SF cell count, SF IL-6 levels, and synovial tissue CD68⁺ macrophage numbers [16]. As such, this stringent study design obviously limits the number of cases that can be included but minimizes the risk of systematic biases and false-positive findings.

In the analysis of the infiltrating leukocytes from the innate immune system, a first striking feature of BD synovitis was the marked infiltration with polymorphonuclear neutrophil (PMN). This neutrophilic infiltration cannot be explained by disease duration as both BD and PsA had very early, untreated disease. It was also not related to a difference in levels of IL-8, a major chemokine for PMN. Moreover, this increase did not extend more broadly to innate immunity in general as cells positive for the mast cell marker CD117 appeared to be decreased in BD versus PsA. This relative increase in BD versus PsA most likely reflects a true increase in BD as previous studies showed that the number of infiltrating PMN was already high in PsA compared with RA synovial tissue [3, 4]. Increased numbers of PMN in BD inflammation have been reported not only in synovium [5] but also in other target organs such as skin [19, 20] and the central nervous system [21]. Moreover, the function of PMN has been reported to be altered in BD [22, 23]. Taken together, these data are consistent with a prominent role of PMN in the disease process and may suggest some degree of similarity between the pathophysiology of the synovitis and skin reactions such as the pathergy test in BD. In contrast, however, we did not find any evidence for neutrophilic vasculitis or any other form of vessel pathology in the synovial tissue. Synovitis is thus clearly different from cutaneous lesions in this respect as leukocytoclastic vasculitis is a prominent feature of skin lesions in BD [24, 25].

A second important finding was the selective increase of synovial T lymphocytes in BD. Again, this was specific for T cells rather than related to a global increase in lymphocyte infiltration as we found similar numbers of B lymphocytes and a similar degree of organization in lymphoid aggregates in both diseases. Moreover, previous studies showed no difference in T-cell infiltration between PsA and RA, suggesting that the increase in BD is actually specific [3, 4]. Confirming previous studies on BD synovitis [5, 7], plasma cells were even lower in BD versus PsA synovitis. Although we did not investigate the mechanism underlying the selective increase in T lymphocytes, previous studies indicated that BD T cells are partially protected against apoptosis [26]. Moreover, a recent report indicates that specific T-cell subsets are associated with sterile neutrophil-rich inflammation as observed in BD synovitis, which may explain the simultaneous increase of both T cells and PMN [27].

As to the potential functional contribution of these T cells to the pathology, both Th1 skewing [28, 29] and cytotoxicity by classical CD8⁺ cells, NK T cells, or gamma-delta cells [28–30] have been proposed. Our SF analysis failed to demonstrate a clear Th1 skewing, with lower IL-2, but not for IFN-γ and TNF-α, levels in BD versus PsA. There was also no significant difference in the number of CD8⁺, CD56⁺, perforin⁺, or granzyme B⁺ cells, defining cytotoxic cells, in BD versus PsA synovitis. However, the levels of perforin released in the SF were fivefold increased in BD versus PsA, suggesting the relevance of cytotoxicity in BD synovitis [30–32].

This systematic comparative analysis of early untreated synovitis identifies both lymphocytes and PMN as important infiltrating cell populations and indicates an increase of cytotoxic molecules in BD versus PsA. Further studies should clarify their functional contribution to the pathogenesis of the disease.