Methods: Consecutive untreated patients, either at diagnosis or during relapse, with biopsy proven active WG limited to the upper and lower airways presenting since 1993 were eligible. Treatment consisted of oral trimethoprim-sulfamethoxazole 160/800 mg bid. Treatment failure was defined as relapse of disease activity or need for additional treatment to control disease activity.

Results: 31 patients, 25 at diagnosis and 6 during relapse of active WG were included. Twenty-seven patients responded (87%, 95% confidence interval, 70 to 96%). Nine achieved partial and eighteen complete remission of WG disease activity after 3 (median, range 1 to 15) months of therapy. Two patients developed side effects, while 2 patients did not respond. During follow up 5 of 9 after partial and 6 of 18 patients after complete remission relapsed after 14 (median, range 2 to 32) months. Treatment failure was more likely in patients with disease activity outside the ENT region and in patients with a Staphylococcus aureus negative nasal culture at initiation of therapy. Actuarial disease controlled survival on intent to treat basis with trimethoprim-sulfamethoxazole was 70%, 60%, and 36% at 12, 24, and 36 months of therapy, respectively.

Conclusion: Trimethoprim-sulfamethoxazole treatment leads to partial or complete remission in a substantial proportion of patients presenting with active WG limited to the upper and lower airways.

Background: Subglottic stenosis (SGS) occurs in ~20% of patients with WG. Lesions are often scarified and have varying degrees of inflammation. In general, systemic therapy for SGS has been ineffective, and tracheostomy has been performed in ~50% of cases. One previous study (Langford et al. A&R,1996) demonstrated utility of dilatation and intralesional glucocortico- steroid injection (D-IL-GCS) for WG-SGS lesions. Although these results were encouraging, there have not been subsequent studies to confirm or refute the utility of D-IL-GCS in the hands of other clinicians.

Patients and Methods: Beginning in 1993, 14 patients with WG and critical SGS (3-4mm), leading to dyspnea or stridor, received D-IL-GCS by the same surgeon (IE). SGS was visualized under general anesthesia (jet ventilation, suspension laryngoscopy). After progressive mechanical dilatation, aliquots of 80mg depomethylprednisolone were injected into the stenotic lesion in each of 4 quadrants. ~50% of injectate would leak into the lumen. Repeat D-IL-GCS was provided if symptoms recurred or severe "silent" restenosis was noted on follow up examination.

Results:In 6 patients with prior procedures including 3 tracheostomies, extensive scar formation led to less satisfactory results. In 8 patients in whom D-IL-GCS was the first intervention, tracheal patency was maintained after 1 or 2 dilatations (mean F/U=24.5 months, range=8 months-6 years). There were no complications associated with therapy. Hospital discharge was possible on the day of the procedure.

Conclusions: SGS dilatation + intralesional GCS injection are effective combined therapies in WG, especially when applied to newly recognized lesions. Although results are less encouraging when applied in the setting of prior scarifying therapies, treatment may be useful in select cases. Our experience is the first to confirm that previously reported in a similar cohort. We propose that dilatation + intralesional GCS be considered as 1st line therapy in WG-SGS.

Objective: Some evidence indicates that tumor necrosis factor (TNF) is a major agent in vasculitis pathogenesis. We studied the short-term effect of anti-TNF-a in systemic vasculitis patients refractory to steroids and immunosuppressive agents. Methods: Ten patients refractory to corticosteroids and at least one immunosuppressant with persistently active disease or a new flare were included. Seven had Wegener’s granulomatosis, 2 had rheumatoid arthritis vasculitis and 1 had cryoglobulinemia with mean disease duration of 9.1, 21.5 and 17 years. They received infliximab (5 mg/kg) on days 1, 15, 45 and then every 8 weeks. Immunosuppressants were stopped between days 0 and 45 for 8 patients, while the steroids dose was the same or lower. Treatment response was evaluated clinically with the Birmingham vasculitis activity score 2000 (BVAS).

Results: Complete or partial remission was observed in all patients. The mean BVAS at entry was 10.6 (range: 4-48) and had declined to 3.7 (range: 0-12) on day 45, when 3 patients had BVAS of 0. The only adverse effect was a cutaneous eruption in 1 patient.

Conclusion: Anti-TNF-a successfully induced prompt symptomatic responses in patients with systemic vasculitis not responding to conventional treatment. Infliximab was well tolerated during the short-term follow-up.

Objective: To study the effect of the chimeric monoclonal anti-TNF-alpha antibody infliximab in Wegener's granulomatosis (WG) refractory to standard treatment with cyclophosphamide and high-dose corticosteroids for the induction of remission.

Patients and Methods: 6 patients with biopsy-proven, active WG refractory to standard treatment were followed prospectively. Infliximab was administered in addition to the standard therapy at a dosage of 3mg/kg in two patients and at a dosage of 5mg/kg in four patients with a 2 weeks interval after the first administration and a 4 weeks interval for the consecutive infusions.

Results: 3 patients had imminent visual loss due to progressive retroorbital granulomas, 2 had rapidly progressive glomerulonephritis, and 1 had progressive pulmonary granulomas and infiltrates. Addition of infliximab resulted in a rapid and significant improvement of vasculitis activity in 5 patients (figure: reduction of vasculitis activity as assessed by BVAS. 1). 1 patient was withdrawn because of suspected systemic infection. The higher dosage (5mg/kg) was more effective. Corticosteroids could be significantly tapered. One patient continues on infliximab, 4 patients remained in remission during follow-up (median: 6 months).

Conclusion: TNF blockade induces remissions in refractory WG. Infliximab appears effective and safe. Close monitoring is mandatory.

Background The aetiology of PSV is unknown but potential risk factors include infection, silica, solvents, metal fumes and rural residence (Churg-Strauss syndrome - CSS). 1We carried out a case-control study to explore these and other factors.

Methods 75 PSV patients (from a prospective vasculitis register), 220 age/sex matched non-disease hospital controls, 19 systemic rheumatoid vasculitis and 34 asthma controls were interviewed using a modified, previously used questionnaire.2 Details included: social class, occupational and residential history, silica, smoking, pets and detailed farm exposure in the year prior to symptom onset (Index Year). Jobs were coded by the Standard Occupational Classification 2000 and job-exposure matrices used to assess levels and duration of silica, solvent and metal exposure. Odds ratios (OR) and 95% confidence intervals(C.I.) were calculated by logistic regression. Total PSV and subgroups (47 Wegener’s Granulomatosis (WG), 12 microscopic polyangiitis (mPA), 16 CSS, 19 pANCA/MPO & 30 cANCA/PR3 positive) were compared to controls.

Results Significantly raised ORs (95% C.I.) were found for farm exposure in the Index Year in PSV [3.15(1.70-5.83)] and WG [3.59(1.83-7.03)]. Exposure to livestock (cows, sheep, chickens) was significantly associated with PSV [3.78(1.17-12.22)], WG, mPA and CSS in contrast to crops [PSV, OR: 2.43(0.99-5.94)]. Direct contact with livestock gave an OR of 3.60(1.33-9.70) in PSV. Working in high silica exposure jobs in the Index Year gave raised ORs for PSV [3.62(1.41-9.31)],WG [3.45(1.16-10.25)] and CSS [5.6(1.34-23.46)]. Employment of >40 years in these jobs gave an OR of 2.57(1.01-6.58) in PSV and 4.58(1.18-17.83) for any duration in mPA. A history of a high solvent exposure occupation was significantly associated with PSV [2.35(1.03-5.37)], WG [3.69(1.54-8.85)] and cANCA [3.43(1.22-9.68)]. There were no significant differences for age, sex, social class, urban/rural residence, pets, metal exposure or specific occupational codes.

Conclusions This is the first study to report an association between farm exposure and PSV. The association with exposure to livestock may suggest an infectious aetiology. Results also support a role for silica and solvent exposure in PSV but not the hypothesised rural association of CSS.1

1. Watts et al; BJR; 1998; 37; suppl., 86; 2. Duna G.F et al; Clin Exp Rheum; 1998; 16; 669-674

PURPOSE. Wegener’s Granulomatosis is a chronic granulomatous inflammatory vasculitis of unknown etiology. We investigated possible environmental agents in precipitating Wegener’s by questionnaire and compared the results to a sample of gout patients serving as controls.

METHODS. We developed a questionnaire on possible environmental triggers in collaboration with members of the Center for Clinical Epidemiology and Biostatistics at the University of Pennsylvania and colleagues at other institutions. We identified 104 patients with Wegener’s who had been seen in the last 3 years through a search of the patient database at our hospital. We also identified 100 patients with gout

RESULTS. 53 patients with Wegener’s and 53 patients with gout responded to the questionnaire and their data were analyzed. Results were tabulated in a series of 2X2 tables resulting in unadjusted odds ratios which were subsequently adjusted for age and race using exact methods. Positive associations with Wegener’s include lead exposure(OR=2.37), methyl mercury exposure (5 in Wegener’s, 0 in gout) and, as would be expected, a history of sinusitis (OR= 2.99). A negative association was observed for woodworking (OR=0.35), trichloroethylene (OR=0.39), kerosene (OR=0.48) and metal machining (OR=0.34). After adjusting for age and race only the negative association with kerosene remained statistically significant (OR=0.30, p=0.037).

CONCLUSIONS. The data presented here are suggestive that certain exposures are associated with an increased risk and others with a reduced risk of Wegener’s Granulomatosis. Further studies with larger patient populations and with alternative control groups will be necessary to confirm these observations.

methyl mercury n=5 in Wegener's, n=0 in Gout 0.0565 - -

This study is a retrospective analysis of a cohort of 256 WG patients to examine the clinical features and sequelae of orbital disease. The occurrence of orbital involvement in WG was 13%. Detailed clinical data on 18 patients with orbital disease (a total of 24 involved orbits) were available and examined. In 5 patients, orbital disease was noted at the time of their initial diagnosis with WG. The remainder of the patients developed orbital disease from 1 year to 16 years after initial diagnosis. Eleven patients had 1 or more relapses of orbital disease. With aggressive immunosuppression, visual acuity was maintained greater than 20/32 in 20 of 24 involved orbits. Optic nerve compression occurred during the acute inflammatory phase (15 patients) with final visual acuities after treatment ranging from 20/20 to no light perception (NLP) in1 patient. Of the 18 patients, 8 had complete resolution of their orbital mass by computed tomography. However, 4 of these 8 patients had recurrent orbital disease that did not resolve by computed tomography despite re-treatment. In comparing patients who had resolution of the orbital mass with those who did not, the choice of immunosuppressive regimen did not consistently correlate with outcome. During the course of therapy, 5 patients developed a previously undescribed orbital contraction syndrome characterized by enophthalmos (5), motility restriction/ptosis (4), chronic pain (3), and NLP from optic nerve compression (1).

The majority of patients with WG orbital disease maintained good vision. However, optic nerve compression with permanent vision loss occurred in 2 patients despite aggressive immunosuppressive therapy. Five patients developed a previously unrecognized orbital contraction syndrome that was not responsive to immunosuppressive therapy.

Aim. To study the course of disease activity in a population-based cohort of Wegener’s granulomatosis (WG) patients and describe predictors for complete remission and relapse.

Patients and methods. Retrospective study of 56 WG patients (62.5% males, median age 50 years) of whom 52 survived 3 months and were followed for 45.5 months (6-173). Disease activity was assessed by Birmingham Vasculitis Activity Score (BVAS-1) and permanent organ damage by Vasculitis Damage Index (VDI). Induction therapy consisted of prednisolone (Pred) 0.5-1 mg/kg and cyclophosphamide (CYC) daily orally 2 mg/kg (19 patients) or iv pulses 15 mg/kg every 2nd week (32 patients). Baseline clinical and laboratory features and cumulative treatment during the first 6 months were recorded. Simple and multiple regression analyses were used to find risk factors (risk ratio (RR) or odds ratio (OR) with [95% confidence interval] for remission and relapse by Cox proportional hazards model or logistic regression analyses). Data are given as median (range).

Results. There was no baseline difference between the two CYC-treatment groups, except that pulse treated patients had higher BVAS-1 scores (27 vs 23, P=0.02). All patients achieved either complete (85%) or partial remission (15%). Higher baseline BVAS-1 increased the chance of complete remission (BVAS-1 increase by 5 points, RR=1.24 [1.06-1.45]), while cumulative dose of CYC during the first 6 months was associated with increased chance of sustained complete remission (dose increase by 5 gram, OR=1.62 [1.02-2.58]). Relapse occurred in 31 patients (59.6%) after 18 months (4-108). The risk of relapse did not decline over time. Relapse risk was reduced with longer time on Pred >20mg/day during the first 6 months (increase by 1 month, RR= 0.72 [0.58.0.90]) and increased in patients with heart involvement (RR= 5.41 [1.79-16.3]) and in females (RR= 2.37 [1.03-5.47]). Therapy resistance, defined as death within 3 months or never achieving complete remission was associated with baseline organ damage (VDI increase by 1 point, OR= 1.56 [1.03-2.38]).

Conclusion. Initial high disease activity increases and the presence of baseline organ damage reduces the chance for complete remission in WG. Sustained remission is associated with more intensive initial treatment in terms of higher CYC doses and longer time on Pred >20mg/day.

Objective: To assess the incidence of Wegener’s granulomatosis (WG) in a population based cohort of patients since the introduction of antineutrophil cytoplasmic antibody (ANCA) testing, and describe the clinical features of WG in a population based study.

In 1994, we began an open-label prospective standardized trial using CYC and glucocorticoids (GC) for induction and MTX for remission maintenance in the treatment of WG. We now report on our extended experience with this regimen.

All patients initially received prednisone 1 mg/kg/day together with CYC 2 mg/kg/day. At remission, CYC was stopped and MTX was begun at 15 mg/week and increased to 20-25 mg/week. MTX was maintained for 2 years after which time it was tapered and discontinued.

Forty-two patients entered this trial and have been followed a median of 26 months (range 5-63). At study entry, 25 patients (60%) had glomerulonephritis and 20 (48%) had severe disease by renal, pulmonary, or neurologic criteria. Remission was achieved in all 42 (100%) at a median of 3 months (range 1-12) after study entry. GC were discontinued after a median of 8 months (range 5-22). One patient died of a myocardial infarction not related to WG, 1 voluntarily withdrew, 2 came off study for MTX pneumonitis, and 20 (48%) have relapsed. The median time from remission to relapse was 14 months (range 5-60). Of these 20, 3 were off all immunosuppressives and 3 were tapering MTX. The remaining 14 were on doses of MTX ³ 17.5 mg but had been off prednisone for a median of 8 months (range 2-54). The likelihood of relapse was not influenced by either severe disease or glomerulonephritis at study entry. Of the 16 who had a renal relapse, only 4 had a rise in their creatinine of > 0.2 mg/dl above baseline (maximum 0.4 mg/dl) and all returned to their prior level of renal function with treatment. Although all relapses involved a recurrence of major organ disease, no patient met the criteria for severe disease at relapse. For the 18 patients in remission, the median follow-up time has been 41 months (range 19-63). All patients have discontinued GC, 12 have discontinued MTX for a median of 14 months (range 4-26). Toxicities were 2 MTX pneumonitis (6%), leukopenia (4-CYC, 4-MTX), 1 elevated LFT requiring MTX dose reduction (3%), 2 cystitis (6%), 3 non-infectious GC toxicities, 2 bacterial pneumonia (6%), 4 herpes zoster (13%).

Use of GC and daily CYC for induction followed by MTX for remission maintenance is an effective and less toxic alternative to the standard CYC regimen. Extended follow-up of these patients indicates that, while additional relapses have been observed since the original analysis, these relapses do not appear to occur more frequently or be more severe than we have historically observed with the standard CYC regimen.

Objective: To estimate the prevalences and the incidences of these 4 vasculitides in a Parisian suburban population during the year 2000 using capture – recapture analysis.

Study design: Cases were collected in Seine – Saint-Denis County, a northern suburb of Paris, which has 1,382,928 inhabitants, 1,093,515 of whom are ³15 years old. The study period encompassed the entire calendar-year 2000. The cases were identified by 2 separate survey sources: 1) mailing with follow-up letter to all the general practitioners (n=1119); 2) mailing with telephone follow-up to the departments of internal medicine, rheumatology, nephrology, pneumology and hemodialysis of all the public hospitals and 2 big private clinics (n=20). The medical charts of all such identified cases were reviewed and diagnoses confirmed according to the Chapel Hill Consensus Conference nomenclature. The point prevalences and incidences were estimated by 2-source capture – recapture analysis using Chapman and Seber’s formula; the 95% confidence intervals (95% CI) were calculated using the Poisson distribution.

Results: The response rates were: 52% for general practitioners and 100% for hospital departments. Of the 59 cases identified (PAN, n=20; MPA, n=11; WG, n =21; CSS, n=7), 17 (29%) cases were retrieved from both sources (matches). The mean age was 59.1 yr (range: 19 – 84 yr) and the male/female ratio was 1.27. Ten diagnoses were made during 2000 (PAN, n=1; MPA, n=4; WG, n=4; CSS, n=1); 0 source matches. The table gives the estimated prevalences and year 2000 incidences (95% CI) in the ³15-year-old population.

Antineutrophil cytoplasmic antibodies (ANCA) are commonly found in over 90% of patients with Wegener’s Granulamatosus (WG). These autoantibodies appear to play a significant role in WG based upon their near universal presence and the modulation of these autoantibody titers with disease activity. Proteinase-3 (PR-3), an enzyme commonly found in neutrophilic granules, is the major target of this autoimmune response. PR-3 has many substrates, but one protein, the soluble endothelial protein-C receptor (s-EPCR) has been found to bind PR-3 external to its active site. Normally, EPCR is a key component of a coagulation pathway involving protein C. These proteins have also been shown to have an inhibitory role in inflammation. The interaction between PR-3 and EPCR could lead to novel epitopes. In addition, the interruption of this normal protein interaction could lead to increased inflammation as seen in the vasculitis of WG. This serves as a potential hypothesis for a role of anti-PR-3 in this pauci-immune disease.

Objective: Chemokine receptors play an important role in lymphocyte activation and recruitment to sites of inflammation. In Wegener's granulomatosis (WG) granulomatous lesions contain abundant CD4-positive T-cells. We analyzed, whether peripheral blood CD4-positive CD45RO-positive T-cells express chemokine receptors suggestive of their capability to respond to chemotactic gradients and of coordinated T-cell migration.

Methods: Patients with biopsy-proven localized WG (n=5), generalized WG (n=17) and age-and sex-matched healthy controls (HC, n=13) were included. PBMC were isolated and labeled with fluorochrome-conjugated monoclonal antibodies for cell surface antigens or appropriate negative (isotype) controls. Expression of CCR3, CCR5 and CXCR3 was determined by flow cytometry (FACS). Lymphocytes were gated for analysis based on light scattering properties and on CD45 and CD4 staining. Positively and negatively stained populations were calculated by quadrant dot plot analysis determined by isotype controls.

Results: The fractions of CCR5-positive and CCR3-positive cells within the CD4-positive CD45RO-positive T-cell population were significantly expanded in localized WG (mean: 15% CCR5-positive T-cells resp. 7% CCR3-positive T-cells) and generalized WG (4% resp. 4%) as compared with HC (1.5%resp. 1.2%, P<0.01). CCR5/CCR3 coexpression was not different in WG or HC (10%). Simultaneous expression of CCR5 and CXCR3 was detected on 24% resp. 11% of CD4-positive CD45RO-positive in localized resp. generalized WG compared with 6% in HC (P<0.05). CCR5 expression on CD28-negative CD4-positive T-cells was higher in localized WG as compared with generalized WG (66% vs. 12%, P<0.05).

Conclusion: Upregulated CCR5 or CCR3 expression on CD4-positive CD45RO-positive memory T-cells indicates previous activation and homing capability of different memory T-cell subsets in WG. Moreover, CD28-negative T-cells displayed CCR5 expression consistent with their Th1-like cytokine production, which has been demonstrated by our group recently.

Disclosure: Supported by grant SFB367/A8 to PL, AM, and WLG.

Background: During inflammation, chemokines control emigration of leukocytes via their G-protein-coupled cell surface receptors. CC chemokine receptor 5 (CCR5) is the receptor for the b-chemokines including RANTES, MIP-1a and MIP-1b. CCR5 is expressed mainly on macrophages, Th1 T cells and dendritic cells. CCR5 D32, a naturally occurring variant of CCR5, has a 32 bp deletion (D32) that results in a non-functional receptor. Leukocytes from individuals heterozygous for CCR5 D32 express significantly lower levels of CCR5.

Patients and Methods: This study investigated allelic and genotypic frequencies of polymorphisms located in genes encoding these chemokines and receptors in 118 Caucasian patients with WG and 127 ethnically matched healthy controls. In addition, protein expression of CCR5 and ligands was studied using immunohistochemistry staining in 4 lung biopsies that had classical features of WG.

Results: Enhanced protein levels of RANTES, MIP-1a and MIP-1b were noted in lung lesions from patients with WG, which was mirrored by the elevated levels of CCR5 expression. These results suggest a critical role for CCR5 signaling in local inflammatory responses of WG.

Genetic analyses revealed similar allelic frequencies and genotypic distributions of CCR5 D32 in patients and controls. However, among patients in whom circulating ANCA was not detected, none were found to carry the CCR5 D32 allele. The significant under-presentation of CCR5 D32 in patients without ANCA (0/19, 16% of WG cohort) suggests that CCR5 signaling exerts an essential role and maximal impact in WG patients with the minimal influence of ANCA.

Polymorphisms located in the promoter regions of the gene encoding RANTES were also examined. No significant difference was noted between patients, subsets of patients and controls, suggesting that genetic polymorphisms in RANTES do not influence expression of WG.

Conclusions: Our data suggest an important role for CCR5 in the mononuclear inflammatory lesions of WG. Strategies to block CCR5 ligation may be useful in the treatment of WG.

Objective: Expansion of T-cells lacking CD28 expression has been reported in Wegener's granulomatosis (WG) previously. We studied, whether the fraction of CD28-negative T-cells within the CD4-positive T-cell population is a major source of cytokine production.

Methods: 12 patients with active WG were analyzed. We assessed surface antigens and intracytoplasmic cytokine expression of the peripheral blood fractions of CD28-negative and CD28-positive T-cells within the CD4-positive T-cell population by flow-cytometry (FACS). Cytokine secretion was additionally confirmed by an enzyme-linked immunosorbent assay (ELISA). Immunohistologic studies were performed on biopsies from the respiratory tract.

Results: The fraction of CD28-negative T-cells within the CD4-positive T-cell population was significantly expanded compared with healthy controls (mean 14.4 vs. 2.1%, P<0.01). CD4-positive CD28-negative T-cells expressed CD18, CD57 - a marker also found on NK-cells - and intracytoplasmic perforin. They generally lacked the activation marker CD25 (IL-2receptor/IL-2R). CD4-positive CD28-negative T-cells appeared as the major source of IFN-g- and TNF-a production and secretion. In contrast, CD4-positive CD28-positive T-cells expressed CD25, but no perforin, and were able to produce and secrete a wider variety of cytokines, including IL-2. Immunohistologic analysis demonstrated that the majority of T-cells lacked CD28 in granulomatous lesions.

Conclusion: CD4-positive CD28-negative T-cells appeared highly differentiated, displayed a Th1-like cytokine production and features suggestive of T-cell mediated cytotoxicity. b2 integrins, i.e. CD18, may promote recruitment of CD4-positive CD28-negative T-cells into granulomatous lesions, where they may promote granuloma formation by IFN-g- and TNF-a secretion.