Version May 2024
INTRODUCTION — Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are related systemic 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 and outcomes, including different patterns of pulmonary involvement and relapse rates. These entities are closely related to renal-limited necrotizing and pauci-immune necrotizing and crescentic glomerulonephritis.
Treatment-resistant GPA or MPA refers to active disease that is organ- or life-threatening despite optimal initial immunosuppressive therapy with glucocorticoids plus either cyclophosphamide or rituximab.
The management of resistant GPA or MPA will be reviewed here. Clinical manifestations and diagnosis, initial therapy, and the management of relapsing disease are discussed separately:
●(See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy".)
●(See "Granulomatosis with polyangiitis and microscopic polyangiitis: Management of relapsing disease".)
DEFINITION OF RESISTANT DISEASE — Treatment-resistant granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) is diagnosed if one or both of the following are present despite optimal immunosuppressive therapy for an adequate period (usually six months, or three months in a patient who is dialysis dependent) [1-3]:
●A progressive decline in kidney function (ie, increase in serum creatinine) plus persistence of an active urine sediment (ie, dysmorphic hematuria with or without red cell casts) that is judged to be due to active vasculitis or a kidney biopsy showing active glomerulonephritis
●Persistence or new appearance of extrarenal manifestations of active vasculitis (see "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis")
INCIDENCE AND RISK FACTORS
●Incidence – In five randomized clinical trials in antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, approximately 60 to 90 percent of enrolled patients achieved disease remission within six months of treatment, and 10 to 40 percent were resistant [4-10]. Rates of resistant disease observed in clinical practice are similarly varied [2,11].
It is important to recognize that some cases may be mislabeled as resistant disease, such as patients with recurrence of non-severe manifestations after tapering of glucocorticoids and for whom low-dose glucocorticoids resolved active disease.
●Risk factors – Older age appears to be a predictor of disease resistance in patients with ANCA-associated vasculitis [2,11]. A community-based cohort study of 350 patients who received a new diagnosis of ANCA-associated vasculitis also found that in addition to older age, other predictors of resistant disease included severe kidney disease at presentation, female sex, African-American race, and the presence of myeloperoxidase (MPO)-ANCA [2]. However, not all of these factors have been confirmed in other studies; these discrepancies in predictors may reflect disparities in access to care. In addition, these studies reported on cohorts treated before the more widespread use of rituximab for induction and/or maintenance of remission of ANCA-associated vasculitis.
MANAGEMENT — The first step in the management of the patient suspected of being treatment resistant is to exclude alternative diagnoses, thereby ensuring that the clinical abnormalities are not due to drug toxicity, nonadherence, an inadequate regimen, consequences of previous organ damage, infection, and/or pathogenic processes other than ongoing inflammation. (See 'Exclusion of alternative diagnoses' below.)
Our general approach to patients with treatment-resistant granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) depends upon which immunosuppressive regimen was attempted for initial induction therapy and the extent and severity of the residual active disease. Our approach, which is primarily based upon limited observational data and our clinical experience, is presented below.
Exclusion of alternative diagnoses — Some patients are incorrectly considered to be treatment resistant. Tissue biopsy may be necessary in some patients to differentiate recurrent vasculitis from infection, damage due to scarring from previously active disease, and other conditions. However, biopsy is not necessary if there is clear evidence of persistent or new active inflammation, such as an active urinary sediment and rising creatinine.
The most important alternative diagnoses of treatment-resistant disease are:
●Permanent tissue damage due to previous inflammatory injury – Failing to distinguish correctly between active disease and signs of permanent damage induced by prior inflammation can result in an incorrect diagnosis of treatment resistance. Differentiating active disease from damage is often quite difficult but is a crucial aspect of management of patients with GPA and MPA. As an example, an elevated serum creatinine (with or without proteinuria of any degree) can reflect chronic injury with scarring and is not considered a sign of active kidney disease in the absence of dysmorphic (glomerular) hematuria (picture 1A-B). (See "Etiology and evaluation of hematuria in adults", section on 'Red cell morphology'.)
Similarly, chronic sinonasal crusting and congestion may be due to permanent damage to the upper respiratory mucosa and architecture and not necessarily active inflammatory disease. Other examples of damage mistaken for resistant disease include the persistence of some part of a lung nodule that is a scar and not active inflammation, or persistent neuropathy, which can take months to years to improve, may lead to waxing and waning symptoms, and in some cases may not completely recover.
●Nonadherence to therapy – In such patients, persistently active vasculitis is present, but it is due to nonadherence to therapy rather than resistance to therapy. The risk of making a mistaken diagnosis of treatment-resistant disease in nonadherent patients is lower when intravenous therapies are used (eg, intravenous rather than oral cyclophosphamide, rituximab). However, nonadherence to glucocorticoids, even at low doses, is common.
●Inadequate initial immunosuppression – Insufficient doses of cyclophosphamide or rituximab, or early discontinuation of these therapies (eg, in the setting of active infection), can result in persistently active vasculitis.
●Medication toxicity – Toxicity related to immunosuppressive therapy may mimic active vasculitis. As examples, cyclophosphamide may cause bladder toxicity and normomorphic hematuria, methotrexate can cause oral ulcers, and azathioprine is associated with hypersensitivity reactions.
●Infection – Patients with GPA and MPA treated with glucocorticoids and other immunosuppressive therapies are at substantially increased risk for infection, and it may be difficult to distinguish between active disease and infection.
This distinction may be especially challenging in patients with upper respiratory tract disease, and some patients may have both active vasculitis and infection. Endoscopic examination by an experienced ear, nose, and throat clinician may establish a definitive diagnosis but often shows only nonspecific acute and chronic inflammation.
Infection may also mimic active disease in the lung (nodules, infiltrates), skin (rash, nodules), brain (meningitis), and elsewhere. Clinicians need to have a high index of suspicion for infection, including unusual and opportunistic organisms.
●Incorrect original diagnosis – It is always reasonable to reconsider the accuracy of the original diagnosis of either GPA or MPA when encountering patients with seemingly treatment-resistant disease. Other diseases, including some malignant conditions and even some infections, may partially respond to immunosuppressive therapy.
Reconsidering the original diagnosis is especially important when the treating clinician is not the one who made the original diagnosis. It may be helpful in such cases to review and confirm the tissue diagnosis and ensure that antineutrophil cytoplasmic autoantibody (ANCA) testing was conducted and interpreted correctly. If not obtained initially, clinicians should have a low threshold to seek a tissue diagnosis or other evidence to distinguish between vasculitis and nonvasculitic conditions.
●Unresponsive disease manifestations – There are at least two manifestations of GPA and MPA that may be relatively unresponsive to immunosuppressive therapies or considered unresponsive to therapy but that are not considered resistant disease:
•Orbital pseudotumor (retrobulbar inflammatory masses) – Even after successful treatment for orbital pseudotumor, some patients may have residual tissue that, given the tight space behind the orbit, may continue to cause unwanted physical changes with functional consequences.
•Subglottic stenosis – If not responsive to systemic therapy (such as rituximab), subglottic stenosis may reflect scar rather than ongoing inflammation; such cases may respond best to local therapies such as triamcinolone injections and dilatation procedures (avoiding laser therapies). (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Management of respiratory tract and upper airway involvement'.)
Approach based on prior therapy
Patients resistant to induction with cyclophosphamide — For patients whose disease is resistant to initial induction therapy with cyclophosphamide, we suggest treatment with rituximab.
The rituximab dosing is the same as is used for induction immunosuppression therapy. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Rituximab-based regimen'.)
Two randomized trials suggest that rituximab is as effective as cyclophosphamide in inducing remission among patients with newly diagnosed or relapsing GPA or MPA [4,5,12]. However, these trials did not include patients with resistant disease. Limited observational data suggest that rituximab is beneficial in patients with persistent disease despite treatment with cyclophosphamide [13-18]. As an example, an observational study including 16 patients with ANCA-associated vasculitis refractory to or intolerant of cyclophosphamide found that after treatment with rituximab and glucocorticoids, 12 patients achieved complete remission, 3 patients achieved partial remission, and 1 patient died during follow-up [14].
Benefit has also been noted in patients with ophthalmic manifestations (eg, scleritis and/or granulomas causing optic nerve compromise) that were resistant to cyclophosphamide therapy [19,20].
Patients resistant to induction with rituximab — For patients whose disease is resistant to initial induction therapy with rituximab, we suggest treatment with cyclophosphamide. Although there are limited data to support this approach [21], it is our experience that some patients who are refractory to initial treatment with rituximab may achieve remission with cyclophosphamide induction. Before administering cyclophosphamide, we check a CD19 count to document B cell depletion with rituximab.
The dose of cyclophosphamide is the same as that used for induction. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Cyclophosphamide-based regimen'.)
Patients resistant to induction with cyclophosphamide and rituximab — For patients who have been treated with both rituximab and cyclophosphamide for at least three to six months but continue to have active disease, we suggest treatment with mycophenolate mofetil (MMF) rather than other therapies. Concurrent therapy with both cyclophosphamide and rituximab is a reasonable alternative in patients with life-threatening illness. However, this combination clearly raises serious concerns for risk of infection, and its use for resistant disease has not been studied in clinical trials. Another option for such patients with refractory disease may include obinutuzumab (another anti-CD20 antibody), which was used effectively in a small case series of three patients who had a hypersensitivity to rituximab [22]. These approaches are based upon our clinical experience given the lack of high-quality supportive evidence.
The target dose of MMF is generally between 1.5 and 3 grams daily, in divided doses. Another regimen that may be used is derived from the International Mycophenolate Mofetil Protocol to Reduce Outbreaks of Vasculitides (IMPROVE) study, in which patients start with MMF 2000 mg per day followed by a reduction to 1500 and 1000 mg per day after 12 and 18 months, respectively [23]. However, our approach is to aim for the maximum daily dose of MMF (up to 3 grams daily) that a patient is able to tolerate. Of note, the IMPROVE study, a study of maintenance therapy, was not designed to evaluate the use of MMF in patients with resistant disease.
A number of small observational studies have evaluated MMF in patients whose disease was resistant to, or who could not tolerate, cyclophosphamide [24-26]; however, all of these studies were performed before the more routine use of rituximab. As an example, a small study of non-life-threatening disease included four patients who failed to improve after at least six months of cyclophosphamide-based induction therapy and two patients who had been treated with azathioprine because cyclophosphamide could not be given [24]. After cyclophosphamide was discontinued, the glucocorticoid dose was maintained, and the patients were started on MMF (500 mg twice daily, which was increased by 250 mg twice daily every two weeks to a maximum dose of 1500 mg twice daily in patients who showed no evidence of response to 1000 mg twice daily). Six other patients had frequently relapsing disease and were included in the analysis. Among the 10 patients who completed the study (target dose given for 24 weeks), improvement in disease activity occurred in all patients, and six had at least a transient complete remission.
The efficacy of mycophenolate in patients who are resistant to rituximab therapy has not been described.
Therapies of unproven efficacy — A variety of unproven therapies can be attempted in patients resistant to cyclophosphamide, rituximab, and MMF:
●Anti-tumor necrosis factor (TNF)-alpha therapy – Insights into the role of T helper (Th)1 cytokines in the pathogenesis of GPA have led to trials involving therapy with antagonists to TNF-alpha and inhibitors of monocyte function, such as interleukin 10 [27]. The rationale for such therapy is discussed separately. (See "Pathogenesis of antineutrophil cytoplasmic autoantibody-associated vasculitis", section on 'Role of T cells'.)
The best available data on the possible efficacy of these agents for ANCA-associated vasculitis come from a randomized trial of 180 patients with GPA (Wegener's Granulomatosis Etanercept Trial [WGET]) that found that etanercept provided no additive benefit to treatment with methotrexate in maintaining remission. None of the patients enrolled in the WGET trial had resistant disease, and patients with MPA were not included.
In an open-label study, infliximab was added to standard immunosuppressive therapy in 16 patients with acute ANCA-associated vasculitis at first presentation or relapse and in 16 with persistent disease despite multiple immunosuppressive regimens [28]. Fourteen patients in each group (88 percent) achieved remission within a mean of 6.4 weeks, but serious infections and death were reported in seven and two patients, respectively. In addition, five patients (three with persistent disease) had a relapse at a mean of 27 weeks. (See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects".)
●Abatacept (anti-CTLA-4 Ig) – In a series of 20 patients with established GPA and active, non-organ-threatening disease, abatacept (a drug that inhibits T cell activation) demonstrated promise as a treatment for relapsing GPA [29]. These patients who received abatacept were also permitted to use glucocorticoids for the initial two months and to continue treatment with azathioprine, MMF, or methotrexate. Sixteen patients (80 percent) achieved remission, and 11 of 15 patients treated with prednisone were able to stop glucocorticoid therapy. Abatacept was well tolerated. A randomized, placebo-controlled trial evaluating the use of abatacept for the treatment of relapsing, non-severe GPA is in progress (NCT02108860).
●Intravenous immune globulin – Intravenous immune globulin has been studied in only a limited fashion in ANCA-associated vasculitis, and none of the available studies provide clear answers regarding potential efficacy [30-33]. The best data come from a randomized, placebo-controlled trial of 34 patients with ANCA-associated systemic vasculitis and persistent disease activity despite previous immunosuppressive therapy [33]. Improvement occurred in 6 of 13 who had lung involvement, but no information was provided regarding the presence or response of kidney manifestations of the disease. A review of the mechanisms of action and potential side effects associated with this modality can be found elsewhere. (See "Overview of intravenous immune globulin (IVIG) therapy".)
●Alemtuzumab – Alemtuzumab is a humanized anti-CD52 monoclonal antibody that depletes lymphocytes. In a report from a single-center cohort of 71 patients with resistant or relapsing GPA and MPA, 60 patients (85 percent) obtained remission with alemtuzumab, although 43 (72 percent) of these patients subsequently relapsed [34]. The rate of adverse events and death was high, including from infection and autoimmune thyroid disease. While alemtuzumab may be an option for patients with severe refractory GPA or MPA, use of this drug is associated with substantial potential toxicity and requires careful monitoring by clinicians experienced in the use of this agent. Alemtuzumab when used to treat multiple sclerosis has been associated with anti-glomerular basement membrane (GBM) disease, which may cause confusion if this occurs in patients with GPA and MPA.
●Stem cell transplantation – High-dose myeloablative chemotherapy with stem cell transplantation has been utilized for the treatment of refractory severe vasculitis. There are case reports of successful treatment of vasculitis with kidney involvement, including a few patients with GPA [35]. Much more study is required to determine whether there is a role for high-dose chemotherapy with stem cell reconstitution in the management of resistant ANCA-associated systemic vasculitis.
PROGNOSIS — Patients with treatment-resistant granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) with kidney involvement have a much worse kidney prognosis than patients who respond. As an example, the rate of progression to end-stage kidney disease (ESKD) according to the response to cyclophosphamide induction therapy was evaluated in the above series of 350 patients with GPA, MPA, or renal-limited disease from the Glomerular Disease Collaborative Network (GDCN) [2]. Of the 76 patients who failed to respond to induction therapy within one month, 60 patients (79 percent) developed ESKD at a median of two months after the initiation of therapy, and 12 patients developed ESKD at a median of one month after initiation of therapy. The rate of ESKD was much lower in patients who attained remission with initial immunosuppressive therapy (19 percent at 9 years in patients who did not relapse and 28 percent at 5.5 years in those who responded initially but then relapsed).
Patient and kidney outcomes in patients with GPA or MPA are discussed separately. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Prognosis and other outcomes'.)
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
●Overview – Treatment-resistant granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) refers to active disease that is organ- or life-threatening despite optimal initial immunosuppressive therapy with glucocorticoids plus either cyclophosphamide or rituximab. (See 'Introduction' above.)
●Incidence and risk factors – Rates of resistant GPA or MPA vary widely, with estimates ranging from 10 to 40 percent. Risk factors for resistant disease include older age, severe kidney disease at presentation, female sex, African-American race, and the presence of myeloperoxidase (MPO)-antineutrophil cytoplasmic autoantibodies (ANCA). (See 'Incidence and risk factors' above.)
●Exclusion of alternative diagnoses – Some patients are incorrectly considered to be treatment resistant. Alternative diagnoses should be excluded before the diagnosis of treatment resistance is established. Alternative diagnoses include permanent tissue damage due to previous inflammatory injury, nonadherence to therapy, inadequate initial immunosuppression, medication toxicity, and infection. (See 'Exclusion of alternative diagnoses' above.)
●Definition of resistant disease – Treatment-resistant GPA or MPA is diagnosed if one or both of the following are present despite optimal immunosuppressive therapy for an adequate period (usually six months, or three months in a patient who is dialysis dependent):
•A progressive decline in kidney function (ie, increase in serum creatinine) plus persistence of an active urine sediment (ie, dysmorphic hematuria with or without red cell casts) that is judged to be due to active vasculitis or a kidney biopsy that shows active glomerulonephritis.
•Persistence or new appearance of extrarenal manifestations of active vasculitis. (See 'Definition of resistant disease' above.)
●Management – Our general approach to patients with treatment-resistant GPA or MPA depends upon which immunosuppressive regimen was attempted for initial induction therapy and the extent and severity of the residual active disease:
•For patients whose disease is resistant to initial induction therapy with cyclophosphamide, we suggest treatment with rituximab (Grade 2C). (See 'Patients resistant to induction with cyclophosphamide' above.)
•For patients whose disease is resistant to initial induction therapy with rituximab, we suggest treatment with cyclophosphamide (Grade 2C). (See 'Patients resistant to induction with rituximab' above.)
•For patients who have been treated with both rituximab and cyclophosphamide for at least three to six months but continue to have active disease, we treat with mycophenolate mofetil (MMF). Concurrent therapy with both cyclophosphamide and rituximab is a reasonable alternative in patients with life-threatening illness. (See 'Patients resistant to induction with cyclophosphamide and rituximab' above.)
●Prognosis – Patients with treatment-resistant GPA or MPA have a much worse kidney prognosis than patients who respond. (See 'Prognosis' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges John H Stone, MD, who contributed to earlier versions of this topic review.
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