ANCA-associated vasculitides (AAVs) are a heterogeneous group of autoimmune diseases, sharing the feature of small-vessel vasculitis. The spectrum of AAV comprises granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with
polyangiitis (EGPA), the later formerly known as Churg-Strauss syndrome (CSS). In Churg-Strauss syndrome small-vessel vasculitis is associated with eosinophilia and asthma.
Effective treatment of Churg–Strauss syndrome requires suppression of the immune system with medication.
Churg–Strauss syndrome (also known as allergic granulomatosis) is an autoimmune condition that causes inflammation of small and medium-sized blood vessels (vasculitis) in persons with a history of airway allergic hypersensitivity (atopy). It usually manifests in three stages. The early (prodromal) stage is marked by airway inflammation; almost all patients experience asthma and/or allergic rhinitis. The second stage is characterized by abnormally high numbers of eosinophils (hypereosinophilia), which causes tissue damage, most commonly to the lungs and the digestive tract. The third stage consists of vasculitis, which can eventually lead to cell death and can be life-threatening.
The clinical manifestations commonly seen in patients presenting with CSS range from upper airway and lung involvement to neurologic, cardiac, cutaneous, and renal manifestations. The pathogenesis of the disease is incompletely understood, but an involvement of eosinophils and T lymphocytes has been demonstrated. In CSS patients, the peripheral T-cell compartment is skewed, and CSS has been considered to be a Th2-mediated disease. Th2 cytokines like interleukin-5 (IL-5) function as growth factors for eosinophils and eotaxin-3 has been identified as an eosinophil recruitment factor.
Churg Strauss Syndrome
Rituximab (trade names Rituxan, MabThera and Zytux) is a chimeric monoclonal antibody against the protein CD20, which is primarily found on the surface of immune system B cells. Rituximab destroys B cells and is therefore used to treat diseases which are characterized by excessive numbers of B cells, overactive B cells, or dysfunctional B cells. This includes many lymphomas, leukemias, transplant rejection, and autoimmune disorders.
Targeting interleukin-5 with mepolizumab is promising for treatment of CSS, but has a temporally limited effect. The conventional treatment of CSS is based on glucocorticoids, which are combined with cyclophosphamide in patients with serious organ involvement. Depending on severity of the disease, immunosuppressants like methotrexate (MTX) or azathioprine (AZA) can also be used for remission induction and are often used along with glucocorticoids for maintenance therapy. To date, no clear disease-stage-specific therapy regimen exists for remission induction and maintenance therapy. The considerable rate of side effects related to the use of higher doses of glucocorticoids or cyclophosphamide, the high rate of relapses on standard therapy regimens, and the fact that some CSS patients either do not respond to CYC therapy or relapse shortly after CYC treatment underline the need for alternative therapies. Recent case reports suggest a favorable effect of the B cell-depleting agent rituximab (RTX) in CSS.
University Medical Center Freiburg, Germany
Jeans Thiel and partners report a single-center cohort of patients with CSS treated with RTX.
The rationale for introducing a B cell-depleting therapy (RTX) into the treatment of EGPA comes from the observation of myeloperoxidase (MPO)-specific ANCA in about 40% of EGPA patients, but the role of B cells in the pathogenesis of ANCA-negative EGPA is less clear. Furthermore, Th2 cells, by producing IL-4 and IL-13 may sustain the activation of not only eosinophils, but also B lymphocytes and promote B-cell class switching to IgE. Eosinophilic granulocytes in turn maintain a vicious cycle of T-cell activation by secreting IL-25. Additionally, increased serum IgG4 concentrations have been described in EGPA. RTX can induce remission in EGPA, but our knowledge on the role of RTX in EGPA is unfortunately based on a very limited number of case reports. Altogether, in studies reporting exclusively EGPA patients, fewer than 15 patients treated with RTX have been reported to date.
Selection of Patients
Patients included in this study had a diagnosis of EGPA defined by the Lanham criteria, the American College of Rheumatology criteria, or the Chapel Hill Consensus criteria. Furthermore, inclusion required RTX treatment for relapsing or refractory disease activity and a
minimal follow-up after RTX infusion of 6 months. The study was approved by the ethics committee of the Albert-Ludwigs-University, Freiburg (file No. 191/11, 46/04). Written informed consent according to the Declaration of Helsinki was obtained from all patients.
Patients included into this retrospective analysis were evaluated by a rheumatologist for diagnosis, sex, and age at application of first RTX infusion. Data analyses of the patients furthermore comprised laboratory values (for example, differential blood count, creatinine, C-reactive protein, creatine kinase, troponin T, myoglobin, lactate dehydrogenase, urine analysis), evaluation of disease extent, and organ involvement. Results of biopsies were included when available. Disease activity was measured by BVAS (Birmingham Vasculitis Activity Score). The prognostic Five-Factor Score (FFS) was determined in all patients at first diagnosis of EGPA. During follow-up after RTX application, patients were seen regularly every 3 to 6 months and evaluated by a rheumatologist.
Definion of disease activity and treatment responses
Complete remission was defined as a BVAS of 0 for at least 3 months and a stable prednisone dose ≤7.5 mg prednisone per day. The persistent BVAS (pBVAS) rated disease status, when patients had some BVAS items that were not new or worsening but persistent (regressing or unchanged). A pBVAS >0 was defined to correspond to partial remission. Treatment response was defined as a
50% reduction of disease-activity score and absence of new manifestations attributable to ANCA vasculitis. Refractory disease was defined as unchanged or increased disease activity in acute EGPA after more than 4 weeks of treatment with standard therapy. Relapse was defined as the occurrence of ≥1 BVAS item caused by active AAV after having achieved remission. Major relapses were defined as the recurrent or new onset of potentially life-threatening disease activity that could
not be treated with an increase in glucocorticoids alone. All other relapses were defined as minor. Low-activity disease was defined as persistence of minor symptoms (for example, arthralgia or myalgia).
The 160 patients with ANCA-associated vasculitides regularly attending the Department of Rheumatology at the University Medical Center for Vasculitides in Freiburg, Germany, were screened for this study. In total, 41 fulfilled the diagnostic criteria for EGPA. Of the 41 patients with a diagnosis of EGPA, nine patients had been treated with RTX for refractory disease activity (n = 8) or relapse (n = 1) on standard immunosuppressive therapy (Table 1). All nine patients (three women; six men), except for one, had a five-factor score of ≥1 at diagnosis. Mean age was 45 years (SEM, 5.5 years). All patients were of Caucasian origin and had systemic disease. Six patients were ANCA positive on indirect immunofluorescence screening, with a perinuclear fluorescence pattern in five patients and a cytoplasmic pattern in one patient. Myeloperoxidase (MPO) antibodies were present in five patients (Table 1). Median MPO titer at diagnosis was 108 U/ml (IQR, 64 to 132). Three patients were ANCA negative on indirect immunofluorescence screening and in PR3- and MPOELISA. Median concentration of C-reactive protein (CRP) before induction therapy was 69 mg/L (IQR, 43 to 119) (normal range below <3.2 mg/L), and median eosinophil count was 3,118/μl (31%) (IQR, 860 to 6,335). Median BVAS before induction therapy was 18 (IQR, 13 to 21). All patients had high disease activity with a baseline BVAS of ≥10 and pulmonary involvement with asthma in all, and nonfixed pulmonary infiltrates in seven (73%) of nine patients. ENT involvement was diagnosed in eight of nine patients. Neurologic manifestations were found in seven patients, all presenting with peripheral neuropathy, and two additionally having central nervous system involvement. Five patients had cardiac involvement with cardiomyopathy and/or pericarditis. Two patients reported ischemic cardiac pain, but results of coronary angiography were normal. Three patients had vasculitic skin lesions, and three patients had renal involvement (Table 1).
Treatment response to RTX therapy
At presentation 3 months after RTX treatment, all patients (n = 9) had responded to RTX treatment, and median BVAS was 3 (IQR, 2 to 3), with a significant decrease compared with the median BVAS before RTX (P < 0.001) (Figure 1). The median decrease in BVAS from the last measurement before RTX was 10 (IQR, 7 to 12). One patient was in complete remission (number 1), and eight patients were in partial remission with persistent neuropathy (seven patients), and improved or stable ENT symptoms (two patients). In six patients, asthma symptoms improved after RTX treatment. Peripheral B cells were measured in six patients, and all analyzed patients had a complete B-cell depletion (median 0/μl; IQR, 0 to 1; and 0, IQR, 0 to 0.1). Median prednisone dose was 8.75 mg/day (IQR, 5.5 to 15; P = 0.036). Prednisone could be tapered by median 9 mg/day (IQR, 5 to 17.5). In six patients, ≤7.5 mg of prednisone was used as maintenance dose. Two patients had 10 mg prednisone per day because of residual asthmatic symptoms, and one patient had 15 mg/day because of recurrent asthma and increased numbers of eosinophils. CRP concentration had normalized (P = 0.004) in all patients, and eosinophil counts had decreased to 245/μl (4.3%; P = 0.05). IgE concentration normalized in all patients analyzed (n = 4) (Figure 1). In three patients, MPO titers were measured 3 months after RTX, and titers were within normal limits.
Mean follow-up after the first RTX course was 9 months (SEM, 1.7). Maintenance immunosuppressive therapy at follow-up analysis was AZA (150 mg/d; n = 7), MTX (15 mg/d; n = 1), MMF (1,000 mg; n = 1). Within the 9-month observation period, no relapse was recorded, and the median BVAS was 3 (IQR, 0 to 3) (Figure 1). At the last available time-point of observation (mean, 9 months) after the first RTX treatment, CRP concentrations were within normal limits in all patients, eosinophils had further decreased (median, 3.5%; P = 0.007), and IgE concentration was 48 IU/ml (P = 0.034) (Figure 1). Median prednisone dose was 7.5 mg/d. In no patient could beginning B-cell recovery be observed (Figure 1). Two of the nine patients (numbers 1 and 7) had a follow-up of more than 1 year after RTX application (13 months in one, and 19 months in another patient), and both neither relapsed, nor repopulated their peripheral B-cell compartment within this observation period. B-cell repopulation has been described to start between 6 and 9 months after B cell-depleting therapy. In four patients, the B-cell compartment was analyzed with high-sensitivity FACS analysis 6 months after RTX treatment.
None of these patients fulfilled the criteria of B-cell repopulation based on peripheral B-cell numbers and percentages. Therefore, a median of 850,000 events was recorded by FACS analysis to allow high-sensitivity analysis. In three of the four patients, events in the CD19+ gate were below 100, and these patients were excluded from further analyses. Only in one patient were we able to record more than 1,000 events in the CD19 gate. The Bcell subpopulations identified were mainly plasmablasts (CD19+CD20-CD38highIgM-/low) and switched memory B cells (CD19+IgD-IgM-CD27+). No transitional B cells were detected (data not shown). Three of the nine EGPA patients (numbers 4, 5, and 6) were subsequently retreated with RTX after a median of 6 months, as part of a preemptive therapy strategy. At retreatment, none of these patients had clinical signs of relapse; all had CRP concentrations within normal limits, and two patients had slightly increased but stable numbers of eosinophils. Both patients with increased numbers of eosinophils were ANCAnegative (patients 4 and 5), and had no PR3 or MPO antibodies before the initiation of RTX therapy. RTX courses (2 × 1 g given 2 weeks apart) were administered every 6 months, with two, four, and six courses in one patient each (Table 1). During the median follow-up time of 3 years in the patients on preemptive RTX treatment regimens, neither in the ANCA-positive nor in the ANCA-negative patients, were relapses observed.
Rituximab in the treatment of refractory or relapsing eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) 2013
Mayo Clinic, Rochester, MN, USA
Rodrigo Cartin-Ceba and partners conducted a single-center, open-label pilot study using RTX (375 mg/m2/week 3 4) for induction of remission in CSS patients with renal involvement [defined as having >25% dysmorphic red cells, red blood cell casts or pauci-immune GN on biopsy]. Written informed consent was obtained from all individuals. Patients were eligible if they were untreated, had failed glucocorticoid therapy or had failed glucocorticoid dose reductions because of disease relapses. The primary outcome was remission of renal disease activity defined as stability or improvement of creatinine clearance, absence of active urinary sediment and reduction of the glucocorticoid dose to <50% of the average dose received over 3 months before enrollment or <10 mg/day (whichever is smaller) at 6 months. Patients were followed up for 1 year.
The study was done between June 2007 and July 2009. Four patients signed consent and were enrolled during the study period, one patient withdrew consent after the first infusion of RTX and only three individuals completed the study and were included in the analyses. All patients were Caucasians and had positive myeloperoxidase (MPO)-ANCA. Table 2 summarizes the clinical characteristics of these three patients. Renal disease at enrollment in all patients was confirmed by active urine sediment in all three patients and two patients underwent renal biopsy that showed pauci-immune crescentic GN. The disease was newly diagnosed in two individuals, and one patient had been previously diagnosed 4 years prior to enrollment in the trial and had failed therapy with cyclophosphamide 3 years prior and more recently therapy with methotrexate and prednisone. Active peripheral neuropathy was present in all three patients: one patient also presented myopathy and one patient presented active biopsy-proven eosinophilic pneumonia. None of the patients presented with active cardiac, central nervous system or skin activity of the disease.
All patients achieved the primary end point of renal remission within the first 3 months and remained in renal remission during the year following RTX treatment. In Patient # 1, proteinuria improved from 2734 to 671 mg/24 h at the end of the study. The other two patients normalized the 24-h proteinuria and all patients showed no evidence of active urinary sediment at the end of the study. The only patient with elevated serumcreatinine at enrollment of 1.9 mg/dL (Patient # 3) experienced significant recovery of renal function to a new baseline serum creatinine of 1.3 mg/dL at the end of the study. Peripheral neuropathy improved in all patients.
Figure 2 summarizes the disease activity and response in all three patients during the year that the patients were followed in the trial. Patient # 1 experienced a non-renal relapse (eye and joint involvement) at 6 months coinciding with the reconstitution of CD191cells; the time of relapse is marked with a solid black arrow in all panels of Figure 2. This patient was retreated with 4 weekly doses of RTX and achieved remission within 6 weeks. Concomitantly with inflammatory markers, eosinophilia and lower doses of prednisone, the disease activity as measured by the BVAS/WG mirrored the results as described in Figure 2.
RTX was effective in depleting CD191 cells at 6 weeks in all individuals; the response was sustained for all patients except for Patient # 1, whose response was previously described. There were no differences during the trial in the levels of hemoglobin, platelets, total white blood cells, electrolytes or liver function tests in all three participants. The levels of immunoglobulins A, M, G and E were measured at baseline, at 12, 24 and 48 weeks after RTX therapy. No significant changes in the levels of any of these were detected throughout the study, and their levels remained within normal ranges.
Rituximab for the treatment of Churg–Strauss syndrome with renal involvement
CONCLUSIONS ABOUT THERAPY
In conclusion, the results of these studies have shown that rituximab was safe and successful in controlling renal and non-renal