rituximab for refractory granulomatosis with polyangiitis (wegener's granulomatosis):...

$: Rituximab for refractory granulomatosis with polyangiitis (Wegener's granulomatosis): comparison of efficacy in granulomatous versus vasculitic manifestations$
Clinical and epidemiological research

Ann Rheum Dis 2012;71:327–333. doi:10.1136/ard.2011.153601 327

ABSTRACTObjective First, to investigate the overall effi cacy and

safety of rituximab (RTX) in refractory granulomatosis

with polyangiitis (GPA) in a tertiary referral centre.

Second, to compare the effi cacy of RTX in granulomatous

and vasculitic manifestations in GPA.

Patients and methods This study comprised a

retrospective, standardised data collection from all

patients who received RTX for refractory Wegener’s

granulomatosis from 2002 to 2010. Patients

were assessed by a standardised interdisciplinary

diagnostic procedure (including ear, nose and

throat and ophthalmology assessment, MRI,

immunodiagnostics, B-cell levels and Birmingham

Vasculitis Activity Score) and were treated by

standardised therapeutic regimens according to

available evidence.

Results 59 patients received 75 cycles of RTX.

9.3% achieved complete remission. A response was

documented in 61.3% (improvement in 52%, unchanged

disease activity in 9.3%), 26.7% had refractory disease.

Birmingham Vasculitis Activity Score, disease extent

index, erythrocyte sedimentation rate, C-reactive protein

and prednisolone demand decreased signifi cantly. All

patients achieved B-cell depletion. Granulomatous

manifestations such as orbital granuloma and

pachymeningitis were more frequently refractory to RTX

than vasculitis or other granulomatous manifestations.

Thus, for example, complete remission/improvement

was found in 89.2% of patients with renal disease and in

only 44.4% of those with orbital masses (p=0.003). The

relapse rate was 44.4% after a median period of 13.5

months. Adverse events occurred in 29%, pneumonia in

15% and death in 3%.

Conclusion The overall response rate of refractory

GPA to RTX was high (61.3% complete remission

or improvement). Response rates of vasculitic

manifestations were excellent; failure of response/

progress was mostly due to granulomatous

manifestations, especially orbital masses. Relapse

rates were high (40%) despite maintenance

treatment.

INTRODUCTIONThe outcome for patients with granulomatosis with polyangiitis (GPA) has constantly improved1–3 since the introduction of immunosuppressive treatment by Fauci et al4 and the implementation of treatment

principles such as remission induction and mainte-nance on the basis of a number of controlled tri-als performed by the European Vasculitis Study Group (EUVAS).5 Yet, a considerable proportion of patients is resistant to standard treatment: refrac-tory GPA was present in 15–20% of patients of large GPA cohorts.1–3 Even in the localised stage of GPA, in which disease manifestations are restricted to the respiratory tract without any clinical signs of vasculitis (and granulomatous manifestations only), refractory disease is common and was reported in 16% of patients,6 7 showing that vasculitic mani-festations and granulomatous infl ammation follow a refractory course in a considerable proportion of patients.

There is almost no evidence from controlled trials to guide further treatment decisions when patients do not respond to standard remission induction in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV).5 Rituximab (RTX) has been shown equally effi cient for stan-dard remission induction in generalised AAV as with oral cyclophosphamide (Cyc).8 Observational studies investigating the effi cacy of RTX in refrac-tory AAV and/or GPA have been published in the past years,9–23 most of which reported high rates of remission (>80%).23 Furthermore, it was found that relapses were common but that re-treatment was effective.23 However, there is continuing debate as to whether RTX may not be as effective in the treatment of granulomatous mass forma-tion compared with vasculitic manifestations such as pulmonary capillaritis or glomerulonephritis. Additionally, whereas the mechanism of action of RTX seems obvious in vasculitis manifesta-tions—namely, ANCA depletion, the mechanism remains unclear for granulomatous manifesta-tions. An initial study reported a lack of effi cacy in fi ve of eight patients with granulomatous GPA manifestations,14 as did several other reports.9

10 16 In contrast to these reports, further studies on refractory ophthalmic manifestations and on refractory head and neck involvement showed a benefi cial response in most patients.21 22 Moreover, some of the studies cannot be compared owing to different RTX dosage, treatment intervals and different regimens of concomitant immunosup-pression. A large study is needed to examine the effi cacy of RTX in granulomatous manifestations

▶ Additional data (supplementary tables and fi gures) are published online only. To view these fi les please visit the journal online (http://ard.bmj.com/content/71/3.toc)

1Department of Rheumatology and Clinical Immunology, Vasculitis Center, University Hospital Schleswig-Holstein, Campus Lübeck and Klinikum Bad Bramstedt, Bad Bramstedt, Germany2Department of Diagnostic Radiology, University of Kiel, Kiel, Germany3Department of Otorhinolaryngology, University of Kiel, Kiel, Germany4Department of Ophthalmology, University of Kiel, Kiel, Germany

Correspondence toDr Julia U Holle, Department of Rheumatology and Clinical Immunology, Vasculitis Center, University Hospital Schleswig-Holstein/Klinikum Bad Bramstedt, Oskar-Alexander-Strasse 26, 24576 Bad Bramstedt, Germany; [email protected]

Received 12 March 2011Accepted 14 August 2011Published Online First 21 October 2011

EXTENDED REPORT

Rituximab for refractory granulomatosis with polyangiitis (Wegener’s granulomatosis): comparison of effi cacy in granulomatous versus vasculitic manifestationsJulia U Holle,1 Christin Dubrau,1 Karen Herlyn,1 Martin Heller,2 Petra Ambrosch,3

Bernhard Noelle,4 Eva Reinhold-Keller,1 Wolfgang L Gross1

03_annrheumdis-2011-153601.indd 32703_annrheumdis-2011-153601.indd 327 2/4/2012 3:38:11 PM2/4/2012 3:38:11 PM

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Ann Rheum Dis 2012;71:327–333. doi:10.1136/ard.2011.153601328

adequately. The largest report published is on 46 patients with GPA, which does not refer to the refractory disease manifesta-tions in detail.23

The aims of this study were (1) to investigate the overall effi cacy and safety of RTX in addition to standard treatment in refractory GPA and (2) to compare the effi cacy of RTX for granulomatous and vasculitic manifestations in a large cohort at a tertiary referral centre.

PATIENTS AND METHODSPatients and inclusion criteriaAll patients who fulfi lled the classifi cation criteria of the American College of Rheumatology24 and the defi nition of the Chapel Hill Consensus Conference25 for Wegener’s granulo-matosis/GPA and who received RTX for refractory GPA in the period from the beginning of 2002 until 2010 were included in the study and followed up retrospectively. Refractory disease was defi ned according to the EULAR/EUVAS—namely, as unchanged or increased disease activity after 4 weeks of stan-dard treatment in acute AAV or as lack of response after 6 weeks of treatment (<50% reduction of the Birmingham Vasculitis Activity Score (BVAS)) or chronic, persistent disease after ≥12 weeks of treatment.26

Clinical, laboratory assessment and treatment protocolAll patients were followed up by a strict interdisciplin-ary approach of our tertiary referral centre as previously described.3 5 6 All patients underwent a regular set of inter-disciplinary clinical (including ophthalmology and ear, nose and throat assessment), technical (including MRI and high-resolution CT, if required), serological and immuno-logical examinations before the introduction of RTX and at 4-monthly intervals after the first RTX infusion to document the effect of RTX on the disease activity as described earlier,3

5 unless complications required an earlier admission of the patient (eg, owing to infection).

RTX was given intravenously as four doses of 375 mg/m2 at weekly intervals (plus prednisolone 100 mg on the day of infu-sion) and conventional immunosuppression was continued after the start of RTX. When Cyc was given orally (2 mg/kg/day), this was continued until re-evaluation; patients receiving intra-venous Cyc had three infusions (15–20 mg/kg body weight) at three weekly intervals in conjunction with RTX. Glucocorticoids (GCs) were tapered according to a standardised protocol (online supplementary material, table 1). Some patients received a second or third course or cycle of RTX if they relapsed and were refractory to standard treatment (fi gure 3, supplementary material).

Disease stages (localised, early systemic, generalised and severe) were defi ned according to EULAR/EUVAS.4 Orbital masses were counted as localised disease manifestation as they represent granulomatous disease manifestations that often originate from the ear, nose and throat tract.6 We differentiated between vasculitis manifestations and granulomatous manifes-tations (supplementary material, table 4). Disease activity was assessed by the BVAS,27 disease extent by the Disease Extent Index28 and chronic organ damage by the Vasculitis Damage Index.29 Remission (absence of disease activity for which stable maintenance immunosuppressive treatment may be continued, including prednisolone at ≤7.5 mg/day), response (≥50% reduc-tion of disease activity assessed by the BVAS and absence of new manifestations) and relapse (reoccurrence of new onset of disease attributable to active vasculitis) were defi ned according

to EULAR.26 For response, we further differentiated between improvement and stable disease in order to better evaluate treatment effects, especially with regard to granulomatous man-ifestations. We defi ned stable disease as an unchanged disease manifestation which equates to a 50% reduction of the BVAS upon re-evaluation (eg, in orbital granulomatous disease) and is therefore consistent with the current EULAR/EUVAS defi ni-tion of response. A patient was considered refractory to RTX if neither remission nor a response had occurred 4 months after the introduction of RTX. Four months after the fi rst RTX infu-sion, assessments of the overall effi cacy of RTX were made. Furthermore, the organ involvements were assessed separately for their response to RTX (supplementary material, tables 4 and 5). Maintenance treatment after successful treatment with RTX is described in the supplementary material.

B-cell count was determined by fl ow cytometry: B-cell deple-tion was defi ned as a cell count <0.02×102/l and B-cell repopu-lation by a rise in cell count ≥0.02×102/l following depletion. ANCA were assessed by indirect immunofl uorescence and direct enzyme-linked immunosorbent assay (ELISA) as described ear-lier.14 Patients received standardised education about RTX, including possible side effects and complications. Side effects and complications were assessed by a standardised interview. Serious adverse events (SAEs) were defi ned as events requiring admission to hospital, intravenous treatment, life-threatening situations or death.

Statistical analysisStatistical analysis was performed using SPSS, version 18 (SPSS, Chicago). Changes in variables were compared by Wilcoxon and Mann–Whitney test; χ2 test was used to compare disease activ-ity before and after RTX administration. Relapses were analysed by Kaplan–Meier survival analysis. p Values <0.05 were consid-ered statistically signifi cant.

Table 1 Baseline characteristics of patients with refractory disease before the administration of RTXNumber of patients, n 59Gender (female/male), n (%) 24/35 (40.7/59.3)Age at fi rst RTX administration, median years (range) 54 (22–76)Disease duration (months), median (range) 37 (3–211)Disease stage (whole course of follow-up), n (%) Localised 9 (15) Systemic (early systemic/generalised) 50 (85)ANCA status (whole course of follow-up), n (%) PR3-ANCA positive 51 (86.4) MPO-ANCA positive 3 (5.1)Cumulative treatment before start of RTX, n (%) Cyc 59 (100) TNFα antagonist 18 (31) Cyc+TNFα antagonist 18 (31) MTX 34 (58)Cumulative Cyc dose at fi rst RTX administration (g), median (range)

27.75 (4.5–450)

Number of cycles per patient, n One cycle 59 Two cycles 12 Three cycles 4 BVAS before introduction of RTX, median (range) 16 (3–26)

ANCA, antineutrophil cytoplasmic antibody; BVAS, Birmingham Vasculitis Activity Score; Cyc, cyclophosphamide; MPO, myeloperoxidase; MTX, methotrexate; PR3, proteinase 3; RTX, rituximab; TNF, tumour necrosis factor.



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RESULTSPatient characteristicsSixty patients were included in the study, 59% were male (n=35) with a median age of 54 years (range 22–76) and a median disease duration of 37 months (range 3–211) at fi rst RTX administration. Fifty (85%) had generalised disease. All patients had received Cyc previously (table 1, cumulative treatment). Directly before RTX treatment, 78.3% of patients (n=47) were receiving treatment with Cyc, eight of whom additionally received a tumour necrosis factor (TNF) α antagonist; the median cumulative Cyc dosage was 27.75 g (range 4.5–450). Further details are shown in table 1.

Refractory disease manifestations at RTX startManifestations such as orbital masses (n=27), active renal disease (n=26, n=12 with non-impaired renal function, but erythrocyturia and proteinuria ≥1 g/day, n=14 with impaired renal function defi ned as creatinine clearance ≤60 ml/min + erythrocyturia and/or proteinuria), pachymeningitis (n=12), pulmonary masses (n=12) and alveolar haemorrhage (n=12) represented the most common indications for RTX. Thirty-seven patients had more than one refractory manifestation before the start of RTX (fi gure 1; supplementary material, table 6). Manifestations such as ground-glass infi ltrates, neutrophil alveolitis and arthritis were accompanied by further refractory disease manifestations.

Treatment protocols and follow-upOne patient had an infusion reaction during the fi rst adminis-tration of RTX and was therefore excluded from further analy-sis. Fifty-nine patients received one cycle of RTX, 12 patients received two and four patients three cycles of RTX (table 1). All patients were additionally treated with GCs (tables 2 and 3 supplementary material). No additional conven-tional immunosuppressant agent was administered in 5.3%; during all other cycles additional medium or highly potent

immunosuppression was given. Co-medication with Cyc was given most frequently (54.7%) (fi gure 2). All patients were fol-lowed up for at least 4 months after the last administration of RTX, 36 patients were followed up for longer than 4 months and analysed for relapse frequency. The median follow-up period of the whole cohort was 7 months (4–58 months); the 36 patients who had entered remission/response were fol-lowed up for 13.5 months (3–54).

Overall effi cacy of RTX (clinical, laboratory)Regarding overall effi cacy of RTX, 9.3% of patients (n=7) achieved a complete remission of their disease manifestations; 52% (n=39) had an improvement/response and in 9.3% of patients (n=7), a stabilisation/response was reached. 26.7% (n=20) were refrac-tory which was consistent with disease progression (table 2). Thirty-two patients received RTX for more than one refractory organ involvement. RTX usually had the same effect on organ involvements (table 6, supplementary material).

Effi cacy of RTX on single organsThe effect of RTX on the most common organ manifesta-tions is displayed in figure 3: 27 patients presented orbital masses, none of them achieved a complete remission (0%), 18 patients showed a response (66.7%) (12 improved (44.4%), six (22.2%) had stable disease) and nine patients (33.3%) were refractory (with progressive disease). Patients with pachymeningitis (n=12) had a similar rate of refrac-tory disease (n=4, 33.3%) as patients with orbital disease, one (8.3%) reached a complete remission, six had a response (five (41.7%) with improvement, one (8.3%) with stable dis-ease). Twelve patients were treated for refractory pulmonary masses with good response rates: two (16.7%) had a com-plete remission, eight (66.7%) improved and two (16.7%) had refractory disease (disease progression); similarly, refrac-tory active renal disease and alveolar haemorrhage responded

Figure 1 Refractory organ involvement/activity before rituximab (RTX) treatment. Thirty-seven patients had more than one refractory organ involvement before the start of RTX granulomatous sinusitis and bony destruction.



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well: of 26 patients with glomerulonephritis, nine (34.6%) had a complete remission, 12 (46.2%) improved and four (15.4%) had refractory disease; of 12 patients with alveolar haemorrhage, eight (66.7%) had a complete remission, two (16.7%) improved and one patient (8.3%) had refractory dis-ease. One patient presenting with refractory renal disease and one with refractory alveolar haemorrhage died. The efficacy of RTX on polyneuropathy/mononeuritis (PNP) and arthritis was also satisfactory: four patients with PNP achieved com-plete remission (n=1, 25%) or response/improvement (n=3,

75%); all patients with arthritis (n=6) had a complete remis-sion (100%).

After RTX treatment, there was a signifi cant decline of (refrac-tory) disease activity in all organ systems/manifestations (refrac-tory manifestation before RTX vs refractory/unchanged disease activity after RTX, p<0.05) except for granulomatous sinusitis (p>0.05), which was probably owing to the small number of patients with granulomatous sinusitis (n=3). When the response of all granulomatous disease manifestations (taken together) were compared with all vasculitic disease manifestations, the proportion of complete remissions/improvement versus unchanged activity/refractory disease was signifi cantly higher for vasculitic manifestations (90.6% and 9.4% for vasculitic vs 58.2% and 41.8%, respectively, for granulomatous manifesta-tions, p<0.05, table 4 supplementary material). Furthermore, the proportion of complete remissions/improvement versus unchanged/refractory disease was lower in some of the granu-lomatous manifestations than in some of the vasculitic manifes-tations, which reached statistical signifi cance for the comparison of orbital masses with alveolar haemorrhage and glomerulone-phritis (p=0.003 and p=0,003, respectively). The comparison of response rates of pachymeningitis and pulmonary masses versus alveolar haemorrhage and glomerulonephritis was not signifi -cantly different (p=0.15 and p=0.14 for pachymeningitis versus alveolar haemorrhage and glomerulonephritis and p=0.94 and p=0.67 for pulmonary masses, respectively). An overview of the effi cacy of RTX on all disease manifestations is provided in the supplementary material (supplementary tables 1 and 2). BVAS, Disease Extent Index, laboratory parameters such as erythrocyte sedimentation rate, C-reactive protein, ANCA titre and required dose of prednisolone declined signifi cantly after RTX treatment (table 3). B-cell count also declined, although this was not sig-nifi cant (see fi gure 1 supplementary material).

Relapses after successful induction of remission/responseFor 36 patients, a follow-up after successful induction of remis-sion/response was available (median follow-up period 13.5 months, range 3–54 months). Sixteen of 36 patients (44.4%)

Figure 2 Co-medication during rituximab treatment in percentage per patient and cycle. All patients additionally received glucocorticoids. AZA, azathioprine; Cyc, cyclophosphamide; Lef, lefl unomide; MMF, mycophenolate mofetil; MTX, methotrexate.

Table 2 Outcome after rituximab (RTX)

Overall disease activity* (per cycle) Complete remission, n (%) 7 (9.3) Response improved/partial remission, n (%) 39 (52) Response unchanged/stable disease, n (%) 7 (9.3)Refractory, n (%) 20 (26.7) Serious adverse events (per cycle) Death, n (%) 2 (2.6) Allergy/infusion reaction, n (%) 1 (1.5) Infection, n (%) 21 (28.9) Infection, non-opportunistic Pneumonia, n (%) 11 (14.5) Upper respiratory tract infection, n (%) 3 (3.9) Endocarditis, n (%) 1 (1.3) Urinary tract infection, n (%) 1 (1.3) Dacryocystitis, n (%) 1 (1.3) Opportunistic infection Herpes zoster, n (%) 2 (2.6) Cytomegalovirus reactivation, n (%) 1 (1.3) Pneumocystis jiroveci pneumonia, n (%) 1 (1.3)Relapses (per patient and cycle), n (%) 16/36 (44.4)No relapse (per patient and cycle), n (%) 20/36 (55.6)Interval to relapse, median months (range) 29 (3–54)

The numbers and percentages refer to number and percentages per cycle administered.*Disease activity was not assessed in two patients as they died before evaluation of RTX effi cacy. Results for each patient are given in the supplementary material (fi gure 3).



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relapsed, 20 patients (56.6%) remained in remission until the end of follow-up. The median time to relapse was 13.5 months (3–54) in patients who had a relapse (see supplementary fi les for Kaplan–Meier relapse-free survival analysis, fi gure 2) and 12 months (3–27) in patients who did not have a relapse. There were no differences in disease stage (localised versus systemic), ANCA status or organ system involvement between patients who relapsed and patients who did not (data not shown). Furthermore, in patients who relapsed, there was no signifi cant difference of ANCA titre at remission compared with the time point of relapse (p=0.673, data not shown). Twelve patients received a second cycle and four patients a third cycle of RTX with similar response rates as with the fi rst cycle (supplemen-tary material, fi gure 3).

Adverse events and complications of RTXTwenty-four SAEs were documented during or after the admin-istration of 75 cycles of RTX (table 2). Infection was the most common SAE and occurred in 28.9%. Pneumonia was most prev-alent (and occurred in 11 cases, 14.5%). IgG/IgM levels declined signifi cantly after RTX but there was no signifi cant association with low IgG/IgM and infection. Two deaths occurred (supple-mentary material).

DISCUSSIONWe confi rm the fi nding of a good overall effi cacy of RTX for the treatment of refractory GPA in this uncontrolled retrospec-tive study (61.3% complete remission or improvement, 9.3% stable disease, 26.7% refractory disease). Refractory disease activity declined in all organ systems. However, the response rates in our study are lower than with other large uncontrolled trials: Jones et al23 reported complete remission rates of 75% and treatment failures of only 2%. This may be because of the high proportion of granulomatous manifestations in our study, some of which responded less well to RTX than the vasculitic mani-festations: complete remission/improvement was documented in 89.2% of renal disease and in 80.8% of patients with alveolar haemorrhage, whereas in orbital masses and pachymeningitis,

a complete remission or improvement was found in 44.4% and 49.9%, respectively. Interestingly, remission/response rates in pulmonary masses were higher than with the other granu-lomatous manifestations. The strength of the study lies in its strict interdisciplinary and standardised diagnostic approach; its weakness is that it is retrospective and that there was some variation in the GC dosing. Furthermore, we cannot defi nitely rule out the possibility that some of the responders with orbital masses might have been in complete remission as the orbital mass might have turned into a scar and, in turn, that a persis-tent mass might indeed be refractory with an increasing infl am-matory activity but unchanged diameter. Yet, all patients with orbital masses termed refractory had further enlargement of the masses so that the percentage of refractory orbital masses is a correct observation. Nevertheless, it would be desirable to develop imaging strategies that differentiate between scar and active infl ammation.

Figure 3 Effi cacy of rituximab (RTX) by organ involvement given for the most frequent organ involvements (in at least four patients or more). For effi cacy of RTX in organ involvements that were less common see online supplementary material.

Table 3 Effect of RTX on overall disease activity and disease extent assessed by BVAS and DEI, on laboratory parameters and prednisolone dose

Before RTX After RTX p Value

Disease activity, BVAS, median (range)

11 (1–28) 5 (0–20) <0.05

Disease Extent Index, median (range)

4 (2–8) 2 (0–6) <0.05

Laboratory parameters ESR, mm after 1 h 40 (6–150) 40 (2–94) <0.05 CRP, mg/dl 1.5 (0–277) 1.1 (0–50.6) <0.05 ANCA titre (l) 128 (0–4096) 32 (0–2048) 0.01Prednisolone dose (mg/day), median (range)

15 (0–90) 8 (0–80) 0.01

Immunoglobulin levels* IgM (g/l), median (range) 0.51 (0.1–1.8) 0.2 (0.1–1.4) <0.05 IgG (g/l), median (range) 8.6 (4.5–13.6) 6.9 (2.1–13.1) <0.05

*Available for 39 cases. (For decline in ANCA titre see online supplementary fi les.)ANCA, antineutrophil cytoplasmic antibody; BVAS, Birmingham Vasculitis Activity Score; CRP, C-reactive protein; DEI, Disease Extent Index; ESR, erythrocyte sedimentation rate; RTX, rituximab.



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The reason for lower treatment response rates, especially of orbital masses, is not clear. Biopsy specimens demon-strated a classic cell composition of orbital lesions as found in other typical granulomatous lesions of GPA,30 but fibrosis and an onion-like arrangement of collagen are also well-doc-umented features,31 32 which are usually not found in other granulomatous Wegener’s granulomatosis lesions (such as pulmonary granuloma). It may be speculated that a differ-ent inflammatory environment of orbital lesions leading to sustained granuloma formation and induction of fibrous tis-sue may account for the relative resistance towards immu-nosuppressant agents, including RTX. Moreover, metabolism may be slower and/or drugs may not spread as easily to remote places such as the orbit surrounded by fibrous tis-sue. Debulking operations in conjunction with immunosup-pression to treat orbital masses have been reported to be successful,32 33 yet this procedure bears the risk of structural damage to the eye. For the future, it will be crucial to under-stand the pathophysiology of granulomatous masses in order to develop targeted treatments to tackle the inflammatory process and prevent fibrosis.

Despite maintenance with conventional immunosup-pression, relapse rates were high (44.1% after a median time of 13.5 months). Similar relapse rates have been doc-umented by others with similar time intervals to relapse.23 Repeated courses of RTX were successful in four patients who did not respond to the first course,22 but this obser-vation requires validation in a larger cohort. We found no differences in disease stage, ANCA status or organ sys-tem involvement (granulomatous vs vasculitic) between patients who relapsed and patients who did not. Similarly to other studies23 re-treatment with RTX upon relapse was successful in the majority of patients. Pre-emptive re-treatment may be of benefit23 and be a future option to reduce the burden of disease in patients resistant to standard treatment and prone to relapse, but long-term data on the safety of RTX are still lacking. Moreover, RTX plus GC should be assessed for refractory disease without additional conventional immunosuppression as this was successful in induction of standard remission.8

Infections were the most common serious adverse event which occurred in nearly 30%. One of the two deaths was due to infection. The infection rate was similar to that found by other studies of RTX in refractory GPA.23 Remarkably, the infection rate of our study and others,23 34 in which patients received RTX in conjunction with conventional medium to highly potent immunosuppression plus GC, was similar to that of patients receiving standard remission induction with Cyc plus GC,4 35 suggesting that concomitant RTX treatment is not associated with an additional increased risk of infec-tions in the short term.

In summary, this study suggests a good overall effi cacy or RTX in refractory GPA. Effi cacy was less pronounced than with other uncontrolled studies of RTX in refractory AAV,23 which is probably owing to the high proportion of granulomatous mani-festations in this study: treatment failures mostly occurred in granulomatous manifestations, in particular in orbital masses and pachymeningitis. A controlled trial is needed to further evaluate the principle of B-cell-depleting treatment with RTX for refractory granulomatous AAV.

Competing interests None.

Ethics approval Ethics approval was obtained from University of Luebeck.

Provenance and peer review Not commissioned; externally peer reviewed.

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doi: 10.1136/ard.2011.15360121, 2011

2012 71: 327-333 originally published online OctoberAnn Rheum Dis Julia U Holle, Christin Dubrau, Karen Herlyn, et al. manifestationsgranulomatous versus vasculitic granulomatosis): comparison of efficacy inwith polyangiitis (Wegener's Rituximab for refractory granulomatosis

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rituximab for refractory granulomatosis with polyangiitis (wegener's granulomatosis):...

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