A disease-specific activity index for Wegener's granulomatosis: modification of the Birmingham Vasculitis Activity Score. International Network for the Study of the Systemic Vasculitides (INSSYS)

OBJECTIVE: To refine and validate the Birmingham Vasculitis Activity Score (BVAS) as a disease-specific activity index for Wegener's granulomatosis (WG). METHODS: Sixteen members of the International Network for the Study of the Systemic Vasculitides (INSSYS) revised the BVAS, with 3 goals: to reduce the redundancy of some component items, to enhance its ability to capture important disease manifestations specific to WG, and to streamline the instrument for use in clinical research. We defined the items and weighted them empirically as either minor (e.g., nasal crusting = 1 point) or major (e.g., alveolar hemorrhage = 3 points). We then validated the new, disease-specific BVAS/WG in 2 simulation exercises and a clinical case series that involved 117 patients with WG. RESULTS: We removed 38 items from the original BVAS, revised 9 items, and added 7 new items. Correlations between the scores on the BVAS/WG and the physician's global assessment (PGA) of disease activity were high, even when patients in remission were excluded. In the clinical case series, Spearman's rank correlation coefficient between the BVAS/WG and the PGA was r = 0.81 (95% confidence interval 0.73-0.87). The interobserver reliability using intraclass (within-case) correlation coefficients in the 2 simulation exercises was r = 0.93 for the BVAS/WG and r = 0.88 for the PGA in the first and r = 0.91 for the BVAS/WG and r = 0.88 for the PGA in the second. There was no significant observer effect in the scoring of the BVAS/WG or the PGA. The discriminant validity of the BVAS/WG was good: r = 0.73 (95% confidence interval 0.43-0.83). CONCLUSION: The BVAS/WG is a valid, disease-specific activity index for WG. Tested in simulation exercises and in actual patients, the BVAS/WG correlates well with the PGA, is sensitive to change, and has good inter- and intraobserver reliability. The INSSYS will use the BVAS/WG to assess the primary outcome in a phase II/III trial of etanercept in WG.     

Assessment of the item selection and weighting in the Birmingham vasculitis activity score for Wegener's granulomatosis

OBJECTIVE: To assess the Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG) with respect to its selection and weighting of items. METHODS: This study used the BVAS/WG data from the Wegener's Granulomatosis Etanercept Trial. The scoring frequencies of the 34 predefined items and any "other" items added by clinicians were calculated. Using linear regression with generalized estimating equations in which the physician global assessment (PGA) of disease activity was the dependent variable, we computed weights for all predefined items. We also created variables for clinical manifestations frequently added as other items, and computed weights for these as well. We searched for the model that included the items and their generated weights yielding an activity score with the highest R(2) to predict the PGA. RESULTS: We analyzed 2,044 BVAS/WG assessments from 180 patients; 734 assessments were scored during active disease. The highest R(2) with the PGA was obtained by scoring WG activity based on the following items: the 25 predefined items rated on >or=5 visits, the 2 newly created fatigue and weight loss variables, the remaining minor other and major other items, and a variable that signified whether new or worse items were present at a specific visit. The weights assigned to the items ranged from 1 to 21. Compared with the original BVAS/WG, this modified score correlated significantly more strongly with the PGA. CONCLUSION: This study suggests possibilities to enhance the item selection and weighting of the BVAS/WG. These changes may increase this instrument's ability to capture the continuum of disease activity in WG.     

Patient-reported outcomes in ANCA-associated vasculitis. A comparison between Birmingham Vasculitis Activity Score and routine assessment of patient index data 3

The objective of this study was to determine health-related quality of life (HRQoL) in patients with ANCA-associated vasculitis (AAV) as measured by the “routine assessment of patient index data 3” (RAPID3) and whether RAPID3 is correlated with disease activity as determined by the Birmingham Vasculitis Activity Score (BVAS). Data from patients at an academic institution vasculitis clinic seen between Jan 2010 and Jan 2012 were collected using chart review. BVAS and RAPID3 scores were calculated at each patient visit. RAPID3 was compared between patients in remission (BVAS?=?0) and patients with active disease (BVAS?>?=1) at all visits for four consecutive visits, when data available, at least 3 months apart during the period mentioned. Robust generalized estimating equations (GEE) in linear regression models evaluated associations between the RAPID3 and BVAS over all available observations, adjusting for intra-subject correlations. Thirty-four patients were included in the study, 26 had granulomatosis with polyangiitis (GPA), five microscopic polyangiitis (MPA), and three eosinophilic granulomatosis with polyangiitis (EGPA). Patients at first visit had impaired HRQoL as measured by RAPID3 [6.8 (3.1–12.6)]. The median RAPID3 scores were higher in patients with active disease as compared to patients in remission (7.0 vs. 3.0, p?=?0.115; 8.8 vs. 1.0, p?=?0.011; 6.1 vs. 2.0, p?=?0.032; and 11.7 vs. 2.0, p?=?0.128 for visits 1, 2, 3, and 4, respectively). In longitudinal GEE models incorporating all observations there was a strong association between the RAPID3 (per 1 unit) and BVAS (per 1 unit) [β 0.21 (0.10, 0.32) p?<?0.001]. RAPID3 can be used to measure HRQoL in patients with AAV. RAPID3 correlated significantly with BVAS. RAPID3 can discriminate between disease states in AAV. This instrument may help document patient experience and add to clinical decisions.     

Wegener's granulomatosis: pitfalls in the management of pulmonary disease: A case of Wegener's granulomatosis with a hilar mass

Wegener's granulomatosis (WG) is a systemic, granulomatous vasculitis that typically affects the upper airways, lungs, and, in most cases, the kidneys. Lung involvement occurs in 85% of patients. A classic feature of WG is multiple pulmonary nodules, which frequently cavitate. Hilar adenopathy or mediastinal masses are rare. These atypical pulmonary findings should raise suspicion of diseases other than WG and lead to biopsy with cultures, even when the diagnosis of WG appears to be certain. These guidelines proved to be reliable in a patient with WG in whom a hilar mass was associated with tuberculosis.     

Vasculitis of the internal carotid artery in Wegener's granulomatosis: comparison of ultrasonography, angiography, and MRI

A 37-year old male with newly diagnosed, untreated Wegener's granulomatosis including glomerulonephritis, sinusitis, conjunctivitis, arthralgias, and positive cANCA, developed a pulsating tumor in the left submandibular region and a reversible ischemic neurologic deficit. Ultrasonography revealed both a hyperechoic wall thickening of the left proximal internal carotid artery as is known in Takayasu's arteritis and a surrounding hypoechoic region typical for perivasculitis. The wall thickening and the perivascular infiltrate could be less clearly seen by MRI. Ultrasonography, angiography, and MRI demonstrated a 3 cm long, 30%, stenosis. Angiography and MRI additionally found a more distally located kinking of the internal carotid artery that was missed by ultrasonography. Carotid artery vasculitis is a rare complication of Wegener's granulomatosis. In this case ultrasonography was superior to angiography and MRI to visualize the artery wall and the surrounding tissue, but it failed to evaluate the whole distance of the vessel.     

Trimethoprim-sulphamethoxazole for the treatment of Wegener's granulomatosis

SIR, I write this in response to the letter by S. Sangle etal     

Etanercept combined with conventional treatment in Wegener's granulomatosis: A six‐month open‐label trial to evaluate safety

Objective

To evaluate the safety of etanercept (Enbrel) in patients receiving conventional treatment for Wegener's granulomatosis (WG).

Methods

We performed a 6‐month open‐label trial of etanercept (25 mg subcutaneously twice weekly) which was added to standard therapies for WG (glucocorticoids, methotrexate, cyclophosphamide, azathioprine, cyclosporine) and prescribed according to disease severity. Evaluations of clinical response were determined by the Birmingham Vasculitis Activity Score for WG (BVAS/WG) in 20 patients with persistently active disease or with new flares of previously established WG. Fourteen of the 20 patients (70%) had etanercept added as the only new therapeutic variable.

Results

Injection site reactions (ISRs) were the most common adverse event related to etanercept (8 episodes in 5 patients [25%]; <1% of all injections). All ISRs were mild. Two patients had a combined total of 5 hospitalizations (1 patient had 4), but no hospitalizations were attributable solely to etanercept‐related adverse events. One patient with severe subglottic stenosis developed pneumococcal tracheobronchitis and subsequently had a localized Herpes zoster infection. Nineteen patients (95%) were still taking etanercept at 6 months, the single exception being a patient who developed progression of orbital (retro‐bulbar) disease at 4 months. There were no deaths. The mean BVAS/WG at entry was 3.6 (range 1–8), which decreased at 6 months to 0.6 (P < 0.001, 95% confidence interval [95% CI] −4.0 to −2.1). Among the 14 patients in whom etanercept was the only new treatment variable, the mean daily prednisone dose decreased from 12.9 mg at entry to 6.4 mg at 6 months. This comparison did not achieve statistical significance (difference −6.5; P = 0.19, 95% CI −16.6 to +3.6). Sixteen of the patients (80%) achieved BVAS/WG scores of 0 at some point. However, intermittently active disease was observed in 15 patients (75%).

Conclusion

In this open‐label trial, etanercept used in combination with standard treatments was well‐tolerated in patients with WG. Adverse events were few. BVAS/WG scores improved at 6 months, but intermittently active WG (occasionally severe) was common. A randomized, double‐masked trial to assess the efficacy of etanercept in WG has begun.

     

Response of Wegener's granulomatosis to anti‐CD20 chimeric monoclonal antibody therapy

We report on the successful, compassionate use of the anti‐CD20 chimeric monoclonal antibody rituximab in a patient with chronic, relapsing cytoplasmic antineutrophil cytoplasmic antibody (cANCA)–associated Wegener's granulomatosis (WG). The patient initially responded to treatment with glucocorticoids and cyclophosphamide. However, bone marrow toxicity during cyclophosphamide treatment of a relapse precluded its further use. Azathioprine and mycophenolate mofetil treatment had failed to maintain remission of the WG, and methotrexate was contraindicated. Because the patient's 5‐year course was characterized by close correlation of cANCA levels with disease activity, selective elimination of cANCA was deemed a treatment option for his latest relapse. He was given 4 infusions of 375 mg/m² of rituximab and high‐dose glucocorticoids. Complete remission was associated with the disappearance of B lymphocytes and cANCA. Glucocorticoid treatment was then discontinued. After 11 months, the cANCA recurred, and rituximab therapy was repeated, without glucocorticoids. At 8 months after the second course of rituximab (18 months after the first course), the patient's WG has remained in complete remission. Elimination of B cells by rituximab therapy may prove to be an effective and safe new treatment modality for ANCA‐associated vasculitis and possibly other autoimmune diseases. This modality warrants closer examination in a carefully conducted clinical trial.     

Wegener's granulomatosis of the penis: diagnosis and management

A 24 year old uncircumcised man presented with a 1 month history of a painful, fungating lesion on his glans penis. Following biopsy, and further clinical developments, a diagnosis of Wegener's Granulomatosis (WG) was made. The penile lesion was treated with surgical debridement, and a penile stump was salvageable. This is only the fourth case of WG initially presenting with a penile lesion to be reported in the literature.     

An analysis of CTLA‐4 and proinflammatory cytokine genes in Wegener's granulomatosis

Objective

The precipitating event(s) that triggers Wegener's granulomatosis (WG) is unknown. Cytokines, costimulatory molecules, and counterregulatory molecules control the quality and intensity of immune responses. Thus, they are relevant candidates for genetic studies of immune dysregulation in WG, the pathogenesis of which may be facilitated by multiple acquired and/or inherited factors. This study was undertaken to investigate possible genetic associations of various proinflammatory cytokines and CTLA‐4, a receptor for T cell inhibition, with WG.

Methods

Using polymerase chain reaction–based DNA genotyping, we investigated the polymorphisms located in the genes encoding a variety of proinflammatory cytokines and CTLA‐4 in 117 American patients with WG and 123 ethnically matched healthy controls.

Results

Compared with controls, patients with WG had a significantly lower frequency of homozygosity for the shortest allele (designated allele 86) of the Ctla4 microsatellite polymorphism (AT)n located in the 3′‐untranslated region (3′‐UTR) of exon 3 (47.0% versus 69.9%; P = 0.0005). Significant differences between patients and controls in the allelic and genotypic frequencies of polymorphisms in the other cytokine and cytokine receptor genes studied (tumor necrosis factor α [TNFα], TNF receptor I [TNFRI], TNFRII, interleukin‐1β [IL‐1β], IL‐6) were not found.

Conclusion

The Ctla4 (AT)n 86 allele has been previously demonstrated to be crucial for maintenance of normal levels of CTLA‐4 expression and balance between T cell activation and inhibition. Our results in American patients confirm findings from a Scandinavian cohort in which a positive association between WG and longer alleles of (AT)n in the Ctla4 3′‐UTR was demonstrated. Diminished frequencies of the most effective allele for CTLA‐4 expression may represent a WG‐related susceptibility mutation that accounts, in part, for increased T cell activation and clonal expansion in WG. Blockade of T cell costimulation using CTLA‐4Ig might be a useful therapeutic intervention, providing an alternative or complementary approach to conventional treatment with immunosuppressive agents.

     

A case report of the limited form Wegener's granulomatosis]

The classical from of Wegener's granulomatosis (WG) is a necrotizing granulomatous angiitis that involves the upper and lower airways, and kidneys. A limited form of WG is characterized by pulmonary lesions identical to those of classical form WG without renal involvement. The authors report a case of limited form WG. A 58-year-old Japanese woman was admitted because of an abnormal pulmonary shadow. Pathological examination revealed granulomatous angiitis consistent with WG. No other organ involvement was found. The pulmonary shadow improved with cyclophosphamide therapy. The patient is now well and without evidence of exacerbation of the disease 18 month after the discharge.     

A disease‐specific self‐help program compared with a generalized chronic disease self‐help program for arthritis patients

Objective

Both the Arthritis Self‐Management Program (ASMP) and the generic Chronic Disease Self‐Management Program (CDSMP) have been shown to be successful in improving conditions in patients with arthritis. This study compared the relative effectiveness of the 2 programs for individuals with arthritis.

Methods

Patients whose primary disease was arthritis were randomized to the ASMP (n = 239) or to the CDSMP (n = 116). Analyses of covariance were used to compare the outcome measures for the 2 programs at 4 months and 1 year. Measures included quality of life outcomes (self reported, health distress, disability, activity limitation, global health, pain, and fatigue), health behaviors (practice of mental stress management, stretching and strength exercise, aerobic exercise), self efficacy, and health care utilization (physician visits and hospitalizations).

Results

Both programs showed positive results. The disease‐specific ASMP appeared to have advantages over the more generic CDSMP for patients with arthritis at 4 months. These advantages had lessened slightly by 1 year.

Conclusion

The disease‐specific ASMP should be considered first where there are sufficient resources and participants. However, both programs had positive effects, and the CDSMP should be considered a viable alternative.