Risk Factors for Treatment Failures in Antineutrophil Cytoplasmic Antibody– Associated Small-Vessel VasculitisVijay R. Karia, MD, and Luis R. Espinoza, MD

Corresponding authorLuis R. Espinoza, MD

Department of Internal Medicine, Section of Rheumatology,

Louisiana State University Health Sciences Center at New Orleans,

1542 Tulane Avenue, New Orleans, LA 70112, USA.

E-mail: lespin1@lsuhsc.edu

Current Rheumatology Reports 2009, 11:416–421Current Medicine Group LLC ISSN 1523-3774

Copyright © 2009 by Current Medicine Group LLC

In the past several years, signifi cant progress has occurred in the therapeutic management of antineu-trophil cytoplasmic antibody–associated vasculitis. This has resulted in improved survival rates for all members of this group of infl ammatory vascular disorders. However, the rate of treatment failure or resistance and relapse has remained relatively constant despite therapeutic advances. This article reviews risk factors associated with these failures, with hopes that better understanding may lead to improved therapeutic responses and less therapy-related toxicity.

IntroductionThe mortality rate in patients with antineutrophil cyto-plasmic antibody (ANCA)–associated vasculitis (AAV) has experienced signifi cant improvement in the past 10 to 20 years. Survival rates have been reported as high as 75% for Wegener’s granulomatosis (WG), 45% to 75% for microscopic polyangiitis (MPA), and 68% to 100% for Churg-Strauss syndrome at 5 years [1]. In the late 1960s, the introduction of combination therapy with glu-cocorticoids and cyclophosphamide (CYC) for the therapy of systemic vasculitis had an immediate major impact on morbidity and mortality. During the 1960s, treatment with glucocorticoids appeared to increase mean survival to 12.5 months, but the eventual outcome in nearly all patients was death [2]. This dismal outcome began to change in the 1970s when the possibility of disease remis-sion became reality with the consistent use of CYC in patients with WG [3]. WG, together with MPA and Churg-Strauss syndrome, constitute AAV and are characterized

by the presence of infl ammatory changes in small blood vessels, similar clinical and serologic (ANCA positivity) characteristics, and similar therapeutic responses.

Throughout the history of AAV, treatment failure or relapse has always been clinically relevant even as treat-ment has evolved. Conventional immunosuppressive therapy is associated with high rates of relapse and toxic-ity. Research into risk factors for these failures has been recorded from the beginning, but these have not been fully characterized.

Severe WG requires urgent treatment with CYC and high doses of glucocorticoids. A longitudinal study from the National Institutes of Health (NIH) used a combi-nation of CYC (2 mg/kg daily, with doses reduced for patients with renal dysfunction) and prednisone (1 mg/kg daily, tapered for 6 mo–1 y) [4]. This regimen converted a disease that once was nearly always fatal into one that responded to treatment in more than 90% of cases. In fact, 75% of patients treated in this fashion entered remis-sion. The Fauci-Wolff regimen called for the continuation of daily CYC for one full year after the achievement of remission [3]. Although this regimen was effective in controlling WG, patients suffered substantial treatment-related morbidity including sepsis and myelosuppression.

Clinical practice regarding the use of either daily or intermittent (eg, monthly intravenous) CYC varies from center to center. In WG, some data suggest that daily CYC is more likely to result in durable remissions, but daily administration is also associated with a greater number of side effects [5]. However, a more recent randomized trial concluded that pulse CYC regimen-induced remission of AAV, as well as the daily oral regimen at a reduced cumula-tive CYC dose, and caused fewer cases of leukopenia [6••]. Groups did not differ in time to remission (HR, 1.098 [95% CI, 0.78–1.55]; P = 0.59) or proportion of patients who achieved remission at 9 months (88.1% vs 87.7%). Even with improvements in treatments and comparisons of pulse versus oral CYC, relapse is still a major clinical prob-lem in patient with vasculitis. Although effective therapy has resulted in long-term survival, relapse occurs in at least 50% of patients [7]. In a Cochrane Database review, insuf-fi cient evidence was found to recommend adjuvant therapy with intravenous immunoglobin [8].

Risk Factors for Treatment Failures in AAV I Karia and Espinoza I 417

B-cell depletion with rituximab has improved the rate of remissions in relapsing or refractory AAV in small and uncontrolled studies. Rituximab dosing regimens, the value of continuing immunosuppression, and investigation of ANCA and B-cell levels as treatment biomarkers have now been studied. Jones et al. [9] supported the notion that B-cell depletion is an effective remission-induction therapy for refractory ANCA-associated vasculitis. In this cohort, 57% of patients who achieved full remission experienced relapse at a median of 11.5 months.

This article reviews risk factors for failed induction of remission (treatment resistance) with CYC and earlier immunomodulators or rituximab, and relapse in AAV with a possible role in calling for aggressive treatment protocols. Knowledge of risk factors for relapse is critical for tailoring maintenance immunomodulating therapy to patients at high risk while sparing those at low risk from receiving unnecessary therapy.

Risk Factors for Treatment ResistanceThe Glomerular Disease Collaborative Network (GDCN) in the southeastern United States and the French Vasculitis Study Group (FVSG) described some important risk factors for treatment resistance. The FVSG cohort (n = 434) and the GDCN cohort (n = 350) had similar median follow-up periods (44 mo vs 45 mo) and initial percentages of patients taking CYC (82% vs 78%). The FVSG cohort included more patients with proteinase-3 (PR3) ANCA (58% vs 40%), lung involvement (58% vs 49%), and upper respi-ratory tract involvement (62% vs 31%). Based on fi ndings obtained in the GDCN cohort, the following risk factors for treatment resistance were identifi ed: female (OR, 1.84

[95% CI, 1.02–3.33]; P = 0.044); African American (OR, 3.10 [95% CI, 1.19–7.85]; P = 0.013); older age (OR per 10 y, 1.21 [95% CI, 1.00–1.47]; P = 0.046); and an elevated serum creatinine level, with each increment of 100 μm/L associated with a 1.22 OR of resistance (95% CI, 1.12–1.34; P = 0.001); and the presence of myeloperoxidase (MPO) ANCA. In the FVSG cohort, age was a statistically signifi cant predictor of treatment resistance (OR per 10 y, 1.32 [95% CI, 1.05–1.66]; P = 0.018), but sex, race, and increasing serum creatinine level were not (Table 1) [10••].

Type of vasculitisPatients with MPA have been shown to have more chronic lesions in renal biopsies than patients with WG, which may be less amenable to therapy [11]. Also, men may have worse outcome as they have been shown to display greater disease extent and renal impairment than women when AAV is diagnosed.

Interestingly, certain organ systems were more affected in 65 patients with AAV refractory to treatment and response to therapy with rituximab. The complex treatment-resistant nature of this cohort of patients had a higher rate of endobronchial disease and retroorbital granuloma, which has also been shown to be diffi cult to treat in other studies [12]. It was also noted that one patient with a retroorbital granuloma failed to respond to rituximab therapy. This patient had previously failed to respond to CYC (> 100 g), azathioprine (AZA), and mycophenolate mofetil (MMF).

In one study evaluating the long-term effi cacy of meth-otrexate (MTX) as maintenance therapy, it was noted that the highest relapse rates (mean, 19.4 mo) occurred in the ear, nose, and throat tract (18 of 26) and the kidney (16 of 26). Of note was the high number of renal relapses that occurred during MTX therapy [13].

Regarding disease activity titers, ANCA is present more often in patients with refractory AAV [14,15]. In one hypothesis, ANCA stimulates neutrophil degranula-tion, neutrophil activation, and apoptosis, causing direct and indirect endothelial damage.

Risk Factors for RelapseClinically, relapse is defi ned as disease activity increase after complete remission is achieved, whereas remis-sion is the absence of disease symptoms and signs with a reduction in steroid dosage [16]. Partial remission has been defi ned as a more than 50% reduction in disease activity, as assessed by the Disease Extent Index [9], a scoring system that accounts for 10 organ systems and constitutional symptoms. Of a maximum score of 21, organ systems affected by active vasculitis are scored as two points and constitutional symptoms as one point. Strictly, relapse has been defi ned as a recurrence of symptoms attributable to vasculitis that warranted therapy escalation beyond a temporary increase in the corticosteroid dosage.

Table 1. Risk factors for treatment resistance and relapse in patients with ANCA-associated vasculitis

Risk factors for treatment resistance Risk factors for relapse

Female sexAfrican American raceOlder age at onsetElevated creatinine levelPresence of myeloperoxidaseMicroscopic polyangiitisOrgan involvement Endobronchial disease Retroorbital involvement Kidney involvement ANCA positivity

Therapy (insuffi cient)PR3-ANCALung involvementUpper respiratorytract involvement

Genetics Cell membrane PR3 expression

Fc-γ polymorphisms HLA-DR antigens MyeloperoxidaseInfection: Staphylococcus aureus nasal carriage

Immune stimulation Dysregulated T-cell response Low levels of interleukin-10Miscellaneous Monocyte chemoattractant protein-1

Circulating endothelial cells

ANCA—antineutrophil cytoplasmic antibody; PR3—proteinase-3.

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Factors related to therapyCyclophosphamide doseSeveral studies have recently shown that the risk for relapse is inversely associated with the cumulative CYC dose received during the induction phase. A cumulative dose of less than 10 g CYC during the fi rst 6 months was associated with more relapses in patients with WG (RR, 2.83; 95% CI, 1.33–6.02) [17–19]. In a trial of 155 patients by the European Vasculitis Study Group, patients were initially treated with daily oral CYC and prednisolone for 3 to 6 months and then randomized to receive either 2 mg/kg daily AZA or continue oral CYC for 1 year [20•]. At the primary end point (relapse by 18 mo), the relapse rate was no different in the AZA and CYC groups. Strategies must be employed to prevent the long-term consequences of therapy because remission without relapse is not certain.

PrednisoloneCurrent randomized, controlled trials show higher relapse rates in trials that discontinued corticosteroids in the fi rst 6 months [21] or 12 months [22] compared with those who continued to administer prednisolone for 18 months and longer [23].

RituximabIn patients who are refractory to treatment with earlier immunomodulators and prednisone, B-cell depletion has started to emerge as the next step for ANCA-associ-ated vasculitis. In studies of small numbers of patients, rituximab has been associated with high rates of remis-sion, often more than 80% in patients with vasculitis who were refractory to standard therapies [24–29]. Relapses of vasculitis following rituximab therapy have occurred, although effi cacy with second and subsequent courses of rituximab has been reported [24–26]. At this point, B-cell and ANCA levels are unsuitable as retreatment guides as shown by larger patient cohorts.

Also, it appears that the two prominent rituximab protocols (4 infusions of 375 mg/m2 each given 1 week apart, or 2 infusions of 1 g each given 2 weeks apart) provide equal durations of B-cell depletion and disease remission. There is no difference in effi cacy between these two regimens. Continuing immunosuppression did not reduce relapses, however. Rituximab was effective and safe for retreatment [9]. Relapse may be more common in patients who have certain variations in Fc-γ receptor IIIa, proteinuria, and human antichimeric antibodies [9].

Specifi c types of vasculitis and relapseAlthough we may associate reduced ANCA titers with disease quiescence, so far no differences in disease sub-type, initial ANCA status (positive vs negative or MPO vs PR3 ANCA), and organ system involvement were noted between patients who experienced relapse and patients who did not. In a study of 156 patients with WG, decreas-ing ANCA titers did not predict time to remission, and

increasing ANCA titers did not predict relapse [30]. Increasing PR3-ANCA levels were associated with relapse in only 40% of cases in the next year. The decision to modify treatment in patients with WG should be based on clinical judgment and not on ANCA titers.

In WG, about 85% of patients are PR3-ANCA positive, whereas patients with MPA and idiopathic necrotizing crescentic glomerulonephritis are more fre-quently MPO-ANCA positive. In the AAV group, these disorders differ in specifi c features and relapse rate; reported relapse rates in cohorts of patients with WG are 50% during a mean 8 years of follow-up and 44% within 3 years compared to 25% to 35% within 2.5 to 5 years in other ANCA-associated vasculitides [31]. Con-sequently, relapses are associated with ANCA specifi city and occur more frequently in PR3-AAV compared with MPO-AAV [32,33]. Patients with PR3-AAV have a more than threefold higher risk for relapse within 5 years fol-lowing diagnosis than patients with MPO-AAV, an effect that seems independent of the specifi c diagnosis. In PR3-AAV, patients who remain or again become cytoplasmic (c)-ANCA positive during induction of remission have an increased relapse risk, which could indicate that these patients may benefi t from prolonged immunosuppressive maintenance therapy [34].

In patients with PR3-ANCA–associated vasculitis, a posi-tive c-ANCA titer upon switching to AZA, after induction of stable remission by CYC, was associated with an increased risk to experience relapse (RR, 2.6; 95% CI, 1.1–8), with a relapse-free survival of only 18% at 5 years [35–38].

Organ involvementPredictors of relapse in the GDCN cohort were PR3-ANCA (HR, 1.77 [95% CI, 1.11–2.82]), lung involvement (HR, 1.68 [95% CI, 1.10–2.57), and upper respiratory tract involvement (HR, 1.58 [95% CI, 1.00–2.48]), whereas predictors in the French cohort were PR3-ANCA (HR, 1.66 [95% CI, 1.15–2.39]) and lung involvement (HR, 1.56 [95% CI, 1.11–2.20]), but not upper respiratory tract involvement (HR, 0.96 [95% CI, 0.67–1.38]) (Table 1) [10]. The presence of pulmonary involvement at initial presentation was also shown to be associated with relapse that occurred after about 2.7 years, even with treatment [39].

GeneticsSeveral genetic factors (ie, constitutive membrane PR3 expression and polymorphisms of Fc-γ receptor, HLA DR antigen, and MPO) have been identifi ed as risk factors associated with relapse.

InfectionA hazard regression analysis identifi ed chronic nasal car-riage of Staphylococcus aureus as an independent risk factor for relapse (HR, 4.56; CI, 2.45–7.65) in patients with lim-ited WG. Chronic nasal carriage of S. aureus characterized patients with WG who are more prone to relapses [40].

Risk Factors for Treatment Failures in AAV I Karia and Espinoza I 419

Immune stimulationDysregulation of cell-mediated immune responses may also play a role in the pathogenesis of AAV. Activation of circulating T cells appears to persist during remission and may point to an ongoing immune-stimulating process, which may predispose to renewed disease activity [41]. Furthermore, patients with AAV have increased inter-leukin (IL)-12 levels, which seem to be counterbalanced by IL-10. It has been reported that low plasma levels of the immunosuppressive T helper 2 cytokine IL-10 during remission were associated with an increased risk of subse-quent relapse in AAV [42,43].

Fc-γ ReceptorsDijstelbloem et al. [44] showed that patients with WG were more prone to experience relapses in the fi rst 5 years after diagnosis when they homozygously expressed both the R131 form of Fc-γRIIa and the F158 form of Fc-γRIIIa, both considered to be low-affi nity phenotypes compared with all other Fc-γR phenotypes. Otherwise, Fc-γ receptors may be involved in ANCA-induced neutro-phil activation [44].

DiscussionKnowledge of the risk factors for refractory or relaps-ing AAV may guide the clinician in the use of preventive therapies and even allow for modifi cation of induction and maintenance regimens. Risk factors for relapse have been ascertained from various studies in AAV.

From the evidence so far, it appears that it can be expected that African American race, older age, higher creatinine level, and likely delay in diagnosis increase the probability of fi nding refractory disease. Sex is still unde-termined as a risk factor. Also, endobronchial disease and retroorbital granuloma may pose a problem, but there are reports of rituximab effi cacy for refractory ophthalmic WG [45]. Patients with proteinuria also must be moni-tored carefully.

If CYC is the chosen regimen for induction, dose goal should be greater than 10 g during the fi rst 6 months to decrease the relapse rate. In maintenance, MTX must be studied further because of evidence suggesting increased rates of renal relapse. Firm evidence demonstrates that ANCA levels should not guide retreatment, but a posi-tive ANCA at diagnosis may indicate refractory or more persistent disease. Corticosteroids should be used for 18 months or longer to decrease the relapse rate.

An important decision for the clinician involves the length and dosing of maintenance therapy. In PR3-ANCA–associated vasculitis, patients who remain or again become c-ANCA positive have shown to have increased relapse rates and therefore may be targeted for prolonged maintenance treatment. Some evidence shows that avoiding AZA for these patients may lower relapse rates.

Rituximab has gained the most attention lately as the rescue drug of choice for AAV with good results in small

trials and case reports [46]. More answers will be avail-able at the end of the Rituximab for ANCA-associated Vasculitis (RAVE) clinical trial. A wide-ranging set of bioassay studies will be performed on clinical specimens obtained during the trial that will attempt to provide more information on disease pathogenesis, which may lead to further insights on the question of relapse.

Emerging technologic developments in imaging and biomarkers may prove useful for tailoring therapy to improve remission and relapse rates. Fluorodeoxy-glucose PET/CT may provide some answers regarding which patients are prone to relapse [47]. In the search for improved biomarkers, monocyte chemoattractant protein 1 has shown some promise in ANCA-associated small-vessel vasculitis [48]. Higher levels of circulating endothelial cells have been associated with relapse in AAV patients [49]. As research and experience evolves, vasculitis treatment will become more complex with a wider range of available interventions. Their optimal combination, sequencing, and tailoring to the indi-vidual clinical situation will also be more feasible with improved results [50•].

ConclusionsThe use of ANCA (perinuclear ANCA and c-ANCA) in the diagnostic approach to systemic vasculitides, espe-cially small-vessel vasculitis, has facilitated their early recognition and therapeutic management. Both morbidity and mortality rates in AAV have signifi cantly improved in the past several years. Both treatment resistance and relapse have remained relatively constant despite advances in therapeutic management. Risk factors for both treat-ment resistance and relapse have been identifi ed and may lead to better therapeutic responses.

DisclosureNo potential confl icts of interest relevant to this article were reported.

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