Wegener's Granulomatosis Research Articles

Identification of the central tolerance checkpoint for autoreactive proteinase 3+ B cells in human bone marrow

Major target antigens of ANCA-associated vasculitis (AAV) are myeloperoxidase (MPO) and proteinase 3 (PR3). High-affinity MPO- and PR3-ANCA immunoglobulins are produced by antigen-experienced, class-switched autoreactive B cells. To prevent autoreactivity, B cells are subjected to several self-tolerance checkpoints, from the early immature stages in the bone marrow (BM), collectively called "central tolerance", to late mature stages, collectively called "peripheral tolerance"; the latter was recently elucidated for autoreactive PR3+ B cells. Here we investigated central tolerance controlling immature PR3+B cells in the BM before their migration into the periphery as transitional B cells. We applied an established flow cytometry-based method using labeled recombinant PR3 (rPR3) to identify the PR3+B cells to compare the phenotype of PR3+B cells in paired samples of BM mononuclear cells (BMMC) and peripheral blood mononuclear cells (PBMC) of non-vasculitis controls (No-AAV), and PBMC of patients with PR3-ANCA-associated vasculitis (PR3-AAV). We observed that the proportion of PR3+B cells within BMMC was higher (median [IQR]; 1.98% [1.77-2.75]) than within PBMC of No-AAV (0.9% [0.63-1.44], p<0.01 by paired comparison) and similar to their proportion within PBMC of patients with PR3-AAV (1.82% [1.66-3.21]; p>0.05). Within CD24++CD38++ B cells, the subset of B cell migrating from BM to the periphery, BMMC contained a greater proportion of PR3+B cells as compared to PBMC in No-AAV (3.35% [1.99-4.92] versus 1.23% [0.62-1.55], p<0.01), showing different surface markers of maturation (i.e. higher proportion of CD27-CD10+ and lower expression of CD21, IgD, IgM). Importantly, we observed a significant decline of the PR3+ fraction from the immature subset (IgD-IgM+; 2.80% [1.23-4.02]) to the early transitional subset (IgD+IgM+; 1.76% [0.96-2.68], p<0.01) in BMMC, while no significant reduction was observed between the early transitional of BMMC and the transitional compartment of PBMC in No-AAV (1.26% [0.62-1.56], p>0.05). In conclusion, to prevent PR3-related autoimmunity, autoreactive PR3+B cells pass a stringent selection in the BM, and their removal by central tolerance checkpoint activity occurs mainly between T1-like/immature to T2-like/early transitional B cells of BMMC.

Persistent Liver Injury Following Avacopan Discontinuation in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A Rare Case of Liver Biopsy in the Chronic Phase of Liver Injury.

Drug-induced liver injury (DILI) is a major concern associated with the use of avacopan, a new therapeutic agent for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Here, we report a rare instance of liver biopsy performed for persistent liver injury following discontinuation of avacopan in an elderly woman with microscopic polyangiitis (MPA). The patient developed cholestatic liver injury after 2 months of avacopan therapy, which led to drug cessation. Despite the discontinuation of avacopan followed by supportive care, the liver enzyme levels remained elevated, necessitating liver biopsy. Histological examination revealed residual inflammation and focal necrosis around the portal vein, indicating ongoing liver injury despite avacopan withdrawal. This case report highlights the hepatotoxic potential of avacopan, the importance of vigilant liver function monitoring, and the value of liver biopsy in the chronic phase of avacopan-induced liver injury. Further research is required to elucidate avacopan hepatotoxicity mechanisms and identify potential risk factors for DILI in patients with AAV.

Abstract 4119470: ST-Elevation Myocardial Infarction as a Complication of Granulomatosis with Polyangiitis

Description of Case: A 19-year-old female with history of granulomatosis with polyangiitis (GPA) presented to the emergency department after a syncopal episode at a concert. She reported a prodrome of feeling hot and dizzy prior to the event, followed by epigastric discomfort, nausea, and vomiting after regaining consciousness. She had been diagnosed with GPA one year prior to presentation based on serology and biopsy results. Because her disease was felt to be well-controlled on azathioprine, she had been tapered off of prednisone one month prior to presentation. Initial vitals included blood pressure of 90/60 mmHg, and heart rate of 94 bpm. A 12-lead EKG revealed ST segment elevation in leads I, II and aVF with T wave inversions in the lateral leads ( Figure 1 ). Initial bloodwork was notable for troponin I of 0.11ng/mL (upper limit of normal 0.034 ng/mL). A diagnosis of inferior ST-elevation myocardial infarction was made. She was treated with oral aspirin and prasugrel load as well as intravenous heparin and taken urgently to the catheterization laboratory. Diagnostic coronary angiography was significant for single vessel coronary artery disease (CAD) of the right coronary artery (RCA), with acute complete occlusion of the mid-RCA ( Figure 2A-B ). She was treated successfully with primary percutaneous coronary intervention and implant of two overlapping drug eluting stents in the mid-RCA ( Figure 2C ). Discussion: GPA is a systemic necrotizing vasculitis associated with antineutrophil cytoplasmic antibodies (ANCA) that predominantly affects small to medium sized vessels in the respiratory tract and kidneys. Cardiovascular manifestations in GPA are uncommon, but include pericarditis, myocarditis, and coronary arteritis. GPA can affect the coronary arteries either primarily through inflammatory changes in the arterial wall or via systemic inflammation leading to accelerated atherosclerosis. No standardized criteria exist to establish the diagnosis of coronary arteritis and to differentiate it from accelerated atherosclerosis. Long-term treatment of vasculitis patients with coronary involvement is also poorly supported by evidence. Optimization of cardiovascular risk factors is advocated as per standard of care, and vasculitis control may slow disease progression. This case not only raises awareness of cardiac complications in GPA, but highlights the current lack of evidence surrounding secondary prevention in young patients with vasculitis and cardiac complications.

Diagnosis and Treatment of Renal ANCA Vasculitis: A Summary of the Consensus Document of the Catalan Group for the Study of Glomerular Diseases (GLOMCAT)

The document provides a comprehensive overview of the diagnosis, monitoring, and treatment of anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) with renal involvement, focusing on granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). It outlines the definitions, clinical presentation, histopathological classification, monitoring strategies, induction and maintenance treatments, as well as special considerations for relapsing, refractory, and frail patients with renal AAV. The document was prepared by the Catalan Group for the Study of Glomerular Diseases (GLOMCAT), which comprises nephrologists with extensive experience in the diagnosis and treatment of AAV patients. Several virtual and face-to-face meetings were held for coordination, section assignments, and content discussion. An exhaustive and systematic search of the literature was carried out, which included, among others, the following databases: PubMed, EMBASE, Cochrane Library, Google Scholar, and ClinicalTrials.gov, as well as the abstract books of national and international congresses. Overall, the document provides a comprehensive guide for clinicians managing patients with renal AAV, offering evidence-based recommendations for diagnosis, monitoring, and treatment across various clinical scenarios.

Respiratory manifestations of pediatric granulomatosis with polyangiitis: A 12-year experience from a tertiary care facility.

Pediatric granulomatosis with polyangiitis (GPA) is associated with several pulmonary manifestations. This study aims to describe these manifestations at time of diagnosis and longitudinally at a tertiary-care pediatric hospital. We performed a retrospective chart review of patients with GPA treated at our facility between 1 January 2010 through 31 December 2021. We collected baseline demographics, reported symptoms, imaging findings, pulmonary function tests (PFTs), and laboratory data at time of diagnosis. Data were collected using 6-month observation intervals to follow recurrence of respiratory manifestations, testing during recurrence, and resultant treatment modifications. Of 13 patients treated for GPA during the study period, 12 developed respiratory tract involvement. A total of 87 6-month observation periods were analyzed. At time of diagnosis, 83% (10/12) of subjects reported respiratory symptoms, 92% (11/12) had abnormal chest computed tomography (CT) imaging, and 42% (5/12) had abnormal PFTs. Fewer than half of the patients were seen by pulmonology within 6 months of diagnosis. Eight subjects (75%) had respiratory manifestations during subsequent observation periods. Chest CT or PFTs were obtained in 23/44 (52%) of observations periods with respiratory symptoms, with pulmonary consultation in only 9/44 (20%). This is the first US study to describe respiratory manifestations in pediatric GPA patients longitudinally, finding they are common and frequently recurrent. Our cohort had almost universally abnormal imaging at diagnosis regardless of respiratory symptoms. Early collaboration with pediatric pulmonology in the care of GPA patients may allow rheumatology teams to efficiently evaluate recurrent symptoms and address concomitant lung disease.

Immune checkpoint molecules performance in ANCA vasculitis

ObjectiveThe PD-1 axis promotes protection against autoimmunity. Immune checkpoint (IC) molecules performance in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) remains unknown. This study aims to assess the IC pathway’s role in...

P20 Persistent anti-PR3 ANCA positivity in patient with extrapulmonary tuberculosis

Abstract Introduction Granulomatosis with polyangiitis (GPA) and tuberculosis (TB) are both granulomatous disease which can have similar clinical manifestations and organ involvement. This report discusses a case of such overlapping clinical presentation and anti-neutrophil cytoplasmic antibodies (ANCA) positivity, leading to diagnostic uncertainty. Case description A 40-year-old female who lived in sub-Saharan Africa until two years ago presented with a two month history of general malaise, significant weight loss, severe anorexia, diarrhoea, vomiting and nausea. She had no night sweats, blood in stool, abdominal pain, respiratory or cardiac symptoms, sino-nasal symptoms, rashes or neurological features. On examination, she appeared severely malnourished. Blood tests revealed microcytic anaemia (Hb 83 g/l, MCV 69fl), thrombocytosis, hypoalbuminemia (15 g/l), CRP 26 mg/l, elevated procalcitonin (1.46 ug/l), elevated LDH 263U/l. She had a positive double-stranded DNA and anti-cardiolipin IgM. ANCA was moderately positive with an anti-PR3 titre of 78 U/ml. Computerised tomography (CT) chest to pelvis revealed widespread necrotic lymphadenopathy, bilateral pulmonary emboli with infarcts, pancolitis and non-specific gall bladder thickening. Endoscopy revealed inflamed featureless colon with no microscopic granulomata. Acid-fast bacilli were isolated on endobronchial ultrasound guided biopsy of the necrotic nodes leading to confirmation of the diagnosis of extrapulmonary disseminated tuberculosis. Clinical improvement and improvement in CRP and anti-PR3 titre (48 U/ml) were seen following two weeks of anti-tuberculous treatment and a weaning course of steroids for colitis. Discussion Often GPA and tuberculosis can have similar presentations including lung and gastrointestinal involvement along with lymphadenopathy. This case demonstrates how ANCA and PR3 positivity can also be a common feature in these two conditions. Correct diagnosis is crucial in preventing harm to the patient as a diagnosis of GPA would require prompt and aggressive immunosuppression which may result in disseminated mycobacterial infection in the case of misdiagnosis; similarly, anti-mycobacterial therapy is unlikely control systemic GPA. In our patient, although the enteritis, general malaise and weight loss can be features of vasculitis and tuberculosis, careful history suggested no convincing other features of GPA, including the absence of ear, nose, throat, skin, neurological or renal involvement. The social history yielded migration from sub-Saharan Africa where tuberculosis is much more prevalent. A useful distinguishing biochemical test was the elevated procalcitonin which points towards a bacterial infection rather than an autoimmune process. Ultimate conclusive evidence of mycobacterial infection requires either positive acid-fast bacilli on staining or culture; lymph node biopsy allowed us to promptly and correctly diagnose this patient in the absence of sputum or pulmonary tuberculosis. Initiation of anti-tuberculous treatment rapidly settled this patient’s symptoms with a falling CRP. This case report highlights the fact that tuberculosis can mimic ANCA-associated vasculitis with positive anti-PR3 antibodies. In such cases, careful history taking, appropriate imaging and positive acid fast bacilli on staining or culture from sputum or tissue are important for prompt diagnosis and treatment. Both disseminated tuberculosis and systemic GPA can be rapidly progressive and severe if untreated. Although literature described the co-existence of both conditions, this is very rare. Correct diagnosis is key in initiation of the widely different treatment strategies, with the treatment for GPA potentially causing harm in disseminated tuberculosis. Key learning points • ANCA positivity in tuberculosis has been documented in the literature and positive anti-PR3 cannot be used solely to diagnose GPA. Therefore, a thorough history, examination, imaging and tissue examination, including tuberculosis culture and acid-fast staining, are recommended.

Hypertension and Cardiovascular Outcomes in Inflammatory and Autoimmune Diseases: A Systematic Review and Meta-analysis.

This review aimed to investigate the prevalence of hypertension and cardiovascular (CV) complications in various inflammatory and autoimmune diseases (IAD). Despite recent improvements in the management of IAD, patients with IAD still have an increased CV mortality and CV complications, mostly related to CV risk factors such as hypertension and inflammation. We systematically searched MEDLINE and EMBASE libraries for controlled studies involving hypertension and CV complications in systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), psoriasis including psoriatic arthritis (PsA), Sjogren's syndrome (SS), or antineutrophil cytoplasmic antibody-associated vasculitis (AAV) between January 2000 and March 2022. We extracted data on the prevalence of hypertension and CV complications. Then, random-effects meta-analyses and exploratory multivariate meta-regression were performed to explore factors related to the prevalence of hypertension.Of 2726 studies screened, 122 were selected for the meta-analysis. The prevalence of hypertension was higher among patients with IAD than controls, with an overall unadjusted odds ratio (OR) [95% confidence interval] of 1.67 [1.58-1.76] and an adjusted OR of 1.36 [1.24-1.50]. All diseases were found to be associated with increased risk of hypertension: SLE, adjusted OR 3.40 [1.93-6.00]; psoriasis, OR 1.32 [1.16-1.51]; PsA, OR 1.49 [1.15-1.94]; RA, OR 1.28 [1.04-1.58]; SS, OR 2.02 [1.19-3.44]. Age and female sex were significantly associated with hypertension in patients with IAD. The risk of CV complications was increased: ischemic heart disease, adjusted OR 1.38 [1.21-1.57]; cerebrovascular disease, OR 1.37 [1.03-1.81]; heart failure, OR 1.28 [1.05-1.55]; atherosclerotic plaques presence, OR 2.46 [1.84-3.29].The prevalence of hypertension and CV complications is higher among patients with IAD. Screening and management of hypertension appears to be of paramount importance in these patients.

OA15 Separating the signal from the noise: multiple diagnoses of infection complicating a case of ANCA-associated vasculitis

OA15 Separating the signal from the noise: multiple diagnoses of infection complicating a case of ANCA-associated vasculitis

Avacopan in the treatment of refractory scleritis secondary to granulomatosis with polyangiitis: A case report.

Avacopan is a novel C5a receptor inhibitor which was recently licensed for treatment of severe granulomatosis with polyangiitis (GPA) in the European Union and the United Kingdom. To the best of our knowledge, this is the first described case on initial ophthalmic outcomes in a patient with severe GPA and concurrent refractory scleritis treated with avacopan. We present a case of de novo scleritis in a 77-year-old male with a background of retinitis pigmentosa with Argus II implant in situ. Severe scleral inflammation occurred following a suture removal from the implant site. Remission was not maintained despite orbital floor injections and high dose oral prednisolone. The diagnostic work-up revealed GPA which quickly progressed to involve vital organs. In view of his systemic deterioration, he was started on avacopan alongside rituximab, cyclophosphamide and high dose oral prednisolone. Sustained remission of scleritis was noted after 7 months of treatment with avacopan and low dose oral prednisolone with no other maintenance immunosuppression. We observed a sustained benefit of avacopan in allowing for successful taper of systemic steroids. We report that avacopan used alongside other immunosuppressants may be a viable option in patients with GPA and concurrent refractory scleritis. Further studies are needed to establish the longer term impact of this agent on the control of scleral inflammation.

Infections in ANCA-associated vasculitis and lupus nephritis treated with rituximab

Objective: Patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and systemic lupus erythematosus (SLE) are prone to infections. This study aims to clarify infectious complications in terms of both the disease and the specific treatments used. Patients and Methods: Sixty-three patients with SLE and AAV with kidney involvement treated with rituximab or cyclophosphamide were included. Patients were examined regarding infections, comorbidities, immunosuppressives, estimated glomerular filtration rate (eGFR), use of prophylactic antibiotics, hospitalization, and death. Results: Patients with SLE experienced more genitourinary infections in general (p=0.009). In the rituximab group, SLE patients had a higher incidence of genitourinary infections, septicemia, and intensive care unit admissions. Furthermore, lupus patients with serious infections were all treated with rituximab and had a higher incidence of low respiratory tract infections (p=0.003). On the contrary, treatment with rituximab did not cause an increased risk of infection among AAV patients compared to cyclophosphamide. In general, patients with serious infections had lower IgG and total Ig levels (p

Comparing Rituximab and Cyclophosphamide in Induction Therapy for Childhood-Onset ANCA-Associated Vasculitis: An ARChiVe registry-cohort study.

Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are chronic life-threatening vasculitides requiring substantial immunotherapy. Adult trials identified rituximab (RTX) as an alternative to cyclophosphamide (CYC) for remission-induction of GPA/MPA. Disease rarity has limited feasibility of similar trials in pediatrics. We aim to evaluate the relative efficacy and toxicity of CYC and RTX for childhood GPA/MPA through registry-based comparative evaluation. From A Registry of Childhood Vasculitis we identified GPA/MPA patients who received induction with RTX or CYC. Pediatric vasculitis activity score (PVAS) and pediatric vasculitis damage index (pVDI) evaluated disease activity and damage. Descriptive statistics summarized patient characteristics. RTX/CYC comparisons used logistic regression for primary outcomes of post-induction remission (PVAS=0) or low disease activity (PVAS<2). Hospital admission for adverse events and pVDI were compared using logistic regression and ordinal regression, respectively. Among 104 patients, 43% received RTX, 46% CYC, 11% both. Treatment groups did not significantly differ for diagnosis PVAS and onset age. There was no difference in remission between groups (63% overall; OR 1.07, 95% CI: 0.45, 2.52). Hospitalizations occurred in 22% of RTX patients versus 10% on CYC (OR 2.27, 95% CI: 0.73, 7.05). The median 12-month pVDI was one in both groups (OR 0.98, 95% CI 0.43, 2.22). This is the first study comparing CYC and RTX for induction in pediatric GPA/MPA. No significant differences were shown in rates of remission, severe adverse events, or organ damage. Limitations included lack of standardized treatment regimens, retrospectivity, and lack of longitudinal adverse drug-related event data.

Immunological characteristics of bronchoalveolar lavage fluid and blood across connective tissue disease-associated interstitial lung diseases.

Interstitial lung disease (ILD) is a serious complication of connective tissue diseases (CTDs). The heterogeneity of ILDs reflects differences in pathogenesis among diseases. This study aimed to clarify the characteristics of CTD-ILDs via a detailed analysis of the bronchoalveolar lavage fluid (BALF) and blood immune cells. BALF and blood samples were collected from 39 Japanese patients with newly diagnosed ILD: five patients with Sjögren's syndrome (SS), eight patients with dermatomyositis (DM), six patients with rheumatoid arthritis (RA), six patients with systemic sclerosis, four patients with anti-neutrophil cytoplasmic antibody-associated vasculitis, and 10 patients with idiopathic interstitial pneumonia. We performed single-cell RNA sequencing to analyze the gene expression profiles in these patients' immune cells. In patients with SS, B cells in the BALF were increased and genes associated with the innate and acquired immunity were enriched in both the BALF and blood. In contrast, patients with DM showed an upregulation of genes associated with viral infection in both the BALF and blood. In patients with RA, neutrophils in the BALF tended to increase, and their gene expression patterns changed towards inflammation. These disease-specific characteristics may help us understand the pathogenesis for each disease and discover potential biomarkers.

Spectrum of Pulmonary Manifestations in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis on Chest CT.

Spectrum of Pulmonary Manifestations in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis on Chest CT.

Clinical associations with thyroid disease in ANCA-associated vasculitis.

To evaluate the frequency and the clinical relevance of thyroid disease in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) patients. A total of 305 AAV patients admitted to the Second Affiliated Hospital of Chongqing Medical University between October 2010 and December 2023 were analyzed. Demographic, clinical, and laboratory data were compared between AAV patients with and without thyroid disease. Univariate and multivariate logistic regression analyses were conducted to identify factors associated with thyroid disease in AAV patients. Among the 305 AAV patients, 52 (17.0%) had concurrent thyroid disease. In univariate analysis, gender, coronary artery disease, renal involvement, anti-Ro/SSA antibodies, anti-Ro52 antibodies, anti-thyroglobulin antibodies (TgAb), and anti-thyroid peroxidase antibodies (TPOAb) exhibited significant differences between AAV patients with and without thyroid disease (P < 0.05). Multivariate analysis revealed that female gender (odds ratio (OR) = 2.423, 95% confidence interval (95% CI) 1.241, 4.729; P = 0.009), concurrent coronary artery disease (OR = 2.998, 95% CI 1.280, 7.019; P = 0.011), and positive anti-Ro/SSA antibodies (OR = 4.697, 95% CI 1.960, 11.257; P = 0.001) were associated with thyroid disease in AAV patients. AAV patients have a higher incidence of thyroid disease. Regular monitoring of thyroid function is advised for AAV patients, particularly for women, those with coronary artery disease, and those who are positive for anti-Ro/SSA antibodies. Key Points • AAV patients have a higher incidence of thyroid disease. • The potential clinical relevance of AAV patients with thyroid disease was explored. • Regular monitoring of thyroid function is advised for AAV patients.

Avacopan for antineutrophil cytoplasmic antibody-associated vasculitis.

Avacopan for antineutrophil cytoplasmic antibody-associated vasculitis.

Circulating B Cells Display Differential Immune Regulatory Molecule Expression in Granulomatosis with Polyangiitis.

Granulomatosis with polyangiitis (GPA) is a B cell-mediated, relapsing, autoimmune disease. There is a need for novel therapeutic approaches and relapse markers to achieve durable remission. B cells express immune regulatory molecules that modulate their activation and maintain tolerance. While recent studies show dysregulation of these molecules in other autoimmune diseases, data on their expression in GPA are limited. This study aimed to map the expression of surface immune regulatory molecules on circulating B cell subsets in GPA and correlate their expression with clinical parameters. Immune regulatory molecule expression on circulating B cell subsets was comprehensively examined in active GPA (n=16), GPA in remission (n=16), and healthy controls (HCs, n=16) cross-sectionally using a 35-color B cell-specific spectral flow cytometry panel. Our supervised and unsupervised in-depth analysis revealed differential expression of inhibitory and stimulatory immune molecules on distinct B cell populations in GPA, with the most notable differences observed in active GPA. These differences include the upregulation of FcγRIIB on non-mature B cells, downregulation of CD21 and upregulation of CD86 on antigen-experienced B cells, and elevated CD22 expression on various populations. Additionally, we found a strong association between FcγRIIB, BTLA, and CD21 expression on specific B cell populations and disease activity in GPA. Together, these findings provide novel insights into the immune regulatory molecule expression profile of B cells in GPA, and could potentially form the foundation for new therapeutic approaches and disease monitoring markers.

Successful stenting of bilateral main pulmonary artery stenoses associated with Wegener's granulomatosis.

Successful stenting of bilateral main pulmonary artery stenoses associated with Wegener's granulomatosis.

Defects in B-lymphopoiesis and B-cell maturation underlie prolonged B-cell depletion in ANCA-associated vasculitis

ObjectivesB-cell depletion time after rituximab (RTX) treatment is prolonged in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) compared with other autoimmune diseases. We investigated central and peripheral B-cell development to identify...

Undetected Takayasu arteritis presenting as severe hypertension in children: a report of two cases

Takayasu arteritis (TA) is a rare chronic granulomatous vasculitis mainly affecting the aorta and its main branches. Clinical presentations of TA are non-specific, especially in the initial phase, which likely contributes to delayed diagnosis besides the rarity of the disorder. Childhood-onset of TA is associated with significant morbidity and mortality. This case report aimed to present two rare cases of acute symptomatic severe hypertension in children due to TA.