Vasculitis Relapse Management Requires Vigilance

BOSTON — Although 3 decades have passed since the introduction of a regimen combining daily oral cyclophosphamide with prednisone transformed antineutrophil cytoplasmic antibody-associated vasculitis from a uniformly fatal disease to one with an 80% survival rate, the management of relapse in this and other small-vessel vasculitides remains a vexatious challenge with no approved treatments, Dr. Carol A. Langford said at the annual meeting of the American College of Rheumatology.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and microscopic polyangiitis are by nature relapsing diseases, and currently no treatment can reliably prevent recurrence.

“Until such time as we can prevent relapse, our approach must be based first on correctly identifying relapse—which sounds straightforward but frequently is not—and then selecting the treatment option that best addresses the patient's treatment history, disease severity, and that takes into account the risks and benefits of the regimen,” said Dr. Langford of the center for vasculitis care and research, department of rheumatic and immunologic diseases, Cleveland Clinic Foundation.

Assessing relapse in these antineutrophil cytoplasmic antibody-associated vasculitides generally relies on obtaining information about disease-related inflammation from the history, physical examination, laboratory studies, and diagnostic imaging. “Unfortunately, there is no blood test that can detect a relapse, and in determining if a relapse is truly a relapse, it's important also to think about infection, medication reactions, and chronic damage,” she said. A new elevation of the erythrocyte sedimentation rate, for example, can be suggestive of relapse but is nonspecific. Remember that one of the most common causes of an elevated sedimentation rate is infection, but an elevation without infection should prompt a careful evaluation to look for sites of disease activity, she said.

Other features that could be considered indicative of relapse also might not necessarily be so. New-onset hematuria or a new pulmonary infiltrate in an immunosuppressed host could represent cyclophosphamide-induced bladder injury or methotrexate pneumonitis, she cautioned.

This evaluation should include not only sites and organ systems that have previously been affected, but also sites of new activity. Some patients predictably relapse in the same way each time, but the suggestion of disease activity in one site should alert the clinician to the possibility of new activity in another site.

“In particular, you always need to watch for emerging glomerulonephritis,” Dr. Langford said.

It's also important to differentiate new disease activity from chronic disease damage, such as changes in the orbital space, sinus mucosal thickening, and even persistent lung nodules, she said.

“Once you have gone through this careful thought process and have determined that your patient is relapsing, the question becomes what approach to use, and whether the treatment of relapse is any different from initial treatment. The answer is yes and no,” she said. Overall, the treatment options remain the same; there are no regimens used solely for initial treatment or maintenance therapy. Aside from cyclophosphamide and prednisone, the most commonly used agents today are azathioprine and methotrexate.

In a recent review of patients treated at Dr. Langford's center, 57 patients with severe disease were initially treated with cyclophosphamide, and 25 with mild to moderate disease were treated with methotrexate. Following initial improvements, all patients continued on methotrexate, with sustained remission being seen in 78%. Although 45% relapsed within 1 year and 66% relapsed within 2 years, 82% of relapsed patients went on to achieve subsequent remission with additional treatment (Medicine [Baltimore] 2007;86:269-77).

Treatment after relapse must consider drug toxicities that might have occurred with past treatment, organ damage, and any new medical conditions. Other considerations include whether the dosages of medications and duration of therapy have been adequate in the past, whether the method and timing of administration have been optimal, and if the patient has been compliant.

A patient who has been doing well for several years on methotrexate and has a mild relapse does not necessarily need to receive the very effective—but very toxic—cyclophosphamide.

“I would look for ways to optimize the methotrexate, keeping in mind that, whenever possible, cyclophosphamide should be reserved for instances when its lifesaving capacity may be needed,” said Dr. Langford.

The site and severity of relapse also are important. “We rarely would consider cyclophosphamide for isolated sinonasal relapse,” Dr. Langford said.

An additional difficult question relates to the optimal duration of maintenance therapy to prevent future relapses, and “the answer unfortunately is, we don't know,” she said. Some patients are able to stop treatment and remain in remission, but studies have shown that relapse rates are higher when patients are no longer on treatment. If a patient has done well for a minimum of 2 years, consideration can be given to tapering treatment depending on risks and benefits, but this must be done on an individual basis. “However, if someone has a residual creatinine of 4 mg/dL and is fighting for every last glomerulus, I would be reluctant to stop their maintenance therapy if toxicity is not an issue,” Dr. Langford said.

Finally, new agents are becoming available, but for patients who are able to tolerate the standard treatments, unproven therapies should not be used except in the context of clinical trials. ANCA-associated vasculitis and microscopic polyangiitis are potentially life-threatening diseases. “If the agent is not effective, the disease could worsen or unexpected toxicities could be seen,” Dr. Langford said.

For example, in a trial that evaluated adding etanercept or placebo to standard therapy with cyclophosphamide or methotrexate, there were no differences between the groups in the rates of sustained remission or severe adverse events, but six patients in the etanercept group developed solid tumors, compared with no patients in the placebo group (N. Engl. J. Med. 2005;352:351-61).

BOSTON — Although 3 decades have passed since the introduction of a regimen combining daily oral cyclophosphamide with prednisone transformed antineutrophil cytoplasmic antibody-associated vasculitis from a uniformly fatal disease to one with an 80% survival rate, the management of relapse in this and other small-vessel vasculitides remains a vexatious challenge with no approved treatments, Dr. Carol A. Langford said at the annual meeting of the American College of Rheumatology.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and microscopic polyangiitis are by nature relapsing diseases, and currently no treatment can reliably prevent recurrence.

“Until such time as we can prevent relapse, our approach must be based first on correctly identifying relapse—which sounds straightforward but frequently is not—and then selecting the treatment option that best addresses the patient's treatment history, disease severity, and that takes into account the risks and benefits of the regimen,” said Dr. Langford of the center for vasculitis care and research, department of rheumatic and immunologic diseases, Cleveland Clinic Foundation.

Assessing relapse in these antineutrophil cytoplasmic antibody-associated vasculitides generally relies on obtaining information about disease-related inflammation from the history, physical examination, laboratory studies, and diagnostic imaging. “Unfortunately, there is no blood test that can detect a relapse, and in determining if a relapse is truly a relapse, it's important also to think about infection, medication reactions, and chronic damage,” she said. A new elevation of the erythrocyte sedimentation rate, for example, can be suggestive of relapse but is nonspecific. Remember that one of the most common causes of an elevated sedimentation rate is infection, but an elevation without infection should prompt a careful evaluation to look for sites of disease activity, she said.

Other features that could be considered indicative of relapse also might not necessarily be so. New-onset hematuria or a new pulmonary infiltrate in an immunosuppressed host could represent cyclophosphamide-induced bladder injury or methotrexate pneumonitis, she cautioned.

This evaluation should include not only sites and organ systems that have previously been affected, but also sites of new activity. Some patients predictably relapse in the same way each time, but the suggestion of disease activity in one site should alert the clinician to the possibility of new activity in another site.

“In particular, you always need to watch for emerging glomerulonephritis,” Dr. Langford said.

It's also important to differentiate new disease activity from chronic disease damage, such as changes in the orbital space, sinus mucosal thickening, and even persistent lung nodules, she said.

“Once you have gone through this careful thought process and have determined that your patient is relapsing, the question becomes what approach to use, and whether the treatment of relapse is any different from initial treatment. The answer is yes and no,” she said. Overall, the treatment options remain the same; there are no regimens used solely for initial treatment or maintenance therapy. Aside from cyclophosphamide and prednisone, the most commonly used agents today are azathioprine and methotrexate.

In a recent review of patients treated at Dr. Langford's center, 57 patients with severe disease were initially treated with cyclophosphamide, and 25 with mild to moderate disease were treated with methotrexate. Following initial improvements, all patients continued on methotrexate, with sustained remission being seen in 78%. Although 45% relapsed within 1 year and 66% relapsed within 2 years, 82% of relapsed patients went on to achieve subsequent remission with additional treatment (Medicine [Baltimore] 2007;86:269-77).

Treatment after relapse must consider drug toxicities that might have occurred with past treatment, organ damage, and any new medical conditions. Other considerations include whether the dosages of medications and duration of therapy have been adequate in the past, whether the method and timing of administration have been optimal, and if the patient has been compliant.

A patient who has been doing well for several years on methotrexate and has a mild relapse does not necessarily need to receive the very effective—but very toxic—cyclophosphamide.

“I would look for ways to optimize the methotrexate, keeping in mind that, whenever possible, cyclophosphamide should be reserved for instances when its lifesaving capacity may be needed,” said Dr. Langford.

The site and severity of relapse also are important. “We rarely would consider cyclophosphamide for isolated sinonasal relapse,” Dr. Langford said.

An additional difficult question relates to the optimal duration of maintenance therapy to prevent future relapses, and “the answer unfortunately is, we don't know,” she said. Some patients are able to stop treatment and remain in remission, but studies have shown that relapse rates are higher when patients are no longer on treatment. If a patient has done well for a minimum of 2 years, consideration can be given to tapering treatment depending on risks and benefits, but this must be done on an individual basis. “However, if someone has a residual creatinine of 4 mg/dL and is fighting for every last glomerulus, I would be reluctant to stop their maintenance therapy if toxicity is not an issue,” Dr. Langford said.

Finally, new agents are becoming available, but for patients who are able to tolerate the standard treatments, unproven therapies should not be used except in the context of clinical trials. ANCA-associated vasculitis and microscopic polyangiitis are potentially life-threatening diseases. “If the agent is not effective, the disease could worsen or unexpected toxicities could be seen,” Dr. Langford said.

For example, in a trial that evaluated adding etanercept or placebo to standard therapy with cyclophosphamide or methotrexate, there were no differences between the groups in the rates of sustained remission or severe adverse events, but six patients in the etanercept group developed solid tumors, compared with no patients in the placebo group (N. Engl. J. Med. 2005;352:351-61).

BOSTON — Although 3 decades have passed since the introduction of a regimen combining daily oral cyclophosphamide with prednisone transformed antineutrophil cytoplasmic antibody-associated vasculitis from a uniformly fatal disease to one with an 80% survival rate, the management of relapse in this and other small-vessel vasculitides remains a vexatious challenge with no approved treatments, Dr. Carol A. Langford said at the annual meeting of the American College of Rheumatology.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and microscopic polyangiitis are by nature relapsing diseases, and currently no treatment can reliably prevent recurrence.

“Until such time as we can prevent relapse, our approach must be based first on correctly identifying relapse—which sounds straightforward but frequently is not—and then selecting the treatment option that best addresses the patient's treatment history, disease severity, and that takes into account the risks and benefits of the regimen,” said Dr. Langford of the center for vasculitis care and research, department of rheumatic and immunologic diseases, Cleveland Clinic Foundation.

Assessing relapse in these antineutrophil cytoplasmic antibody-associated vasculitides generally relies on obtaining information about disease-related inflammation from the history, physical examination, laboratory studies, and diagnostic imaging. “Unfortunately, there is no blood test that can detect a relapse, and in determining if a relapse is truly a relapse, it's important also to think about infection, medication reactions, and chronic damage,” she said. A new elevation of the erythrocyte sedimentation rate, for example, can be suggestive of relapse but is nonspecific. Remember that one of the most common causes of an elevated sedimentation rate is infection, but an elevation without infection should prompt a careful evaluation to look for sites of disease activity, she said.

Other features that could be considered indicative of relapse also might not necessarily be so. New-onset hematuria or a new pulmonary infiltrate in an immunosuppressed host could represent cyclophosphamide-induced bladder injury or methotrexate pneumonitis, she cautioned.

This evaluation should include not only sites and organ systems that have previously been affected, but also sites of new activity. Some patients predictably relapse in the same way each time, but the suggestion of disease activity in one site should alert the clinician to the possibility of new activity in another site.

“In particular, you always need to watch for emerging glomerulonephritis,” Dr. Langford said.

It's also important to differentiate new disease activity from chronic disease damage, such as changes in the orbital space, sinus mucosal thickening, and even persistent lung nodules, she said.

“Once you have gone through this careful thought process and have determined that your patient is relapsing, the question becomes what approach to use, and whether the treatment of relapse is any different from initial treatment. The answer is yes and no,” she said. Overall, the treatment options remain the same; there are no regimens used solely for initial treatment or maintenance therapy. Aside from cyclophosphamide and prednisone, the most commonly used agents today are azathioprine and methotrexate.

In a recent review of patients treated at Dr. Langford's center, 57 patients with severe disease were initially treated with cyclophosphamide, and 25 with mild to moderate disease were treated with methotrexate. Following initial improvements, all patients continued on methotrexate, with sustained remission being seen in 78%. Although 45% relapsed within 1 year and 66% relapsed within 2 years, 82% of relapsed patients went on to achieve subsequent remission with additional treatment (Medicine [Baltimore] 2007;86:269-77).

Treatment after relapse must consider drug toxicities that might have occurred with past treatment, organ damage, and any new medical conditions. Other considerations include whether the dosages of medications and duration of therapy have been adequate in the past, whether the method and timing of administration have been optimal, and if the patient has been compliant.

A patient who has been doing well for several years on methotrexate and has a mild relapse does not necessarily need to receive the very effective—but very toxic—cyclophosphamide.

“I would look for ways to optimize the methotrexate, keeping in mind that, whenever possible, cyclophosphamide should be reserved for instances when its lifesaving capacity may be needed,” said Dr. Langford.

The site and severity of relapse also are important. “We rarely would consider cyclophosphamide for isolated sinonasal relapse,” Dr. Langford said.

An additional difficult question relates to the optimal duration of maintenance therapy to prevent future relapses, and “the answer unfortunately is, we don't know,” she said. Some patients are able to stop treatment and remain in remission, but studies have shown that relapse rates are higher when patients are no longer on treatment. If a patient has done well for a minimum of 2 years, consideration can be given to tapering treatment depending on risks and benefits, but this must be done on an individual basis. “However, if someone has a residual creatinine of 4 mg/dL and is fighting for every last glomerulus, I would be reluctant to stop their maintenance therapy if toxicity is not an issue,” Dr. Langford said.

Finally, new agents are becoming available, but for patients who are able to tolerate the standard treatments, unproven therapies should not be used except in the context of clinical trials. ANCA-associated vasculitis and microscopic polyangiitis are potentially life-threatening diseases. “If the agent is not effective, the disease could worsen or unexpected toxicities could be seen,” Dr. Langford said.

For example, in a trial that evaluated adding etanercept or placebo to standard therapy with cyclophosphamide or methotrexate, there were no differences between the groups in the rates of sustained remission or severe adverse events, but six patients in the etanercept group developed solid tumors, compared with no patients in the placebo group (N. Engl. J. Med. 2005;352:351-61).