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Granulomatosis with polyangiitis and microscopic polyangiitis: Management of relapsing disease

Granulomatosis with polyangiitis and microscopic polyangiitis: Management of relapsing disease
Literature review current through: Jan 2024.
This topic last updated: Mar 16, 2023.

INTRODUCTION — Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are related systemic small-vessel vasculitides. Both are associated with antineutrophil cytoplasmic autoantibodies (ANCA) and have similar histologic features on kidney biopsy (eg, a focal necrotizing, pauci-immune, crescentic glomerulonephritis). They have somewhat different clinical features, serologic findings, and outcomes, including different patterns of pulmonary involvement and relapse rates. These entities are closely related to kidney-limited pauci-immune necrotizing and crescentic glomerulonephritis.

Relapsing disease refers to recurrence of signs or symptoms of active vasculitis in any organ system after remission is achieved, in the absence of another cause.

The management of relapsing GPA or MPA will be reviewed here. Clinical manifestations and diagnosis, initial therapy, and the management of treatment-resistant disease are discussed separately:

(See "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis".)

(See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy".)

(See "Granulomatosis with polyangiitis and microscopic polyangiitis: Management of disease resistant to initial therapy".)

DEFINITION OF RELAPSE — A clinical relapse is defined by the presence of both of the following [1,2]:

The recurrence of signs or symptoms of active vasculitis in any organ system after remission is achieved (see "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Definitions of response'). Examples of recurrence include:

An active urine sediment (dysmorphic [glomerular] hematuria with or without red cell casts), which may be accompanied by a rise in serum creatinine

Hemoptysis or pulmonary hemorrhage or new or expanding pulmonary nodules in the absence of evidence of infection

Iritis or uveitis, mononeuritis multiplex, rhinitis, sinusitis, any of several types of skin lesions, or necrotizing vasculitis on biopsy of any tissue

Such signs or symptoms are judged to be due to active granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) and not to another cause. As an example, not all instances of new hematuria or pulmonary nodules in a patient with GPA or MPA are due to active vasculitis. This differentiation between manifestations of active vasculitis and manifestations of another process can sometimes be difficult. (See 'Diagnosis of relapse' below.)

EPIDEMIOLOGY

Rates of relapse — The reported rates of relapse vary widely among studies, ranging from approximately 10 to 60 percent [1-9]. This wide range of reported relapse rates may be due at least in part to differences in induction or maintenance therapy, the proportion of patients with anti-proteinase-3 (PR3) antineutrophil cytoplasmic autoantibody (ANCA) serotype (PR3-ANCA) versus anti-myeloperoxidase (MPO) ANCA serotype (MPO-ANCA) or that of granulomatosis with polyangiitis (GPA) versus microscopic polyangiitis (MPA), the duration of follow-up, and the criteria used to define relapse. The following examples are illustrative:

In a community-based cohort in which 258 patients attained remission, 109 (42 percent) relapsed. Patients who were anti-PR3 seropositive were nearly twice as likely to relapse as compared with patients who were anti-MPO seropositive, suggesting that patients with PR3-ANCA are more likely to relapse than those with MPO-ANCA [1]. (See 'Risk factors for relapse' below.)

In a randomized trial comparing daily oral versus intravenous pulse cyclophosphamide for initial immunosuppressive therapy, the relapse rate at a median of 4.3 years was greater in the intravenous pulse group (40 versus 21 percent), suggesting that difference of therapy may affect relapse rates [4].

Among patients in the Rituximab in ANCA-Associated Vasculitis (RAVE) trial who attained a complete remission, relapse occurred in approximately 30 percent at 18 months [5]. The relapse rate was higher among those with PR3- as compared with MPO-ANCA, with GPA as compared with MPA, and with a prior history of relapsing disease (approximately one-half of all patients in the study).

Risk factors for relapse — The following have been identified as risk factors for relapse:

Seropositivity for PR3-ANCA

Prior history of relapsing disease

Involvement of the lung prior to remission

Involvement of the upper respiratory tract prior to remission

Persistence of elevated ANCA titers, particularly PR3-ANCA, and rising ANCA titers

The association of PR3-ANCA seropositivity, lung involvement, and upper respiratory tract involvement with the risk of relapse was evaluated in a community-based cohort study of 350 patients with newly diagnosed ANCA-associated vasculitis who were followed for a median of four years [1]. The rate of relapse was much higher in patients with all three of these risk factors compared with those who had none (73 percent at a median of 17 months versus 26 percent at a median of 62 months; the median time to relapse was 15 and 20 months, respectively). Other cohorts have confirmed a higher relapse rate in patients with lung involvement and in those with PR3-ANCA [5,9-13].

Relapses are also more common in patients with GPA, occurring in 25 to 80 percent of patients, than in those with MPA, in whom relapse has been reported in 8 percent at 18 months and 30 to 35 percent at four to seven years [1,5,14,15]. Why relapses are more common in GPA is not well understood. Proposed mechanisms include persistent granulomata [16] and persistent PR3 expression on the membrane of neutrophils [17].

In addition, chronic nasal carriage of Staphylococcus aureus is associated with relapse [18,19], although flares in such patients are not related to active staphylococcal infection [18]. The mechanisms by which S. aureus might act are not understood but may involve the staphylococcal toxic shock syndrome toxin-1 or changes in the nasal microbiome [19-21].

A history of prior flares greatly increases the risk of a subsequent flare compared with patients who have never flared. Such patients are often treated with more prolonged maintenance therapy.

Precipitants of relapse — Infections have been hypothesized to trigger some disease flares by inducing expression of the ANCA antigens (PR3 and MPO) on the surface of circulating neutrophils. This can, in the presence of ANCA, lead to neutrophil degranulation, the release of oxygen radicals, and vascular injury [16]. In addition, the interaction between the nasal microbiome and disease activity remains an area of active investigation [21]. (See "Clinical spectrum of antineutrophil cytoplasmic autoantibodies".)

Discontinuation of glucocorticoids may also be associated with a greater risk of flare [22]. However, the severity of such relapses is not clear, since reemergence of minor symptoms may often be easily treated with resumption of low-dose glucocorticoids. The role of low-dose glucocorticoids and duration of glucocorticoid dosing in the treatment of GPA and MPA are discussed elsewhere. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Glucocorticoid dosing and taper'.)

ESTABLISHING RELAPSING DISEASE

Monitoring for relapse — Regular, indefinite follow-up and monitoring is needed even for patients in remission for several years. Most relapses of granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) occur within the first 12 to 18 months after the cessation of immunosuppressive therapy [1,2,23,24] and may or may not affect the same organ as the initial presentation [2,3,25]; however, relapses can occur more than 10 years after the initial presentation or a prior relapse. The majority of relapses are discovered early and are limited in nature in patients who are closely followed and who have been educated about their disease and when to report new symptoms.

Patient self-monitoring — Early detection of relapse before severe tissue injury has occurred is an important component of monitoring since reinduction of remission can usually be attained more quickly. Patients should be evaluated promptly if they develop new or increasing hematuria or any other clinical manifestations.

The primary components of patient self-monitoring include:

Patient education about the clinical manifestations of relapse, which include active lung disease (eg, cough, dyspnea, wheezing, hemoptysis), neurologic disease (eg, muscle weakness, numbness, hearing loss, headache), skin disease (purpura, nodules, ulcerations), upper respiratory tract manifestations (eg, sinusitis, otitis media, nasal ulcers and crusting, and/or subglottic disease), or general symptoms (fevers, fatigue, arthritis/arthralgias, weight loss). (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis", section on 'Clinical manifestations'.)

The use of urine dipsticks every one to two months or more frequently at home in patients who had kidney involvement prior to achieving remission. Urine dipstick monitoring at home may also be of value in patients without a history of kidney disease since manifestations of a relapse may differ from those of the initial presentation.

If there is recurrent hematuria with or without proteinuria, the urine should be tested again in four to seven days (since transient hematuria can occur from other causes), and if the dipstick is still positive for heme and/or protein, the patient should be evaluated without delay.

A potential confounding issue can occur in premenopausal patients who often have blood in the urine due to contamination from menstrual bleeding. Thus, for premenopausal patients, testing should be performed at least a few days before or after their menstrual period. (See "Etiology and evaluation of hematuria in adults".)

It is important to recognize that persistent hematuria in patients with GPA or MPA is associated with an increased risk of relapse, but patients can have persistent hematuria for extended periods of time in the absence of active vasculitis, and not all recurrent hematuria is necessarily due to vasculitis [26]. Thus, screening for hematuria is advisable, but positive findings should lead to appropriate clinical evaluation and not an automatic decision to change or initiate immunosuppressive therapy.

Prompt communication with the treating clinician if any new signs or symptoms of disease occur.

Monitoring by the clinician — Assuming that the patient is self-monitoring and remains asymptomatic, and that screening urine dipstick testing does not reveal hematuria, we follow patients in the office at one- to three-month intervals during the first year after remission has been induced and then every three to four months thereafter. During each visit, we perform the following evaluation:

Assessment for signs or symptoms of active disease (see "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis", section on 'Clinical manifestations')

Measurement of serum creatinine, electrolytes, and aminotransferases

Complete blood count

Urinalysis with examination of the urinary sediment

Spot urine protein-to-creatinine ratio

The practice of measuring antineutrophil cytoplasmic autoantibody (ANCA) titers during follow-up visits varies among clinicians. This is largely because ANCA titers are not a reliable marker of disease activity. A reasonable approach is to closely follow patients with rising ANCA titers but not to alter their therapy unless there are clear clinical signs of active disease. Some experts measure an ANCA titer when a patient attains remission and then repeat the titer if a flare is suspected. Others monitor ANCA at regular intervals, and patients who have a rise in serum ANCA titers are monitored more frequently for early signs of clinical relapse. Some expert centers do not monitor ANCA titers at all. However, patients should not be treated for relapse based solely upon ANCA titers.

While some observational data suggest serum ANCA titers appear to parallel the course of vasculitis in some patients [13,27-30], other studies, including some larger cohort studies, have found that a rise in ANCA titer is not consistently predictive of a disease flare, with discordant ANCA titers and disease activity occurring in as many as 60 percent of patients [23,24,27,31-37]. The best data come from a meta-analysis of nine studies that examined the association of a rise in ANCA titer (or persistently positive ANCA titers) during remission with likelihood of relapse [38]. As a predictor of relapse, a rise in ANCA titer had a sensitivity of 56 percent and a specificity of 82 percent; a persistently positive titer had a sensitivity of 38 percent and a specificity of 78 percent. Thus, rising titers or persistently positive titers are not likely to be sufficiently reliable to guide therapeutic decisions.

If a patient was ANCA positive during a period of active disease, a persistently ANCA-negative status is consistent with, but not absolute proof of, remission. The same meta-analysis that examined the value of persistently positive ANCA titers discussed above also analyzed the value of persistently negative titers and found that this scenario should not lead to a change in therapy [38]. Similarly, another study reported that 37 of 100 patients with ANCA-associated vasculitis suffered flares during the period of observation [27]. Of these, three (8 percent) were ANCA negative at the time of relapse.

Diagnosis of relapse — A diagnosis of relapsing disease is made if there is recurrence of signs or symptoms of active vasculitis in any organ system [1,2]. In some cases, relapse can be diagnosed clinically if the patient has systemic symptoms and the same organ involvement as the initial presentation [14,25]. In other patients, tissue biopsy may be required to verify recurrent vasculitis rather than other factors such as infection.

It is important to recognize that, if any presumed disease-related manifestation of GPA or MPA does not respond to reinstitution or escalation of immunosuppressive therapy, the cause of the manifestations should be reevaluated, possibly with a tissue biopsy.

Disease flares typically involve the same organs that were affected at the time of initial presentation [3], although new manifestations of disease are not uncommon [25]. Thus, diagnosing relapse of GPA or MPA is not always straightforward, and alternative diagnoses must be excluded:

Differentiating disease activity from damage – It is important for clinicians and patients to differentiate disease-associated "activity" from disease-associated "damage" in GPA and MPA. Damage is the result of prior activity and is generally considered permanent and not reversible with immunosuppression. Examples of damage that can mimic active disease in GPA and MPA are chronic rhinosinusitis, a scarred pulmonary nodule, or chronic proteinuria or some cases of progressive kidney disease. Tissue biopsy may sometimes be required to determine if a manifestation is due to active disease, prior damage, or another disease process.

Relapsing upper respiratory tract disease versus infection – Patients treated with glucocorticoids, cyclophosphamide, rituximab, and other therapies for ANCA-associated vasculitis remain immunosuppressed for significant periods following the cessation of these medications, thereby increasing the risk for infection. Infections are particularly important to exclude in patients with respiratory tract disease. It may be difficult, for example, to distinguish between active disease and infection (and some patients have both) in patients who develop manifestations limited to the upper respiratory tract, such as nasal ulcers and crusting. Endoscopic examination by an experienced ear, nose, and throat clinician may establish a definitive diagnosis but often shows only nonspecific acute and chronic inflammation. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Respiratory tract involvement".)

Relapsing glomerulonephritis versus nonimmunologic progression of chronic kidney disease – Late progression of kidney disease, as defined by a rise in serum creatinine, is common. However, such progression does not necessarily imply active renal vasculitis, since two nonimmunologic mechanisms may be important in the absence of active disease:

Glomerular ischemia and subsequent glomerulosclerosis resulting from progressive narrowing of the vascular lumens during the healing phase of the vasculitis

Secondary hemodynamic and metabolic factors induced by nephron loss, such as intraglomerular hypertension in the remaining functioning glomeruli (see "Secondary factors and progression of chronic kidney disease")

Patients with nonimmunologic progression have slowly progressive disease characterized by gradual increases in the serum creatinine concentration and proteinuria, which is usually subnephrotic but can reach the nephrotic range. Both hypoalbuminemia and edema are unusual, even when protein excretion exceeds 3 to 4 g/day.

Patients with nonimmunologic progression should not have an active urinary sediment (eg, red cells and cellular casts) or other signs of disease activity; such findings may indicate relapsing ANCA-associated glomerulonephritis, although persistent hematuria can be present and not be associated with active vasculitis [26]. However, some renal "relapses," characterized by acutely worsening kidney function and hematuria, are not due to reactivation of GPA or MPA but rather to a distinct second form of glomerulonephritis, such as immunoglobulin A (IgA) nephropathy [39-41].

Lower respiratory tract disease versus malignancy or infection – The appearance of a new pulmonary nodule may be due to recurrent vasculitis, especially if there is contemporaneous appearance of other disease-related manifestations. However, clinicians should always be concerned that the nodule may be due to infection or malignancy.

MANAGEMENT — The goal of managing relapsing disease is reinduction and maintenance of complete remission, which is the absence of any signs of active disease. The definition of complete remission in patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) is discussed in more detail elsewhere. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Definitions of response' and 'Monitoring for relapse' above.)

Organ- or life-threatening relapse — Severe relapses are usually treated with reinstitution of induction therapy followed by maintenance therapy.

Reinduction therapy — For patients who relapse after successfully achieving remission with a cyclophosphamide-based or a rituximab-based regimen, we suggest readministering induction therapy with rituximab rather than cyclophosphamide. This regimen is discussed in more detail elsewhere. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Rituximab-based regimen'.)

Data from randomized trials suggest that rituximab is at least as effective for treating disease relapses and may also be associated with less cumulative toxicity compared with cyclophosphamide. Rituximab is also the preferred agent in women who wish to preserve their potential to conceive a child.

Cyclophosphamide is a reasonable alternative for patients whose relapse is characterized by advanced and progressive crescentic glomerulonephritis or severe pulmonary disease with massive hemorrhage. However, there are no trial data to guide the choice between cyclophosphamide and rituximab in such patients. In addition, some experts treat such patients with both cyclophosphamide and rituximab (eg, four weekly infusions of rituximab plus two intravenous pulses of cyclophosphamide) [42-44].

Most trials on remission induction in GPA and MPA do not distinguish between those patients treated for a new or relapsing presentation of their disease, and the evidence for new or relapsing disease comes from the same studies. One of the larger trials to distinguish patients with relapsing disease randomly assigned 101 patients with relapsing GPA or MPA to either rituximab or cyclophosphamide [5,45]. The majority of patients had received cyclophosphamide for initial induction therapy or prior relapse (74 percent of the cyclophosphamide group and 82 percent of the rituximab group). The rate of remission induction in these patients with relapsing disease at six months was higher with rituximab (67 versus 42 percent; odds ratio 1.40, 95% CI 1.03-1.91) [45]. At 18 months, however, rituximab and cyclophosphamide produced similar remission rates in these patients, and there were no differences in the number of adverse events [5]. In another prospective study of 188 patients with relapsing GPA or MPA who were treated with rituximab plus glucocorticoids, 171 (90 percent) achieved remission by four months [46].

If patients cannot tolerate cyclophosphamide or rituximab, we attempt to achieve remission with mycophenolate mofetil (MMF). (See 'Patients who have multiple relapses' below.)

Maintenance therapy after reinduction — Relapse can occur while patients are being treated with maintenance therapy or after maintenance therapy has been discontinued [1]. The choice of drug and the duration of maintenance therapy after reinduction of remission are determined in part by the timing of relapse:

Relapse during maintenance therapy – For patients who exhibit a severe relapse while on the original course of maintenance therapy, we suggest using a different drug for maintenance therapy after reinduction of remission. In such patients, the duration of maintenance therapy may be similar to that suggested for the original course of maintenance therapy (usually 12 to 18 months, but this can vary with the estimated likelihood of relapse).

The usual drugs for maintenance therapy are rituximab, azathioprine, and in patients with an estimated glomerular filtration rate (eGFR) above 60 mL/min/1.73 m2 and no renal vasculitis, methotrexate. MMF is an alternative agent for patients who do not respond to, cannot tolerate, or have contraindications to these drugs.

(See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Dosing of rituximab'.)

(See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Dosing of azathioprine'.)

(See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Dosing of methotrexate'.)

(See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Dosing of mycophenolate'.)

Glucocorticoid therapy is part of the maintenance immunosuppression regimen. The median duration of glucocorticoid therapy after the first induction of remission is less than six to eight months. Some experts recommend long-term, low-dose maintenance therapy in patients who have had multiple relapses. (See 'Patients who have multiple relapses' below.)

Relapse after maintenance therapy – For patients who relapse after the discontinuation of the original course of maintenance therapy, we suggest using the same drug for maintenance therapy after remission has been reinduced. However, the duration should be longer than the initial course (eg, 12 months or longer if the original course of maintenance therapy was 6 to 12 months). For patients who have frequent relapses, lifelong maintenance therapy may be appropriate, similar to that in recipients of organ transplants. (See 'Patients who have multiple relapses' below.)

The approach to maintenance therapy is extrapolated from data in patients receiving maintenance therapy for new-onset disease and our clinical experience. A discussion of the relevant data is presented in more detail elsewhere. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Choice of maintenance therapy'.)

There is some evidence that trimethoprim-sulfamethoxazole is an effective maintenance drug for the prevention of relapses limited to the upper respiratory tract. However, toxicity is an issue, since in the randomized trial suggesting benefit compared with placebo in this setting, 20 percent of patients treated with trimethoprim-sulfamethoxazole maintenance discontinued therapy due to side effects, most of which are minor (anorexia, nausea, rash) [47]. In addition, high-dose trimethoprim-sulfamethoxazole cannot be used in patients receiving methotrexate and should be used cautiously in patients with advanced chronic kidney disease.

Non-organ- and non-life-threatening relapse — The approach to the treatment of a mild, non-organ-threatening relapse varies, depending upon whether the relapse occurs while the patient was still receiving maintenance therapy (see "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Non-organ- and non-life-threatening disease'). A non-organ-threatening relapse includes patients with recurrent dysmorphic hematuria who do not have in increase in serum creatinine:

Relapse during maintenance therapy – For patients who develop a non-organ- and non-life-threatening relapse while still receiving maintenance therapy, we suggest increasing the dose of glucocorticoids and, when relevant, increasing the dose of the immunosuppressive agent used for maintenance therapy. In a patient receiving tapering doses of prednisone and methotrexate, for example, the prednisone dose can temporarily be increased back to 60 mg/day (although lower starting doses may also be adequate), and the methotrexate dose can be increased back to 25 mg once weekly.

When the clinician is unsure that a relapse is mild, a tissue biopsy should be obtained to confirm that reinduction therapy is not needed.

Relapse after maintenance therapy – For patients who develop a non-organ- and non-life-threatening relapse after maintenance therapy has been discontinued, we suggest reinstitution of the prior maintenance therapy in combination with a short course of glucocorticoids. However, maintenance therapy should be continued for a longer period of time than was given prior to the relapse (eg, 12 to 18 months if the original course of maintenance therapy was 6 to 12 months).

There are limited data to guide the optimal therapy of patients with a non-organ- and non-life-threatening disease relapse, and our approach is largely based on clinical experience and observational data. One observational study of 44 patients with their first non-severe relapse found that treatment with a temporary increase in the glucocorticoid dose restored disease remission in most patients (80 percent), but recurrent relapses occurred in the majority of patients by approximately 12 months [48].

Specific clinical scenarios

Patients who have multiple relapses — Patients who have multiple relapses despite treatment with cyclophosphamide and/or rituximab, or who cannot tolerate these therapies, can be treated with MMF. Azathioprine and methotrexate (in patients with an eGFR above 60 mL/min/1.73 m2 and no renal vasculitis) are reasonable alternatives and may be preferred based on other patient-specific factors. Dosing of these agents is discussed in detail elsewhere:

(See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Dosing of mycophenolate'.)

(See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Dosing of methotrexate'.)

(See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Dosing of azathioprine'.)

The potential efficacy of MMF was illustrated in a series of 32 patients with relapsing antineutrophil cytoplasmic autoantibody (ANCA)-positive vasculitis who could not be treated with cyclophosphamide [49]. Complete and partial remissions were achieved in 78 and 19 percent, respectively. Relapse during follow-up occurred in 19 of 25 patients (76 percent) who attained complete remission and in all six who attained partial remission. Patients who had previously been treated successfully with cyclophosphamide had a better response than those who had not (complete remission was 84 versus 50 percent; relapse was 50 versus 100 percent). The median time to relapse was similar to the previous median time to relapse (16 versus 17 months), and all but two patients were still taking MMF at the time of relapse. The other two patients relapsed after MMF had been discontinued (at 16 and 41 months) and were successfully treated with a second course of MMF and prednisone.

Relapses limited to the upper airway — It may be difficult to distinguish between active disease and infection (and some patients have both) when the manifestations of possible relapse are limited to the upper respiratory tract, particularly with nasal disease, where ulceration and crusting over granulation tissue can result from both vasculitis and infection. (See 'Diagnosis of relapse' above.)

The therapeutic approach varies with the presumed diagnosis:

When infection is thought to be the predominant problem, oral antibiotics are often required (eg, trimethoprim-sulfamethoxazole). However, some prefer topical mupirocin ointment for less severe infections. The ointment can be applied directly inside of each nostril or mixed into a saline irrigation solution. Topical antibiotics have the advantage of permitting a long course of therapy without the systemic side effects that may be seen with oral antibiotics. (See "Uncomplicated acute sinusitis and rhinosinusitis in adults: Treatment", section on 'Antibiotics'.)

When active vasculitis is thought to be the predominant problem and the relapse is limited to the upper respiratory tract, we increase the prednisone dose for at least four weeks and continue or increase the dose of the drug used for maintenance immunosuppression.

When possible, we avoid treating for infection and active vasculitis simultaneously since this leads to diagnostic confusion and possibly to overexposure to medication.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Glomerular disease in adults".)

SUMMARY AND RECOMMENDATIONS

Definition of relapse – In patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA), relapsing disease refers to recurrence of signs or symptoms of active vasculitis in any organ system after remission is achieved, in the absence of another cause. (See 'Definition of relapse' above.)

Monitoring for relapse – All patients with GPA or MPA should have regular, indefinite follow-up and monitoring. Patient self-monitoring may include the use of urine dipsticks every one to two months or more frequently at home in patients who had kidney involvement prior to achieving remission. Routine monitoring by the clinician includes assessment for signs and symptoms of active disease; measurement of serum creatinine, electrolytes, and aminotransferases; complete blood count; urinalysis with examination of the urinary sediment; and spot urine protein-to-creatinine ratio. (See 'Monitoring for relapse' above.)

Diagnosis of relapse – A diagnosis of relapsing disease is made if there is recurrence of signs or symptoms of active vasculitis in any organ system. In some cases, relapse can be diagnosed clinically if the patient has systemic symptoms and the same organ involvement as the initial presentation. In other patients, tissue biopsy is required to verify recurrent vasculitis rather than other factors such as infection. Diagnosing relapse of GPA or MPA is not always straightforward, and alternative diagnoses must be excluded. (See 'Diagnosis of relapse' above.)

Management of relapse

Organ- or life-threatening relapse – Patients with organ- or life-threatening relapse are usually treated with reinstitution of induction therapy followed by maintenance therapy:

-For patients who relapse after successfully achieving remission with a cyclophosphamide-based or a rituximab-based regimen, we suggest readministering induction therapy with rituximab rather than cyclophosphamide (Grade 2B). (See 'Reinduction therapy' above.)

-For patients who exhibit a severe relapse while on the original course of maintenance therapy, we suggest using a different drug for maintenance therapy after reinduction of remission rather than the same drug (Grade 2C). In such patients, the duration of maintenance therapy may be similar to that suggested for the original course of maintenance therapy (usually 12 to 18 months, but this can vary with the estimated likelihood of relapse). The usual drugs for maintenance therapy are rituximab, azathioprine, mycophenolate mofetil (MMF), and in patients with an estimated glomerular filtration rate (eGFR) above 60 mL/min/1.73 m2 and no renal vasculitis, methotrexate.

-For patients who relapse after the discontinuation of the original course of maintenance therapy, we suggest using the same drug for maintenance therapy after remission has been reinduced (Grade 2C). The duration of maintenance therapy should be longer than the initial course (eg, 12 months or longer if the original course of maintenance therapy was 6 to 12 months). For patients who have frequent relapses, lifelong maintenance therapy may be appropriate, similar to that in recipients of organ transplants. (See 'Maintenance therapy after reinduction' above and "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Choice of maintenance therapy'.)

Non-organ- and non-life-threatening relapse – Our approach to the treatment of a mild, non-organ-threatening relapse varies, depending upon whether the relapse occurred while the patient was still receiving maintenance therapy:

-For patients who develop a non-organ- and non-life-threatening relapse while still receiving maintenance therapy, we suggest increasing the dose of glucocorticoids and, when relevant, increasing the dose of the immunosuppressive agent used for maintenance therapy rather than switching to another therapy (Grade 2C).

-For patients who develop a non-organ- and non-life-threatening relapse after maintenance therapy has been discontinued, we suggest reinstitution of the prior maintenance therapy in combination with a short course of glucocorticoids (Grade 2C). Maintenance therapy should be continued for a longer period of time than was given prior to the relapse (eg, 12 to 18 months if the original course of maintenance therapy was 6 to 12 months). (See 'Non-organ- and non-life-threatening relapse' above.)

Multiple relapses – Patients who have multiple relapses despite treatment with cyclophosphamide and/or rituximab, or who cannot tolerate these therapies, can be treated with MMF. Azathioprine and methotrexate are reasonable alternatives and may be preferred depending on patient-specific factors. (See 'Patients who have multiple relapses' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges John H Stone, MD, MPH, who contributed to earlier versions of this topic review.

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Topic 3040 Version 37.0

References

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