January 2013: An article in Clinical and Experimental Rheumatology (2012,30,4,Suppl.73, Pg. 0149-0153) provides an overview of the pathophysiological drivers that may lead to the identification of speciﬁc targets that can “turn off “ the disease. The article is written by Prof. Raashid Luqmani, NIHR Musculoskeletal Biomedical Research Unit, Nufﬁeld Department of Orthopaedics, Rheumatology and Musculoskeletal Science at the University of Oxford.
In the last 20 to 30 years, the treatment of systemic vasculitis has shifted keeping patients alive to maintaining high-quality disease control, avoiding the development of co-morbidities and preventing relapses. This is due in part to more effective therapies, but also clearer deﬁnitions of what constitutes clinical disease activity, relapse, remission and morbidity. Now we are shifting toward the most important target: curing disease.
The ﬁrst step is to move from clinically-based targets towards mechanistic targets based primarily around the pathophysiological drivers of disease. This could lead to more focused therapies addressing specific targets for personalized therapy of each patient and his/her condition. Many vasculitis patients are treated with large doses of glucocorticoid therapy for a relatively short duration. When this approach starts to fail, the opportunity arises to introduce more effective immunosuppressive therapy that makes allowances for the burden of toxicity.
• Pathophysiological targets: Similar to the approach in inﬂammatory arthritis, we need to examine disease mechanisms and identify which aspects are vulnerable to attack by our current therapies. We also need to be selective about those therapies so that we minimize toxicity and maximizing therapeutic beneﬁt.
• Serological targets: A recent meta-analysis of ANCA titres in the management of systemic vasculitis suggests that they are of very limited value in determining how long and how much to treat. If ANCA does not disappear in patients who have achieved clinical remission using induction therapy with cyclophosphamide, the persistence of ANCA increases the risk of relapse if the patient is subsequently switched to azathioprine. Potentially, this could serve as a target in this setting i.e. the target is to ensure that the ANCA titer is negative before induction therapy is stopped.
• Imaging biomarkers: More sophisticated development of CT scans and MRI scans has enabled more anatomical detail to identify both the presence of active granulomatous inﬂammation in GPA and the presence of damage particularly to bony structures. This has not been quantiﬁed to allow a standardized approach, but this could be an area for development.
• New approaches: A recent study found that genes in the interleukin-7 receptor pathway, T-cell receptor signaling and genes expressed by memory T cells can be used as predictors of subsequent relapse in patients with ANCA vasculitis. These targets appear to be independent of current clinical evidence of disease activity or any other known biomarkers. This may allow us to identify in advance patients who are likely to do badly. Though the data are preliminary, this approach might assist in biomarker discovery at much earlier phases of the disease, creating a new set of targets.
The main aim is to bring patients into clinical remission by reducing their overall disease activity by controlling active inﬂammation, but at the same time avoiding the accumulation of damage either induced by the disease activity, complicating infection or drug toxicity or the emergence or worsening of co-morbidity.
The treat-to-target concept remains relatively simple, but its application in vasculitis is complex because there is a need to achieve at many levels. Using a standard structured approach to patient evaluation and having preset targets in mind, response to treatment can be measured. This means it should be possible to implement an effective standardized approach to the care of all patients with ANCA vasculitis.
These approaches require regular and careful characterization of the patient’s clinical state at the onset of treatment and during follow-up to determine whether or not a target has been achieved. In time, we aspire to a similar targeted approach in other forms of vasculitis.