Marcus Both

Lack of efficacy of rituximab in Wegener's granulomatosis with refractory granulomatous manifestations.

Objective: To investigate the safety and efficacy of rituximab (RTX) in patients with refractory Wegener’s granulomatosis (WG). Patients and methods: Eight consecutive patients with active refractory WG were included. In all patients disease activity had persisted despite standard treatment with cyclophosphamide and prednisolone, as well as tumour necrosis factor α blockade 3 months before inclusion in the study. Patients had particular granulomatous manifestations like retro-orbital granulomata (n = 5), nodules of the lungs (n = 1), and subglottic stenosis (n = 2). RTX was given intravenously every 4th week in combination with the standard treatment in five patients and with methotrexate in two others. Disease extent and activity were monitored clinically by interdisciplinary care, immunodiagnostics (ANCA serology, B cells by flow cytometry), and magnetic resonance imaging. Results: Beneficial response and a reduction in disease activity were seen in three patients, two of whom went into complete remission. In three other patients, disease activity remained unchanged while the disease progressed in the remaining two patients. In all patients peripheral blood B cells fell to zero during treatment with RTX. cANCA titres remained unchanged in all except one patient. Conclusion: In this pilot study, B lymphocyte depletion was not associated with a change of the ANCA titres or obvious clinical improvement of refractory granulomatous disease in patients with WG. Further studies are needed to evaluate the role of RTX in WG.

Prospective long-term follow-up of patients with localised Wegener's granulomatosis: does it occur as persistent disease stage?

Objective To identify patients with localised Wegeners granulomatosis (locWG) to assess whether it occurs as a long-term disease stage or phenotype and to characterise its outcome. Methods Patients in a ‘localised stage’ with histological criteria compatible with WG and a follow-up period of ≥1 year were included. They were prospectively followed at the Vasculitis Center Schleswig-Holstein from 1989 to 2009 and the clinical manifestations, antineutrophil cytoplasmic autoantibodies (ANCA) status and damage were evaluated. Immunosuppression was adapted to disease activity and severity in a step-up regimen. Results Of 1024 patients with suspected WG, 99 were clinically diagnosed with locWG and 50 fulfilled the inclusion criteria (72% women, median age 43 years, 46% ANCA-positive). The median follow-up was 48 months. All achieved a response to treatment, 34% achieved complete remission, 1–4 relapses occurred in 46%, 5 (10%) had generalised disease (median 6 years after onset). ANCA status was not associated with relapse (p=0.98), transition to generalised disease (p=0.51) or refractory manifestations (p=0.60). 47% required cyclophosphamide for localised manifestations, 36% of them for pulmonary masses and 24% for orbital masses. 66% developed organ damage, mostly due to bony destruction or space obturation (28% saddle nose, 24% septal perforation, 10% orbital wall destruction). There were two deaths that were not related to WG. Conclusion There is evidence that locWG is a long-term disease stage or phenotype (5% of all patients with WG), 46% of whom are ANCA-positive. LocWG is characterised by destructive and/or space-consuming lesions associated with high relapse rates (46%) and local damage.

Giant Cell Arteritis: Diagnostic Accuracy of MR Imaging of Superficial Cranial Arteries in Initial Diagnosis—Results from a Multicenter Trial

PURPOSE To assess the diagnostic accuracy of contrast material-enhanced magnetic resonance (MR) imaging of superficial cranial arteries in the initial diagnosis of giant cell arteritis ( GCA giant cell arteritis ). MATERIALS AND METHODS Following institutional review board approval and informed consent, 185 patients suspected of having GCA giant cell arteritis were included in a prospective three-university medical center trial. GCA giant cell arteritis was diagnosed or excluded clinically in all patients (reference standard [final clinical diagnosis]). In 53.0% of patients (98 of 185), temporal artery biopsy ( TAB temporal artery biopsy ) was performed (diagnostic standard [ TAB temporal artery biopsy ]). Two observers independently evaluated contrast-enhanced T1-weighted MR images of superficial cranial arteries by using a four-point scale. Diagnostic accuracy, involvement pattern, and systemic corticosteroid ( sCS systemic corticosteroid ) therapy effects were assessed in comparison with the reference standard (total study cohort) and separately in comparison with the diagnostic standard TAB temporal artery biopsy ( TAB temporal artery biopsy subcohort). Statistical analysis included diagnostic accuracy parameters, interobserver agreement, and receiver operating characteristic analysis. RESULTS Sensitivity of MR imaging was 78.4% and specificity was 90.4% for the total study cohort, and sensitivity was 88.7% and specificity was 75.0% for the TAB temporal artery biopsy subcohort (first observer). Diagnostic accuracy was comparable for both observers, with good interobserver agreement ( TAB temporal artery biopsy subcohort, κ = 0.718; total study cohort, κ = 0.676). MR imaging scores were significantly higher in patients with GCA giant cell arteritis -positive results than in patients with GCA giant cell arteritis -negative results ( TAB temporal artery biopsy subcohort and total study cohort, P < .001). Diagnostic accuracy of MR imaging was high in patients without and with sCS systemic corticosteroid therapy for 5 days or fewer (area under the curve, ≥0.9) and was decreased in patients receiving sCS systemic corticosteroid therapy for 6-14 days. In 56.5% of patients with TAB temporal artery biopsy -positive results (35 of 62), MR imaging displayed symmetrical and simultaneous inflammation of arterial segments. CONCLUSION MR imaging of superficial cranial arteries is accurate in the initial diagnosis of GCA giant cell arteritis . Sensitivity probably decreases after more than 5 days of sCS systemic corticosteroid therapy; thus, imaging should not be delayed. Clinical trial registration no. DRKS00000594 .

Orbital masses in granulomatosis with polyangiitis are associated with a refractory course and a high burden of local damage

OBJECTIVES To identify and characterize patients with orbital masses in a monocentric cohort of 1142 GPA patients followed up from 1990 until the end of 2010 with regard to disease stage, local orbital inflammation, course of disease and outcome and to assess the efficacy of immunosuppressive treatment. METHODS All GPA patients fulfilling ACR criteria or Chapel Hill Consensus Conference definitions or who had localized GPA and who developed orbital masses were evaluated regarding the course and outcome of the orbital masses (assessed by MRI, ophthalmologist and ENT specialist), all other clinical manifestations, disease stages, ANCA status, immunosuppression and its side effects and surgical procedures. RESULTS Of 1142 GPA patients 58 developed orbital masses during a median follow-up of 101.5 months (range 23-255 months). Forty patients fulfilled the inclusion criteria and had complete clinical assessments [44% females, median age 43 (20-74) years, 85% ANCA positive]. Seventy-five per cent (29/40) had systemic disease when orbital masses occurred; both orbits were affected in 30%. Seventy-two per cent had evidence of infiltration from paranasal sinuses. Under highly potent immunosuppression (mostly CYC and glucocorticoids), 41% were refractory, 24% had unchanged activity, 24% showed a response and 8.1% had complete remission. Forty-four per cent had relapses of orbital masses. Seventy-two per cent developed visual impairment, 19% suffered blindness. Blindness was associated with a longer time to remission and a relapsing and refractory course. CONCLUSION Orbital masses are a rare manifestation of GPA and are characterized by a refractory course and by a high rate of local damage. Patients with a refractory or relapsing course are at higher risk of developing blindness.

Correlation of serum level of high mobility group box 1 with the burden of granulomatous inflammation in granulomatosis with polyangiitis (Wegener's)

Objectives To investigate the correlation of serum levels of high mobility group box 1 (HMGB1) with the extent of granulomatous inflammation in granulomatosis with polyangiitis (GPA). Methods From 169 patients with GPA, 17 patients with granulomatous inflammation, without evidence of vasculitis were identified and 36 patients without measurable ‘granuloma’ formation. HMGB1 serum levels were determined and compared between the two groups, using a Mann–Whitney U test. Serum levels of 26 healthy individuals served as controls. In a further 21 patients with GPA with a pulmonary granulomatous manifestation from the study population, CT volumetry of ‘granuloma’ was performed. Volumes were compared with serum levels of HMGB1 (Spearman rank order test). Results Serum levels of HMGB1 were significantly higher in patients with predominant granulomatous disease than in patients without measurable ‘granuloma’ manifestations (6.44±4.53 ng/ml vs 3.85±2.88 ng/ml; p=0.0107). In both groups, levels of HMGB1 were significantly higher than in controls (2.34±2.01 ng/ml; p<0.01). A positive correlation of HMGB1 serum levels with volumes of pulmonary ‘granuloma’ (r=0.761, p<0.0017) was seen. Conclusions HMGB1 serum levels are significantly higher in GPA with predominant granulomatous manifestations and correlate with volumes of pulmonary ‘granuloma’. HMGB1 may be used as a marker of the burden of granulomatous inflammation in GPA.

Clinical presentation and long-term outcome of 144 patients with microscopic polyangiitis in a monocentric German cohort

OBJECTIVE To evaluate the clinical presentation and long-term outcome of a vasculitis centre cohort of patients with microscopic polyangiitis (MPA) with respect to organ manifestations, treatment, chronic damage and mortality. METHODS We performed a retrospective chart review at our vasculitis referral centre. MPA patients admitted between 1991 and 2013 classified by a modified European Medicines Agency algorithm were diagnosed and treated according to a standardized interdisciplinary approach. RESULTS Comprehensive data from standardized interdisciplinary workups was available for 144 patients (median follow-up 72 months). The overall standardized mortality ratio was 1.40 (95% CI 0.91, 2.07; P = 0.13). We observed a higher mortality [hazard ratio (HR) 4.04 (95% CI 1.21, 13.45), P = 0.02] in 17 patients with MPA-associated fibrosing interstitial lung disease (ILD) and 56 patients with peripheral nervous system involvement [HR 5.26 (95% CI 1.10, 25.14), P = 0.04] at disease onset. One hundred and fifteen patients (79.9%) responded to the initial treatment. Sixty-one (42.3%) achieved complete remission and 54 (37.5%) achieved partial remission. Twenty (13.9%) showed a refractory disease course. CONCLUSION MPA patients at our tertiary rheumatology referral centre seemed to have a less severe phenotype resulting in a less severe disease course and better outcome than reported in other cohorts. Fibrosing ILD was significantly associated with mortality in this cohort.

Salivary Gland Swelling in Wegener’s Granulomatosis: A Rare Cause of a Frequent Symptom

To the Editor: Wegener’s granulomatosis (WG) is a multisystemic disease with a complex genetic background. The clinical presentation is characterized by necrotizing granulomatous inflammation of the upper and lower respiratory tract, glomerulonephritis, and small-vessel vasculitis1. We describe an unusual primary manifestation of WG with salivary gland swelling. A 68-year-old man who was admitted to the hospital presented with progressive swellings of his right cheek and bilateral submandibular space over a period of several weeks. Extraoral examination revealed a bilateral enlargement of both submandibular glands and the right parotid gland, which were solid, plain, and painless to pressure (Figure 1.1). The oral cavity showed no pathologies of the mucosa, and no putrid secretion from the Stenon’s duct was determined. His history was notable for eye complications with dryness and reddening, ear complaints with bilateral hearing impairment, severe headache, night sweats, muscular weakness, and weight loss of about 8 kg during the 6 weeks before presentation. Blood tests revealed increased values for erythrocyte sedimentation rate (110/115 mm), C-reactive protein (203.7 mg/l), and leukocytes (13.18/nl). On magnetic resonance imaging (MRI), the right parotid gland and the submandibular glands were enlarged, demonstrating low signal intensity in T1-weighted and T2-weighted imaging … Address correspondence to Dr. V. Gassling, Department of Oral and Maxillofacial Surgery, University Hospital of Schleswig-Holstein, Campus Kiel, Arnold Heller Strasse 3, Haus 26, 24105 Kiel, Germany. E-mail: gassling{at}mkg.uni-kiel.de

THU0216 Subglottic stenosis and tracheobronchitis in granulomatosis with polyangiitis (GPA, wegener’s) are associated with a high burden of disease and damage

Background Localized disease manifestations including inflammatory subglottic stenosis in GPA have been associated with a refractory disease course in case series and small cohorts [1, 2]. Objectives To identify and characterize GPA patients with inflammatory subglottic stenosis (SST) and/or tracheobronchitis (TB) retrospectively within our monocentric cohort of 1184 GPA patients followed from January 1990 to August 2011 with respect to disease stage, disease manifestations, course of disease, treatment (including interventional procedures) and outcome. Methods All patients who fulfilled the American College of Rheumatology criteria or the Chapel Hill Consensus Conference Definition (n=70) or the EMEA algorithm for GPA (n=20) [3] or had localised GPA [2] and developed SST and/or TB were included. Patients were assessed in 4-6 monthly intervals by a standardized interdisciplinary setting [2] with respect to SST and/or TB (including ENT opinion and/or bronchoscopy and/or high-resolution CT), all other clinical manifestations, disease stages and activity, ANCA-status, duration and intensity of immunosuppressive treatment, interventional procedures, treatment effect, relapse rate, chronic organ damage and side effects of treatment. Results 1184 GPA patients were seen during the follow-up period, 90 of whom (7.6%; 94.4% ANCA positive, 62.2% female) developed SST and/or TB and had a follow-up of >6 months (median follow-up: 56 months, range: 6-262 months). 33 (36.7%) patients were under immunosuppression when SST/TB occurred; 58 (64.4%) received cyclophosphamide and glucocorticoids for remission induction (47.2% for SST/TB, 52.8% for other disease manifestations), 18 (20%) medium-potent immunosuppression. 78 (86.7%) achieved response/remission, 12 (13.3%) were refractory. Interventional procedures during remission induction were required in 30 patients (33.3%) including tracheostomas in 12 patients. 40 patients (44.4%) developed chronic SST and 19 (21.1%) developed chronic bronchial stenosis, 35 (38.9%) of whom required interventional procedures for scarring. 29 patients (32.2%) had 1-4 relapses. Conclusions ST/TB is a less common disease manifestation (7.6%) which was treated successfully by immunosuppression in the majority of cases (86.7%) but frequently recurred. SST/TB is associated with a high burden of disease and damage (44.4% chronic SST, 21.1% chronic bronchial stenosis) requiring interventional procedures in 35 patients (38.9%) to secure airways during active disease or to treat scarring processes during remission. References Langford CA, Sneller MC, Hallahan CW, Hoffman GS, Kammerer WA, Talar-Williams CW et al. Clinical features and therapeutic management of subglottic stenosis in patients with Wegener’s granulomatosis. Arthritis Rheum 1996; 39: 1754-1760. Holle JU, Gross WL, Holl-Ulrich K, Ambrosch P, Noelle B, Both M et al. Prospective long-term follow-up of patients with localized Wegener’s granulomatosis: does it occur as persistent disease stage? Ann Rheum Dis 2010; 69: 1934-1039. Watts R, Lane S, Hanslik T, Hauser T, Hellmich B, Koldingsnes W et al. Development and validation of a consensus methodology for the classification of the ANCA-associated vasculitides and polyarteritis nodosa for epidemiological studies. Ann Rheum Dis 2007; 66: 222-227. Disclosure of Interest None Declared

OP0184 Retrospective monocentric cohort of orbital masses in granulomatosis with polyangiitis (GPA, wegener’s): rare disease manifestation with a refractory disease course

Background Few studies with small patients numbers (n=15) [1, 2] have addressed the disease course of orbital masses in GPA. These studies suggest an aggressive course of orbital masses in spite of intense immunosuppression including biologics [2]. Objectives To identify and characterize GPA patients with orbital masses in our monocentric cohort of 1142 GPA patients followed from 1990 to the end of 2010 with respect to disease stage, orbital masses and other disease manifestations, course of disease and outcome including chronic damage. Furthermore, to describe efficacy of immunosuppressive treatment, surgical procedures and side effects of therapy. Methods All patients who fulfilled the American College of Rheumatology criteria or the Chapel Hill Consensus Conference Definition of GPA or had localised GPA [2], developed orbital masses and had a follow-up >6 months were included. Patients were assessed in 4-6 monthly intervals by a standardized interdisciplinary setting with respect to orbital masses (evaluated by MRI and ophthalmology opinion), all other clinical manifestations, disease stages and activity, ANCA-status, immunosuppressive treatment and effect, surgical procedures, relapse rate, chronic organ damage and side effects of treatment. Results During the follow-up period, 1142 patients with GPA were seen, 51 (4.5%) of whom with orbital masses. 40 patients fulfilled the inclusion criteria (44% females, median age 44 years, range 20-74, 85% ANCA positive) and had an overall median follow-up period of 101.5 months (23-255 months). 37 patients had a follow-up of >6 months after first manifestation of orbital masses and were included into the analysis. 40.5% (n=15) had a refractory course (disease progression of orbital mass) under standard remission induction with cyclophosphamide and glucocorticoids, 24.3% showed unchanged disease activity, 24.3% achieved a response and 8.1% a complete remission. 44.1% had relapses of orbital masses. 72% of patients developed visual impairment, 19% suffered from blindness of at least one eye. Patients who went blind had a significantly longer time to remission compared to patients who did not (median time to remission 24 vs. 9 months, p=0.0008), and had significantly more often a refractory course (5 out of 6 vs. 7 out of 26, p=0.01) and relapses of orbital masses (5 out of 6 vs. 7 out of 26, p=0.01). Conclusions Orbital masses are a rare manifestation of GPA and occurred in 4.5% of patients in this cohort. Orbital masses are characterized by a refractory course in spite of highly-potent immunosuppression, high rates of relapse and local damage. Patients with a delayed treatment response, a refractory and/or relapsing course are at higher risk to develop blindness. References Fechner FP, Faquin WC, Pilch BZ. Wegener’s granulomatosis of the orbit: a clinicopathological study of 15 patients. The Laryngoscope 2002; 112: 1945-1950. Holle JU, Dubrau C, Herlyn K, Heller M, Ambrosch P, Noelle B, et al. Rituximab for refractory granulomatosis with polyangiitis (Wegener’s granulomatosis): comparison of efficacy in granulomatous versus vasculitic manifestations. Ann Rheum Dis 2011 Oct 21 [Epub ahead of print]. Disclosure of Interest None Declared