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

Treatment of Small Vessel Vasculitis

Under the rubric of AAV, we find disorders with clearly different presentations, complications and prognoses. It follows from my prior comments that I would not endorse a uniform approach to treatment for SVV and would not design a protocol to include what are related, but heterogeneous disorders. In a clinical practice situation, vasculitis treatment should be determined on a case-by-case basis, depending on severity of disease as defined by whether critical organ systems are involved, severity of involvement and rate of change. This approach does not imply that treatment for any form of SVV should be delayed while awaiting adequate data for a definitive diagnosis. Systemic vasculitis always requires prompt decision making and initiation of therapy. Formal clinical trials should demand a yet more rigorous approach. For outcomes to be meaningful, study enrollment should strive for relative diagnostic homogeneity within patient populations.

The combination of cyclophosphamide and high-dose glucocorticoids is generally agreed to be the standard of care for the induction of remission in severe SVV, whether that be WG, MPA or CSS. It has also been demonstrated that methotrexate plus glucocorticoids is usually effective in patients with WG who have renal disease that is not far advanced. The latter has been defined in prospective trials as being a serum creatinine that is less than 2 mg/dl.[25]

In my own practice, strategies that limit or completely avoid the use of cyclophosphamide have been employed for almost 20 years. The data to support these strategies has been the subject of publications since 1992.[26] Numerous studies have since demonstrated the feasibility of avoiding cyclophosphamide in patients with disease that is not an immediate threat to critical organs and limiting duration of cyclophosphamide in patients with certain severe forms of SVV in whom disease has remitted or markedly improved after 3-6 months of cyclophosphamide therapy.[2,22,27,28] This approach has allowed us to avoid the frequent and severe adverse events that are well known to follow chronic cyclophosphamide use. Recommendations from these studies fully recognize that referral bias may exist in certain subspecialty practices such as nephrology or critical care. Patients with rapidly progressive glomerulonephritis or those so ill as to require intensive care unit care would not be well served if treated with cytotoxic agents other than cyclophosphamide.

In the rheumatology community, it is generally accepted that daily cyclophosphamide therapy is superior to intravenous intermittent pulse treatment because daily cyclophosphamide is associated with fewer relapses, toxicity in the form of hemocytopenia can be closely monitored, predicted or avoided and long-term cyclophosphamide toxicity minimized if transition to alternative agents successfully occurs within 3-6 months. These arguments have been made before[29] and will not be reviewed again here. Several cautions and guidelines about initial cyclophosphamide use and maintenance therapy with other agents should, however, be emphasized:

  1. The effects of cyclophosphamide on bone marrow reserve are additive. Normal complete blood counts on a fixed stable dose of cyclophosphamide do not guarantee that severe hemocytopenias (especially leukopenia) may not follow in an unpredictable fashion, depending on each patient's unique bone marrow status and possible change in renal function. This has led us in our practice and formal studies to always monitor complete blood counts and serum creatinine every 1-2 weeks while patients are receiving daily cyclophosphamide.

  2. The goal of treatment is remission, not achieving an arbitrary low white blood cell count. Our methods and previously published National Institutes of Health vasculitis protocol guidelines have been misquoted and misunderstood by some in the past. Our cautions to avoid leukopenia (white blood cells below 3500 cells/mm3) have been misconstrued to mean one should attempt to achieve a white blood cell count of 3500/mm3. Indeed, dose reduction or temporary withdrawal of therapy is mandated in this setting, until the white blood cell count is normal. When normalization of the white blood cell count occurs, treatment should be restarted at a lower dose.

  3. If remission or dramatic improvement follows within 3-6 months, but the serum creatinine is above 2.0 mg/dl, methotrexate is contraindicated for maintenance therapy because of unpredictable effects on bone marrow reserve, especially if renal function is unstable. If remission is present and the creatinine is abnormal, but below 2.0 mg/dl after 3-6 months, methotrexate can be used, but with caution, and monitoring should occur not less than every 2-4 weeks. If the creatinine and complete blood counts are persistently normal, monitoring is advised at no less often than at 4 week intervals.

  4. In making a transition to methotrexate or azathioprine (if creatinine is above 2.0 mg/dl), treatment should begin immediately after the last dose of cyclophosphamide, so as to not leave the patient untreated.

  5. Studies of transition to maintenance therapy have not advocated 'overlapping' cytotoxic agents (that is use cyclophosphamide and either methotrexate or azathioprine concurrently) to sustain remission and because of concerns that such an approach would risk producing unnecessary hemocytopenias.

  6. Patients who receive cyclophosphamide or transition to glucocorticoids plus an additional immunosuppressive agent should be treated to prevent Pneumocystis infections.

How well does this approach work over an extended period of time? During the first 12 years of my practice at the Cleveland Clinic within the Center for Vasculitis Care and Research, over 250 patients were referred for care for WG. Eighty-two patients have had their care guided by me personally from the beginning of their illness. Support and monitoring was also provided by members of our Vasculitis Center, and, when appropriate, consultants in pulmonary medicine, critical care, nephrology, otolaryngology and patients' referring doctors. Seventy percent of these patients initially had 'severe' disease. In over half of this group, illness was judged to be severe because of pulmonary hemorrhage, rapidly progressive glomerulonephritis, including need for dialysis or neurologic abnormalities. Sixty-three percent of patients with severe illness presented with serum creatinine values that were above 2.0 mg/dl. Severely ill patients received a short course of daily cyclophosphamide (3-6 months) for remission induction. All patients with mild (initially methotrexate treated) and severe disease improved. Remission was achieved in 50% within 6 months and 72% within 12 months. Sustained remission (longer than 6 months) was ultimately achieved in 77% of all patients. Among those who achieved remission of any duration (91%), 45% relapsed within 1 year and 66% relapsed within 2 years. Eighty-two percent of relapsed patients achieved subsequent remissions after additional treatment. About three-quarters of relapses were mild and promptly responded to treatment. None of the patients developed cyclophosphamide-induced cystitis or bladder cancer. Only 17% of patients developed serious infections, one being the cause of death. Over a median follow-up period of 4.5 years, 9.8% (8/82) of patients had worsening renal function. Seven of these eight patients originally had severe WG, including glomerulonephritis and renal impairment when cyclophosphamide therapy was begun. Only three patients (3.7%) died. Two of these patients were elderly (ages 74 and 79). No deaths were due to active WG.[30]

We have demonstrated that cyclophosphamide therapy, used in a limited fashion, in conjunction with close clinical and laboratory monitoring, can usually avoid toxicities that are inherent to chronic, extended cyclophosphamide use. While our approach has dramatically diminished mortality compared to prior studies, relapses were common. The rate of relapse is in close agreement with that noted in the recent WGET trial. Although our experience is only relevant to WG, we do use this approach to guide treatment for other types of SVV. We do not, however, have an adequate experience with those other disorders to provide data-based recommendations.

Our physician group practice includes a rheumatologist, Mary Anne Dooley, and another nephrologist, Patrick Nachman, in close working relationship with an ENT surgeon, Brent Senior, and a pulmonologist, David Henke. From 40 to 80 patients with glomerular disease, systemic lupus erythematosus or SVV are followed by our group every week and we have seen several hundred patients with vasculitis. It is fair to say that there is some referral bias in that many of the patients have some form of kidney disease - perhaps because we look so hard to find it. We worry about loss of glomeruli and, akin to the EUVAS experience, we are anxious about initiating therapy. Loss of glomeruli that are not able to repopulate influences the care of a patient with diabetes mellitus, systemic lupus erythematosus or any disease process that affects the kidney. In all studies of kidney disease, the degree of renal dysfunction at the time of treatment predicts long-term renal outcome.[31,32] Waiting for abnormal kidney function invites substantial and usually irreversible loss of kidney function. Pulmonary bleeding also prompts immediate intervention. We recommend induction therapy with oral glucocorticoids including either plasmapheresis or pulse methylprednisolone. Typically, we use pulse Medrol for necrotizing and crescentic glomerulonephritis and plasmapheresis for pulmonary hemorrhage,[33] and perhaps for dialysis-dependent patients if the MEPEX trial is published in its entirety.

The choice of intravenous or oral cyclophosphamide should be based on evidence and there is no grade A evidence that oral cyclophosphamide is superior to intravenous cyclophosphamide. Without question, the cumulative dose of oral cyclophosphamide will be two to three times the cumulative dose for intravenous cyclophosphamide. Since 1992, we have attempted to limit patient exposure to cyclophosphamide therapy, thereby avoiding the complications observed in the early National Institutes of Health WG cohort. We have used either intravenous cyclophosphamide or oral cyclophosphamide in our patient population. There have been a number of concerns about relapse and remission rates.[34] The end of this controversy is now in sight. De Groot et al.[23] have performed pooled and multivariate analysis of oral vs. intravenous cyclophosphamide, suggesting that there are equal remission rates. In fact, the intravenous cyclophosphamide remission rate was superior and the relapse rate was not statistically higher in the intravenous cyclophosphamide group. The EUVAS CYCLOPS study, which compares oral vs. intravenous cyclophosphamide, also adds significant insight into comparative use of these modes of administration.[23,35] Their data, available from the American Society of Nephrology Abstracts in the 2005 Annual Meeting, suggest that there are no differences in terms of remission or relapse with intravenous vs. oral therapy and that the cumulative dose of cyclophosphamide was one-half when given intravenously compared to orally. This transition to intravenous cyclophosphamide is not as difficult in the nephrology community, where intravenous cyclophosphamide has been used for some time in other glomerular diseases. Nonetheless, the search for induction therapies that may exclude cyclophosphamide while preserving all glomeruli needs to be a focus of further studies.

What is the best method for treating milder forms of disease? Milder disease requires milder therapy. 'Milder' disease involving the skin, lung or ear and nose disease alone without resultant scarring may allow therapy with glucocorticoids in conjunction with azathioprine and mycophenolate mofetil, or even methotrexate. In our practice, patients with any signs of kidney involvement do not receive therapy of methotrexate and we have experienced the expected poor long-term outcomes with methotrexate therapy in other patients.

In our experience, induction of remission is on the order of 85%.[12] Relapses occur in 22-50% of patients, depending on their risk factors for relapse.[12] It is our intent to stop therapy for many patients, yet continue remission maintenance therapy for those who require it. We have patients who become resistant to sequential attempts with multiple types of immunomodulating therapies and these patients are a challenge to all of us.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.