RAASHID A. LUQMANI, DM, FRCP, FRCPE,
Consultant Rheumatologist,

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Rheumatology Department,
Nuffield Orthopaedic Centre;
Senior Lecturer in Rheumatology,
Botnar Research Centre,
University of Oxford;
OLIVER FLOSSMANN, MRCP (UK),
EULAR Research Fellow in Vasculitis,
Botnar Research Centre,
Nuffield Orthopaedic Centre,
University of Oxford, Oxford, UK.
Address reprint requests to Dr. R.A. Luqmani, Rheumatology Department, Nuffield Orthopaedic Centre, Oxford OX3 7LD, UK. E-mail: raashid.luqmani@ndos.ox.ac.uk

There are many questions to address in our current understanding of the natural history of systemic vasculitis. What is the outcome of small vessel systemic vasculitis as a result of current management? In other words, how effective are our current therapies in influencing the likely disease morbidity and mortality? Patients with primary small-vessel antineutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis (AASV) have a potentially life-threatening disease. As a result of the introduction of chemotherapy, particularly cyclophosphamide, their outcome has been transformed from a mortality of 80% at one year¹ to survival of 55% in microscopic polyangiitis (MPA) and 75% in Wegener's granulomatosis (WG) at 10 years². The subsequent disease course is unsatisfactory for most patients, due to low-grade grumbling disease, relapse, and the added effects of damage due to established disease or drug toxicity^2-5. As a result, the burden of disease remains considerable in this group of survivors, so that their quality of survival is very inadequate and has driven the search to improve our current therapeutic strategies in vasculitis.

Although most patients with vasculitis survive their initial illness, late diagnosis remains a problem; patients may present with vague nonspecific features at an early stage of disease, and a diagnosis may be missed. Even after a diagnosis, delays in starting therapy can contribute to mortality if the disease is very active, with a timescale of days from initial presentation to end-organ failure in extreme cases⁶.

Are there risk factors that would predict a worse outcome and for which we should take different management decisions? Guillevin and colleagues have proposed a 5-factor score based on the presence of raised serum creatinine, proteinuria, cardiac involvement, central nervous system involvement, or gut involvement⁷. Having any one of these 5 factors adversely affects the outcome of patients with Churg-Strauss syndrome (CSS) and polyarteritis nodosa (PAN). The 5-factor score has not been validated in other diseases such as WG or MPA. Assessment of disease activity can be standardized using clinical measures such as the introduction of the Birmingham Vasculitis Activity Score⁸. Disease damage can be evaluated in a systematic way, applying the Vasculitis Damage Index⁴. These clinical tools provide an accurate description of the current status of an individual patient; but more than this, they provide an opportunity to compare groups of patients in a standardized way.

In a new study by Pavone, et al reported in this issue of The Journal⁹, 75 patients with primary systemic vasculitis have been evaluated for longterm prognosis and risk factors for poor outcome. There are organ-specific differences in rates of relapse. Gastrointestinal involvement in patients with CSS is associated with a high rate of relapse. By contrast, the presence of renal disease and the presence of a perinuclear-ANCA has a negative relationship with relapse; in other words these patients are less likely to relapse. A new finding is of an increased risk of relapse in Churg-Strauss patients with Staphyloccocus aureus nasal carriage; by contrast, the relapse risk is reduced in patients with WG who also carry S. aureus. These findings are difficult to explain when compared to previous evidence demonstrating a potential role for S. aureus and its toxins in exacerbating WG, and a 6-fold increase in relapse risk in patients with WG who are nasal carriers of S. aureus compared to those who are not. The authors suggest that these differences may be explained by the routine prescription of cotrimoxazole for all patients with WG, therefore artificially reducing the number of patients carrying S. aureus, or having a direct effect on the disease itself¹⁰. Interestingly, there was no influence of type of vasculitis on survival in this cohort. Clinical presentation may predict future outcome, at least in the first year of disease^8,11. The Pavone study suggests that in CSS, patients have an increased risk of relapse if there is gastrointestinal involvement, supporting the concept that some clinical features can predict outcome^7,8,11-13.

The outcome in MPA differs from that of WG². The mortality in patients with MPA is higher than in WG. However, the mortality rate in MPA is highest in the first year after diagnosis. By contrast, there is progressive mortality associated with WG over a number of years, perhaps reflecting the nature of the underlying disease process. In addition, the relapse rate in WG is higher than in MPA¹⁴.

We have summarized the outcome of therapy from vasculitis in Tables 1 and 2, examining all large randomized prospective and selected retrospective studies of AASV with a minimum of one year followup. We have put the Pavone study into the tables for comparison with other large cohort studies of vasculitis.

Table 1. Mortality in prospective and selected retrospective outcome studies in PSV.

Table 2. Relapse in prospective studies and selected retrospective outcome studies. For definitions see Table 1.

The underlying pathogenesis of the systemic vasculitides is becoming better understood. Differences in the pathomechanisms may explain some of the variation in disease characteristics¹⁵. Why should organ-specific manifestations herald a risk of general relapse? Are there specific features in that organ that are critical to the relapse, or are they simply organs where subclinical disease can evolve into clinically overt manifestations at an earlier stage into recognizable symptoms, signs, or serological evidence of active vasculitis? For example, it is easier to detect a recurrence of skin vasculitis, manifesting as a rash, than to detect the presence of glomerulonephritis, which may only be found by careful testing of urine, assessment of renal function, and regular monitoring of blood pressure. Alternatively, some organs might be more prone to flares due to a higher likelihood of infection. Nasal colonization with S. aureus is, for example, associated with an increased risk of relapse of WG¹⁰. The pattern of organ involvement in a number of vasculitides is quite specific, even though in theory all vascular beds could be affected. Vascular flow, trauma, different vessel characteristics, and external agents such as infection or toxins may all influence the specific disease phenotype¹⁵.

It is unlikely that our current therapies for systemic vasculitis will result in long-lasting drug-free remission or cure in the majority of cases. The quality of survival for most patients is unsatisfactory^2-5. Measuring the morbidity of patients with vasculitis is an important advance in our ability to compare the effectiveness of different treatment regimens^4,8.

Controlled trials in systemic vasculitis are testing the effectiveness of different protocols utilizing existing drugs to their best ability to improve disease control while at the same time limiting toxicity^14,16. Cyclophosphamide use can be limited to a comparatively short initial treatment at presentation or relapse¹⁴, followed by a switch to azathioprine as a maintenance therapy. In limited forms of AASV without vital organ involvement, methotrexate could be used as a substitute for cyclophosphamide¹⁶. Conventional strategies with cyclophosphamide and steroid are being challenged by the increasing use of biologic agents. Thus far the evidence for disease control is disappointing for etanercept¹⁷, but there may be a better response to other biologic agents.

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