Age at diagnosis influences the clinical phenotype, treatment strategies and outcomes in patients with giant cell arteritis: results from the observational GCAGE study on a large cohort of 1004 patients.

BACKGROUND: Immune and vascular ageing are proposed risk factors for giant cell arteritis (GCA). Data on the impact of age at diagnosis of GCA on the clinical presentation and course of the disease are scarce. METHODS: Patients with GCA followed at referral centres within the Italian Society of Rheumatology Vasculitis Study Group were enrolled up to November 2021. Patients were grouped according to age at diagnosis: ≤64, 65-79 and ≥80 years old. RESULTS: The study included 1004 patients, mean age 72.1±8.4, female 70.82%. Median follow-up duration was 49 (IQR 23-91) months. Patients in the oldest group (≥80 years) had significantly more cranial symptoms, ischaemic complications and risk for blindness compared with the groups 65-79 and ≤64 years (blindness: 36.98% vs 18.21% vs 6.19%; p<0.0001). Large-vessel-GCA was more frequent in the youngest group (65% of patients). Relapses occurred in 47% of patients. Age did not influence the time to first relapse, nor the number of relapses. Older age was negatively associated with the number of adjunctive immunosuppressants. Patients >65 years old had 2-3 fold increased risk for aortic aneurysm/dissection up to 60 months follow-up. Serious infections, but not other treatment-related complications (hypertension, diabetes, osteoporotic fractures), were significantly associated with older age. Mortality occurred in 5.8% of the population with age >65, cranial and systemic symptoms as independent risk factors. CONCLUSIONS: The highest risk of ischaemic complications, aneurysm development, serious infections and the possible undertreatment make of GCA a very challenging disease in the oldest patients.

New onset and flare of rheumatic diseases following COVID-19 vaccination are mild and respond well to treatment: 9-month follow-up data from a single centre cohort.

OBJECTIVES: Anti-COVID-19 vaccines have proved to be effective and well tolerated. Great attention is now being paid to the characterisation of possible adverse events associated to their administration. We report a case series of suspected rheumatic diseases (RDs) following anti-COVID-19 vaccination. METHODS: We included patients evaluated at first-aid rheumatologic consultancy and at rheumatologic outpatient and inpatient clinic at Padova University Hospital between May and September 2021 presenting with a RD within 30 days after an anti-COVID-19 vaccine dose. Our selection was in accordance with the World Health Organisation guidelines for adverse event following immunisation (AEFI) surveillance. Patients were regularly re-evaluated by telemedicine or face-to-face visit. RESULTS: We identified 30 cases of RD following vaccination: 24 (80.0%) new onsets and 6 (20.0%) flares. Most of patients (76.6%) received the BNT162b2 vaccine. The mean time to RD onset/flare was 12±9 days. The most common manifestations were inflammatory arthritis (40.0%), rheumatic polymyalgia (33.3%) and adult-onset Still's disease (13.3%). At the last FU visit (9.6±2.2 months), 83.3% of patients showed complete response to first- or second-line therapy, 13.3% a partial response and one patient (3.3%) was still experiencing an active disease. CONCLUSIONS: Considering the amount of vaccine doses administered during the evaluation period we overall detected a limited number of cases. We noted a clear prevalence of autoinflammatory conditions and seronegative manifestations. The great majority of patients had mild features and showed a good response to therapy.

Fully integrated [18F]FDG PET/MR in large vessel vasculitis.

BACKGROUND: The aim of this study is to evaluate the usefulness of [18F] fluorodeoxyglucose (FDG) positron emission tomography (PET)/magnetic resonance (MR) in large vessels vasculitis (LVV) patients. METHODS: We performed an observational retrospective study based on our records. Images were acquired on a PET/MR scanner using [18F]FDG-PET whole body imaging. For each PET scan, a qualitative analysis and a semi-quantitative measure using the maximum of the standardized uptake value (SUVmax) were performed. SUVmax measurements normalized to the liver uptake were categorized using a grading scale. Vessel's wall thickness (WT) was measured at five fixed points (inferior margin of T5, T9, T12, L3, thickest area [max WT]). RESULTS: Twenty-three LVV patients were included, 56.5% giant cells arteritis, 34.8% Takayasu's arteritis and 8.7% isolated aortitis, all Caucasian, mostly females (82%). We considered 32 PET scans for the LVV group (from a minimum of one to a maximum of three scans per patient) mainly during follow-up (29/32 scans), and 23 PET scans from a control group of non-metastatic malignancies patients. We found higher SUVmax compared to controls, in all sites, irrespective of clinical disease activity. Mean WT resulted higher in patients than in controls but was not correlated to SUVmax. Mean WT positively correlated with age in both cohorts, inversely correlated to disease duration, while no correlation with SUVmax was observed. The concordance between clinically active disease and PET hypermetabolism was poor (Cohen' κ=0.33). CONCLUSIONS: PET/MR is a safe imaging technique capable of detecting inflammation in aortic wall. Low radiological exposure of PET/MR should be considered especially in young women receiving follow-up studies.

Health-Related Quality of Life in Patients With ANCA-Associated Vasculitis and Sinonasal Involvement: A Single-Center Cross-Sectional Study.

BACKGROUND/OBJECTIVE: The aim of this study was to assess the impact of sinonasal morbidity on quality of life (QoL) in antineutrophil cytoplasmic antibody-associated vasculitis (AAV). METHODS: This cross-sectional case-control study enrolled 71 patients-44 AAV cases with (ear, nose, and throat [ENT]-AAV) or without ENT involvement (non-ENT-AAV) undergoing multidisciplinary evaluations and 27 chronic rhinosinusitis (CRS) cases. Three validated QoL questionnaires (Sino-Nasal Outcomes Test-22 [SNOT-22], Nasal Obstruction Symptom Evaluation [NOSE], and Short-Form 36) were administered, and the 3 groups were compared. RESULTS: The ENT-AAV patients were significantly younger (p = 0.01), with less antineutrophil cytoplasmic antibody positivity frequency (p = 0.035) and lower renal involvement (p = 0.003) than the non-ENT-AAV patients.The SNOT-22 questionnaire demonstrated significantly greater sinonasal morbidity in ENT-AAV patients compared with CRS patients (p < 0.001). The NOSE score of ENT-AAV patients was comparable to those of CRS patients, but higher than that of non-ENT-AAV patients (p < 0.001). The SNOT-22 and NOSE scores positively correlated with disease activity (p = 0.037; p = 0.004, respectively). Short-Form 36 domain-by-domain analysis revealed a significantly poorer QoL in ENT-AAV patients, especially with physical functioning being progressively impaired in CRS, non-ENT-AAV, and ENT-AAV patients (p < 0.001). No significant differences in QoL came to light when AAV patients were stratified according to current systemic o local treatments. CONCLUSIONS: The QoL in AAV patients is significantly reduced, especially in the presence of ENT involvement. The AAV-related nasal morbidity is consistent and comparable to that reported by CRS patients. It significantly affects patients' QoL and in particular social functioning, leading to limitation in daily/work activities. Organ-focused questionnaires and multidisciplinary management are warranted to pursue a treat-to-target approach in these patients.

IgG anti-Pentraxin 3 antibodies are a novel biomarker of ANCA-associated vasculitis and better identify patients with eosinophilic granulomatosis with polyangiitis.

OBJECTIVE: To investigate prevalence of anti-Pentraxin 3 (PTX3) antibodies in sera of anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) patients. METHODS: Anti-PTX3 and PTX3 levels were analysed by enzyme-linked immunosorbent assays in sera from unselected patients with AAV and compared with patients with systemic lupus erythematosus (SLE, n = 130), other connective tissue diseases (CTDs, n = 97) and matched healthy controls (n = 97). Optical density (OD) cut-off for positive anti-PTX3 antibodies was determined by ROC curve analysis and set as 0.234. Indirect immunofluorescence (IIF) on fixed human granulocytes was used to analyze the fluorescence pattern of anti-PTX3 antibodies. Liquid-phase inhibition tests were conducted to assess potential interferences. RESULTS: We included 101 AAV patients (females 58%, median age 60[51-69] years) affected either with granulomatosis with polyangiitis (GPA, n = 51), microscopic polyangiitis (MPA, n = 12) or eosinophilic granulomatosis with polyangiitis (EGPA, n = 38). Anti-PTX3 antibodies were detected in 29.7% AAV patients, being significantly higher than in healthy controls (p < 0.001) and CTDs (p = 0.030) but lower than in SLE (p = 0.004). Anti-PTX3 antibody prevalence was 44.7% in EGPA, 25% in MPA and 19% in GPA (p = 0.034). Among ANCA negative patients, 35.7% displayed positive anti-PTX3 antibodies. Anti-PTX3 were associated with a lower prevalence of systemic (p = 0.002), ear-nose-throat (p = 0.006) and renal manifestations (p = 0.016). Anti-PTX3 antibodies were characterized by a specific IIF pattern on fixed granulocytes. PTX3 serum levels resulted lower in AAV than healthy controls (p < 0.001). PTX3 inhibited anti-PTX3 binding in a dose-dependent manner. CONCLUSIONS: Anti-PTX3 autoantibodies appear a promising novel biomarker of AAV, especially EGPA.

Significance of PR3-ANCA positivity in eosinophilic granulomatosis with polyangiitis (Churg-Strauss).

OBJECTIVES: Only a third of patients with eosinophilic granulomatosis with polyangiitis (EGPA) are ANCA-positive, mainly directed against MPO. ANCA directed against PR3 are rarely found in EGPA. We aimed to examine the significance of PR3-ANCA in EGPA. METHODS: We set up a retrospective European multicentre cohort including 845 patients. Baseline characteristics and outcomes were analysed and compared according to ANCA status. RESULTS: ANCA status was available for 734 patients: 508 (69.2%) ANCA-negative, 210 (28.6%) MPO-ANCA and 16 (2.2%) PR3-ANCA. At baseline, PR3-ANCA patients, compared with those with MPO-ANCA and ANCA-negative, less frequently had active asthma (69% vs 91% and 93%, P = 0.003, respectively) and peripheral neuropathy (31% vs 71% and 47%, P < 0.0001), more frequently had cutaneous manifestations (63% vs 38% and 34%, P = 0.03) and pulmonary nodules (25% vs 10% and 8%, P = 0.046), and lower median eosinophil count (1450 vs 5400 and 3224/mm3, P < 0.0001). Vasculitis relapse-free survival was shorter for PR3-ANCA (hazard ratio 6.05, P = 0.005) and MPO-ANCA patients (hazard ratio 1.88, P = 0.0002) compared with ANCA-negative patients. CONCLUSION: PR3-ANCA EGPA patients differ from those with MPO-ANCA and negative ANCA, and share clinical features with granulomatosis with polyangiitis. This suggests that PR3-ANCA EGPA could be a particular form of PR3-ANCA-associated vasculitis.

Anti-neutrophil cytoplasmic antibody specificity determines a different clinical subset in granulomatosis with polyangiitis.

OBJECTIVES: It has been suggested that anti-neutrophil cytoplasmic antibody (ANCA) specificity, rather than clinical diagnosis influences the phenotype and course of ANCA-associated vasculitis (AAV). However, preliminary evidence suggests that further combined levels of categorisation might be of clinical relevance. The aim of this study was to investigate differences in clinical presentation at disease onset and outcomes based on clinical diagnosis and ANCA specificity. METHODS: Newly diagnosed patients with GPA or MPA assessed in three referral centres between 2000 and 2016 were included. Patients were grouped as MPO-ANCA-positive granulomatosis with polyangiitis (MPO-GPA), PR3-ANCA-positive-GPA (PR3-GPA), and MPO-ANCA-positive microscopic polyangiitis (MPO-MPA). RESULTS: Of the 143 AAV patients included (female 52%), 87 were categorised as PR3-GPA, 23 as MPO-GPA, and 33 as MPO-MPA. Patients with MPO-GPA were significantly younger than MPA patients (age 49±15 versus 63±10; p<0.001). MPO-GPA had significantly more frequent subglottic stenosis compared to PR3-GPA. Ear, nose, throat involvement was significantly more frequent in both GPA groups compared to MPA. Type of pulmonary involvement differed between both GPA groups and MPA with diffuse pulmonary haemorrhage being significantly more frequent in the latter (7% in PR3-GPA, 0% in MPO-GPA, 27% in MPOMPA; p<0.001). Renal involvement was more frequent in MPO-MPA compared to both MPO-GPA and PR3-GPA (impaired renal function in 84%, 39%, and 36%, respectively; p<0.001). PR3-GPA relapsed significantly more than the other two groups. After adjusting for age, MPO-GPA was a significant risk factor for mortality [HR 4.44 (95%CI 1.46-13.52), p=0.009]. CONCLUSIONS: ANCA specificity identifies specific subsets of disease characterised by different clinical presentation and outcome within the clinical diagnosis of GPA.

Alveolar haemorrhage in ANCA-associated vasculitis: Long-term outcome and mortality predictors.

INTRODUCTION: Alveolar haemorrhage (AH) is considered an important cause of morbidity and early mortality in anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitides (AAV). OBJECTIVES: The aim of this study was to identify predictors of outcome in patients with AH-AAV and to evaluate outcome and causes of death in this subset. MATERIALS AND METHODS: A multicenter retrospective study was conducted in 29 Italian Centers. Clinicians were asked to recruit all patients diagnosed with AAV-associated AH during the last 10 years, from 2007 to 2016. Univariate and multivariable analysis were performed. RESULTS: One-hundred and six patients were included (median age at onset of 55 years [IQR 42-67]). The majority were ANCA-positive (PR3 57.1%, MPO 33.7%) and 72.6% had also renal involvement. At presentation, anaemia was shown in 97 (92.4%) patients, hemoptysis in 54 (51.9%), respiratory failure in 68 (66.7%), of whom 48 (70.6%), requiring respiratory support. At the end of the 37 months [IQR 13-77] follow-up, 19/106 (17.9%) patients were dead. The main causes of death were active disease and infections. By stepwise regression analysis, age >65 years (HR 3.66 [95% CI 1.4-9.51], p = 0.008) and the need for respiratory support (HR 4.58 [95% CI 1.51-13.87], p = 0.007) at AH onset were confirmed to be predictive of mortality. CONCLUSIONS: Predictors of outcome in AAV-AH were determined. Factors related to the patient's performance status and the severity of the lung involvement strongly influenced the outcome. Balancing harms and benefits for the individual patient in induction and maintenance treatment strategies is crucial.

Rituximab-associated hypogammaglobulinaemia in ANCA-associated vasculitis and connective tissue diseases: a longitudinal observational study.

OBJECTIVES: The burden of hypogammaglobulinaemia following rituximab (RTX) treatment in rheumatic diseases has not been fully elucidated yet. Our aim was to evaluate the frequency and predictors of hypogammaglobulinaemia in patients affected by ANCA-associated vasculitis (AAV) and connective tissue diseases (CTD). METHODS: We retrospectively reviewed prospectively collected data of patients receiving RTX. Immunoglobulins (Ig) levels and lymphocyte subsets were recorded at RTX administration and 3-6 months later. We assessed frequency of hypogammaglobulinaemia (serum IgG<6 g/L) and its related events. Univariate and multivariable analysis were performed using SPSS 20.0 package. RESULTS: Sixty-eight patients (30 AAV, 25 systemic lupus erythematosus, 9 systemic sclerosis and 4 idiopathic inflammatory myopathies) were treated with RTX (95 infusions, median 2 [2-6]). Following RTX, IgG<6 g/L were observed in 15/68 patients (15.8%), IgM<0.4 g/L in 28/68 (41%) and IgA<0.7 g/L in 7/68 (10.2%). Hypogammaglobulinaemia was more common in patients with AAV (p=0.008), short disease duration (p=0.001), low IgG levels at baseline (p=0.008), high cyclophosphamide exposure (p=0.018), high daily and cumulative prednisone dosage (p=0.001 and p=0.006). At multivariate analysis, cumulative cyclophosphamide dosage (OR 1.1 [1.0-1.3] p=0.045), daily prednisone intake >15mg (OR 9.5 [2.2-41.7] p=0.03) and IgG levels before RTX (OR 0.74 [0.59-0.93] p=0.009) were independent predictors of hypogammaglobulinaemia. Five patients experienced severe infections within 12 months, more frequently in those with IgG<6 g/L (26.7% vs 1.9%, p=0.007). CONCLUSIONS: Hypogammaglobulinaemia following RTX is uncommon in AAV and CTD and is more likely in patients with high glucocorticoids and cyclophosphamide exposure and low IgG levels at baseline.

Renal involvement at baseline can predict major renal relapse in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis.

OBJECTIVES: In ANCA-associated vasculitis (AAV), renal relapses are cause of concern as they are unpredictable and predictors of end-stage renal disease (ESRD). We aimed to assess the frequency of major renal (MR) relapses in AAV and to identify independent base-line predictors. METHODS: We performed a retrospective monocentric observational cohort study of patients affected by granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and renal limited vasculitis (RLV), diagnosed from 2000 to 2019, and who achieved clinical remission defined as Birmingham Vasculitis Activity Index version 3 (BVASv3)=0 and/or clinical judgment. MR relapse was defined as the occurrence of major items of renal BVASv3. Univariate and multivariable analysis was performed with competitive risk analysis. RESULTS: We included 96 patients: 73 GPA, 21 MPA and 2 RLV. Eighty-five (90%) patients were ANCA-positive: 56 c-ANCA/PR3, 28 p-ANCA/MPO and 1 double positive. During the follow-up, 17/96 patients developed at least one MR relapse, 2/96 progressed to ESRD and 3/96 died without events; 74 did not develop MR relapse. Patients with MR relapse were all ANCA positive and had higher frequency of skin (p=0.034), kidney (p=0.004) and nervous system (p=0.024) involvement and lower fre¬quency of ear, nose and throat (ENT) manifestations (p=0.043). At multivariable analysis, renal involvement at baseline (sHR 20.4, 95% confidence interval (95% CI) 2.6-158.2, p=0.004) and remission-induction treatment without cyclophosphamide and/or rituximab (sHR 4.2, 95% CI 1.5-12.0, p=0.007) were independent predictors of MR relapses. CONCLUSIONS: Baseline renal involvement predicts MR relapse in AAV while intense initial treatment seems to be protective.

Nasal polyps in eosinophilic granulomatosis with polyangiitis: Structured histopathology and CD105 expression.

PURPOSE: Distinguishing the prodromal nasal polyposis of eosinophilic granulomatosis with polyangiitis (EGPA) from chronic rhinosinusitis with nasal polyps (CRSwNP) is a challenge for rhinologists and rheumatologists. It has recently been reported that angiogenesis and CD105 expressed on vascular endothelial cells could have a role in the pathogenesis and development of nasal polyps. This exploratory study examined the structured histopathology of nasal polyps in patients with EGPA and CRSwNP, comparing CD105 expression in their nasal tissue with that of a control group with no chronic sinonasal inflammation. METHODS: A structured histopathological study was performed on surgical specimens of nasal tissue from 32 adults (13 with EGPA, 14 with CRSwNP, 5 controls), considering CD105 as a marker to determine microvessel density (MVD). RESULTS: The mean eosinophil count was higher in EGPA patients with tissue inflammation (p = .002), and in CRSwNP patients with sub-epithelial edema (p = .009). Neutrophil infiltration was significantly associated with severe tissue inflammation in EGPA patients (p = .04), but with the absence of fibrosis in CRSwNP patients (p = .04). In the EGPA group, CD105-MVD correlated with tissue eosinophil count (p = .05). Mean CD105-MVD was significantly higher in EGPA patients with mucosal ulceration (p = .004). In the CRSwNP group, a CD105-MVD correlated positively and significantly with tissue eosinophil count (p = .01). CONCLUSION: Alongside the known abundance of eosinophils, other cells might contribute to inflammatory processes. Neutrophils may amplify inflammation, eosinophil recruitment and tissue damage. CD105 expression in CRSwNP and EGPA nasal polyps supports the hypothesized involvement of angiogenesis in the pathogenesis and development of nasal polyps.

Overall Disability Sum Score for Clinical Assessment of Neurological Involvement in Eosinophilic Granulomatosis With Polyangiitis.

AIM: The aim of this study was to verify the application of Overall Disability Sum Score (ODSS) for standardized clinical assessment of neurological involvement in patients with eosinophilic granulomatosis with polyangiitis (EGPA) and its correlation with treatment response and long-term outcomes. METHODS: Consecutive EGPA patients referred to our tertiary vasculitis center were retrospectively evaluated. Patients' neurological damage and disability were systematically assessed with Vasculitis Damage Index and ODSS. RESULTS: Fifty EGPA patients were included in the study with a median follow-up of 75 months (9-180 months). Twenty-five (50%) developed peripheral neuropathy, 17 (68%) presented mononeuritis multiplex, whereas 8 (32%) had symmetric polyneuropathy. Patients with neurological involvement were older (56.3 ± 13.4 vs. 44.4 ± 12.1 years, P < 0.0009), more frequently antineutrophil cytoplasmic antibody positive (48% vs. 16%, P = 0.015), and were more likely to have renal involvement (24% vs. 0%, P = 0.022). An early clinical response to therapy was observed within 6 months of treatment, resulting in a significant decrease in ODSS, which fell from the baseline value of 4.2 ± 2.4 to 2.9 ± 1.5 (P = 0.0001), whereas only a slow decreasing pattern was noted over the long-term period. However, all subjects developed neurological impairment and disability despite remission from active vasculitis. Patients with ODSS of greater than 3 at baseline (n = 13 [52%]) retained a higher score at the last examination (P < 0.001), predicting a low therapeutic response. Furthermore, ODSS of greater than 3 was found associated with more neurological relapses (53.8% vs. 0%, P = 0.027). CONCLUSION: Overall Disability Sum Score could be a rapid, simple, reliable instrument to evaluate the severity of disability and nerve damage due to neurological involvement caused by vasculitis and to predict, at presentation, improvement and risk of neurological worsening.

The 158VV Fcgamma receptor 3A genotype is associated with response to rituximab in rheumatoid arthritis: results of an Italian multicentre study.

OBJECTIVE: The polymorphism 158V/F of Fc fragment of IgG (FCGR) type 3A may influence the response to rituximab (RTX) in rheumatoid arthritis (RA). We investigated the FCG3A polymorphism in a large cohort of RA patients treated with RTX, also by considering the possible loss of response from month +4 to +6 after RTX and the presence of established predictors of response. METHODS: The study analysed 212 RA patients. European League Against Rheumatism (EULAR) response was evaluated at months +4 and +6 after the first RTX infusion. The FCGR3A polymorphism was analysed by PCR followed by Sanger sequencing. RESULTS: The FCGR3A genotypes were associated with EULAR response (good or moderate) at month +6 (response in 34/38 (89.5%) VV vs 70/106 (66%) VF and in 51/77 (66.2%) FF patients; p=0.01), but not at month +4 (response in 32/37 (86.5%) VV vs 69/102 (67.6%) VF and 53/73 (72.6%) FF patients; p=0.09). Loss of response was observed only in VF and FF carriers ((VV vs VF vs FF: 0/37 (0%) vs 11/102 (10.8%) vs 12/73 (16.4%); p=0.02)). Probability of response at month +6 was very high when at least two of the three following items selected by multivariate analysis were present: positive rheumatoid factor and/or anticyclic citrullinated peptide antibodies, previous treatment with ≤ 1 anti-tumor necrosis factor (TNF) agent, and 158VV FCGR3A genotype (p<0.0001; OR 7.9, 95% CI 4.1 to 15.1). CONCLUSIONS: The 158VV FCGR3A genotype was associated with response to RTX in a large cohort of RA patients. Patient genotyping may be helpful to plan RTX treatment, and may be integrated with clinical predictors.

The TTTT B lymphocyte stimulator promoter haplotype is associated with good response to rituximab therapy in seropositive rheumatoid arthritis resistant to tumor necrosis factor blockers.

OBJECTIVE: To investigate the polymorphisms in the promoter region of the B lymphocyte stimulator (BLyS) gene as markers of response to rituximab (RTX) in rheumatoid arthritis (RA). METHODS: The study was first conducted in 152 Italian RA patients and then replicated in an additional 117 RA patients (73 Italian, 44 British). The European League Against Rheumatism response criteria were used to evaluate the response rate at months 4 and 6 after the first cycle of RTX, by means of the Disease Activity Score in 28 joints using the erythrocyte sedimentation rate; patients were classified according to the best response shown between months 4 and 6. BLyS promoter polymorphisms were analyzed by polymerase chain reaction followed by the analysis of the restriction fragments, BLyS promoter haplotypes were analyzed using the expectation-maximization algorithm, and BLyS serum levels were analyzed using enzyme-linked immunosorbent assay. Odds ratios (ORs) were calculated with 95% confidence intervals (95% CIs). RESULTS: The TTTT BLyS promoter haplotype appeared to be significantly associated with response to RTX only in the subset of seropositive patients (those positive for rheumatoid factor and/or anti-cyclic citrullinated peptide). The replication study confirmed that this association was limited to seropositive RA patients in whom treatment with anti-tumor necrosis factor (anti-TNF) agents had previously failed. In the whole series of seropositive patients in whom anti-TNF agents had previously failed, patients carrying the TTTT BLyS promoter haplotype were more prevalent in good responders (18 of 43 [41.9%]) than in moderate responders (20 of 83 [24.1%]) or in nonresponders (1 of 21 [4.8%]) (for good responders versus nonresponders, OR 14.4 [95% CI 1.77-117.39], P=0.0028). Furthermore, multivariate analysis selected the TTTT BLyS promoter haplotype as an independent marker of good response to RTX (for good responders versus nonresponders, OR 16.2 [95% CI 1.7-152.5], P=0.01; for good responders versus moderate responders and nonresponders combined, OR 3.1 [95% CI 1.2-7.8], P=0.02). The relationship between BLyS polymorphisms and BLyS serum levels remained unclear. CONCLUSION: BLyS promoter genotyping may be suitable for identifying seropositive RA patients who may have a good response to RTX after anti-TNF agents have failed.

Validation of the Italian version of the ANCA-associated vasculitis patient-reported outcome (AAV-PRO) questionnaire.

Objectives: The primary objective of this study was the translation and validation of the ANCA-associated vasculitis patient-reported outcome (AAV-PRO) questionnaire into Italian, denoted as AAV-PRO_ita. The secondary objective was to evaluate the impact of ANCA-associated vasculitis (AAV) on quality of life (QoL) and work impairment in a large cohort of Italian patients. Methods: The study design took a prospective cohort study approach. First, the AAV-PRO was translated into Italian following the step guidelines for translations. The new AAV-PRO_ita questionnaire covered three disease domains: organ-specific and systemic symptoms and signs; physical function; and social and emotional impact. Second, Italian-speaking AAV patients were recruited from 17 Italian centres belonging to the Italian Vasculitis Study Group. Participants completed the AAV-PRO_ita questionnaire at three time points. Participants were also requested to complete the work productivity and activity impairment: general health questionnaire. Results: A total of 276 AAV patients (56.5% women) completed the questionnaires. The AAV-PRO_ita questionnaire demonstrated a good internal consistency and test-retest reliability. Female AAV patients scored higher (i.e. worse) in all thee domains, especially in the social and emotional impact domain (P < 0.001). Patients on glucocorticoid therapy (n = 199) had higher scores in all domains, especially in the physical function domain (P < 0.001), compared with patients not on glucocorticoid therapy (n = 77). Furthermore, patients who had at least one relapse of disease (n = 114) had higher scores compared with those who had never had one (n = 161) in any domain (P < 0.05). Finally, nearly 30% of the patients reported work impairment. Conclusion: The AAV-PRO_ita questionnaire is a new 29-item, disease-specific patient-reported outcome measuring tool that can be used in AAV research in the Italian language. Sex, glucocorticoids and relapsing disease showed the greatest impact on QoL.

Long-term efficacy and improvement of health-related quality of life in patients with Takayasu's arteritis treated with infliximab.

OBJECTIVES: To explore the efficacy in the long-term and the impact on Health Related Quality of Life (HRQOL) of infliximab in patients suffering from Takayasu's arteritis (TA). METHODS: Clinical data were retrospectively collected in 15 patients with TA. Evaluation of Medical Outcomes Study Short Form 36 (SF-36) questionnaires was made at baseline and at the last follow-up in 10 patients continuing infliximab at the last follow-up. RESULTS: Follow-up after initiation of infliximab was 71±44 months (range 10-162). Remission at the last follow-up was noted in 11/15 (73.3%). Significant reduction in BVAS score was noted at the last follow-up [from 4.0 (1-16) to 3.0 (0-9), p=0.003]. Significant steroid dose reduction was recorded [from 10 mg/day (0-50) to 2.5 mg/day (0-15), p=0.005)]. Steroid suspension occurred in 5/11 responder patients. Inflammatory markers were normalised in about two thirds of the patients. Radiological disease activity was assessed in 13/15 during infliximab therapy, with evidence of improvement in 2/13, stable disease activity in 9/13, and worsening in 2/13. No relevant side effects or severe infections were recorded during the whole follow-up under infliximab. One patient stopped infliximab at the third infusion for acute reaction. HRQOL in patients with TA was impaired, with major involvement of physical domains [(body pain (BP) and global health (GH)]. Infliximab significantly improved HRQOL, in particular BP (40.0±32.3 vs. 67.2±27.6, p=0.035), GH (31.2±21.5 vs. 54.9±21.1, p=0.007) and Vitality (VT) (47.0±28.7 vs. 67.0±20.3, p=0.01) domains. CONCLUSIONS: Infliximab determined a sustained clinical improvement in the long-term in TA, with significant benefits on HRQOL.

Current clinical and therapeutic approach to tumour-like mass lesions in granulomatosis with polyangiitis.

Granulomatosis with polyangiitis (GPA) is a systemic autoimmune disorder classified among the anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and characterized by a triad of upper and lower respiratory tract disease, systemic vasculitis involving small-to-medium vessels and renal manifestations. Mass lesions, also described as inflammatory lesions, pseudotumor or tumour-like masses, are uncommon manifestations of GPA and are often called granuloma since histology examination shows granulomatous inflammation and rarely vasculitis. Masses could represent a localized manifestation of GPA or develop as part of a systemic disease. Unusual clinical presentation together with nonspecific radiological and histological features may delay the correct diagnosis leading to disease progression and organ damage. Diagnosis of GPA in such cases may be challenging and malignancy or infections must be considered as alternative diagnostic options. Here we reviewed all the different sites where mass lesions were reported in GPA, focusing on atypical localization, and summarized current therapeutic options and their different outcomes. We retrieved and discussed the cases reported since 2010, bearing in mind the advances in the therapeutic management of AAV patients in the last decade, namely biological therapy such as rituximab. Despite treatment regimens with glucocorticoids and immunosuppressive agents, mass lesions have a refractory course in a high proportion of patients. Invasive surgical procedures may be considered only when drug therapy fails.

Biologic therapy in relapsing polychondritis: navigating between options.

INTRODUCTION: Relapsing polychondritis (RP) is a rare systemic inflammatory disease of unknown etiology, primarily affecting cartilaginous tissue and proteoglycan-rich structures. Clinical manifestations vary from mild symptoms to occasional organ or life-threatening complications. Treatment can be challenging and is mostly based on experience or case reports/series. AREAS COVERED: There is growing literature investigating the role of biologics in the management of RP. TNFα antagonists, abatacept, tocilizumab, rituximab, anakinra and tofacitinib have been prescribed in several RP patients, mainly as second-line treatment, after conventional immunosuppressive agents' failure. EXPERT OPINION: Glucocorticoids represent the gold standard treatment of RP. Conventional immunosuppressants should be administered in refractory patients or when a glucocorticoid-sparing effect is needed. Biologic therapy should be used after failure of conventional treatments or in severe manifestations. TNFα inhibitors are the most prescribed biologic agent, with partial or complete response in several cases, but loss of efficacy may occur over time. Infliximab and adalimumab should be preferred among TNFα antagonists. Abatacept and tocilizumab proved to be effective as second-line biologic agents, but infections are reported with the former. Data on anakinra and rituximab are controversial, therefore they are not recommended as first-line biologic drugs. The use of JAK inhibitors is still anecdotal.