Controversies in Small Vessel Vasculitis - Comparing the Rheumatology and Nephrology Views

Ronald J. Falk; Gary S. Hoffman


Curr Opin Rheumatol. 2007;19(1):1-9. 

In This Article

Duration of Treatment

Ideally, if treatment was more effective, we would define excellent outcomes as percent cures or 5 year-relapse-free remissions, independent of maintenance therapies. In WG, however, we have come to accept that with current treatment, cure is not within our grasp and relapse rates are extremely high.[11,22,28]

The EUVAS trial led by De Groot et al.[22] compared methotrexate with cyclophosphamide, and found similar sustained remission rates in patients with mild to moderately severe WG and MPA. Their protocol called for stopping all immunosuppressive therapies after 10-12 months of treatment in patients who had achieved remission (around 90% of patients). After treatment withdrawal, patients in both groups experienced a high rate of relapse. This study contrasts with another EUVAS trial performed by Jayne and colleagues[2] in 155 patients with severe WG, MPA and RLPIGN in which following induction with cyclophosphamide, maintenance therapy with either cyclophosphamide or azathioprine was compared. This study continued maintenance therapy (azathioprine) for at least 18 months. Relapse rates in each treatment group from both studies were similar through the initial 12 months of treatment, but were far less in the study in which prolonged maintenance therapy was continued for at least 18 months (13.7 and 15.5%, cyclophosphamide and azathioprine, respectively, vs. 69.5 and 46.5%, methotrexate and cyclophosphamide, respectively).

The ideal time over which maintenance therapy should be continued in any form of SVV is not clear, and may differ based on the type of vasculitis and subsets within diagnostic categories. It is clear that long-term maintenance therapy with cyclophosphamide is not feasible. The risk-benefit properties of many years of therapy with methotrexate, azathioprine or other agents in SVV populations are, however, less well understood. The safety profiles for methotrexate in rheumatoid arthritis or azathioprine in transplant recipients are encouraging, but it is not known whether that data can be directly applied to patients with other illnesses. Until guidance for duration of maintenance therapy from prospective trials is available, I have used the experience cited above to justify maintenance treatment in patients with WG, MPA and severe CSS for at least 1 year beyond unequivocal remission. If, however, a patient had repeated relapses upon tapering prednisone and adjunctive immunosuppressive maintenance therapies, maintenance treatment would be continued indefinitely.

Here is where we have the largest divide in opinion. In our practice, it is our intent to stop therapy when patients are in remission and their chances of relapse are small. To date, there is no randomized clinical controlled trial data suggesting that patients need to be treated over the course of many years. It is certain that prolonged years of therapy with any kind of immunomodulating therapy will engender complications over the course of time, including the development of tumors, cancers and repetitive bouts of infectious illness. The burden of proof should be the need for continued therapy with toxic medications and not necessarily on stopping therapy. In a prospective observational study of patients with ANCA SVV, all of whom had an ANCA and glomerulonephritis, factors that predicted a relapsing course were examined.[12] Hogan et al. found that proteinase 3 ANCA, or upper or lower respiratory tract disease resulted in a 2.0-fold increase in relapse risk, which was increased to 3.7-fold for those who had all three risk factors. These variables, and not the diagnosis of MPA or WG, were the predictors of relapse. Of 350 patients in this study, 143 patients were able to stop therapy and relapse rates were similar whether they were treated for 6 months or less, or more than 6 months. Thus, a patient with myeloperoxidase ANCA and glomerulonephritis and cutaneous vasculitis may not require long-term therapy. If the patient continues to be in remission at 6 months, they may do well with extensive and attentive clinical follow-up with no immunomodulating therapy. Patients should monitor hematuria with self-performed dipstick analysis and frequent clinic visits for assessment of clinically worsening symptoms. The absence of recurrent disease over the course of years and even decades suggests that there is a subset of patients with SVV who will not require long-term therapy, and in whom additional immunomodulating therapy is toxic. More patients are now referred to our group for evaluation of whether long-term cyclophosphamide, methotrexate or other therapy is warranted. Without question, all of us have patients with relapsing disease in any organ system that requires long-term immunomodulating therapy. It is difficult in those patients to ascertain whether infection, allergy or true recurrence of disease is occurring. Ferreting out the form of immunomodulating therapy that is best in this population is an art with which all of us wrestle. We are coming closer to consensus on this point as well.

Dr Hoffman writes that he uses maintenance therapy for 1 year after unequivocal remission. I would respectfully submit that even he is changing his views on long-term therapy. The length of time may be individual, probably dictated by the experience of the patient, the severity of their disease, the degree of baseline organ dysfunction, and the ability of the patient and physician to maintain close contact. Hopefully, the era is soon coming when we have accurate and easily obtainable markers that assure us of remission or of pending disease exacerbation.


  1. Patients with primary SVV should be treated as soon as possible.

  2. Multidisciplinary clinics or teams best serve patients with multisystem autoimmune disorders.

  3. Treatment should not be delayed until definitive diagnosis is made.

  4. ANCA plays a role in disease expression.

  5. Only a minority of patients with CSS make ANCA, but when ANCA is present it appears to influence disease expression.

  6. ANCA titers should not be used as the principal guide to assess disease status or make treatment modifications.

  7. For patients with mild forms of SVV, initial therapy with agents other than cyclophosphamide may be adequate to induce remission.

  8. When cyclophosphamide is utilized, transition to other agents should be considered following improvement. Transition is often possible within 3-6 months for most patients.

  9. Better and less-toxic therapies need to be developed for patients with SVV.


  1. ANCA are an essential component to the pathogenesis of WG, MPA and 'renal-limited' vasculitis.

  2. Preferences for cyclophosphamide administration (intravenous vs. daily).

  3. Duration of therapy following remission.


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