SNOWMASS, COLO. – Some of the most widely accepted core concepts regarding the pathogenesis of psoriatic arthritis are probably incorrect.
Conventional wisdom holds that psoriatic arthritis – like rheumatoid arthritis – is an autoimmune disease, that the mechanisms underlying the two inflammatory diseases run parallel, and that the therapeutic response of psoriatic arthritis (PsA) to a variety of agents is similar to that in RA. All three of these paradigms are likely headed for the scrap heap, according to Dr. Christopher T. Ritchlin, professor of medicine and director of the translational immunology research center at the University of Rochester (N.Y.).
Dr. Christopher T. Ritchlin
Here’s why:
• Autoimmunity. RA is an autoantibody-mediated disease involving MHC (major histocompatibility complex) class II. In contrast, no autoantibodies have been linked to PsA, an MHC class I–related disorder.
Moreover, the foci of joint inflammation are quite different in the two diseases. In RA, the primary site of inflammation is synovial tissue, whereas in PsA the targets of inflammation – including the bone marrow and entheses as well as synovium – are strikingly heterogeneous.
The alterations in bone are very different in RA and PsA. The bone remodeling characteristic of RA is a catabolic process marked by focal bony erosions and osteopenia. In contrast, patients with PsA can have bone destruction and bone formation going on simultaneously in the same hand.
The extra-articular manifestations of the two diseases are different as well. RA is associated with vasculitis, Sjögren’s syndrome, and nodules. PsA has psoriasis, uveitis, and bowel inflammation as its chief extra-articular manifestations. Indeed, acute or chronic bowel inflammation has been detected in 15%-30% of PsA patients without abdominal symptoms; it’s most common in patients with axial involvement.
"I have in my own practice three patients whose psoriatic arthritis has been effectively controlled with etanercept. Then I get a phone call that they’re having fevers, they’re not feeling well, losing weight. A work-up for infection ensues, and it turns out after a couple of weeks that the bowel symptoms are predominating and these patients have developed florid Crohn’s disease. In talking to rheumatologists around the country, this is something others have seen as well. It’s an intriguing phenomenon: You can control one arm of inflammation in the joints and the skin, but the bowel seems to break through by mechanisms that are not well understood," Dr. Ritchlin said.
PsA is also distinct from RA in terms of potentially modifiable environmental risk factors. Epidemiologic studies have linked an increased risk of PsA to more-severe psoriatic skin disease, nail dystrophy, moving to a new home, trauma leading to medical care, vaccination for rubella, and obesity (Arch. Dermatol. 2010;146:785-8). The link with rubella vaccination definitely needs confirmation before gaining acceptance. However, the association between obesity and increased risk of PsA has been validated, Dr. Ritchlin observed.
"My view and that of many others in the field is that perhaps psoriatic arthritis is not a typical autoimmune disease. But rather, it involves a more innate immune response that has yet to be fully understood," the rheumatologist said.
• Divergent cellular pathobiology. The T cell clearly plays a crucial role in the pathogenesis of RA. But there is little evidence to suggest that T lymphocytes are key cells in the pathobiology of psoriatic arthritis. Instead, the monocyte appears to be the most important cell in that disease, Dr. Ritchlin noted.
Increased levels of circulating osteoclast precursor cells are a feature of both psoriatic arthritis and psoriasis but not RA.
Interleukin-17’s exact role in the immunopathology of psoriatic arthritis isn’t yet understood. Three major clinical trials are looking at the therapeutic impact of blocking IL-17 in psoriatic arthritis, including two recently completed phase III studies of ustekinumab (Stelara); the first, conducted in TNF (tumor necrosis factor) inhibitor–naive subjects, will be presented at EULAR in Berlin in June, with data from the other two studies to come in the following half-year. One of the trials involves a monoclonal antibody to the IL-17 receptor; this agent has shown spectacular efficacy in psoriasis but is not effective in RA, so its impact in PsA will be of particular interest.
"I think having the data from these trials will make for a major advance in helping us to understand the pathogenic pathways," Dr. Ritchlin said.
• Treatment response. There is no evidence that the conventional DMARDs (disease-modifying antirheumatic drugs) that have well-established benefit in RA also slow radiographic progression of PsA. Moreover, recent studies of abatacept and rituximab (biologic agents that are highly effective in RA) failed to show benefit in PsA.